Molecular Biotechnology

Electron Transport in Mitochondria

2009-09-23T16:30:00.003+05:30

The cells of almost all eukaryotes contain intracellular organelles called mitochondria, which produce ATP. Energy sources such as glucose are initially metabolized in the cytoplasm. The products are imported into mitochondria. Mitochondria continue the process of catabolism using metabolic pathways including the Krebs cycle, fatty acid oxidation, and amino acid oxidation.

The end result of these pathways is the production of two kinds of energy-rich electron donors, NADH and succinate. Electrons from these donors are passed through an electron transport chain to oxygen, which is reduced to water. This is a multi-step redox process that occurs on the mitochondrial inner membrane. The enzymes that catalyze these reactions have the ability to simultaneously create a proton gradient across the membrane, producing a thermodynamically unlikely high-energy state with the potential to do work. Although electron transport occurs with great efficiency, a small percentage of electrons are prematurely leaked to oxygen, resulting in the formation of the toxic free-radical superoxide.

The similarity between intracellular mitochondria and free-living bacteria is striking. The known structural, functional, and DNA similarities between mitochondria and bacteria provide strong evidence that mitochondria evolved from intracellular bacterial symbionts

Four membrane-bound complexes have been identified in mitochondria. Each is an extremely complex transmembrane structure that is embedded in the inner membrane. Three of them are proton pumps. The structures are electrically connected by lipid-soluble electron carriers and water-soluble electron carriers.

Complex I

Complex I (NADH dehydrogenase, also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) removes two electrons from NADH and transfers them to a lipid-soluble carrier, ubiquinone (Q). The reduced product, ubiquinol (QH2) is free to diffuse within the membrane. At the same time, Complex I moves four protons (H+) across the membrane, producing a proton gradient. Complex I is one of the main sites at which premature electron leakage to oxygen occurs, thus being one of main sites of production of a harmful free radical called superoxide.

The pathway of electrons occurs as follows:

NADH is oxidized to NAD+, reducing Flavin mononucleotide to FMNH2 in one two-electron step. The next electron carrier is a Fe-S cluster, which can only accept one electron at a time to reduce the ferric ion into a ferrous ion. In a convenient manner, FMNH2 can be oxidized in only two one-electron steps, through a semiquinone intermediate. The electron thus travels from the FMNH2 to the Fe-S cluster, then from the Fe-S cluster to the oxidized Q to give the free-radical (semiquinone) form of Q. This happens again to reduce the semiquinone form to the ubiquinol form, QH2. During this process, four protons are translocated across the inner mitochondrial membrane, from the matrix to the intermembrane space. This creates a proton gradient that will be later used to generate ATP through oxidative phosphorylation.

Complex II

Complex II (succinate dehydrogenase; EC 1.3.5.1) is not a proton pump. It serves to funnel additional electrons into the quinone pool (Q) by removing electrons from succinate and transferring them (via FAD) to Q. Complex II consists of four protein subunits: SDHA,SDHB,SDHC, and SDHD. Other electron donors (e.g., fatty acids and glycerol 3-phosphate) also funnel electrons into Q (via FAD), again without producing a proton gradient.

Complex III

Complex III (cytochrome bc1 complex; EC 1.10.2.2) removes in a stepwise fashion two electrons from QH2 at the QO site and sequentially transfers them to two molecules of cytochrome c, a water-soluble electron carrier located within the intermembrane space. The two other electrons are sequentially passed across the protein to the Qi site where quinone part of ubiquinone is reduced to quinol. A proton gradient is formed because it takes 2 quinol (4H+4e-) oxidations at the Qo site to form one quinol (2H+2e-) at the Qi site. (in total 6 protons: 2 protons reduce quinone to quinol and 4 protons are released from 2 ubiquinol). The bc1 complex does NOT 'pump' protons, it helps build the proton gradient by an asymmetric absorption/release of protons.

When electron transfer is hindered (by a high membrane potential, point mutations or respiratory inhibitors such as antimycin A), Complex III may leak electrons to oxygen resulting in the formation of superoxide, a highly-toxic species, which is thought to contribute to the pathology of a number of diseases, including aging.

Complex IV

Complex IV (cytochrome c oxidase; EC 1.9.3.1) removes four electrons from four molecules of cytochrome c and transfers them to molecular oxygen (O2), producing two molecules of water (H2O). At the same time, it moves four protons across the membrane, producing a proton gradient.

Coupling with oxidative phosphorylation

The chemiosmotic coupling hypothesis, as proposed by Nobel Prize in Chemistry winner Peter D. Mitchell, explains that the electron transport chain and oxidative phosphorylation are coupled by a proton gradient across the inner mitochondrial membrane. The efflux of protons creates both a pH gradient and an electrochemical gradient. This proton gradient is used by the FOF1 ATP synthase complex to make ATP via oxidative phosphorylation. ATP synthase is sometimes regarded as complex V of the electron transport chain. The FO component of ATP synthase acts as an ion channel for return of protons back to mitochondrial matrix. During their return, the free energy produced during the generation of the oxidized forms of the electron carriers (NAD+ and Q) is released. This energy is used to drive ATP synthesis, catalyzed by the F1 component of the complex.
Coupling with oxidative phosphorylation is a key step for ATP production. However, in certain cases, uncoupling may be biologically useful. The inner mitochondrial membrane of brown adipose tissue contains a large amount of thermogenin (an uncoupling protein), which acts as uncoupler by forming an alternative pathway for the flow of protons back to matrix. This results in consumption of energy in thermogenesis rather than ATP production. This may be useful in cases when heat production is required, for example in colds or during arise of hibernating animals. Synthetic uncouplers (e.g., 2,4-dinitrophenol) also exist, and, at high doses, are lethal.

Summary

The mitochondrial electron transport chain removes electrons from an electron donor (NADH or QH2) and passes them to a terminal electron acceptor (O2) via a series of redox reactions. These reactions are coupled to the creation of a proton gradient across the mitochondrial inner membrane. There are three proton pumps: I, III, and IV. The resulting transmembrane proton gradient is used to make ATP via ATP synthase.

The reactions catalyzed by Complex I and Complex III exist roughly at equilibrium. This means that these reactions are readily reversible, simply by increasing the concentration of the products relative to the concentration of the reactants (for example, by increasing the proton gradient). ATP synthase is also readily reversible. Thus ATP can be used to make a proton gradient, which in turn can be used to make NADH. This process of reverse electron transport is important in many prokaryotic electron transport chains.

Electron transport chain. (2009, September 7). In Wikipedia, The Free Encyclopedia. Retrieved 21:19, September 7, 2009, from
link

Cancer cell migration

2009-08-28T15:03:00.000+05:30

What is Cancer ?

2009-08-28T14:48:00.002+05:30

Ida - Overwhelming or Over-Hyped ?

2009-08-28T11:33:00.003+05:30

Last week, the fossil skeleton known as “Ida” was introduced to the world with a fanfare rarely seen in the scientific community. Touted by publicists as the find “that will change everything”, Ida’s arrival on the world scene has provoked a mixed reaction from researchers and commentators.

Ida was a lemur-like mammal that roamed central Europe about 47 million years ago. She died at a relatively young age of 9 months, on the banks of the volcanic Lake Messel in modern-day Germany. The circumstances of her death play a large part in her current fame – researchers involved in the find speculate that Ida was overwhelmed by a belch of carbon dioxide gas from the lake, causing her to slip into the oxygen-deprived lake. The unique concoction of Messel’s volcanic water coupled with the lack of trauma to her body meant that Ida’s corpse was preserved almost perfectly preserved within the lake bed, gradually fossilizing over millions of years. In 1983, Ida’s fossilized remains were resurrected but the significance of this find only came to light in the past week.

Ida is remarkable because her fossilized skeleton is almost 95% complete. It includes almost every bone, fur, and even Ida’s final meal – fruit and leaves. In the past, similar fossils have been found but none so exquisitely preserved. Ida’s almost fully intact frame allows researchers to address questions that have frustrated them for decades.

In particular, it offers some intriguing clues to human origins. She dates from a time when primates split into two branches – anthropoids, whose descendants include humans, apes, and monkeys, and prosimians, whose descendants include lemurs. Ida has characteristics of both groups, and may hold the key to a shared lineage.

A commonly-held view among paleontologists is that anthropoids (and therefore humans) evolved from Eosimias, whose fossilized remains have been dated to 45 million years ago.

Jørn Hurum of the Natural History Museum of the University of Oslo and Philip Gingerich of the University of Michigan, Ann Arbor, the main players in the Ida discovery, do not agree. Hurum and Gingerich believe that anthropoids arose from a more primitive group of primates called adapids.

Ida has a number of features not found in lemurs – namely a grooming claw on her second toe and front teeth arranged into a toothcomb. Furthermore, Ida’s front teeth and ankle resemble the anthropoid branch of primates. Together, these features suggest that adapids link primitive primates and anthropoids, and therefore the lineage leading to humans.

Many paleontologists are skeptical, however. Science magazine points out that Hurum and Gingerich’s analysis examined only 30 traits, where standard practice is to compare 200 to 400 traits. They quote Richard Kay, of Duke University, who says “There is no phylogenetic analysis to support the claims, and the data is cherry-picked.

Many in the science community have rolled their eyes at the manner of the announcement, which included an international press conference, publication of a book, and exclusive prime-time television special documentary. Hurum’s suggestion that “Any pop band is doing the same thing” did little to allay the criticism.

Ultimately, Ida is an important fossil and will doubtless shed considerable light on human origins. At the same time, the media blitz that accompanied the announcement seems to have tainted its significance and put critics on the offensive. Ida has changed some things – namely the debate about whether anthropoids come from the suborder strepsirrhinae or the suborder haplorrhinae. The “scientific find that will change everything”? Possibly not.

Depression Genetics Suffer Major Setback

2009-08-28T11:28:00.003+05:30

A 2003, a paper by Caspi and colleagues offered tantalizing clues about the genetics of depression, in what was widely-acclaimed as a breakthrough paper for psychiatric genetics as a whole. Now, new research by Katleeen Merikangas at the National Institute of Mental Health queries the results taking us, according to Science magazine, back to the drawing board.

What was so important about Caspi et al.?
The original Caspi paper of 2003 looked at a sample of 847 New Zealanders, and examined whether gene-environment interactions might lead to depression. The research team were particularly interested in genes involved in serotonin transportation and reception - serotonin has long been recognized as an important biochemical in the neurobiology of depression. They identified short and long versions of 5-HTT’s regulatory region. The short allele led to decreased gene expression and therefore fewer serotonin transporters in the the cell. Results of the study found that individuals with the short variant of the serotonin transporter 5-HTT predicted the onset of depression – but only if the individual was exposed to repeated environmental stress. The finding was important because it provided a blueprint for understanding gene-environment interactions: genes came to be viewed not so much as rigid determinants of fate, but part-players in a complex narrative.

What has changed?
A lot. The new paper by Merikangas and colleagues failed to substantiate the gene-environment association for 5-HTT. Normally, this might be viewed as a minor setback, but this study was a meta-analysis of 14 papers covering approximately 12,500 individuals – a huge data-pool by anybody’s standards. The group did confirm an association between stressful circumstances and depression (hardly big news). However, the serotonin transporter, 5-HTT did not enter into the equation. For many researchers in the field this is very disappointing and may force a rethink in our whole understanding of the disorder.

Caspi and co-author Terrie Moffitt are sticking by their guns, however. Science quotes them as saying that the new resarch “ignores the complete body of scientific evidence”, including studies in mice who have an elevated stress response as a result of their 5-HTT genotype. This may be the case, but Caspi and Moffitt are now swimming against the tide. It hard to argue with a sample of 12,500. Moreover, other sources had already begun to question the validity of the 5-HTT association. Recent whole-genome association studies, which have scanned a huge amount of genomes and found several thousand biomarkers did not turn up anything on 5-HTT.
While it is not time yet to close the book entirely on the association, I think it is time for some serious re-evaluation.

Psychosis - New Study Links Gene Variant to Brain Structures

2009-08-28T11:20:00.004+05:30

A study published in last week’s Science magazine shows how genomic science and neuroimaging can be combined to deliver insights into cognitive disorders. As well as providing an intriguing look into the neurobiology of psychosis, the study reflects a growing trend toward inter-disciplinary research in the neurosciences,

What did the study show?

Psychosis is a disordered cognitive state that can include disorganized thoughts, delusions, or hallucinations. It is a common symptom of schizophrenia and has been linked to a number of brain areas, including the the dorsolateral prefrontal cortex (DLPFC) and the hippocampus. Schizophrenia is also strongly associated with a number of genes, and a recent genome-wide association study identified a single nucleotide polymorphism in ZNF804A as particularly important. Now, for the first time, a German research team has confirmed a link between ZNF804A and these brain structures. The group compared 115 participants who were either risk-allele carriers or non-risk-allele carriers and found differences in how their brains connect. For risk-allele carriers, connections were reduced within the DLPFC and also between left and right DLPFC . Conversely, risk-allele carriers showed increased connectivity between the DLPFC and hippocampal areas.

The study, primarily based at the University of Heidelberg, Germany, focused on a single nucleotide polymorphism (SNP) in ZNF804A (rs1344706)

Schizophrenia is a devastating, highly heritable brain disorderof unknown etiology. Recently, the first common genetic variantassociated on a genome-wide level with schizophrenia and possiblybipolar disorder was discovered in ZNF804A (rs1344706). We show,by using an imaging genetics approach, that healthy carriersof rs1344706 risk genotypes exhibit no changes in regional activitybut pronounced gene dosage–dependent alterations in functionalcoupling (correlated activity) of dorsolateral prefrontal cortex(DLPFC) across hemispheres and with hippocampus, mirroring findingsin patients, and abnormal coupling of amygdala. , show thatrs1344706 or variation in linkage disequilibrium is functionalin human brain, and validate the intermediate phenotype strategyin psychiatry.

The study is important for a number of reasons. Firstly, it highlights the importance of connectivity (or dysconnectivity) as a neurobiological marker of schizophrenia. Secondly, it establishes ZNF804A as functional in the human brain. Thirdly, it is an example of how genome-wide association studies can align with anatomical data – to quote the authors, it affirms that “the pathophysiology of overt disease” can “mirror candidate gene effects”.

Functional Genomics and Big Picture Science

This third point is important to how we view science as a whole. Scientific research has traditionally relied upon reductionism as the primary means of discovery. To understand the world, reductionism tells us, we must strip it down to its barest elements. The sequencing of the human genome represents the ultimate triumph of this principle — the dis-assembly of an enormously complex living thing into its three billion molecular constituents. While unraveling the genomic structure ushered in a new era for biology and medicine, it laid bare a new problem—that of genomic function. Now that we have disassembled the machine, we have to figure out how to put it back together again.

Scientists have, in many ways, been forced to abandon reductionism and to look instead at the bigger picture – to see how things fits together. Increasingly we see large multi-disciplinary groups, each of which holds a different piece of the picture. In the current example, we have neuroimaging experts, who look at the gross structure of the brain, collaborating with geneticists, who look at m0lecules, and psychiatrists who look at behavior. These collaborations are exciting, because they integrate a number of different perspectives. Ultimately, this represents a triumph for “big picture” science

Schizophrenia and Autism - Opposite Ends of the Same Spectrum

2009-08-28T11:07:00.003+05:30

Bernard Crespi, an evolutionary geneticist at the Simon Fraser University in Burnaby, Canada, has proposed that schizophrenia and autism are the opposite ends of the same social spectrum. Speaking at the Sackler Colloquium on Evolution in Health and Medicine at the National Academy of Sciences, Crespi noted that copy number variations (CNVs) in the human genome are similar for both schizophrenia and autism. What are CNVs and what evidence is their to support Crespi’s hypothesis?

What are CNVs?

Copy number variations are spontaneous mutations in the genome that result in duplications or deletions of the genomic sequence. Duplications can produce extra copies of a gene, deletions can remove it altogether. CNVs are an interesting biological phenomenon because they are not inherited from ones parents. Rather, they are acquired de novo when certain sequences of genetic code fail to copy properly. Acquisition of CNVs is unpredicted, random, and spontaneous. Smaller variants are probably very common—each one of us may have one or two.

A raft of studies over the last five-years has propelled CNVs to the forefront of mental health research. CNVs have been linked with a number of disorders including Alzheimer’s (e.g. Rovelet-Lecrux, 2006), autism (e.g. Sebat et al. 2007), bipolar disorder (e.g. Lachman, 2007), and schizophrenia (e.g. Walsh, 2008). The broad theme of these association studies is that individuals with these disorders have more CNVs than the general population. As such, CNVs may be a major causal factor in cognitive (and other) illness.

What is the evidence?

Currently, there is not a great deal of evidence to support Crespi’s hypothesis. A 2008 Nature review paper by Cook & Schere, highlights two genomic loci particularly associated with both: 15q11 – 15q13 and 22q11. However, these are also associated with other disorders including mental retardation. Similarly, there are many loci associated with schizophrenia and not autism and vice-versa. These findings are not a fatal blow to Crespi’s hypothesis, but do recommend a certain level of skepticism.

Crespi also invokes behavioral (phenotypic) evidence, noting that these disorders have similar symptoms, which manifest in opposite directions. Language, social skills, etc., the hypothesis states, are underdeveloped in autistic-spectrum conditions and overdeveloped on the psychotic spectrum. Again, I am not convinced that there is sufficient evidence to substantiate these claims. Crespi points out that glutamate, the brain’s main neurotransmitter, is deficient in schizophrenia and overactive in autism. However, glutamate is associated with a myriad of disorders. Conversely, many biochemicals are associated with schizophrenia and autism.

Professor Jeffrey Lieberman discusses the glutamate hypothesis of schizophrenia.

To Conclude..

Crespi’s hypothesis is interesting and certainly worthy of further comment. Right now, the evidence is not there to substantiate the hypothesis, but that is not to write it off entirely. As genomic technology becomes more powerful, it is increasingly likely that it will be used to inform how we think about diagnosis and psychiatric disorders. Psychologists are compelled to take note of developments in molecular biology, and the two communities are beginning to merge in places. I suspect we will be seeing many papers of this kind in the next few years.

Read more…

G2C Online, schizophrenia resources:

http://www.g2conline.org/#Schizophrenia

G2C Online, autism resources:

http://www.g2conline.org/#Autism

CSHL Harbor Transcript article on CNVs (written by me!):

http://www.cshl.edu/public/HT/pdfs/07_summer_autism.pdf

A review from Science magazine:

http://www.sciencemag.org/cgi/content/full/324/5924/162b?rss=1

Can we Diagnose PTSD with Brain Scans ?

2009-08-28T10:53:00.005+05:30

Duke University’s Rajendra Morey was in the news this week following a presentation at the World Psychiatric Association Congress in Italy. Dr Morey’s group recently published a paper equating symptoms of post posttraumatic stress disorder (PTSD) with “markedly different neural activity”. Dr. Morey raised the possibility of using brain scans to diagnose PTSD, thereby catapulting herself into the science pages of Forbes, Reuters et al. She joins a lengthy list of researchers that have whetted our appetite with tantalizing suggestions about the predictive power of neuroimaging. Sadly, the list of those who have followed through on this promise is not quite so long.

What are PTSD and fMRI?

PTSD is an anxiety disorder commonly seen in individuals who have survived extremely stressful situations such as war, assault, or other events that lead to severe psychological trauma. There is some evidence of a genetic association – an intriguing paper by Binder et al. (2008) links PTSD with genetic polymorphisms at the stress-related gene FKBP5. A number of recent studies (e.g. Bryant et al., 2005) have used functional magnetic resonance imaging (fMRI) to link PTSD with specific brain networks including the anterior cingulate and amygdala. Dr. Morey’s group essentially replicates these findings, with PTSD patients showing greater activity in emotion-processing areas (the cingulate and amygdala are often associated with fear-processing) and reduced activity in the prefrontal cortex (often associated with vigilance and monitoring).

FMRI, the neuroimaging technique used by Morey’s group, uses a large magnet to monitor blood flow, which is very precisely related to activity in the brain. When a region becomes active, there is an increase in blood flow to neurons, which leads to a very slight change in the magnetic signal. Although very slight, this change can be detected by extremely powerful magnets. By tracking magnetic changes in the brain, researchers can infer increased or reduced neural activity.

What is the evidence?

Every week, at least 3 or 4 neuroimaging papers report a neurological correlate to a particular emotion, behavior, or even voting preference. I recently interviewed Thomas Insel, Director of the National Institute of Mental Health (NIMH) and he made the point that despite over 19,000 neuroimaging publications in the last two decades, he could not point to a single neuroimaging study that affected practice, that changed the way we diagnose or treat any cognitive disorder. This, I think, is a very important point. There is no doubt that neuroimaging has potential, but, to date, its promise remains unfulfilled.

There is no grounds, therefore, for claiming that fMRI or any other neuroimaging technique can be used to diagnose PTSD. Accepted, the groups’ claims relate to future uses of fMRI, presumably an off-hand to an ill-informed news source. Nevertheless, this is an irresponsible comment given that there is currently no consensus among researchers about what the neural correlates of PTSD actually are. Sure, your study may have pointed to differences in prefrontal cortex and amygdala, but these areas are 1) associated with a host of executive and emotional processes, and 2) in the case of the prefronal cortex (or even the dorsolateral prefrontal cortex), extremely large and therefore unspecific.

Alzheimer’s disease is realistically the only cognitive disorder, where researchers have come close to developing a neuroimaging diagnosis. This is because Alzheimer’s has a very specific neuropathology that is clearly visible with autopsy. PTSD is absolutely different, any speculation linking PTSD to a neuroimaging diagnosis is distracting and misleading. When there are so many interesting science studies published each week, it is extremely disappointing to see stories such as this grab the limelight.

To conclude…

The short answer to my title question is a firm no. Maybe in the future it will be possible to make diagnoses of this kind, but we are currently not even close to this scenario. Any comments to the contrary are misguided, sensationalist, or downright untrue.

Vision of the Future (Part 1) - Susumu Tonegawa, Sydney Brenner, Richard Axel, Ira Flatow

2009-08-23T07:31:00.003+05:30

Susumu Tonegawa

Susumu Tonegawa has received the highest honors for his work, including the 1987 Nobel Prize in Physiology or Medicine, the Albert and Mary Lasker Award and the Bristol Myers Squibb Prize in Cancer Research. He was awarded his Ph.D. in Molecular Biology from the University of California at San Diego and trained at the Salk Institute as a postdoctoral student. In 1981, he was appointed Professor of Biology at MIT and a member of the Center for Cancer Research. He founded the Picower Center for Learning and Memory in 1994.

Sydney Brenner

Sydney Brenner is one of the past century’s leading pioneers in genetics and molecular biology. Among his many notable discoveries, Brenner established the existence of messenger RNA and demonstrated how the order of amino acids in proteins is determined. He also conducted pioneering work with the roundworm, a model organism now widely used to study genetics.

Brenner received the Nobel Prize in Physiology or Medicine in 2002,and the Albert Lasker Medical Research Award in 1971. He is a Fellow of the Royal Society; and a Foreign Associate of the National Academy of Sciences. He received his undergraduate education at the University of Witwatersrand, South Africa, and earned a Ph.D. in Chemistry from Oxford University.

Richard Axel

Richard Axel was awarded the Nobel Prize in Physiology or Medicine in 2004, with Linda Buck. His laboratory is interested in how sensory information is represented in the brain. He performs imaging experiments in concert with electrophysiologic recordings to determine how this map is represented in higher olfactory centers to allow for the discrimination of odors and appropriate behavioral responses.

He received an A.B. from Columbia University; and an M.D. from Johns Hopkins University School of Medicine.

About the Lecture

What better way to inaugurate one of the world’s premiere neuroscience research centers than a tour highlighting some of the field’s most exciting work.

Susumu Tonegawa provides not only a history and overview of the Picower Institute, but a rundown of the latest insights about memory and cognition emerging from his and colleagues’ labs. Morgan Sheng has figured out how to visualize at high resolution the molecular architecture of neuronal synapses; Matthew Wilson can detect a pattern of firing neurons in the formation of spatial memories as rodents explore a new environment, and then watch these neurons firing in the same pattern as the animals sleep—suggesting a mechanism for consolidating memory; Mark Bear is delving into the molecular mechanism behind fragile X mental retardation, and exploring possibilities for pharmacological correction; Earl Miller’s work with monkeys indicates that learning may happen first in a more primitive area of the brain, monitored and then ‘approved’ by the brain’s executive branch, the prefrontal cortex. And Tonegawa has zeroed in on the genes responsible for specific kinds of memory circuits in the brain’s hippocampus. As for the future, Tonegawa calls for “new technology, based on totally new principles, which can analyze what’s going on in the brain at the level of a single synapse,” as well as new diagnostic and therapeutic methods for psychiatric and neurodegenerative diseases.

Sydney Brenner says the “connection between genotype and phenotype, especially for complex animals, will remain the most challenging problem in biology.” He says there are deep intellectual problems to be solved, such as computing behavior “from a wiring diagram,” which must be accomplished if we are to gain understanding of the brain.

Richard Axel probes the mechanism of perception, from the bottom up and top down. He asks how the brain “creates its own selective pictures of the world” from different sensory input, which exist as “bits of electrical activity, excitable neurons.” Whether for vision, hearing, touch or smell, the brain has receptors that are specific for certain stimuli. Different odors, for example, will activate a different combination of receptors, which will in turn activate specific parts of the brain. When the fruit fly smells banana, one set of neurons fire, and when apple, quite another. The same is true for humans. But the problem of how our brains reconstruct this information in a meaningful way hasn’t been solved. Says Axel, “Perception is only a hypothesis, a best guess that never truly approaches reality.” Since “the brain does not have eyes,” wonders Axel, “who reads the map?”

Opening the Mind’s Eye- Learning to See - Pawan Sinha

2009-08-20T12:28:00.001+05:30

About the Lecture

It’s rare to find research that simultaneously advances basic science and brings good into people’s lives, but Pawan Sinha’s Project Prakash does precisely that. An investigator of human visual processing, Sinha is interested in how these brain mechanisms develop. For his work, Sinha realized the ideal subjects would be individuals who developed sight after blindness. Since he could not ethically create such an experimental population, he had to “rely on natural experiments” -- children born blind, but who recovered their vision.

Sinha found these subjects in his native India, which has the world’s highest number of blind children -- more than one million. They are victims of Vitamin A deficiency, congenital cataracts, and absent or atrocious medical care. But salient to Sinha’s research, many of these blind children could be treated. He glimpsed a humanitarian and scientific opportunity, and Project Prakash (Sanskrit for light) was born.

Starting a few years ago, Sinha and his team began screening blind children in a few villages to identify cases of treatable blindness, and remedy their disorders. More recently, he’s gained support from hospitals and schools for the blind, reaching many more children. He began to establish a test population. Research on this unique group has yielded many original insights into the development of vision, and shaken some major scientific dogmas. Sinha found that after years without visual stimuli, the brains of these children could process new information flooding in -- challenging the notion of early critical periods in brain development. He discovered that patients who once learned about objects simply via touch could, once they gained sight, identify the same objects simply by looking at them.

Sinha has also delved into the mechanisms of visual integration -- how our brains make sense of visual cues containing diverse colors, illumination, and patterns. He’s learned that newly sighted patients have difficulty parsing overlapping images (such as triangles, squares, circles), but moving these images around magically sparks recognition. Research results are consistent across all ages, and show that early stages of sight acquisition involve seeing the world in a fragmented way, compromising recognition, and that motion cues are critical for putting pictures together meaningfully, serving “a critical bootstrapping function for visual learning.”

The kinds of integrative difficulties experienced by Project Prakesh children bring to mind similar difficulties in autistic children, for whom motion processing also seems to be deficient, and Sinha is now seeking a possible “causal chain in autism” that leads to the disorder’s devastating social impairments -- a research path that might someday yield new therapies.

“Whenever we’re asked how the brain does X or Y, the impulse is to work with this beloved creature, the human infant, to see how it acquires different capabilities... But there are challenges: Babies are not interested in being experimental subjects. They’d rather sleep than give us good data. ”

Pawan Sinha...

Neurobiology of Fear, Anxiety and Extinction: Implications for Psychotherapy - Dr. Michael Davis

2009-08-20T12:23:00.002+05:30

About the Lecture

Few scientists have charted the grim territory of fear and anxiety with the same doggedness and precision as Michael Davis.

Nearly four decades ago, researchers learned that animals, including humans, startle more when fearful. A sudden noise in a dark, creepy alley provokes a greater reaction than in a well-lit room, for instance. That got Davis and his colleagues wondering what neural mechanisms underlie the startle reflex, and how fear plays a part in the response.

In his talk, Davis describes the meticulous experiments he and others have conducted over many years. Starting with the fear potentiated startle test -- where animals are trained to pair a stimulus such as light, or sound, with a shock -- researchers began to track the pathways that mediate the response in the nervous system. Using chemical tracers that could follow electrical activity in the brain, Davis found a group of cells in the central nucleus of the amygdala that are critical for fear conditioning. “It was a nice day in the laboratory,” he says. When he knocked out this part of the amygdala with drugs or a lesion, it selectively decreased fear potentiated startle.

More studies produced maps showing that outputs of the central nucleus affect other areas of the brain involved in the symptoms of fear and anxiety, such as elevated blood pressure, sweating, clammy skin, panting and pupil dilation. Of particular interest to Davis, though, were the connections between the central nucleus and another part of the amygdale long thought to be interrelated, the bed nucleus of stria terminalis (BNST). When drugs inactivated the BNST, the startle response was completely blocked.

Davis began disentangling the mechanisms of these two areas, and found that a specific peptide, corticotrophin releasing hormone (CRH) “produces a constellation of behaviors that look very much like fear and anxiety” -- and acts on receptors only in the BNST. He began to test the idea of two systems acting in parallel in the brain: fear, of relatively short duration, orchestrated by the central nucleus; and anxiety, more diffuse and sustained, originating in the BNST.

Davis proposes that cognitive inputs (perhaps bad experiences and memories) help drive the release of CRH and long-term anxiety, including common debilitating phobias (fear of heights, darkness) and post-traumatic stress disorder. Research has shown that to extinguish such fears, new kinds of ‘inhibitory’ learning must take place. Davis recently discovered a compound, D-cycloserine, that has proved extremely promising in psychotherapy aimed at extinguishing phobias.

Using Psychoacoustics to Explore Cochlear Function: Basic Mechanisms and Applications to Hearing Aids - Brian C. J. Moore

2009-08-20T12:23:00.001+05:30

About the Lecture

Anyone who suffers from hearing loss as well as those less familiar with this affliction should attend closely to this lecture. Brian Moore describes different kinds of damage to the cochlea, and he plays tapes that simulate what it’s like to hear with these impairments. Moore also offers the solace that research is leading to improved technology for the hearing impaired.

Moore first takes us on an animated ride into the ear canal, through the ear drum, to look at a part of the cochlea, the basilar membrane, which plays a crucial role as a frequency analyzer. Two classes of hair cells lying on top of the membrane serve distinctive purposes, and damage to them leads to common types of hearing loss.

Injuries to the outer hair cells result in a higher than normal threshold for detecting sounds, and inability to hear high and low sounds at the same time. People have difficulty separating sounds they want to hear from background noise, especially speech. Current hearing aids don’t compensate well for this impairment. Describes Moore, “Imagine sitting there listening to a concert with a friend with normal hearing and suddenly they’re playing quietly and you can see that they’re playing. You can’t hear a damn thing, you turn up the volume control on your hearing aid, they come back to a loud passage and aiyee! That’s why people say ‘Don’t shout’ when they’re wearing hearing aids.”

Inner hair cells on the basilar membrane send signals to the auditory nerve, and if they’re impaired, then the message they send to the brain gets scrambled. “It really screws up the ability to understand speech,” says Moore. There are “dead regions” where large sections of these cells are completely nonfunctioning at different sound frequencies. Scientists are learning how to compensate for these dead regions by moving sounds to other frequencies that will be audible. Moore also discusses damage to auditory processing that affects the ability to hear changes in pitch -- the “dips of normal talkers” in which people with ordinary hearing “grab information.”

Moore and other researchers are trying to tailor hearing aids that compensate for reduced frequency selectivity and for insensitivity to pitch, and which feel more comfortable. In development are open ear canal aids with refined digital feedback algorithms, directional microphones and signal processing. Farther down the road are implantable hearing aids that use mechanical vibration to transmit a wide frequency range without distortion, and beyond that, the possibility of regenerating hair cells: “Don’t bother with aids at all, let’s fix the ear,” says Moore.

Worms, Life and Death: Cell Suicide in Development and Disease - H. Robert Horvitz

2009-08-20T12:17:00.003+05:30

H. Robert Horvitz

H. Robert Horvitz won the 2002 Nobel Prize in Physiology or Medicine (with Sydney Brenner and John Sulston), for his work on programmed cell death (apoptosis), and for his studies concerning organ development in C. elegans. His apoptosis studies may also improve the understanding of neurological disorders such as amyotrophic lateral sclerosis (ALS), a disease that killed Horvitz's father in 1989. In collaboration with others, Horvitz identified a gene involved in the inherited form of ALS, and he is also pursuing other genes involved in the disease. "My hope is that my discoveries will one day lead to advances in medicine that alleviate human suffering and contribute to the world in ways that will benefit mankind," Horvitz has said.

He is also an investigator for the Howard Hughes Medical Institute and a member of the McGovern Institute for Brain Research at MIT, and a member of the MIT Center for Cancer Research. He holds appointments at the Massachusetts General Hospital in neurology and in medicine.

Horvitz received bachelor's degrees in mathematics and economics from MIT (1968) and an M.A. and Ph.D. (1974) in biology from Harvard University. He was a postdoctoral researcher at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. He joined the faculty of MIT in 1978 and became professor of biology in 1986 and an investigator of the Howard Hughes Medical Institute in 1988.

About the Lecture

In October 2002, The Nobel Prize in Physiology or Medicine was awarded to H. Robert Horvitz, Sydney Brenner and John El Sulston "for their discoveries concerning genetic regulation of organ development and programmed cell death."

About the Lecture

A microscopic roundworm has come to play a dominant role in some of the most pivotal medical research of our time. In the labs of Robert Horvitz and his colleagues, C. elegans has helped reveal cell death as a normal part of biological development.

In this talk, Horvitz painstakingly delineates the series of discoveries based on C. elegans that identified the genetics behind programmed cell death (apoptosis), the disorders that emerge if this normal process stalls, and human counterparts to these disorders, which suggest potential targets for therapy.

Because the mature roundworm consists of just 959 cells, it was possible for scientists to track the organism’s entire lineage of cell divisions, and to characterize what genetic accidents created mutant worms.

Scientists figured out genetic pathways that were essential to normal development in the worm, and which, if disrupted, led to harmful mutations. For instance, the immature roundworm contains 131 cells that are not found in the adult, because they are genetically programmed to die. Every animal, Horwitz says, undergoes apoptosis as a “normal aspect of development.” Tadpoles lose their tails to become frogs; lots of animals have webbing “sculpted out by the process of programmed cell death.” Over years, Horvitz and his colleagues determined the precise genes responsible for programmed cell death in C. elegans, as well as the genes that protect cells from dying, and the way these genes interact. Horvitz’s teams also found likely human equivalents to these critical genes and pathways. If these genes go awry, says Horvitz, “then something is going to lead to disease.”

Cancer, autoimmune diseases and viral infections result from too little programmed cell death. That’s because cell division goes unchecked. There are also human diseases that occur because cells die when they should not: neurodegenerative disorders, retinal degeneration, liver disease, and heart attacks. As a result of Horvitz’s work, many new targets have emerged for these diseases, some of which Horvitz himself is pursuing. Horvitz is now aiming his sights at different genetic regulators that tell certain types of cells to live or die, leading to novel therapies for some of our most formidable diseases.

Neuroethics - Stephan Chorover, Mriganka Sur

2009-08-20T12:14:00.001+05:30

About the Lecture

Philosophers have long sought to answer questions about who we are, where we come from and where we’re going. Stephan Chorover frets that a widening circle of contemporary scientists embrace Sigmund Freud’s approach to these questions, which is to say, “Biology is destiny.” Neuroscientists are promoting an even narrower dogma, says Chorover, where “everything we are trying to understand can be understood in terms of underlying brain mechanisms, neurons and molecules.” How can we cultivate individual ethical acts, and how can society hope to respond to such challenges as violent conflict, or social and economic inequity, if all human behavior reduces to a set of neurological inevitabilities? Chorover describes and discredits the long history of biological reductionism, from phrenology (inferring faculties or traits from the shape of the skull), to Freud. He says that “chaotic interactions” derail determined behaviors. Says Chorover, “Complexity, contingency and context dependency argue against reductionism.” Mriganka Sur asks Chorover to go easy on neuroscience, pointing out that the discipline does take into account contingency and uncertainty, studying the impact of internal and external states on the complex system of the brain. He says, “we may never know everything about how our brains work but that does not mean we should not try to find out something.” He adds, “every scientific measurement involves reduction and possibility. You measure what you can with the tools you have….We measure to dig deeper to seek explanations that may well be part of the cognitive architecture.” Sur acknowledges that science “is hugely influenced by the values of the age” and can be used “to justify prevailing beliefs.” Yet he wonders if there are “universals in human behavior that might drive the quest for justice.”

The Invisible Forest: Microbes in the Sea - Sallie (Penny) Chisholm

2009-08-20T12:09:00.000+05:30

About the Lecture

After listening to Penny Chisholm, you’ll view pond scum or aquarium slime in a different light. In fact, Chisholm aims to instill a sense of reverence and concern for the organisms behind this phenomenon, which turn out to be blue-green algae. They’re part of a family of microbes called phytoplanktons that are essential to the earth’s health.

Chisholm sketches the history of phytoplanktons, which first emerged on earth 3.5 billion years ago, and created the oxygen in our atmosphere that made possible all other plant and animal life. “They can live perfectly well without us,” says Chisholm, “but we can’t live without them.” Energized by sunlight, phytoplankton are the ultimate recyclers. Chisholm’s research focus, Prochlorococcus, discovered in 1985, plays a supremely important role in climate control. The smallest and most abundant photosynthetic cell on the planet, it takes carbon from the atmosphere and deposits it safely to the ocean floor.

We must stop viewing all microbes as bad guys, Chisholm says, and instead, start to worry about the collective health of the organisms that regulate the world’s metabolism. Those hard at work clearing our air of global warming gases may not fare so well as the earth heats up. When ocean temperatures rise, Chisholm says, waters get more stratified, and this may make photosynthesis more difficult for the microbes. There are proposed attempts to manipulate or work around phytoplanktons – such as ocean fertilization or deep-sea injection of CO2 – but Chisholm is deeply skeptical. We may end up sucking oxygen out of the water and creating dead zones in the ocean “that release methane, nitrous oxide and other wonderful greenhouse gases that molecule for molecule, prove more powerful than CO2 in absorbing solar energy,” she warns.

Science has only just begun to study the world’s microorganisms. Just .1% of all microbes have been cultured, and who knows what other kinds of unique and essential properties we’ll find when we start looking, says Chisholm. It’s time we begin “to build the knowledge necessary to predict, regulate and sustain these vital functions of earth systems for future generations,” she says.

“Biomedicine has done amazing things for human health. Now we need to focus on planetary health. ...It’s preventive medicine for the earth, basically. The challenge is orders of magnitude greater.”

Penny Chisholm...

Form from the Formless: The Awesome Power of the Embryo - Hazel Sive

2009-08-20T12:07:00.000+05:30

About the Lecture

How does a single cell become a complex organism? The fascination and challenge of this question, says Hazel Sive, “drives me out of bed each day, makes me work long hours and keeps me excited about coming here.” Sive’s Whitehead lab investigates developing embryos for clues about how cells organize and form tissues and organs. Not only must an embryo determine what kinds of cells to grow, it must also place them in precise patterns, along three dimensions. As the embryo develops, cells signal to each other to move to a specific position, or a regulatory protein sends a command for a cell to align itself in a certain way. Sive’s particularly interested in the evolution of brain structure. Zebrafish serve as her model. The tiny, transparent embryos of this fish enable her to “look directly into the brain in a noninvasive way.” Sive plays a video showing how a brain forms from a sheet of cells that first rolls up into a tube. Then, three distinct areas emerge that correspond to key neural functions. If a gene responsible for this patterning of early brain structure goes awry, then the zebra fish embryo may emerge with a brain cavity that’s too big or too small to permit the intricate folding of neural tissue. This early process transpires the same way in all brains, whether zebrafish or human, says Sive. So study of mutant zebra fish brains and the genes that play a role in abnormal development shed light on brain malfunction in humans, including autism and mental retardation.

“Why study development? It’s fascinating, to think I was once a single cell. There’s a sense of personal interest, and also a fundamental biological interest. It’s universal across biological kingdoms. ”

Hazel Sive...

Introduction/Overview of Brain Disorders - Dr. Susan Hockfield, Mriganka Sur

2009-08-20T12:00:00.001+05:30

About the Lecture

In their symposium introduction, Susan Hockfield and Mriganka Sur place MIT at the forefront of a revolution in neuroscience. Hockfield, a neuroscientist by training, recaps the evolution of the discipline at MIT, from its 1964 start in the Department of Psychology to the more recent establishment of the Department of Brain and Cognitive Sciences. These changes mirror the transformation of a field in which, says Hockfield, “at first you could do little more than make qualitative observations about behavior and only speculate about causes, to one that can examine brain function at the level of molecules and cell circuits; that can conduct quantitative experiments with genetically targeted model systems and can directly observe the living human brain in action.”

We are now poised “for the first time in human history to deliver scientifically designed, rational therapies for some crippling disorders of the brain.” Hockfield credits MIT’s progress to “meta-experiments,” specifically collaborations among scientists and engineers, and the generosity of patrons.

Mriganka Sur and his colleagues believe “the vast majority of brain disorders have their roots in brain wiring gone awry,” so a solution to such disorders lies in understanding the wiring, and its associated functions. MIT gets at these questions from many angles of research, including the genetic underpinnings of brain development, the architecture of synaptic pathways and networks, and the brain’s response to environmental stimuli. MIT addresses research problems through a “unique interdisciplinary effort” comprising molecular biology, neuron and cognitive science, and computation. What’s more, researchers have united behind a singular mission -- a “wish to make a difference in the world” -- which involves a specific focus on addressing such brain disorders and diseases as dyslexia, Alzheimer’s, schizophrenia, and autism. “There is not one other entity like this anywhere else,” says Sur, who believes MIT’s potential for future impact is “virtually limitless.”

“At MIT we love bold experiments, the kind that change the rules, and we have an impressive record of making bets that win. That fearless experimental spirit coupled with intense collaboration among investigators, with the support of philanthropic friends, is exactly what will drive us to next level in brain research.”

Susan Hockfield...

Cognitive Control: Understanding the Brain's Executive - Earl K. Miller

2009-08-20T11:41:00.000+05:30

About the Lecture

We often take it for granted that we know the difference between a cat and a dog. Where and how do we store the visual information that categorizes “catness” in our minds, so that the next time we see a cat, we know that it is not a dog?

Earl Miller has studied this process of categorization with monkeys to better understand the human brain’s processes. Miller’s research is focused on the prefrontal cortex, the part of the brain responsible for higher level intellectual or “executive activities”. A monkey’s brain is monitored to see how its “cat- recognition” neurons fire electric signals that enable this process to work. He has determined that the prefrontal cortex is extremely active when the monkey learns a task, and then goes “offline” when the task becomes automatic. Like humans learning to drive a car, at first we focus mental effort on each act of steering or braking, but eventually driving becomes somewhat routine. Mapping neural and chemical pathways for these executive brain functions may ultimately lead to therapies for dysfunctions such at attention deficit hyperactivity disorder and autism.

“You’re not like video cameras taking in everything. You actively construct your world by paying attention to some things and ignoring others…. (The) prefrontal cortex is the puppet master telling the rest of the brain what to do and ignore.”

Earl Miller...

Vision: Challenges and Prospects - Pawan Sinha

2009-08-20T11:40:00.000+05:30

About the Lecture

In a fraction of a second, most of us can recognize a face in a crowd, or make out a face from a blurry image. Pawan Sinha focuses on our uncanny ability to recognize faces as a way of getting at one of the key problems of neuroscience: how our brains represent and then encode objects. He theorizes that facial perception is a holistic process: we broadly take in the relationship, for instance, of eyes, nose and mouth. He tested this hypothesis by creating a computer program that could similarly grasp facial structure, and the program was able to “see” a face within a larger picture. In his Hirschfeld Project, Sinha is trying to distill the caricaturists’ understanding about the important landmarks of a face. He’s discovered that you can shrink an image of a face to 13% horizontally or vertically, and it will still be recognizable. Sinha’s work on how the brain perceives faces has immediate application in security surveillance systems, pedestrian-alert systems for cars, and in robotics. But closest to Sinha’s heart is a new project in India, home to 30% of the world’s blind, where he will assist and study children with recovered sight following congenital blindness.

Architecture of the Brain - Elly Nedivi

2009-08-20T11:38:00.001+05:30

About the Lecture

In this lecture Elly Nedivi provides an overview on the basics of brain anatomy, working her way up the spinal column to the deepest recesses of the cerebral cortex. Using vivid slides, we learn that physically distinguishable areas of the brain are responsible for specific functions, and that you can, for instance, build maps of the cortical areas dealing with each of the senses. Nedivi explains precisely why there is a safety zone in the spine for an epidural, and also show images of the earliest stages of embryonic brain development. While there are still deep mysteries hidden inside the human brain, Nedivi sheds light on the fascinating things that are known about this very complex human organ.

“The way the brain works is so fast and immediate…it’s hard to imagine some computer getting all that information in such a short time and making such a quick response in judgment.”

Elly Nedivi...

Neurobiology of Memory: How Do We Acquire, Consolidate and Recall Memory - Susumu Tonegawa

2009-08-20T11:36:00.004+05:30

Susumu Tonegawa

About the Lecture

In labs around the world, mice learn to navigate complex mazes, locate chocolaty rewards, and after an interval, run the mazes again with maximum efficiency, swiftly collecting all the sweets. But in Susumu Tonegawa’s lab, the mutant mice he has created cannot perform these tasks. Tonegawa “ knocks out” a gene that impairs a specific part of the mouse hippocampus, the area of the brain responsible for spatial memory, among other things. Mutant mice struggle to acquire and recall information about their surroundings. Tonegawa’s work involves manipulating genes to explore memory and learning from the most basic biochemical and cellular levels, up to the most complex behaviors. One of Tonegawa’s goals in designing defective mice is to simulate profound human disorders, like schizophrenia.

The Changing Brain - Mark Bear

2009-08-20T11:33:00.000+05:30

About the Lecture

How do our right and left eyes take in two separate streams of visual information and end up with a single view of the world? This question has come under intense scrutiny from neuroscientists for decades, and Mark Bear brings us up to date in his lecture. Single neurons in the visual cortex respond to particular stimuli (such as direction or color) and then the brain does some fancy filtering to process only the stimuli that match up in both eyes. Bear describes breakthrough experiments where researchers closed the eye of a kitten for just a day or so, and found that it was effectively “blind” after it opened. Correlating visual information to produce binocular images depends on neural connections that are forged during a “critical period” of visual cortex development. Bear’s work with visual system neurotransmitters has turned up intriguing connections to conditions like Fragile X syndrome. This form of mental retardation may result from a similar loss of neural connections during a parallel critical period after birth.

The Wonders of Electricity and Magnetism - Walter Lewin

2009-08-20T11:31:00.000+05:30

About the Lecture

The inimitable Walter Lewin gives a literally hair-raising performance in this MIT Museum lecture/demonstration for learners young and old. He unveils the real meaning behind words and things most of us use everyday without reflecting on what marvels they really represent.

Here are some of the mysteries exhibited, explored, and explained in this talk: How can you make two perfectly normal balloons zoom apart from each other? What happens when you connect a 12-volt light bulb to a 110-volt outlet? If you toss a handful of confetti onto a comb, why does some of it stick and some of it fly away? What’s the best way to make sure your flashlight will work the next time you really need it? (If you guessed putting in new batteries, go to the back of the class.)

Lewin is at his electrifying best when working with children from the audience. He gives a 12-year-old girl the worst hair day of her life, and offers a young boy 10 cents for 10 hours of backbreaking labor. But Lewin reaches a new high (low?) when he repeatedly beats one of his young assistants with a swatch of cat fur. Lewin doesn’t exempt himself from the torture, though: he even makes a serious attempt to electrocute himself with a 150,000-volt Van der Graaf generator.

Lewin indulges the armchair physicist who’s mathematically challenged, by covering all the basics of electricity and magnetism while introducing just one equation. If you’re still undecided, check out some of the unique special effects – sparks, flashes, smashes, and more –pinpointed in the Video Index. Keep watching, and you will find out why Walter Lewin was recently honored with MIT’s Everett Moore Baker Memorial Award for Excellence in Undergraduate Teaching.

The Emergence of a “Renewable Feedstock-Based” Chemical Industry - Douglas C. Cameron

2009-08-20T11:30:00.000+05:30

About the Lecture

If the future once lay in plastics, as the film “The Graduate” claimed, today the watchword may be “feedstocks.” This term includes corn, wheat, soy, sunflower, rapeseed (canola)—the array of carbohydrates and proteins growing in fields across the planet. The news, as Douglas Cameron makes clear, is that these crops no longer serve just as staples for animal and human diets, but as the basis for a “revolution in the chemical industry.” Cameron’s company, Cargill, is exploring a host of biotech applications for carbohydrates, fats and proteins found in common crops. For instance, they’re attempting to convert a plastic derivative of lactic acid (derived from fermented starch) into inexpensive polymers for medical implants. Another application: polylactide fibers that not only give comfort to clothing but provide high wicking power. Cameron also sees soy and vegetable oils as a promising industrial “platform.” Cargill envisions transforming them for use in engines, as lubricants, hydraulic and transformer fluids, replacing environmentally unfriendly chemicals. If industry can find effective conversion methods, grains and legumes may emerge as primary sources of fuel, key ingredients in drugs and diet supplements, clothing and paper products, and as heightened versions of themselves—more nutritious food for people and animals.

An Introductory Science Curriculum for 21st Century Biologists - David Botstein

2009-08-20T11:22:00.002+05:30

About the Lecture

How will biology move beyond the Human Genome Project and the task of reducing living things to their genetic sequences? According to David Botstein, the answer lies in “educating the biologist of the 21st century”—someone who will be conversant not just with molecular biology, but with computer science, physics and chemistry. At Princeton’s new Lewis-Sigler Institute, Botstein is spearheading an innovative effort at interdisciplinary undergraduate education. Students will take advantage of state of the art laboratories and computers capable of crunching vast amounts of data generated by actual research. Professors will “provide essential fundamental concepts as required, using the just-in-time-principle”-- no more of the “learn this now, it will be good for you later” approach, which Botstein likens to hazing. Botstein says there is “lots of overhead in teaching historical and traditional origins” so his students will learn instead “with ideas and technologies of today.” He wants to create a new basic language that will enable his biology students to make sense of the fundamental issues of other disciplines.

“At the turn of the century, it’s time to rethink undergrad education: the genome and computer invite a new curriculum that integrates biology with other sciences.”

David Botstein...

Opening Remarks/How the Brain Invents the Mind - Dr. Susan Hockfield, Rebecca Saxe

2009-08-20T11:11:00.006+05:30

About the Lecture

In trying financial times, Susan Hockfield remains optimistic and committed to pursuing MIT’s massive, multi-year initiatives in energy and life sciences. She prefaces her “whirlwind” tour of MIT for an alumni audience by referencing the campus-wide relief at the change in presidential administrations, which promises to make science and engineering more central, and to make “MIT values more mainstream.” If it indeed becomes “cool to be smart,” Hockfield believes MIT can count on taking a prominent national role in research, policy and education.

One key area in which MIT hopes to make a major contribution is sustainable energy. The MIT Energy Initiative, two years old, brings together faculty and students across all disciplines to develop a portfolio of new technologies (although the focus seems increasingly to fall on solar). Campus interest is so intense that the Institute has committed to a minor in energy, and it’s seeking five new professorships in the area. The other major enterprise involves fusing biological sciences with engineering, especially in the study of cancer. At the new Koch Institute, cancer biologists and engineers have already made “fundamental discoveries underlying new targeted cancer drugs,” and they are hard at work decoding the disease, and devising new methods for diagnosis and treatment.

Hockfield also candidly describes the impact of the economic downturn on the Institute, acknowledging that “most revenue streams have been compromised,” except for research. With the endowment down by 20-25%, departments across the board are making significant but strategic cuts for the next two to three years. MIT will not compromise on providing financial aid to needy students, a cost that understandably has risen in the past year, nor on hiring faculty. Hockfield hopes that private philanthropy will help MIT “preserve core strengths and values.” At the end of the recession, she says, “We want to come out with a leaner, stronger Institute.”

Fellow neuroscientist Rebecca Saxe outlines her research investigating the neural basis for a Theory of Mind -- how the human mind seems geared to “glean what others are thinking and feeling.” From her work with children and adults, Saxe has determined that there’s a very specific region of the brain -- the right temporal-parietal junction -- dedicated to thinking about how others think. This area lights up in the fMRI scanner when people read stories involving another person’s beliefs and moral judgments, but not when they digest other kinds of written material. The RTPJ develops this special function slowly (young children don’t have it), and Saxe has discovered that she can interfere with this region’s activities, altering her subjects’ sense of what constitutes morally permissible behavior. She’s exploring whether these distinct neural networks develop differently in children with autism, with the hope of finding therapies that might someday help treat the disorder.

“There’s a new administration in Washington, one that values science, analysis, and research... We hope that it will be cool to be smart.”

Susan Hockfield...

New Frontiers in Schizophrenia and Bipolar Disorder Research - Edward Scolnick

2009-08-20T11:11:00.005+05:30

About the Lecture

In contrast to cardiovascular disease, few breakthrough remedies for psychiatric illness have emerged in the past half century. Edward Scolnick lays blame for this dismal situation on barriers to understanding the genetic basis behind such illnesses. But the research drought may be over, as the current revolution in human genetics opens wide a door into the molecular biology and brain physiology behind diseases like schizophrenia and bipolar disorder.

These common, chronic and disabling mental illnesses are complex, involving abnormal behaviors that vary in expression. They have also lacked the kind of quantitative tests that enable precise diagnosis. While science has demonstrated that the single biggest risk factor for both schizophrenia and bipolar disorder is genetic, it has not been able to design tools for exploring how the genetics relates to the evolution of the disease in people. But just in the last two years, with the sequencing of the human genome and maps of human genetic variation, ignorance has given way to major findings.

In schizophrenia and bipolar disease, researchers have discovered that gene deletions and duplications (called copy number variants) cause significant brain circuit mischief. They’ve also learned there are gene variants common to both diseases, as well as clusters of genes that malfunction. Scolnick describes diverse research at MIT, proceeding at a “breakneck pace,” that uses this genetic information “to delve into the malfunctioning of brain circuits.”

Scientists have applied functional magnetic resonance imaging to compare the brains of ordinary people and schizophrenia patients, and discovered that the schizophrenic’s brain in a resting state is hyperactive. Other researchers found that schizophrenics generate the gamma brainwaves involved with higher mental activities in a different manner than control subjects.

Another MIT lab has begun to manipulate specific brain circuits using optical technology -- shining different wavelengths of light at special interneurons that regulate the firing of other neurons, and which are postulated to have a critical role in the malfunctioning of schizophrenics’ brains. Two other MIT labs are examining the biochemical disruptions due to altered genes, and developing “safe, specific chemical inhibitors” that might yield potential treatments for schizophrenia and bipolar illnesses. In Japan, researchers are growing stem cells into brain cells, which may lead to precise experiments that relate genetic problems to malfunctions in brain wiring. Indeed, adding up this research, a central biochemical pathway central to the pathogenesis of psychogenic illness seems to be emerging, knowledge that “can be exploited to understand illness and to find drug treatments.”

“For the first time, science has the ability to unravel the underlying causes of severe mental illness ... For the first time in the history of the field, there’s a way forward that can lead to significant improvement in diagnosis and therapy, and there’s no place in the world better than this university to carry out the work. ”

Edward Scolnick...

The Autistic Neuron - Mark Bear

2009-08-20T11:11:00.004+05:30

About the Lecture

This self-described “basic neuroscientist” confesses he never thought he’d give a talk on autism, but as Mark Bear recounts, decades of research in the basics are now paying off with important insights into the etiology and treatment of brain disorders, including autism.

Bear provides a primer on this developmental disorder, noting that its roots are biological, it is highly heritable, and astonishingly prevalent: one in 150 people express some of the symptoms of autism. These fall on a spectrum, from severely reduced social behavior, abnormal language, repetitive movements, seizures and mental retardation, to the milder Asperger’s Syndrome, where individuals are often academically successful, but socially awkward. Particularly significant to Bear: Autism’s underlying genetic changes manifest themselves in problematic communication between neurons.

To unravel autism, researchers are examining its clinical heterogeneity, “genetic risk architecture,” and how it alters brain connections and function. One of the difficulties in approaching autism is that a variety of genetic mutations can result in autistic behaviors, and only a few of these mutations have been identified. Bear himself has been probing the single gene disorder, Fragile X syndrome (responsible for about 5% of the cases “of full-blown autism.”) In Fragile X, the FMR1 gene is silenced, leading to a missing protein that serves as a key regulator of brain proteins involved in neuron communication. Without FMR1, “the brakes are missing,” and there’s excessive protein synthesis leading to altered brain function.

Bear hypothesized that it might be possible to correct Fragile X by bringing the system back in balance. He created mice models of the disease, and found that by reducing the number of neurotransmitter receptors that respond to the excessive brain proteins, he could ameliorate or correct Fragile X defects. These receptors are “druggable targets,” and, says Bear, “if the treatment works in fly, fish or mouse, it better work in humans or Darwin was wrong.”

Based on this work, drug companies are devising compounds to test in human clinical trials of Fragile X syndrome. In addition, Bear notes, colleagues have discovered that other mutations connected with autism also involve protein regulation problems. “This gets us excited, because it looks like a common pathway that causes synaptic dysfunction in different diseases that may ultimately manifest as autism. If that’s the case, then treatment for the disorder may be efficacious in multiple disorders.”

“No single lab can answer all the questions (about autism). But the payoff will be tangible and huge. ... By understanding the pathobiology, the pathophysiology, we hope to come up with therapeutic interventions that are more than palliative -- that is, disease modifying interventions to correct the course of the disease and let children grow up normally. ”

Mark Bear...

Alzheimer’s Disease: Current State and Hope for the Future - Li-Huei Tsai

2009-08-20T11:09:00.001+05:30

About the Lecture

Measured in human suffering, and by statistics, Alzheimer’s Disease (AD) presents a formidable specter: with incidence approaching 30 million worldwide and growing rapidly, it is now the sixth leading cause of death in the US. As life expectancy lengthens, AD is anticipated to triple in prevalence over the next few decades. The disease is found in nearly 50% of people age 85 and older. Triply higher medical costs are incurred by seniors with AD. These daunting facts give urgency and weight to molecular neuroscientist Li-Huei Tsai’s research.

Tsai begins her presentation with an historical perspective of Alzheimer’s, first documented in 1901 in Germany as “strange behavioral symptoms and loss of short-term memory.” Post-mortem examination of a patient’s brain showed “the hallmark pathological lesions: amyloid plaques and neurofibrillary tangles.” Telltale manifestations include “forgetfulness, …confusion, disorganized thinking, impaired judgment,” difficulty expressing oneself, spatial and temporal disorientation, and incapacity in daily activities. Family members must often quit jobs to provide round-the-clock care. In the advanced disease, becoming bedridden engenders chronic infections, secondary conditions, and eventual demise.

Definitive clinical diagnosis can be elusive. Imaging techniques with radioactive tracers, using a compound that selectively binds with amyloid plaques, help to identify AD. Tsai describes several cognitive tests developed by fellow MIT researchers to aid in confirming the disease. One method assesses retention of verbal facts and geometric figures. Another diagnostic tool is functional MRI, pinpointing brain areas activated upon exposure to new versus repeated scenes, a challenge for memory. Both approaches reveal notable distinctions between AD patients and control subjects.

“Currently there is no treatment that can prevent, delay or reverse Alzheimer’s Disease,” says Tsai. FDA approved drugs that act upon neurotransmitters postpone cognitive deterioration by only a few months.

Using a transgenic mouse model, Tsai’s pioneering research seeks to target compounds that can preferentially manipulate proteins to assume a desired structure. Resulting cellular differentiation into neurons could help correct deficits of AD by augmenting brain volume in specific regions, thereby enhancing learning and memory.

Just as experimental mouse subjects perform better with “environmental enrichment…by keeping them very physically engaged,” Tsai recounts that “people with higher education, more active lifestyles” benefit cognitively as they age. As to the respective contributions of genetic and environmental factors, she believes “it’s really a combination.” Though treatment for Alzheimer’s will not be solely pharmaceutical, Tsai hopes to identify chemical compounds to ameliorate the characteristic brain atrophy that robs one of vitality and dignity.

“Today, Alzheimer’s Disease is the leading cause of senile dementia…affecting probably 25 to 30 million people worldwide…With increasing life expectancy, the number is expected to triple over the next two to three decades.”

Li-Huei Tsai

The Brain and Mind - Mriganka Sur

2009-08-20T11:03:00.003+05:30

About the Lecture

In his kickoff lecture for this series on neuroscience, Sur provides both a current overview of brain models and function, and a peek at his own research. From the moment of conception, a developing animal begins to grow cortical pathways and networks that will eventually allow it to respond to the world outside. These increasingly sophisticated networks—for hearing, vision, touch—provide feedback to the evolving brain. For humans, at least half the brain is devoted directly or indirectly to processing vision, says Sur. Yet there is a single model for understanding how vision works: orientation selectivity. Regions of neural cells react only to specific stimuli, such as vertical or horizontal stripes, obliques or diagonals. Images of these activated cell networks from Sur’s lab resemble pinwheels. In Sur’s research on newborn ferrets, he rewired visual inputs to the animals’ hearing center, and found the same patterned responses to specific shapes among cells—more pinwheels. In essence, Sur enabled ferrets to “see” through their hearing cortex. This dramatic experiment demonstrates the plasticity of brain networks, and suggests there might be ways to repair human brains after stroke or other traumas.

“We have learned more about the brain in the last 20 years than in all of previous human history…(but) if we have a stroke, neurologists can do little more than hold our hands even today.”

Mriganka Sur...

DNA Mutation, Repair and the Environment - Leona Samson

2009-08-20T11:03:00.000+05:30

About the Lecture

Forget cigarette smoking (well, not completely). The really bad news, says Leona Samson, is that by virtue of the act of living, a human body will be exposed to destructive threats from the environment, and from within itself. Charbroiled burgers, sunlight, pollution, and even how our bodies use oxygen all pose what Samson calls “insults” to the DNA of our cells.

Our success in fending off these inevitable DNA-damaging agents in the environment depends a lot on inheritance, Samson tells us. For instance, victims of the rare disease Xeroderma pigmentosum don’t have the capacity to repair DNA that’s been corrupted by UV radiation from the sun. Children with Xeroderma pigmentosum develop skin cancers. In the larger population, such cancers tend to occur much later in life. The reason, Samson says, is that most of us have a formidable array of mechanisms within our cells for detecting and mending defective DNA. Cells with flawed DNA that goes unrepaired must either die, or go on to mutate in often dangerous ways.

Samson wants to figure out how to protect cells against carcinogenic effects in the environment, and whether a tumor cell will be susceptible to treatment. She has been painstakingly studying the Saccharomyces cerevisiae yeast organism, trying to identify all the factors that determine whether or not DNA damaging agents kill or mutate cells. She interrogated each of this organism’s 5,800 genes, “asking one by one, which of you is making a product that’s important to helping a cell recover from damage.” In what was a “huge surprise,” Samson learned that there are more than 2,000 gene products involved in helping a yeast cell repair itself, “from areas of the cell never suspected before for being important” in this way. Now Samson must elucidate the complex cellular pathways that “talk to each other” when DNA is damaged -- and figure out “how to extend to humans, ultimately.”

“Eventually, we’ll be able to take a tumor and know every gene that’s different in that tumor from a normal cell. And hopefully by understanding how all these pathways integrate with each other, we’ll figure out where the weak points are so we can attack tumor cells.”

Leona Samson...

The Cell Cycle and Cancer - Angelika Amon

2009-08-20T11:01:00.000+05:30

About the Lecture

We all start out as a single fertilized cell, and wind up, as fully formed humans, with 10 to the 13th cells. “The name of the game,” says Angelika Amon, is to replicate the genetic information in those cells accurately. “Only if that happens all the time and with high fidelity will you end up with a healthy individual.”

Amon shows a beautiful video of dance-like cell division in the African blood lily, which demonstrates the migration of chromosomes to opposite ends of the cell -- prelude to a single cell becoming two daughter cells. It’s “like a curtain opening,” Amon says in wonder. This process of cell division, she continues, is “highly conserved” among organisms. For instance, if a yeast cell contains a defect that prevents it from dividing correctly, plugging in the human equivalent of a protein to correct the defect will enable the yeast to begin dividing again.

Amon describes how cells contain special proteins called growth factors that work together to inhibit or initiate cell division. “The cell puts in place layers and layers of controls, like an onion,” says Amon. If someone inherits a mutation that affects one of these growth factors, then cells may proliferate uncontrollably. Another route to cancer is if a cell’s internal mechanisms for detecting DNA damage malfunctions, perhaps due to exposure to X-rays or UV rays. When these checkpoints break down, instead of putting the brakes on cell division, the cell will proceed unchecked through division with broken chromosomes, or extra chromosomes. Pieces of DNA lie around, information gets lost or amplified and “a mess ensues.”

Researchers have identified several key chromosomes in which defects lead to malfunctioning growth factors or checkpoints. And they’ve begun to design new drugs that target the specific proteins involved in these errant cell growth pathways.

Computational and Systems Approaches to Cancer - Michael Yaffe

2009-08-20T10:53:00.001+05:30

About the Lecture

Early on in his lecture, Michael Yaffe serves up an amazing fact: If the distance between each DNA base pair were one foot apart, then each time a cell divided, it would have to copy 568 thousand miles of DNA. This, says Yaffe, is enough to go around the circumference of the earth more than 22 times. What’s more, the cell has to copy its DNA with no errors. “I don’t know (if) civil engineers ... could make 10 miles of road without making single error,” says Yaffe.

In the 12 hours a cell takes to copy its DNA to create two daughter cells, “it goes to great pains to make sure everything is done correctly. It initiates checkpoints, like border crossings.” Because everyday life exposes DNA to all kinds of damage, cells have evolved “an elaborate surveillance mechanism” to “blow the whistle, signal repair, and recruit repair machinery,” or if damage is too great, essentially commit suicide. If something goes wrong with this mechanism at crucial times during cell division, cancer frequently results.

Yaffe’s in the business of exploring and mathematically mapping the elaborate signal pathways inside cells that sense broken DNA and coordinate damage response. While studying one such process, cell death in the colon, Yaffe found that the traditional biochemistry approach -- picking one molecule, one stimulus and one readout-- doesn’t work. “It’s like the blind man feeling the elephant’s tail, and saying it’s a long, thin animal.” Yaffe learned that one signal may activate a series of proteins, triggering an amplification loop. A slight change might yield a “whopping response.”

Just as engineers test integrated circuits at a variety of points, Yaffe came up with a method of testing cell signaling with a variety of proteins. His team came up with 7,000 signaling measurements in 760 dimensions, and 1,400 signal responses. But this data-heavy model for predicting which molecules lead to cell death didn’t satisfy Yaffe. With additional mathematical sleight of hand, Yaffe’s group boiled down the cell signaling measurements to what Yaffe calls two “canonical super axes”: “a global measure of cell stress and death, and another of survival signaling.” He hopes to use this slimmed-down model to think about drugs targeting cancer and inflammation.

“If the distance between each DNA base pair were one foot apart, to divide, a cell would have to copy 568 thousand miles of DNA. That’s enough to go around the circumference of the earth over 22 times. And it must copy this much DNA with no errors.”

Michael Yaffe...

How Did We Get Here? - Robert A. Weinberg

2009-08-20T10:53:00.000+05:30

About the Lecture

Robert Weinberg plots the 200-year course of cancer research, finding neglected byways, wrong turns, and astonishing advances. He starts with Percival Pott, a London surgeon who noticed that chimney sweeps often developed a rare kind of cancer. In Europe, where people bathed more often, this cancer was much less evident, leading to “the first indication in public literature that there was a close correlation between one’s experience in life and the incidence of rare cancer,” says Weinberg. In 1910, Japanese scientist Katsusaburo Yamigiwa, painted coal tars onto the ears of rabbits and produced tumors, which “led to the realization that one can experimentally provoke cancer rather than wait for it to arise spontaneously.” He was “overlooked by Nobel,” Weinberg notes. Other similarly unrecognized scientists discovered that transferring leukemic tissue into healthy tissue could induce cancer, and that cancer could be caused by infectious disease. But there were major missteps, says Weinberg. In one notorious episode, a Danish Nobel Prize winner’s cancer research was discovered to be in error. And when Howard M. Temin suggested that cancer originated through an atypical genetic process called reverse transcription, he “was shunned as a pariah.”

In 1970, Temin was vindicated as he and David Baltimore separately discovered an enzyme central to such a process. Next came the Nixon Administration’s ‘war on cancer,’ which was attacked as a fraudulent waste of taxpayers’ money when seven years of searching for viruses in human tumors produced no results. Yet this dead end suddenly yielded scientific pay dirt in the 80s, when researchers found viral ‘oncogenes’ in the DNA of normal cells, which caused malignancies. Scientists then demonstrated that by altering normal genes, they too could create cancerous cells. Advances in biochemistry have led to “a rapidly evolving conceptualization of how cancer occurs,” says Weinberg. “We’re beginning to talk about cancer as aberrations of an integrated signaling circuit, which if we could only understand its design….would lead us to be able to restore normalcy to a cancer cell or preferentially, kill it.”

How Cancer Begins - Robert A. Weinberg

2009-08-20T10:50:00.000+05:30

About the Lecture

If you’re worried about getting cancer, do yourself a favor: steer clear of red meat and rich foods, and avoid cigarettes. In this lecture, Robert Weinberg provides the scientific basis for this commonplace advice, as well as a layman’s look at the genetic, biochemical and environmental factors that make good cells go bad.

Normal cells are civic-minded, lining up together in a precise architecture that gives structure to body tissue. When the cell’s genes are damaged, they send out faulty instructions, turning orderly structure into a chaotic mess. This kind of injury to cells likely comes from the outside – as many as 90% of human cancers are due to bad diets and smoking. Weinberg wants to understand the specific pathways by which the cells’ enemies invade and do their damage, in hopes of then being able to halt the process and freeze a cancer’s growth. But, cautions Weinberg, better to count on prevention than a cure in the fight against cancer.

“…if we were to survive all other diseases, then if we got old enough, in one organ or another, a cancer would appear. ”

Robert Weinberg...

Animal Models of Cancer - Jacqueline Lees

2009-08-20T10:48:00.001+05:30

About the Lecture

Jacqueline Lees holds the lowly mouse in high regard. It is “beautifully developed” as a model system for cancer. Lees says that while researchers can learn much from cells in a Petri dish, they require living organisms to observe, for instance, the interplay of immune system and tumor cells, or how malignancies recruit new blood vessels to feed themselves. Because scientists now understand how to switch genes on and off to promote mutations in cells and specific cancers, Lees and other researchers can trigger the growth of malignancies in mice, to explore methodically the disease’s progression from first mutation through metastasis. They also test new cancer detection methods and potential therapies. The point, says Lees, is to “always ask if our understanding can be applied to human disease.”

Lees discusses how researchers have learned to induce both hereditary-type cancers and sporadic (non-familial) cancers, through a range of procedures, including engineering an “inducing” agent that “flips a gene into being mutant;” and creating a gene that carries a mutation and inserting it into the mouse genome. Through various manipulations, researchers have created mouse equivalents for human cancers of the colon, breast and ovaries, as well some leukemias. Lees points in particular to MIT’s success with modeling lung cancer. She presents dramatic 3-D images of lung cancer progression in a mouse over the course of several months, after scientists induce a mutation in its K-ras gene. By comparing mouse data with data on the human form of the disease, MIT researchers have strongly linked a mutation in the human K-ras gene to lung cancer.

Lees and colleague Nancy Hopkins hope to make even more rapid advances in identifying the genetic bases for cancers, using the humble zebrafish. Since it fully develops in 72 hours, lives up to five years, and is transparent to boot, the zebrafish provides the opportunity for “large scale screens for novel cancer genes.”

“Now we’re looking at the gene expression pattern of resistant tumors to understand what are the genetic changes that occur that correlate with resistance. If we understand what genetic events correlate with the acquisition of resistance, we will know the additional genes involved in the process. Maybe we can design drugs that target those resistant genes, or maybe prevent those changes from occurring in the first place.”

Jacqueline Lees...

Introduction to Cancer Genetics - Robert A. Weinberg

2009-08-20T10:30:00.002+05:30

About the Lecture

During the human lifetime, there are 10 million billion cell divisions and each division represents, as Robert Weinberg puts it, “an opportunity for disaster, for chaos to occur.” The longer-lived the organism, the more likely it is that one cell eventually “will lose the ability to collaborate with its neighbors” in maintaining structure and function, and just start multiplying uncontrollably.

Weinberg and other researchers are delving at the molecular and genetic level to understand why and how this single cell begins to proliferate, leading over years and through different stages, to cancer. Weinberg offers a primer on the process of cancer formation, which he likens to Darwinian evolution but within the microcosm of human tissue.

Healthy organisms carry tumor suppressor genes, and proto-oncogenes. If these genes become corrupted somehow or prevented from functioning, the result may be cell proliferation. There are, unfortunately, lots of ways these genes become damaged: via a virus, or chromosomes changing places, or by chemical carcinogens, for instance. Weinberg describes how high rates of liver cancer in China were traced to a DNA-mutating mold found in damp rice, grain and fruit. Given the number of ways genetic alternations can come about, it’s a relief that as many as five changes are required to convert a normal human cell into a malignant one. “If single mutations sufficed, we would all be covered by tumors by age three. Our cells are wired to be highly resistant,” says Weinberg.

The latest cancer therapies attempt to capitalize on advancing knowledge of genetic and cellular networks. Weinberg points to two drugs that shut down growth stimulatory signals: Herceptin, which has proven very successful in a specific class of breast cancers, and Gleevec, for chronic myelogenous leukemia.

“We work with the faith that the only way to develop new, rational ways of treating cancer is to understand what makes cancer cells tick. The great majority of therapies used currently against cancer were developed at a time when people had no idea why cancer cells grew abnormally. Now we know about this in great detail and only now are we beginning to exploit this information to translate basic research findings into new therapies. ”

Robert Weinberg...

Video Player Cancer Research in the Genomic Era - Eric S. Lander

2009-08-20T10:25:00.000+05:30

About the Lecture

Eric Lander likens the current age of biological discovery to the days of great ocean-going exploration. After the world was mapped, no one could imagine what it was like to live “before you knew what would happen if you sailed west.” Following the current revolution in biology, we “won’t be able to imagine what science was like...” This transformation, claims Lander, will be complete in the next decade or so. “MIT students in 2020 will look back with a mixture of amusement and horror at the late 20th century and say, ‘Imagine, people spent years looking for the gene for something.’”

Lander views biology as a vast library that will soon contain information not just about the DNA sequences of species, but ‘volumes’ on individuals, tissues, and cells. With great effort, researchers deciphered the secrets of chromosomes, the double helix, and more recently, the human genome and that of other species. But progress in such discoveries is now moving at a much faster clip due to high-speed computing and the Internet. MIT currently sequences ¼ million pieces of DNA per day, says Lander. He projects this pace will quicken by 20 fold in the next several years.

Fortified by this progress, Lander has compiled an ambitious ‘to-do list:’ identifying “everything that matters” in the human genome, from proteins to the things that control genes; knowing all human genetic variation in the population; knowing how to recognize when a cell “is thinking of one thing or another” based on how genes are turned on or off; knowing all the mechanisms that cause cancer and how to modulate all the genes.

Astonishingly, he says, “This is not the to-do list of the next century, but the next decade.” Lander is confident that researchers will in the not-distant future generate a catalog of the unique genetic signatures associated with “different flavors” of a type of cancer. Scientists will find patterns in diseases, genes and drug responses, and eventually assemble a list of all the genetic variants in the human genome that put individuals at risk for different diseases. These various gene databases will serve “as foundational information for biology for centuries to come,” concludes Lander.

Engineering New Approaches to Cancer Detection and Therapy - Robert S. Langer

2009-08-20T10:13:00.000+05:30

About the Lecture

With his 500-plus patents, Robert Langer, Jr. surely has dibs on the title of MIT’s Mr. Wizard. This talk, which concludes the series on cancer research, deals with Langer’s efforts to design materials for safer and more effective cancer treatment.

Langer describes his groundbreaking work of 30 years ago to inhibit angiogenesis, the growth of blood vessels on which tumors depend. He came up with a way of packaging proteins inside plastic polymers, essentially microspheres of drugs, which could be injected directly into a target site. These tiny beads released an angiogenic inhibitor in a slow and steady way, starving the tumor of nutrients. He notes dryly that it took the FDA 28 years from the time these results were published to approve the first implantable angiogenic inhibitors. Today, this approach is heartily embraced, says Langer, because it “gives you a whole new other avenue of attack” against tumors.

Because many large proteins are effective at combating cancers but can’t be swallowed, taken nasally, injected directly, or put in a patch, they now end up in Langer’s microspheres. One hormone-releasing microsphere attacks advanced prostate cancer. This drug delivery system has even spread to treatments for schizophrenia and alcoholism.

Langer’s recent forays in the lab have yielded dime-sized, gold-covered, degradable microchips conveying multiple, small quantities of a drug. In response to a one-volt zap (“via telemetry like a garage door opener”), these devices release just the right dose. Chips might someday also carry imaging agents. Says Langer, “The beauty of the chip is that information could be transmitted from the body to a computer, your house, doctor’s office, or hospital, so you could have a record of whatever happened.”

In the surgical arena, Langer’s come up with a “shape memory” polymer that can phase from a string at room temperature, to a coil at body temperature -- acting as a self-tying suture in hard-to-reach places.

Langer is now moving into even smaller domains, experimenting with nano-sized drugs for use in the blood stream. Coated with a polymer to prevent attack from the body’s immune system, these nanoparticles show promise in shrinking tumors.

Langer cites his career-long commitment to devise materials for medical treatment that are biologically and chemically compatible with the human body. (Dialysis tubing was based on sausage casing, and the artificial heart from ladies’ girdle material.) His polymers often faced opposition from the research establishment. “When you’re at a place like MIT, you often do speculative work, and when you do speculative work, you’re not always greeted that well in the scientific community,” he says.

“When you’re at a place like MIT, you often do speculative work, and when you do speculative work, you’re not always greeted that well in the scientific community.”

Robert Langer, Jr...

Immunology and Cancer - Jianzhu Chen

2009-08-20T10:12:00.003+05:30

About the Lecture

Jianzhu Chen lays out the thorny challenges of harnessing the immune system to fight cancer. He starts with the basics: how the body employs two levels of defense against pathogens: native and adaptive immunity. The latter type of protection specifically interests Chen, because it can recognize and remember “an almost unending number” of specific pathogens, both inside and outside cells.

B cells, produced in the bone marrow, can generate antibodies for clearing out bacteria, and T cells, originating in the thymus, go after viruses and other intracellular threats. They work by identifying an antigen (foreign substance) and expressing receptors -- cell surface proteins -- that bind to those antigens.

Early on, the immune system learns to distinguish between what is self and what is a pathogen. It develops, says Chen, “layers of self-tolerance,” without which the body might launch an assault on itself. But cancers can manipulate this useful feature of the immune system. Some tumors express chemicals, or summon naturally occurring suppressor cells in order to prevent T-cells from attacking them. So, says Chen, to mount an immune response against cancer, says Chen, you “need to induce a response against the self—you have to overcome the built-in tolerance mechanism of the immune system.”

Chen sees evidence of the possibility of overcoming “tumor-induced tolerance.” For instance, some tumors spontaneously shrink, and there’s an accumulation of immune cells at tumor sites. Researchers are focusing on three areas: using antibodies or T cells in cancer therapy; developing a therapeutic vaccine that would induce cancer specific antibodies or T-cells; and designing a vaccine to prevent cancer that would induce the memory of B or T cells for a specific cancer. Much hard work remains: identifying tumor associated antigens, most of which, says Chen, the body sees as “normal self proteins;” and then coming up with T or B cells specifically targeting these tumor associated antigens.

“Someday we should be able to harness the power of T cells to directly kill tumor cells, but we need a better understanding of T cell-tumor interaction, how to overcome self-tolerance mechanisms, and tumor induced tolerance too. ”

Jianzhu Chen...

The RNAi Revolution - Phillip A. Sharp

2009-08-20T10:09:00.001+05:30

About the Lecture

When a Nobel Prize-winning pioneer of molecular biology embraces a new area of research as revolutionary, attention must be paid. Phillip A. Sharp’s own discoveries involving gene expression opened up new territory in the search for the genetic causes of cancer and other diseases. He now has great hopes for similar breakthroughs with the process of gene silencing.

This latest advance in understanding gene regulation is quite recent. In 1998, Andrew Fire and Craig Mello discovered the process of RNA interference in the worm C. elegans. When they introduced short, double strands of synthesized RNA into a cell, the RNA silenced a gene in the cell and turned off a specific protein. (Fire and Mello were awarded the 2006 Nobel for this work.) Previously, scientists had viewed RNA as simply “the slave molecule between DNA and protein,” as Sharp puts it, or in spliced form, capable of generating a great number of diverse proteins. But revelation of the mechanism of interfering RNA has made the field “a lot more interesting,” says Sharp.

In just a few years, researchers have learned that small RNA “taps into a pathway that’s present in every cell,” says Sharp. “At minimum, one in four or one in five of our genes is controlled by small RNAs.” Researchers also suspect RNA pathways may occupy a central role in establishing controls in the “human germ line” to prevent redundant pieces of DNA from being expressed in a destructive way. This offers researchers more than a powerful, new investigative tool. Says Sharp, “This is MIT. If you’ve got something in the lab that’s new and you know people need it outside of the lab, you’re under an obligation to try to translate it into therapy.” One big question is whether small RNA can be used to treat cancers.

There’s evidence that small RNAs injected directly into the eyeball can potentially silence interconnecting genes responsible for cancers in the back of the eye. The same technique might also work for cancers in the brain and lung, says Sharp. One challenge involves getting the highly water soluble RNA across the cell membrane. Nanoparticle packaging may help prevent the RNAs from being absorbed before they’re delivered to the target area. Sharp also mentions experiments that suggest misregulation of small RNAs can cause cancer. “We as a field are now struggling with the issue of just what role short RNAs play in general in control of our genes and our normal physiological processes. It’s getting really interesting.”

New Lessons in Cancer Research - Jacqueline Lees

2009-08-20T10:06:00.003+05:30

About the Lecture

Cancer is a conniving enemy. Try to kill it off through surgery or chemotherapy, and it finds a way to sneak back in. Jacqueline Lees tells an engaged Soap Box audience what insights and tools research now offers in the longstanding battle against this relentless disease.

Big gains have come from molecular study of tumors at different stages, Lees says. It often takes many years for a cancerous cell to develop into a dangerous tumor, one that can yield metastases. There might be six phases of development over 15 years in a cancer’s evolution, and scientists have formed a good understanding of what these different lesions look like in various cancers, and how they behave. Lees calls this process “actually a beautiful example of evolution,” since the cell that mutates and begins to divide uncontrollably evolves to become more successful relative to other cells in the tissue.

Other research focuses on the genetic basis of cancers. Two “flavors” of genes appear responsible for provoking cancerous changes in cells: oncogenes and tumor suppressor genes. It may be possible to intervene along the genetic pathways underlying cancer growth, says Lees. Her own work, involving mutant mice and zebrafish, hopes to identify the mechanisms involved in specific kinds of tumors, and to figure out ways of inhibiting cancer cell growth. Understanding the nature of specific cancers might help prevent treating people with chemical agents that don’t work for their kind of cancer, and that actually increase their tumor’s growth.

With the advent of fast and inexpensive genetic screens, it may soon be possible to determine whether each of us carries genes that predispose us toward certain kinds of cancers. But Lees questions the universal adoption of DNA testing, not just because of privacy concerns, but because there may very well be no known cure if a predisposition to disease is found. “If we sequenced every baby, and said you’re highly predisposed to a cancer, and there’s nothing we can do, would that be information people want to have?” Lees wonders. “If we could find a rapid way to sequence small subsets of genome, identify people with high risk and we could treat them if we knew they had those diseases, there’d be an argument for that, much as we do testing for diseases where we know can intervene if find children carrying them,” says Lees.

Zebrafish and Cancer: What's the Connection? - Nancy Hopkins

2009-08-20T10:04:00.000+05:30

About the Lecture

Through her rapport with the zebrafish, Nancy Hopkins has made large contributions to the fields of developmental biology and cancer research. But her model organism, and to some degree her particular slant on molecular biology, were a matter of serendipity, as she relates to this MIT Museum audience.

When Hopkins was 10, her mother developed a form of mild cancer, terrifying to her, but also a catalyst for her interest in medical research. Later in college, after a lecture about DNA by James Watson, Hopkins realized that “the secret of life was being placed in front of you, that molecular biology someday had the potential to explain everything worth knowing: the meaning of life, why I looked like my mother...”

After obtaining a Ph.D. in molecular biology, Hopkins was determined to enter the field of cancer research, although colleagues warned it would be the “end of my career.” Fortunately for her, Richard Nixon was just as energized about finding cures for cancer, and poured money into the field. Even better, scientists had begun to make some key discoveries about the source of some cancers. After years working on viruses and oncogenes, Hopkins “thought it would be fun to move on to something else.” On sabbatical in Germany to study the genetics of behavior, she encountered zebrafish in her colleague’s lab. The evolution of the zebrafish from fertilized egg to adult occurs in five days, and Hopkins found it a perfect subject for studying an organism’s early development.

In her own words, she came back to MIT completely obsessed with finding all the genes “that make things work properly” in the zebrafish. After years of painstaking study, Hopkins and her team figured out how to remove one gene at a time from the zebrafish (with its 20,000-25,000 genes), in order to understand what those genes did. She built 4,200 fish tanks with almost 100 thousand fish, and ended up with 550 mutant lines of fish.

Then “a funny thing happened to bring me back to cancer,” says Hopkins. A lab assistant noticed some fish were developing tumors. She screened 17 mutant lines and found a family of cancer genes that appeared comparable to a group of human cancer genes. This discovery may explain the genetic basis for other human tumors.

As she continues work with her fish, Hopkins embraces new and faster technologies to accomplish genetic screens, as well as better detection and imaging capability. “I look forward to the day when I can just sit at home and do experiments with existing data,” she says.

Human Genetics: Our Past and Our Future - David Altshuler

2009-08-20T10:02:00.000+05:30

About the Lecture

Will genomics vanquish our most common diseases, or create a society based on vile eugenics – or both? David Altshuler outlines these possibilities in his informal talk and conversation at the MIT Museum.

Altshuler is a self-described optimist, and sees promise in current genetic research that attempts to pinpoint why some people develop diseases like adult-onset diabetes or schizophrenia. If we can identify the precise mechanisms inside cells that go haywire in individuals with an inherited predisposition to a certain disease, then it may be possible to design drugs much more accurately. “We’re searching for a culprit who committed a crime, where the culprit is a mutation in a DNA sequence that made somebody get sick …. And scientists are the detectives -- CGI: Crime Gene Investigators,” says Altshuler.

Scientists have a very powerful tool in the human genome sequence, and they are quickly mapping out genes that cause diseases. But the very tools that permit insight into illness may also permit researchers to isolate genes for other human traits. And this has Altshuler musing: “How about hair loss, intelligence, criminality, athletic ability….Should society regulate the use of genetic information in reproductive choices?” What if insurance companies gain access to individuals’ genetic predictors, and use this to determine risk, and rates? “There’s no federal legislation to prevent someone from shaking your hand, scraping off DNA, doing a genetic test and not hiring you or refusing to give you insurance,” Altshuler points out. Ultimately, he says, it will be in the hands of the public to strike a balance between restricting the use of genetic information, and permitting its application to cure disease.

Nuclear Cloning and Cell Therapy: Fact and Fiction - Rudolf Jaenisch

2009-08-20T09:59:00.001+05:30

About the Lecture

The subject of cloning can instantly spark passionate debate: Will it enable us to resurrect beloved family members, or create Frankensteins? Rudolf Jaenisch wants to remove “hot air” from the discussion. His talk provides a clear picture of what is and is not scientifically feasible. Animal cloning, first pioneered in Dolly the sheep, used non-reproductive cells to create a carbon copy of the donor animal. This technique, tested many times, fails frequently and yields severe abnormalities. Consequently, Jaenisch believes the cloning of humans will never prove practical. But another variety of cloning generates far fewer genetic glitches and holds immense medical promise. The earliest cells of embryos can be manipulated to develop into neurons, or blood, or muscle, making them very useful tools in therapy for diseases like diabetes, Parkinson’s or leukemia. Jaenisch says these embryonic stem (ES) cells could be “an inexhaustible source of any tissue type and tailored to the needs of the patient.” But in spite of the potential rewards of this work, federal agencies and many others oppose it because so far the only source of ES cells has been human embryos. Jaenisch seeks a middle ground: scientists may not attempt cloning a human being, but may harvest and grow ES cells for therapeutic purposes from a human embryo.

Innovation Everywhere—How the Acceleration of “GNR” (genetics, nanotechnology, robotics) Will Create a Flat and Equitable World - Ray Kurzweil

2009-08-20T09:54:00.001+05:30

About the Lecture

Ray Kurzweil may be the closest thing we have to a crystal ball. And if anyone has the right to some credibility in the prognostication arena, this overachieving inventor can. With crackling speed, Kurzweil powerpoints through charts illustrating the growth of various technologies over the centuries. His main points: technology evolves exponentially; the rate of technical progress itself is accelerating, so expect to “see 20,000 years of progress in the 21st century, about 1000 times greater than the 20th century.” Before you can say, “Hold your horses,” Kurzweil is off and running.

Say goodbye to cancer and heart disease within 15 years, and hello to living way past 80. And try to survive until the year 2029, which according to Kurzweil’s mathematical models, represents “25 turns of the screw in terms of doubling the power of information technology in every aspect of our lives.” We’ll see reverse engineering of the human brain, and computers that “will combine the subtlety and pattern recognition of human intelligence with the speed, memory and knowledge sharing of machine intelligence.” The marriage of nanotechnology and AI will bring us “a killer app”-- nanobots that can keep us healthy from the inside. These will also enable “full immersion virtual reality from within nervous systems” and expand human intelligence, facilitating “brain to brain communication. As for human conflict, Kurzweil sees an end to starvation and energy concerns, but doesn’t quite complete his utopia. New technologies may be used in anti-social ways, say, by a bioterrorist. “I’m less optimistic we can avoid all painful issues; we certainly did not do that in the 20th century,” concludes Kurzweil.

Ending Global Poverty - Muhammad Yunus

2009-08-19T11:40:00.004+05:30

Muhammad Yunus

Muhammad Yunus made his first loan of $27 to a group of 42 Bangladeshi village women, to help free them from debt to moneylenders and allow them to build their furniture business. He established the Grameen Bank in 1983 to help millions of Bangladeshis escape from poverty. The bank now has branches in more than 36 thousand Bangladeshi villages and in other countries.

Yunus, a Fulbright Scholar, earned a Ph.D. from Vanderbilt University in 1969. Yunus has received the Ramon Magsaysay Award (1984) from Manila; the Aga Khan Award for Architecture (1989) from Geneva; the Mohamed Shabdeen Award for Science (1993) from Sri Lanka; and the World Food Prize by World Food Prize Foundation (1994) from the US. His autobiography, Banker to the Poor, was published in 1998.

About the Lecture

Imagine a bank that loans money based on a borrower’s desperate circumstances -- where, as Muhammad Yunus says, “the less you have, the higher priority you have.” Turning banking convention on its head has accomplished a world of good for millions of impoverished Bangladeshis, as the pioneering economist Yunus has demonstrated in the last three decades. What began as a modest academic experiment has become a personal crusade to end poverty. Yunus reminds us that for two-thirds of the world’s population, “financial institutions do not exist.” Yet, “we’ve created a world which goes around with money. If you don’t have the first dollar, you can’t catch the next dollar.” It was Yunus’ notion, in the face of harsh skepticism, to give the poorest of the poor their first dollar so they could become self-supporting. “We’re not talking about people who don’t know what to do with their lives….They’re as good, enterprising, as smart as anybody else.” His Grameen Bank spread from village to village as a lender of tiny amounts of money (microcredit), primarily to women. Yunus heard that “all women can do is raise chickens, or cows or make baskets. I said, ‘Don’t underestimate the talent of human beings.’ ” No collateral is required, nor paperwork—just an effort to make good and pay back the loan. Now the bank boasts 5 million borrowers, receiving half a billion dollars a year. It has branched out into student loans, health care coverage, and into other countries. Grameen has even created a mobile phone company to bring cell phones to Bangladeshi villages. Yunus envisions microcredit building a society where even poor people can open “the gift they have inside of them.”

The Second Law and Energy -Steven Chu

2009-08-18T20:52:00.007+05:30

Steven Chu

Steven Chu was sworn into office on January 21, 2009. Prior to his appointment, he was a professor of Physics and of Molecular and Cell Biology, University of California, Berkeley, and director of the Lawrence Berkeley National Laboratory.

Chu joined the Physics Department faculty at U.C. Berkeley in 2004. He had served earlier as professor of Physics at Stanford University. Before 1987, he was at Bell Laboratories where he conducted the research that led to his 1997 Nobel Prize in physics, which he shared with Claude Cohen-Tannoudji and William D. Phillips, for methods to cool and trap atoms with laser light.

Chu is a member of the National Academy of Sciences, the American Philosophical Society, the American Academy of Arts and Sciences, the Academia Sinica, and is a foreign member of the Chinese Academy of Sciences and of the Korean Academy of Science and Engineering.

He serves on the Boards of the Hewlett Foundation, the University of Rochester, and NVIDIA. He served on the Augustine Committee that produced the report “Rising Above the Gathering Storm” in 2006.

Chu received his Ph.D. from the University of California at Berkeley in 1976 and was a post-doctoral fellow there until 1978. He got his B.S. in 1970 from the University of Rochester

About the Lecture

This Nobel Prize-winning scientist admits to staying up late the night before his talk to bone up on thermodynamics. He puts his research to good use, discussing the history and application of the laws of thermodynamics, which have served as “the scientific foundation of how we harness energy, and the basis of the industrial revolution, the wealth of nations.”

Taking Watt’s 1765 steam engine, Stephen Chu illustrates basic principles of thermodynamics -- that energy is conserved, that you can do work from heat, especially when you maximize the difference in temperature in the system and minimize heat dissipation from friction. Chu offers another form of the laws: You can’t win; you can’t break even; and you can’t leave the game.

The game hasn’t changed all that much in the past few centuries. Nations now burn coal for electricity, achieving around 40% thermal efficiency. Natural gas can be harnessed at higher efficiencies still, and if we could deploy temperature-resistant metals for boilers, even less energy would go to waste. This is a pressing matter, points out Chu, because the planet can no longer afford wanton use of carbon-based fuels. With too much CO₂, our global “heat engine” has begun to tip toward a point of no return. So the big question for Chu is whether science can design “entropy engines that can generate sustainable (carbon-free) energy sources.

He describes efforts to capture sunlight with improved solar cells, but notes that a silicon shortage, expensive chips, and a learning curve dictated by Moore’s law mean the technology won’t be widely deployed for 10-15 years -- not fast enough in the battle against climate change. Chu likes the efficiencies of power generation from wind, but there’s a limit to turbine size, and the U.S. high voltage transmission network needs a complete and expensive makeover to take full advantage of wind. Forget corn as biofuel, he counsels, since it “barely breaks even in terms of CO₂ saved,” and focus instead on perennial grasses like miscanthus. Chu’s lab and others are looking for microbes that can help turn these plants more readily into fuels.

Another potentially rich energy source, Chu says, involves converting sun light into fuel the way plants do in photosynthesis. But “how does nature split water?” asks Chu. Science hasn’t entirely figured out the molecular machinery that turns water into oxygen and hydrogen. Deriving bioenergy through artificial photosynthesis may mean considering entropy and other basic laws in a different light, Chu suggests. “Nature turns out to be very good.”

Peace and Chemistry Global Environmental Issues: Effects on the Atmosphere and the Biosphere - Mario J. Molina, Eric Chivian

2009-08-18T20:40:00.003+05:30

Eric Chivian

Eric Chivian is Director of the Center for Health and the Global Environment and Assistant Clinical Professor of Psychiatry at the Harvard Medical School. He is a former psychiatrist with MIT Medical. He co-founded International Physicians for the Prevention of Nuclear War, which was awarded the Nobel Peace Prize in 1985.

About the Lecture

In this lecture Mario Molina defines the causes of global warming as a direct result of human behavior. He points out that local environmental concerns have become global ones and reminds us that "we only have one planet." Eric Chivian discusses the loss of biological diversity and its implications for the planet. He explains for example, why Lyme disease is more prevalent in the northeast, lessons to be learned from hibernating bears and the natural sources for some of the worlds most frequently prescribed drugs. He takes on SUV's unnecessary gadgets, and wasteful consumption.

Vision of the Future (Part 2) -Eric R. Kandel, James D. Watson

2009-08-18T20:18:00.004+05:30

Eric R. Kandel

Kandel, who fled with his family from the Nazi occupation of Austria in 1939, was educated at Harvard University and New York University School of Medicine and began his career at the National Institute of Mental Health. He pursued studies in psychiatry, but soon shifted to neurobiology in an effort to understand the biological underpinnings of psychological phenomena. He came to Columbia in 1974 as professor of physiology and psychiatry and became the founding director of the Center for Neurobiology and Behavior in 1975. He is the coauthor, along with Columbia colleagues Thomas Jessell and James Schwartz, of Principles of Neural Science, a widely used neuroscience textbook.

Kandel has received 15 honorary degrees, is a member of the National Academy of Sciences as well as the National Science Academies of German and France. He has been recognized with the Albert Lasker Award, the Heineken Award of the Netherlands, the Gairdner Award of Canada, the Wolf Prize of Israel, the National Medal of Science USA and the Nobel Prize for Physiology or Medicine in 2000.

James D. Watson

For proposing the double helical structure of DNA, James Watson and Francis Crick, together with Maurice Wilkins, were awarded the Nobel Prize in Physiology or Medicine in 1962.

While at Harvard, Watson wrote the seminal text, Molecular Biology of the Gene. He has also generated a best-selling autobiographical volume, The Double Helix, and recently published DNA: The Secret of Life.

Watson was a driving force behind the Human Genome Project. Among other honors, Watson was elected in 1962 to the National Academy of Sciences and, in 1977, received from President Ford the Medal of Freedom. Watson received the National Medal of Science in December 1997; the Philadelphia Liberty Medal on July 4, 2000; and the Benjamin Franklin Medal awarded by the American Philosophical Society. Queen Elizabeth II proclaimed him an honorary Knight of the British Empire on January 1, 2002.

About the Lecture

If the century just passed was “the province of the gene,” then the next hundred years shall be “the province of the mind,” believes Eric Kandel. Brain science is poised to reveal the biology of conscious and unconscious mental processes involved in perception, emotion, thought and action. There will also be “a revolution in understanding mental illness,” with animal models revealing the “mechanism of pathogenesis.” We shall gain an understanding of the biological underpinnings of personal wellbeing, using imaging to reveal the pathways in the brain involved in joy. Scientists have singled out one gene that in such animals as voles determines whether they will socialize, or act as loners, suggesting the possibility of molecular insight into social and aggressive behaviors. What’s more, says Kandel, neuroscience will suffuse all the disciplines: sociology will have to consider a “biology of free will;” economics must take up the biology of decision and choice; art appreciation will have to account for how sensory information gets processed, such that when “two people look at the same object, one finds it beautiful and the other finds it boring.” And psychology will become indistinguishable from neuroscience, leading to a common base of training for neurologists and psychiatrists.

A contrary James Watson offers a dose of skepticism around the direction of brain research described by his colleagues. In the words of his old partner Francis Crick, “we haven’t found the double helix of the brain and don’t know how to think about it.” Some “gigantic problems” exist, says Watson: How is perceptual information stored; what does it look like; and how does information get pushed from one part of the brain to another? Key to cracking these questions, in Watson’s opinion, will be a deep understanding of brain evolution. He also recommends delving further into the genetic basis of mental disease, which might uncover an underlying defect in neurogenesis -- the growth of new brain cells. Perhaps all mental disease will ultimately be characterized as a “deep learning defect.” Watson is much concerned with “why we lose the ability to learn as we get older.” He believes it must be because “the brain is finite—we can only have so much stored.” But while he plays tennis and reads books partly in the hope that they will expand his mind, Watson also looks to biology for a way “to speed up neurogenesis in adults, and raise

The Human Genome Project - Eric S. Lander

2009-08-18T18:02:00.007+05:30

About the Lecture

Dr. Lander is a geneticist, molecular biologist and a mathematician, with research interests in human genetics, mouse genetics, population genetics and computational and mathematical methods in biology.

He and his research group have developed many of the tools of modern genome research including genomic maps of the human, mouse and rat genomes in connection with the Human Genome Project and techniques for genetic analyses of complex, multigenic traits. He has applied these techniques to the understanding of cancer, diabetes, hypertension, renal failure and dwarfism.

The Many Facets of NF-Kappa B - Dr.David Baltimore

2009-08-18T18:02:00.006+05:30

Dr. David Baltimore

Prior to becoming Caltech's seventh President in 1997, Dr. Baltimore was an Institute Professor at MIT and founding director of the Whitehead Institute for Biomedical Research. He received the Nobel Prize in 1975 for his work in virology.

About the Lecture

California Institute of Technology President and Nobel Laureate Dr. David Baltimore delivered the 2001 Howard Hughes Lecture entitled The Many Facets of NF-Kappa B on Friday March 23, 2001. The lecture was hosted by the Biology Undergraduate Students Association (BUSA). Dr. Baltimore served as professor of biology at MIT and founding director of the Whitehead Institute for Biomedical Research before becoming President of Caltech.

Evolution: From the Fossil Record to Genomic Revolution

2009-08-18T17:59:00.001+05:30

About the Lecture

Evolution: From the Fossil Record to Genomic Revolution

Probing the Origin of the Planets from Spacecraft

The Origin of the Universe

2009-08-18T17:59:00.000+05:30

About the Lecture

The Origin of the Universe

The Human Genome and Beyond

Personalized Medicine

2009-08-18T17:57:00.000+05:30

About the Lecture

We've deciphered the human genome and moved into proteomics-the study of the individual proteins that the genes code for. Such advances anticipate the day when drugs are not only targeted at molecular workings or specific diseases but tailor-made for each individual's genetic makeup.

Video Player Biotechnology - Will It Create a New Industry?

2009-08-18T17:54:00.003+05:30

About the Lecture

Henri Termeer discusses growth of the 25-year-old biotech industry, including international mergers, R&D challenges and "product based" companies verses "platform based" companies.

The Pharmaceutical Industry in the Global Economy

2009-08-18T17:53:00.000+05:30

Mammalian Cloning and Stem Cell Therapy: Problems and Promise

2009-08-18T17:49:00.004+05:30

About the Lecture

In this talk, leading genetist Rudolf Jaenisch delivers a clear overview of the challenges facing the cloning, dispelling many of the misconceptions about cloning that are pervasive in popular media. The Q&A session with the alumni audience led to animated discussions about the ethics of cloning. Jaenisch has been a leader in expressing the ethical issues connected to cloning and is strongly against the practice of human cloning.

Transforming Health Care

2009-08-18T17:49:00.003+05:30

About the Lecture

MIT research is helping to speed the diagnosis of disease, and easing our most common afflictions.

Dennis Freeman is working on a better hearing aid. He describes how our ears can perceive sounds that make the eardrum vibrate less than the diameter of a hydrogen atom. He envisions a computer chip that will emulate sensitive cells in our inner ear that both react to sounds and communicate them to the brain.

Martha Gray is developing methods to look inside joint tissue, at the molecular level, to diagnose arthritis early enough for useful therapies. An estimated one in three Americans suffer from this painful disease.

Fifty to 100 thousand people a year are killed by medical errors. Peter Szolovits imagines a computer health record devised and controlled by a patient over a lifetime, which could play a key role in avoiding mistakes in medical diagnosis and treatment.

Eric Grimson says the imaging techniques he’s developing will bring nothing short of a revolution in surgery. His animated, 3D models are strikingly successful at guiding surgeons before and during such high-wire acts as the removal of brain tumors.

Video Player The Evolution of Sex: Rethinking the Rotting Y Chromosome David C. Page

2009-08-18T17:49:00.002+05:30

About the Lecture

According to David Page, “the Y chromosome is the Rodney Dangerfield of the human genome.” Regarded for 50 years as a genetic wasteland, the Y chromosome just doesn’t get any respect…until now. Page’s lab has made some startling discoveries that reverse the prevailing view.

Recall from basic biology that pairs of chromosomes exchange genetic material through a process of crossing over. This leads to genetic variation in offspring, and can weed out dangerous mutations. Although there’s limited gene swapping between the sex-determining X and Y chromosomes, the popular belief has been that a large portion of the Y could not recombine, and therefore will sooner or later self destruct. The long-term outlook for the Y chromosome was bleak.

But now there is hope and renewed respect for the Y. Page has found vast sequences of DNA on the Y that appear like palindromes (words like “mom” that read the same backwards and forwards). Page believes the two halves of the palindrome engage in a kind of crossing over. This can lead to repairing mutations, just as in ordinary chromosomes. Through this unique method, the Y chromosome not only endures but prevails.

Keynote Presentation: Academic Perspectives

2009-08-18T17:49:00.001+05:30

About the Lecture

Very simply stated, systems biology attempts to “capture the dynamic nature of living systems.” To accomplish this, says Hood, you “have to bring together the flavors of biology, chemistry, computer science, engineering and physics,” among others. It’s a vast area to tackle. But with tools like the internet and digital DNA and protein sequencers on hand, it’s now possible to perform research aimed at unraveling the complex interaction of genes and environment in simple organisms.

Hood describes knocking out yeast cell genes, and turning off the machinery that metabolizes simple sugars. This sort of microscopic tampering allows scientists to build models of increasing complexity. A blueprint of gene regulation in sea urchins helped one scientist figure out a way to redesign the organism with two guts. But the ultimate prize is a deep understanding of human biology. Hood foresees a database—built with the help of nanotechnology — that categorizes and quantifies all proteins in the human genome. Scientists will be able to predict disease by detecting defective genes in blood samples, and then manipulate the genes to prevent the disease. “The integration of biology and medicine,” says Hood, “is where the rubber meets the road.”

Academic Perspectives/Panel Discussion

2009-08-18T17:48:00.001+05:30

About the Lecture

In this wide-ranging discussion, panelists seized on redesigning science education as a way of ensuring the success of systems biology. The first challenge lies in improving instruction in the earliest years. David Botstein said, “K-12 education has never been that great…(kids) don’t need to know everything in excruciating detail….Anything they find out by themselves is worth 10 or 20 of anything you tell them to do." Mark Kirschner remarked, “What’s left out is appropriate kinds of inquiry, and at the appropriate age.” Leroy Hood spoke with master teachers and “understood that the worst way to teach was lecture.” Another obstacle lies with the culture of higher education, where scientists are rewarded for focusing on a single specialty and for research, not teaching. George Poste pointed to “rampant egotism that’s destructive,” preventing collaboration. Peter Sorger commented, “Autonomy is given to faculty members in classroom. We need expectations. Students will gravitate to those courses that are taught well.” A major hurdle for budding systems biologists involves embracing a larger biology. Matt Scott spoke of building “excitement about things beautiful and mysterious.” Other panelists expressed hope that the diversity of living things would generate a passion not only to understand the fundamental interdependence among all living things but to preserve species as well.

“The biggest bad thing about molecular biology and the genome is detail orientation. We have all descended into the weeds.”

David Botstein

Innovation at the Interface: Technological Fusion at MIT

2009-08-18T17:46:00.000+05:30

About the Lecture

When disciplines converge, innovation results. To prove the point, two inventers offered rich and varied examples from their respective areas: artificial intelligence and biomedicine. Rodney Brooks describes robots exploring dangerous bunkers in Iraq and Afghanistan, and intelligent prosthetic limbs. He predicts that in a few decades, helper robots will be as prevalent as computers are today. Aging baby boomers, says Brooks, will insist on remaining in their own homes as long as possible. They’ll require high tech caretaking, as well as entertainment and education opportunities. Brooks believes that low-paid assisted living jobs, as well as agricultural and manufacturing work, will gradually migrate to smart machines. Robert Langer has a string of remarkable biomedical inventions to his credit. He tells us that not so long ago, sausage casing was used for dialysis tubing and mattress stuffing for breast implants. Langer turned the medical world on its head by creating new materials for clinical application: chemical compounds for skin grafts and for targeted cancer therapy. He has created an artificial scaffold for tissues and organs that may also help rebuild spinal cords. The latest research involves microchips that can deliver precise doses of drugs, and respond by remote control like a garage door opener.

“Whenever you come up with what you think is an important idea, you can be sure that other people won’t like it. ”

Robert Langer

Engineering a New Attack on Disease

2009-08-18T17:43:00.000+05:30

About the Lecture

Out of a world population of 6 billion, 57 million people die each year. And while we have gained 20 years in life expectancy since World War 2, diseases like HIV have taken a toll on morbidity in many developing nations. But according to Rick Young, “the global disease burden is much larger than the number of deaths.” Countless millions suffer from cardiopulmonary diseases, cancer, and malaria, to name but a few, at a nearly incalculable cost to their families and society. Young’s mission is to attack the problem of global disease at the genetic level: he’s hunting for specific proteins that can turn the genetic machinery of diseases on, or off. These “gene regulators” can be knocked out of whack by a virus like HIV or by a mutation that results in a disease like mature onset diabetes. Young’s group has developed a DNA microarray technology that helps them link gene regulators to their corresponding genes. They’ve worked out the connections in yeast, and they’re targeting the human genome next. Young’s ultimate goal: “By continuing to focus on your 2000 gene regulators, we could eventually develop great insights into how organ systems work… (And) in all instances where disease is associated with misregulation, we could develop new strategies for drug development based on that.”

Why do We Need Differential Pricing?/Industry Perspective

2009-08-18T17:41:00.000+05:30

About the Lecture

Why do We Need Differential Pricing?/Industry Perspective

The very first tablet or drop of a new medicine comes at a dear price-- $800 million – according to recent studies of R&D in pharmaceutical industries. But manufacturing subsequent pills costs literally pennies. What’s a fair way to price life-improving, or life-saving medicine? The two speakers in this part of the forum vigorously defend charging different prices for medicines in different parts of the world. Judy Lewent argues that differential pricing ensures global access. She says, “There would be little sense selling drugs at prices people can’t afford.” It also generates the revenues necessary to generate new cures. “When we price for access, it’s a reflection of our belief in the power of free markets to advance the social good. We can meet the world’s health needs and also make a profit and continue to prevent, treat and cure disease.” Mark McClellan sees on the horizon a new order of drug treatments, such as tailoring molecules to the needs of an individual patient. But, he says, we won’t reap the benefits of these potential cures if current trends continue: nations that band together to lower drug costs for their citizens, and the reimportation of brand name innovator drug products. McClellan says if we don’t “provide financial rewards that reflect the value of innovation, we may not continue to get improvements that biotech makes possible.” Both speakers endorse more affordable medicines, but through insurance coverage rather than price controls.

Alternative Models Of Differential Pricing For Medicines

2009-08-18T17:39:00.000+05:30

About the Lecture

Each speaker on this panel proposes a unique approach to the problem of making medicines universally affordable. Dr. David Meeker works in the area of rare diseases. Genzyme’s hormone replacement therapy for Gaucher disease, which affects roughly 30 thousand globally, costs $150k to $200k per year. For patients in nations with poor health care systems, Genzyme discounts the medicine steeply. “Don’t say free drugs,” says Meeker. “We’ll help individual patients as best we can but we’re going to work on developing a health care system in that country that will eventually be able to take over.”

At Avant Immunotherapeutics, Una Ryan’s company tackles new vaccines for travelers, bio-defense, global health and food safety uses. “We’re trying to making vaccines people will actually take: safe, effective, oral, single dose, rapid protection and no refrigeration.” There are enormous development costs involved, which are hard for a small company to shoulder, she says. Perhaps “all developed nations should pay their fair share for pharma R&D…and for developing countries’ drugs,” indexing drug prices to each nation’s GDP.

Patricia Danzon suggests that drug manufacturers sell “products to wholesalers at uniform prices worldwide, then negotiate confidential rebates with final purchasers... This way, the lower prices offered to lower income countries won’t spill over to higher income countries.” Hannah Kettler describes the Gates Foundation’s efforts to invest funds in public-private partnerships to reduce pharmaceutical RD costs. The foundation is also trying to build a fund to cover the costs of vaccinating in developing countries. Our expectation, she says, “is that if we pay the higher prices now, supply will expand and over time the price of vaccines will come down.”

The Emergence of a “Renewable Feedstock-Based” Chemical Industry

2009-08-18T17:38:00.001+05:30

About the Lecture

Video Player Human Cloning and Human Rights: Promises and Perils

2009-08-18T17:37:00.000+05:30

About the Lecture

Ignore the noisy debate around cloning, Rudolf Jaenisch quietly insists, and instead look closely at the biology involved. First, note that there are two different kinds of cloning: reproductive cloning, the attempt to create an exact replica of a human being, which Jaenisch believes to be both biologically flawed and morally questionable; and therapeutic cloning, which offers potential cures to some of mankind’s most devastating diseases, and from Jaenisch’s point of view, sidesteps ethical pitfalls. Both involve transferring the genetic material from a somatic cell (from the skin, for instance) into an individual egg cell. The fertilized cell gives rise to embryonic stem cells, which have the near miraculous capacity to differentiate into every kind of tissue found in the body. Jaenisch says human embryonic stem cell research could help reveal the mechanisms behind biological growth, and enable a customized approach to treating such diseases as diabetes and Parkinson’s. Once scientists create these ES cells, they can grow them in vitro.

Ethical problems emerge, Jaenisch believes, when a cloned embryo is implanted in a uterus with the intent of creating a full-term clone, or with the intent of harvesting stem cells from an aborted fetus. These involve the “destruction of potential life.” The creation of cloned ES cells for research purposes, however, is the “propagation of existing life,” says Jaenisch.

Stephen Marks delineates the various human rights arguments around cloning: Are we at risk “of turning people into products?” Can “we pursue genetic health and enhancements” while maintaining the individual’s dignity? He describes the U.S. administration’s current opposition to any form of cloning and in particular, its attempt to throttle international treaties that might eventually permit therapeutic cloning.

Bioengineering at MIT: Building Bridges Between the Sciences, Engineering and Health Care (Part One)

2009-08-18T17:35:00.001+05:30

About the Lecture

In Doug Lauffenburger’s view, MIT’s new bioengineering degree program is not merely justified, it is essential. Revolutionary changes in biological sciences—specifically, in molecular biology and genomics—have given scientists the means to understand and control both the building blocks and larger systems of living things. Now, says Lauffenburger, the “operation of biological functions needs to be understood in terms of biomolecular machines.” But the hard part, he says, is “predicting what happens when you manipulate them. It’s almost trial and error. That’s where engineering comes in.”

Linda Griffith provides one paradigm for such research. She is designing a scaffold on which to grow human cells for use in tissue implants. Using a “computer controlled process that builds complex 3D objects up from scratch,” Griffith creates a device that mimics the complex structures of joints and other body parts – suited for joint repair, or bone regeneration. Her research might someday produce organs for transplant. But Griffith’s grander goal involves “putting surgeons out of business,” by eliminating transplants altogether. She’s building a “liver on a chip” – growing liver cells on a tiny wafer with the architecture and molecular properties of actual liver cells. This biomechanical product can be used to test drug toxicity and gene therapies, and perhaps someday to model and block the growth of cancers.

Angela Belcher models her bioengineered devices on some of nature’s most ingenious products, such as the incredibly strong and exquisitely structured abalone shell. She designs on a nanoscale, getting viruses and antibodies to work with inorganic materials. “How far can you push organisms?” Belcher wonders. To date, she’s taught a nontoxic virus to recognize a specific metal used in a semiconductor wafer. Someday viruses could detect atomic defects in electronics. Belcher also describes virus scaffolds for growing semiconductor wires, and for generating lightweight batteries woven into soldier’s uniforms. She’s even looking into ways of spinning viruses, as spiders spin silk, for generating optical materials.

Bioengineering at MIT: Building Bridges Between the Sciences, Engineering and Health Care (Part Two)

2009-08-18T17:35:00.000+05:30

About the Lecture

Glycomics, the study of sugars’ role in living systems, is a relative newcomer to the revolution in molecular biology. In fact, Ram Sasisekharan remembers how colleagues told him “not to work on carbohydrates -- that it was useless.” But his research has shown that glycans, observed as long chains or intricate branches of sugars on the surface of all cells, are significant players in the complex drama of cell growth, migration and death. Tracking down the function of sugars from their structure has turned out to be trickier than determining what protein a segment of DNA codes for. Sasisekharan likens it to “image processing, with six blind men and an elephant.” His team, deploying diverse analysis techniques, learned that sugars affect such properties of proteins as the ways in which they fold. Sasisekharan has also discovered that tumor cells contain sugar sequences that keep tumors dormant, or signal them to start dividing. He has found that pathogens such as viruses and bacteria bind to glycans. This opens the possibility for using glycans in subtle diagnostics as well as for “novel drug delivery strategies.”

Martha Gray provides some vignettes from the Division of Health Sciences and Technology (HST), demonstrating stunning advances in medical engineering. Leaping beyond RotoRooter methods for treating plugged blood vessels, HST researchers have developed stents for opening arteries that deliver drugs and function longer. And in a major breakthrough, scientists have managed to produce a polymer seeded with rat heart cells, and stimulate this living tissue to beat the way actual heart muscle does. Gray’s own research involves arthritis, and she describes new imaging techniques “that allow you to see things you didn’t see before,” including tiny defects in cartilage that may predict the emergence of joint disease.

Innovation in Post-Launch Surveillance and Pharmaco-Vigilance (Part Two)

2009-08-18T17:34:00.000+05:30

About the Lecture

These panelists describe struggling to transform their approach to drug safety, while acknowledging the need to regain public trust after troubling episodes involving drug side effects.

Névine Zariffa points out that “no clinical trial program known to man will ever help predict every single instance of everything that might happen in the big, wide world.” But, she wonders, “What can we do better to link up what we discover through the clinical trial process relative to what happens in the real world?” One idea: a Center for Biomedical Information SWAT team to deal with FDA drug alerts.

“The whole country is moving slowly, but moving” toward capturing patient records, imaging information, and even genomic and proteomic data electronically, reports John Glaser. Partners HealthCare holds a clinical data repository for 3.3 million people, from academic medical centers to community hospitals. This kind of database may help track “consistent drug interactions” as well as notify patients at risk when a side effect becomes apparent.

“Even if you think that drug reviewers look at newspaper accounts, if they focus more on drug safety, wouldn’t that slow review times? The answer is no,” claims Randall Lutter. He says that the FDA has not slowed approval times to appease a worried public, nor has it sacrificed science to please manufacturers eager for rapid drug approval. Rather, the agency’s concerned with getting accurate warnings on drug packages at the time of their launch, and disseminating information earlier to the public.

In the early 60s, says Johanna Haas, when the use of Thalidomide was linked to terrible congenital deformities, legislation resulted that transformed the safety rules: “The onus shift(ed) to the company to prove the drug should be marketed, rather than to the FDA to prove it shouldn’t.” Now, a post-Vioxx paradigm is emerging, where drug makers are trying to track subtle side effects in enormous populations. The only answer is to set up databases running from the earliest clinical trials through the drug’s launch. “You take something that’s going to evolve over the course of years. You don’t want it forgotten and tucked into a clinical study report that’s forgotten until it emerges as a public policy issue later on and you say, ‘Hmm, curious."

Innovation in Manufacturing and Distribution Systems (Part Three)

2009-08-18T17:31:00.001+05:30

About the Lecture

Genzyme is a leader in personalized medicine, as Mark Bamforth demonstrates. For instance, the company collects cartilage from a single patient, grows it in the lab, and sends it back securely to that same patient. The system, says Bamforth, tolerates “no mix ups.” But the company also deals in drugs sent to hundreds of thousands of kidney dialysis patients. Each kind of product must adhere to a specific kind of manufacturing and distribution process, and the regulations of the FDA and other countries. Bamforth must navigate “a complexity and diversity of supply chains.”

Peter Walsh works behind the scenes at UPS, making sure those brown trucks deliver to the right location at the right time. He believes that “healthcare is a good 20 to 30 years behind other industries” in terms of getting the goods from supplier to manufacturer to consumer. “We see in big pharma a silo approach. That needs to change … and means sharing of information—scary to think of in this industry.”

Abbott Weiss sees in pharmaceuticals “a highly fragmented set of supply chains” at a time when globalization poses increased risks, such as theft and diversion, and cost pressures. He describes working at Polaroid, and shipping out 120 million packs of film a year, with 140 countries each requiring different labeling. “Exception management is the rule in supply chains,” says Weiss. And unlike film, there are “life and death implications of getting the right medicine at the right time and right place.” The good news is that much of the technology for solving tracking and distribution problems already exists, Weiss says.

One such technology, radio frequency identification (RFID), is a good first enabling step for pharmaceutical makers, says Daniel Engels. “If I know what I have and where it is, I can do something about it.” The critical problem will be “asset visibility,” communicating this unique product information to suppliers and customers. And this kind of tagging will prove especially difficult for generic or bulk drugs, sent through distributors. The “end game” is information sharing.

Innovation in Bio-Safety Testing from Pre-Clinical to Product Launch (Part Four)

2009-08-18T17:31:00.000+05:30

About the Lecture

“To me, systems biology is the religion you switch to when target-based drug discovery doesn’t work,” Noubar Afeyan states boldly. He claims that after losing billions of dollars, the pharmaceutical industry and academia are beginning to see the value in testing drugs by measuring outcomes in biological networks. He calls this systems pharmacology, where you “measure in living systems multiple analytes in the same organism, perturbing the state and taking thousands of measurements per sample.” Researchers use computer images to visualize the differences and similarities in drug response across many networks, and then try to correlate these responses statistically.

The inability to predict toxicity early in drug development cost the pharmaceutical industry an astonishing $8 billion in 2003, says Joseph Bonventre, approximately one-third the cost of all drug failures. “We generally can’t pick up toxicity until it’s too late,” he says, so key challenges are developing better preclinical studies with useful biomarkers, improved animal models, and high throughput techniques; and on the clinical side, coming up with a “safe harbor approach to amass kidney and other toxicity data,” developing consortia to validate biomarkers, dealing with IP issues and building “an improved bedside to bench flow of information.”

Linda Griffith's vision is “building a human body on a chip.” She’s not talking about an individual’s genome or health history, but “a living, 3D interconnected set of tissues on a chip. If you perturb it, you make it develop a disease.” Such a device would enable researchers to predict negative drug interactions and even to build models of disease. Griffiths’ version of liver tissue, built on a silicon scaffold, may prove especially useful for drug toxicity tests.

At Biogen, “the holy grail for any justification of a new approach or technology is that we’re going to chop a significant amount off the time it takes to move a new product from bench to bedside,” says James Green. He believes that “drugs and paradigms are orders of magnitude more complicated than 24 years ago.” He hopes that new techniques “that take us into the genome, interpreting data as patterns” offer some promise.

Change Your Mind: Memory and Disease

2009-08-18T17:30:00.000+05:30

About the Lecture

How do we distinguish our friends from foes? How does dementia destroy memory? And how can past experience invade the present with destructive force? Scientists are closing in on the biochemical roots of these neurological puzzles.

Thomas Insel describes the profound impact of a small group of neuropeptides on social behavior in animals, from worms to humans. Oxytocin, the hormone which turns on maternal behavior and cognition, turns out to play a large role in determining social memories. Mice whose genes for producing oxytocin are knocked out can’t seem to remember animals they’ve met 30 minutes earlier – what Insel describes as “dense social amnesia.” An area of the brain’s amygdala is particularly rich in oxytocin receptors, and when the peptide is injected into a nearby ventricle, the animals’ social interactions revert more closely to normal behavior. Oxytocin is a useful tool for interrogating the circuitry that enables humans to determine “who’s important to me, who I’d die for, who I’m pair-bonded with, who will take care of me,” says Insel.

Alzheimer’s Disease (AD), which afflicts 20 million people worldwide, begins by literally clogging and tangling the hippocampus, the part of the brain essential for learning and memory. Li-Huei Tsai and other researchers have found “compelling evidence” that a small protein may be critically important in activating AD’s awful atrophy of memory. By manipulating specific enzymes, Tsai has managed to model in animals “all the pathological hallmarks of Alzheimer’s Disease,” and zero in on the source of the plaques and tangles seen in human Alzheimer’s patients. Tsai foresees drug interventions that inhibit these enzymes. But, she says, a big task remains “even after we’re successful in halting a deleterious process--how can we restore learning and retrieve lost memory in AD patients?”

Why is it that only some people exposed to a shocking event develop post-traumatic stress disorder (PTSD)? Kerry Ressler’s research posits that some kind of learning must take place in the brain’s amygdala -- its fear response center—that cannot readily be extinguished. Researchers have tracked down a molecular factor that increases “after learning of fear or extinction of fear.” He believes that if this molecule is somehow blocked from doing its job, then someone suffering from PTSD cannot extinguish fear. In a fortuitous medical convergence, the drug D-cycloserine, which has been approved for years to treat tuberculosis, proves very effective in enhancing the effects of the molecule, and reducing fear of all kinds. One example: When people with fear of heights were given D-cycloserine as they took rides in elevators, they reported a significant, long-lasting reduction in their phobias.

The Implications of Synthetic Biology

2009-08-18T17:28:00.000+05:30

About the Lecture

There’s no mistaking Drew Endy’s profession: “I like to make things -- that’s what I do.” From his engineer’s perspective, the slow and painful methods of bioengineering demand a solution. Endy hopes to refine the tools necessary to move the field forward. “We’re going from looking at the living world as only coming from nature, to a subset of the living world being produced by engineers who design and build hopefully useful living artifacts according to our specifications,” says Endy.

Thirty years ago, scientists figured out how to use enzymes to cut and paste genetic material, leading to recombinant DNA technology. But the techniques involved are painfully slow, requiring very specific physical materials and “know-how via the guild-like structure of biology.” Endy points to methods coming on line that will make it easier to design and build biological systems.

One is DNA synthesis, in which a machine fed information and sugars generates a physical piece of DNA. It reminds Endy of the “matter compilers” seen on Star Trek, where “food materializes from a cubby in the wall.” This technique will allow the economical production of long sequences of DNA. Another key ingredient in bioengineering will be the development of standards for making and measuring DNA, in the same way that machining hardware came to be governed by common standards in the 19th century. Endy also suggests that biotechnology will be increasingly informed by useful abstraction, so that scientists will manipulate raw materials less and refined and repackaged materials more, in order to make new things simply and more reliably. These advances will also enable bioengineers to “be experts in our own domains without having to be masters of everything.”

But as bioengineering becomes easier, and “people start to engineer biology,” we’ll need to worry about new issues, says Endy: Will people synthesize pathogens from scratch? Will groups pool knowledge legally? Will there be accreditation and oversight of those who create biological systems?

“We’re going from looking at the living world as only coming from nature, to a subset of the living world being produced by engineers who design and build hopefully useful living artifacts according to our specifications.”

Andrew (Drew) Endy...

Nanotechnology and the Study of Human Diseases

2009-08-18T17:26:00.000+05:30

About the Lecture

Subra Suresh fleshes out the promise of nanotechnology, at least in regard to our understanding of disease. His talk, which focuses on malaria and its impact on red blood cells, demonstrates how the fields of engineering, biology and medicine are converging.

To function properly, he explains, a red blood cell -- eight micrometers in diameter or 1/10th the thickness of a human hair -- must be able to squeeze through three micrometer openings in blood vessels. Working with a “laser tweezer” and two tiny (nano-sized) glass beads, Suresh can apply pressure to stretch single cells so that they become thin enough to fit through small openings. He uses a computer to simulate in three dimensions how red blood cells might fold and lengthen under normal conditions in the human body.

With malaria, infected red blood cells lose their ability to stretch, and Suresh can measure precisely the degree of deformation. The parasite changes the molecular structure of the cell, which “becomes stiff and sticky,” unable to move through small blood vessels. So the spleen, which normally clears impurities from the body, can’t do its job, and the disease progresses.

With a global group of collaborators, Suresh is working on genetic manipulation of the malaria parasite to see how knocking out individual proteins might impact the structure of the infected cell. This kind of biomolecular measurement and manipulation may some day lead to new therapies for a disease that infects more than 400 million people per year.

Suresh is also applying nanotech approaches to other diseases. He is looking into how cancer cells “become less stiff, move more easily, leading to metastatic invasions.” This may ultimately prove useful in studying breast cancer, he says.

“In the last 10 years, we have developed tools so we can take atoms from a position in a bulk material and put them in a different location. We can take interfaces between two materials, engineer them in a way so that atom by atom we can manipulate their properties. We can take a single DNA molecule, pull on it and measure extreme tiny forces. We can study protein folding and links to diseases by reverse engineering. ”

Subra Suresh...

Globalization of Science: Opportunities for Competitive Advantage from Science in China, India and Beyond

2009-08-18T17:23:00.000+05:30

About the Lecture
When Fiona Murray visited research centers in China recently, scientists greeted her quizzically: “People were baffled about what a business school professor was doing in stem cell and gene sequencing labs,” Murray says.

As it turns out, Murray’s tour was integral to her own MIT Sloan research exploring how science serves as a source of competitive advantage. As China and India and other developing countries produce scientists and engineers at a quickening pace, Murray hopes to find out if their capacity to capitalize on scientific ideas is expanding in a comparable way.

One challenge to this kind of research, says Murray, is that the market for scientific ideas “is poorly functioning.” Traditional markets, say for pork bellies, oil or diamonds have well-defined products, well-established metrics,” but how do you measure the quality of scientific ideas?

Murray’s solution is to visit key scientific and engineering institutes in other countries to observe both scientific infrastructure -- the physical state of laboratories -- and how researchers collaborate and generate useful knowledge. She also scans the scientific literature to see how many papers a particular country publishes, in what subdisciplines, and how many citations scientists receive.

Murray’s work may aid commercial enterprises intent on taking advantage of growing global scientific and engineering expertise. Some initial insights: places like China and India hold tremendous potential for firms, whether through their permissive regulatory climates or unique natural resources. But, she advises, don’t enter one of these countries expecting to hire scientists at bargain basement prices, since “the real costs of scientific labor are hidden.” Also, expect poor lab facilities, enormous bureaucracies and a crazy quilt of intellectual property and licensing rules.

Counsels Murray, “Start by collaborating on R&D with research institutes and labs. That allows you to understand their expertise, social rules of engagement and to potentially shape the rules.”

Fundamentals of Cancer Research: Introduction and Overview - Dr. Susan Hockfield, Robert J. Silbey, Tyler Jacks

2009-08-18T17:19:00.003+05:30

About the Lecture

This inaugural address lays the groundwork for an 11-part series on MIT’s efforts in cancer research. Susan Hockfield views MIT’s Center for Cancer Research as a central example of how “life sciences are coming into conversation with engineering in a powerful way.” Robert Silbey provides historical background on the notion of faculty ‘short courses’, and positions the Center as “the jewel in the crown of MIT, a spawning ground for scientific discovery and rewards.”

Tyler Jacks introduces the key research areas and scientists who will speak in the succeeding sessions. He offers a thumbnail sketch of cancer as a molecular genetic progression involving sequential alterations in, and the proliferation of, abnormal cells. “Think of a cancer cell like an integrated circuit: the same kinds of complexities in electronic networks also exist within cells,” notes Jacks. Because of work on the human genome, and advances in scientists’ ability to untangle these complex molecular interactions, “We now have the first generation of anti-cancer drugs targeted against molecular alterations in cancer,” says Jacks. Two highly successful drugs have already been derived from MIT research.

In addition, says Jacks, collaboration among biologists, engineers and mathematicians are yielding “a tremendous collection of tools and technologies.” These include tiny probes that enable diagnosis of cancers at earlier stages, nanoparticles that deliver a therapeutic payload directly to cancer cells, and devices that can be implanted in the body.

“Better understanding of molecular alterations in cancer has translated over the years into the development of better drugs. This is the future. Application of these techniques and others will enable us to treat cancers more widely... more thoroughly and durably, with fewer side effects.”

Tyler Jacks...

Leading Innovation

2009-08-18T17:16:00.002+05:30

About the Lecture

Since innovation is “not necessarily always predictable,” Daniel Vasella declines to discuss it in a systematic way, and instead, focuses on a case study of one of his company’s flagship pharmaceuticals, Gleevec. The discovery, development and marketing of this drug, which fights the rare chronic myeloid leukemia (CML), may point to some of the things Novartis does right, suggests Vasella.

Many significant drugs result from years of basic research that takes place outside of industry. Pathbreaking work that occurred decades ago uncovered chromosome damage in patients with CML, and revealed an abnormal protein secreted due to this mutation. In the early 1990s, Novartis began the creative work of trying to block the signal of this cancer-causing protein.

After testing numerous compounds, Gleevec was synthesized in 1992, and “then the problems started,” says Vasella. When the drug was delivered intravenously, there were toxic effects, and they couldn’t reproduce results from cell cultures. With 100 researchers laboring on the problem, recounts Vasella, “marketing said, ‘stop this damn thing.’”

Despite the setbacks, “We persisted,” says Vasella. Indeed, the first clinical human trials, on 31 patients, were so spectacular -- 100% remission rates -- that Vasella didn’t believe the data. The company moved into frenetic pitch to complete the additional clinical trials necessary for FDA approval, and then on to production. Employees volunteered to work in 24-hour shifts, seven days a week. Vasella faced another issue: “We had to come up with a way we’d make money,” since CML affected a relative handful of patients globally. And the fewer the patients, the higher the price of the drug, potentially keeping it out of the hands of those who most needed it. The company decided to subsidize the cost of Gleevec for patients of little means. In spite of this, Gleevec “has surpassed all expectations.” Sales this year alone will exceed $2.4 billion.

What elements might have led to this triumph and Novartis’ more recent successes? Vasella cites “intrinsic motivation” in each Novartis staff member, high standards, savvy risk-taking and persistence in both research and marketing, and a company culture that brings out the best in everyone.

Creativity: The Mind, Machines, and Mathematics: Public Debate

2009-08-18T17:16:00.000+05:30

About the Lecture

Two of the sharpest minds in the computing arena spar gamely, but neither scores a knockdown in one of the oldest debates around: whether machines may someday achieve consciousness. (NB: Viewers may wish to brush up on the work of computer pioneer Alan Turing and philosopher John Searle in preparation for this video.)

Ray Kurzweil confidently states that artificial intelligence will, in the not distant future, “master human intelligence.” He cites the “exponential power of growth in technology” that will enable both a minute, detailed understanding of the human brain, and the capacity for building a machine that can at least simulate original thought. The “frontier” such a machine must cross is emotional intelligence—“being funny, expressing loving sentiment…” And when this occurs, says Kurzweil, it’s not entirely clear that the entity will have achieved consciousness, since we have no “consciousness detector” to determine if it is capable of subjective experiences.

Acknowledging that his position will prove unpopular, David Gelernter launches his attack: “We won’t even be able to build super-intelligent zombies unless we approach the problem right.” This means admitting that a continuum of cognitive styles exists among humans. As for building a conscious machine, he sees no possibility of one emerging from even the most sophisticated software. “Consciousness means the presence of mental states strictly private with no visible functions or consequences. A conscious entity can call on a thought or memory merely to feel happy, be inspired, soothed, feel anger…” Software programs, by definition, can be separated out, peeled away and run in a logically identical way on any computing platform. How could such a program spontaneously give rise to “a new node of consciousness?”

Kurzweil concedes the difficulty of defining consciousness, but does not want to wish away the concept, since it serves as the basis for our moral and ethical systems. He maintains his argument that reverse engineering of the human brain will enable machines that can act with a level of complexity, from which somehow consciousness will emerge.

Gelernter replies that believing this “seems a completely arbitrary claim. Anything might be true, but I don’t see what makes the claim plausible.” Ultimately, he says, Kurzweil must explain objectively and scientifically what consciousness is -- “how it’s created and got there.” Kurzweil stakes his claim on our future capacity to model digitally the actions of billions of neurons and neurotransmitters, which in humans somehow give rise to consciousness. Gelernter believes such a machine might simulate mental states, but not actually pass muster as a conscious entity. Ultimately, he questions the desirability of building such computers: “We might reach the state some day when we prefer the company of a robot from Walmart to our next-door neighbor or roommates.”

“Can we build a robot with a physical need for a non-physical thing? Maybe, but don’t count on it.”

David Gelernter

Biological Large Scale Integration

2009-08-18T17:01:00.000+05:30

About the Lecture

Though Stephen Quake’s research is confined to the smallest of scales, his achievements have already made a large impact on the study of biology. Quake’s area of microfluidics involves fabricating tiny devices akin to those a plumber uses, but useful on the molecular level. Quake modestly describes his “plumbing tools” as “very simple stuff, not rocket science,” but these mini valves and chambers, which enable him to manipulate the behaviors of fluids in minute volumes, are already proving useful in some of the toughest problems of bioscience.

Quake has fashioned microfluidic technology to analyze DNA sequences in a large-scale way, and to determine protein structure. Borrowing from computer engineering, Quake uses nanoliter amounts of fluids on chips in order to grow protein crystals. These new methods allow for much finer control and manipulation of protein crystal growth than conventional structural biology methods. His lab has figured out not only how to tie single DNA molecules into knots, but how to sequence them. Confronting the limits of conventional microscopy, Quake’s lab “stumbled upon the discovery of small colloidal particles that act as microlenses.” These tiny beads concentrate light and provide a “higher effective aperture, which works phenomenally well.” Now as they automate their miniature DNA and protein factories for mass production, they can observe their work in real time.

“Many limits, even physical ones, are somewhat arbitrary. ... If you expand your mind a little bit, you can find ways to go around them. The initial limit is a philosophical one: we’ll ask the question, is it beyond the reach of physics to predict biology? ”

Stephen Quake...

Electronics on Plastic: A Solution to the Energy Challenge, or a Pipe Dream?

2009-08-18T16:58:00.000+05:30

About the Lecture

As urgency to address climate change mounts, there’s ever greater interest in harnessing the unlimited potential of the sun to replace fossil fuels. This tantalizing prospect has inspired a raft of new scientific ventures, reports Stephen Forrest.

A theoretical field of silicon solar cells that is 120 miles on one side and 120 miles on the other, plunked down in a temperate zone, has the capacity to generate 20 terawatts of power. While such a solar array could more than address the needs of today’s global population, the scheme is impractical and the costs prohibitive. Silicon is expensive, says Forrest. “On the world market today, if you put a gallon of gas in your car, you’re paying 10 times less money than if the same energy were supplied through solar, due to the materials, production, packaging, installation and storage cost.”

So scientists are exploring how organic materials -- not living cells, but carbon-containing compounds -- might make solar power more economical. Organic photovoltaic cells, made of thin layers of fluorescing molecules, seem to hold out hope of an inexpensive alternative to silicon. But so far, these cells don’t offer the same kind of power efficiency as silicon-based technologies. Organic materials tend to break down over time, and present challenges in terms of reproducibility, scalability and reliability. While researchers are trying to manipulate these materials so they function better, an organic photovoltaic device to rival silicon remains out of reach.

But there’s much more optimism surrounding organically based lighting materials. Keep in mind that interior lighting consumes 20% of the power used in buildings, notes Forrest. Replacing incandescent bulbs would make a great difference in residential and commercial energy usage. Current compact fluorescents have long operational lifetimes, but may not be the most satisfying to the human eye. Make way for organic light emitting diodes (OLEDs), using molecules that when excited give off extremely bright light. Researchers have found combinations of chemicals that mix blues, greens and reds in pleasing ways, and these displays will soon emerge in next generation handheld gadgets and computer screens. Researchers are experimenting with white OLEDs, which appear to exceed the power efficiencies of incandescents, and at a low cost as well.

“On the world market today, if you put a gallon of gas in your car, you’re paying 10 times less money than if the same energy were supplied through solar, due to the materials, production, packaging, installation and storage cost.”

Stephen Forrest...

A.B.L.E. Tech: Achieving Better Life Experiences for People with Injury, Disability and Aging Challenges Through 21st Century Technologies

2009-08-18T16:56:00.001+05:30

About the Lecture

Imagine a time when technology trumps injury and disease, and the very notion of disability begins to fade. These panelists suggest that we are at the dawn of such an era.

John Hockenberry, who zips around the stage in his flashing light –equipped wheelchair, tells us that “vast, extraordinary and sometimes frightening physical change can instead of being feared … actually be embraced and become an opportunity for people to take authorship of their own lives, using products and tools made by technology to make their life experiences better.” He sees an aging and longer-lived demographic necessitating new and better devices, and the likelihood that such tools may find broader use among a larger, able-bodied population.

Hugh Herr lost both legs below the knee to frostbite while hiking Mt. Washington in 1982. But his drive to climb compelled him to invent replacements that from his perspective far surpass the clumsy, skin-colored prostheses generally available. Herr demonstrates his biomechanical inventions, which provide not only a natural gait but additional energy to each stride – like an airport walkway, he says. Herr believes with some tweaking, his device could help stroke victims walk with better balance, and that the advantage conferred by such a device could make it desirable beyond the disabled population – think physical improvement by way of robotics, rather than steroids. As technology once intended exclusively for disabled people finds wider applications, there will be a transformation, says Herr, which “creates a world where there is not disability, but in fact augmentation. It makes it sexy. It’s the muscle car.”

Dean Kamen performs astonishing pirouettes in his iBOT, a device inspired by his desire to give wheelchair users the same view of the world taken for granted by those able to stand. This machine can give physically challenged people the independence to climb stairs, take a walk in the woods or at the beach.

Kamen also presents, through video clips, breathtaking developments in a robotic artificial arm – the result of U.S. government efforts to fast track (in two years!) a state-of-the-art prosthesis for victims of the conflicts in Iraq and Afghanistan. Nerve and muscle-sensing electrodes enable this arm to pick up small blocks, pieces of paper, and rotate at the wrist. Without government funding, this device would not have been developed, Kamen notes, due to market limitations. Kamen himself subsidizes development of other high tech tools for disabled people (his more lucrative day job involves making insulin pumps and stents). While he’d like these technologies to become “a killer app among people who can pay,” Kamen says, “We will continue to fund them with the naïve notion that it’s the right thing to do, and hope that we will meet our original objective of making the world a better place.”

“The technology and entrepreneurial communities are inventing extraordinarily powerful tools: Neural prostheses, external robotics, machine learning. As we march into the future, you will see a world where amputees can run faster; you’ll see a person who’s suffered a stroke no longer limping. These powerful tools will do a tremendous service to society, in that they’ll rid society of human disability. ”

Hugh Herr...

The Next Frontier: Bioelectronic Interfaces

2009-08-18T16:54:00.000+05:30

About the Lecture

In the beginning, there was ENIAC. The first electrical computer could do 5,000 additions or subtractions per second, recounts Mark Reed, as long as people with shopping carts full of vacuum tubes jumped to the rescue each time the behemoth suffered a burnout. Then came transistors, and integrated circuits, greatly increasing the number of operations machines could perform, even as their components shrank. But now researchers face a serious barrier in miniaturization, called power dissipation.

As technologies scale down, and more computer chips get packed together, the number of watts per square centimeter reaches a point “when materials start to do nasty things, like break down,” says Reed. To break through the power dissipation barrier Reed and others look to biologically inspired systems. DNA could prove the ultimate scaffolding for new computational structures, believes Reed. He shows some examples of DNA folded like origami, and assembled into such patterns as stars, and even a map of the world. So why not create a simple component, like a switch? Researchers have fashioned RNA into just such a device, providing input signals via metal atoms, proteins, and other simple chemicals. They have even figured out how to send the signal from one artificial biological structure to another. This “is not far afield from the typical input/output of modern computers,” says Reed.

Scientists are developing a new generation of biosensors that can detect an electrical signal that might emanate from the smallest building blocks of life. Reed has developed “nanowires,” and applying etching techniques like those used for current semiconductors, fashioned biosensors that can detect minute changes in various biochemical environments. “Not only can we measure things like DNA and other proteins, but we can also talk to cells,” says Reed. The nanowire sensor has a future as a diagnostic tool, because it can read the biochemical messages cells send out when they’re sick -- in real time.

Eventually, Reed sees integrating complicated DNA structures with electronics that look like those found in our computers, and devising sensible interfaces to the biochemical world, “involving two-way communication with this environment.” Computation using such structures may start out slow, but massively parallel processing could bring speeds up without using a lot of power.

Whales to Wood, Wood to Coal/Oil- What’s Next?

2009-08-18T16:51:00.001+05:30

About the Lecture

In 1845, the Dietz Company of New York introduced the sperm oil lantern, which nearly wiped out some whale species. A decade or so later, Dietz began to manufacture lamps using other oils, and gas lighting fixtures, giving whales a reprieve. More than a century has passed, and we’re “about to do it again,” says Daniel Nocera, consuming a precious resource and endangering this time not whales but our world. Nocera wonders, “What will be the savior,” the answer that will save the entire planet?

He ticks off the grim details of our fossil fuel habit -- how the world is rapidly moving from its energy consumption of 12.8 terawatts per year, to 28 terawatts by 2050. This is a simple calculation, Nocera tells us, requiring only population, GDP per capita and energy intensity. The upshot, unfortunately, is that though we do have enough carbon-based energy (oil, methane, coal) to last all of us quite a while, the CO2 we’re emitting may choke off our current way of life long before the end of the fuel.

Nocera advises his audience to put aside dreams that biomass or nuclear energy will give us what we need. Plaster the entire planet with crops we can convert to energy, and you’d still only get seven to 10 terawatts. And you’d “need one nuclear plant every 1.6 days for the next 45 years” to get eight terawatts of power. “There aren’t enough whales to get there in 45 years,” says Nocera.

His alternative for saving the planet is “far from pragmatism and reality.” Nocera’s ultimate solution seems almost magical: “water plus light equals oil.” The proposal is to emulate photosynthesis, the process by which plants convert the energy of sunlight to fuel. Scientists are racing to design structures that can catch light the way a leaf does, then capture the energy of this light using chemical bonds, and then somehow store this energy. Some researchers are focusing on photobiological water splitting. Nocera’s group is working “on a wireless current, an artificial leaf.” While the goal “is to see what nature’s structures tell you,” Nocera acknowledges that “if you try to place what’s in nature in a beaker, it probably won’t work.”

There’s massive urgency to working out the basic science of solar energy conversion. Forget 2050, says Nocera. “Science has got to get it done in the next 10 years, because it will take an enormous amount of time to implement".

“Become friends with a chemist because the carbon neutral energy solution involves light capture and conversion with materials and storage in bonds.”

Daniel Nocera

Do-It-Yourself Biology

2009-08-18T16:46:00.001+05:30

About the Lecture

Inspired by the vast potential of bioengineering, ordinary people are seeking their inner Frankenstein -- doctor, not monster. Two speakers who know their way around Petri dish and beaker discuss the possibilities and pitfalls of do-it-yourself biology with an MIT Museum crowd.

Showing ads from a 1980 Omni magazine, Natalie Kuldell reflects on the vast changes in computer engineering in the past few decades – from 20-lb PCs to laptops and handhelds. In contrast, she laments, genetic engineering today still resembles in large part its 1980 antecedents -- inserting bits of DNA into organisms like E. coli. She avers that computer engineering made such leaps because its technology was widely available to amateurs, who helped drive many advances. Biotech hasn’t moved as fast, and won’t, believes a nascent do-it-yourself (DIY) community, until basic components of biology become accessible to a larger population.

Synthetic biology aims to make new biological forms easier to engineer. Kuldell complains that “much of my time is spent doing things to do the experiments I need to do. It would be terrific not to have to build things in advance.” But building biological components and streamlining processes is difficult in biology, because biosystems are complex, and unpredictable. Can amateurs working with “Tupperware, thermometers and genetic engineering in the kitchen” discover “something remarkable doing their biology at home?”

Reshma Shetty thinks engineered organisms can do more than sense toxic metals in the environment or determine whether seawater is contaminated. She can “imagine a DIY bioengineer…doing something more fantastical, ambitious…. What about growing your own house?” Shetty describes a home experiment that can make bacteria smell like bananas. This is a small feat, but to achieve something significant, a real contribution to science, Shetty says DIY biologists need bio-engineered friendly organisms that will serve as common models, safe, easy to grow “and fun to use.” Candidates include moss, an easy to grow bacterium called Acinetobacter, and the salt-loving Halobacterium. By giving people the right tools, “they can build something fun and creative others can appreciate.”

“Some people may want to use the technology for good, some for bad. This probably won’t change anytime soon. We must think how to put in place a community that overwhelmingly uses technology for good, for constructive purposes.”

Reshma Shetty...

Human Augmentation

2009-08-18T13:00:00.003+05:30

About the Lecture

These two MIT Museum speakers hope you’ll walk away from their talk with a good case of augmentation envy – or at least a healthy respect for what technology can do for the human body and soul.

John Hockenberry has used a wheelchair for 30 years, since a car accident left him a paraplegic. He tells us the public has viewed spinal cord injuries like his as “something horrific,” or “staggeringly poignant.” But in the last 10 years, disability has moved from being “an extraordinarily fringe activity” to a central issue facing society, that of “marrying technology with humanity in a way that is organic to the body, appropriate to the spirit and sustainable to the community.” Hockenberry believes that the needs and demands of disabled people are helping push science toward creating a set of design principles “that will allow this issue of human restoration and augmentation to merge into a kind of seamless unity.”

In illustration of this claim, Hugh Herr describes the astonishing strides engineers are making in the development of “Human 2.0.” He starts with himself -- a victim of frostbite during a 1982 mountain climbing accident. After losing both feet below the knee, Herr headed for the machine shop, and realized he didn’t have to accept the version of his body provided by nature. So he cobbled together a pair of prostheses perfect for climbing (which made him over 7 feet tall), followed by other foot-ankle replacements made lightweight and responsive through carbon composite materials and computers. These designs are better than his originals, suggests Herr. “What’s fun about having part of your body artificial is that you can upgrade. It’s depressing to me, too bad that you folks have biological limbs.”

Wars in Iraq and Afghanistan have fueled the work in Herr’s lab. He’s now building robotic versions of arms and legs that restore capability, using computers and powered systems with sensors and motors. Stroke victims can use similar models, wrapped around an impaired limb, to restore symmetry between their left and right sides. The big prize will be a neural interface, a way of growing and reactivating an amputated nerve, so that it begins to convey sensory information through the complex networks of the brain. “The dream here is that one day I and other people with limb amputations will not only be able to walk across a sandy beach but feel the sand against their prosthesis,” says Herr.

Researchers haven’t imposed limits on their attempts at augmentation – or improvement. An MIT lab has designed a “socio-emotional prosthesis,” Herr tells us – using deep brain stimulators that leave subjects feeling “happy, calm, content.” Hockenberry wonders in conclusion whether we are “blowing away the notion of normal entirely and creating a completely improvisational notion of what it means to be human.” Herr proposes that in the future, “when we have many, many types of intimate technologies that are inside and attached to our bodies, it will unleash a renaissance in expression.”

“The dream here is that one day I and other people with limb amputations will not only be able to walk across a sandy beach but feel the sand against their prosthesis. ”

Hugh Herr...

METASTASIS

2009-08-12T09:22:00.003+05:30

“Screens are revealing a lot of different mechanisms by which metastatic cells learn new tricks, and suborn the mechanism of the host to get them where they’re going. The appealing thing is, these alterations offer opportunities for therapies: you can interfere with circuits between cells, restore growth suppression, interfere with blood vessel formation.”

About the Lecture:-

No diagnosis of cancer is welcome, but some scenarios are more dreaded than others. Richard Hynes discusses what happens “when cells in the primary tumor lose their sense of address and wander off to places they’re not supposed to go.” His talk lays out the process of invasion, by which the cancer spreads into tissues adjacent to the tumor, and that of metastasis, where the cancer disseminates to distant sites.

Hynes describes the transitions a cancer undergoes as it spreads. He explains how tissue in our bodies is made of sheets of epithelial cells that are carefully arranged on a “basement membrane” by a series of adhesion receptors. These receptors, if functioning properly, don’t usually allow the cells to go anywhere. When a cell becomes tumorigenic, it loses some adhesion, and then if it becomes more damaged “wanders off into the underlying tissue.” This is called invasion. Hynes and other researchers are looking at the molecules responsible for cells’ adhesive qualities, and at the mutations in genes that trigger a loss of adhesion. Some of these processes are part of normal development, but occasionally, a “switch gets thrown in cells that should have stayed epithelial” and they become migratory instead.

Once on the move, cancer cells “need plumbing to grow,” says Hynes. Tumors recruit blood vessels to feed them and remove waste, and they can also exploit the body’s white blood cells and platelets to promote their own growth. Hynes describes “cross talk between tumor cells and cells in bone,” where the “two cells get together in evil combination to damage the bone and enhance the growth of metastases.” Scientists have discovered “a lot of different mechanisms by which metastatic cells learn new tricks and suborn the mechanism of the host to get them where they’re going.” Hynes finds such insidious workings an “appealing thing, since these alterations offer opportunities for therapies.” Researchers can tinker with circuits between cells, restore growth suppression and interfere with blood vessel recruitment. It’s “a complex problem,” says Hynes, but there are “lots of ways to get at this.”

About the Speaker:-

Richard O. Hynes PhD '71

Daniel K. Ludwig Professor for Cancer Research, Department of Biology Investigator, Howard Hughes Medical Institute

Richard Hynes received his B.A. in biochemistry from the University of Cambridge, U.K., and his Ph.D. in biology from MIT. After postdoctoral work at the Imperial Cancer Research Fund in London, where he initiated his work on cell adhesion, he returned to MIT as a faculty member.

Hynes is a fellow of the Royal Society of London, the American Academy of Arts and Sciences, and the American Association for the Advancement of Science, and a member of the National Academy of Sciences and the Institute of Medicine. He has received the Gairdner Foundation International Award for achievement in medical science and recently served as president of the American Society for Cell Biology.

Bovine spongiform encephalopathy (BSE)

2009-08-07T11:05:00.034+05:30

commonly known as mad-cow disease(MCD), is a fatal, neurodegenerative disease in cattle, that causes a spongy degeneration in the brain and spinal cord. BSE has a long incubation period, about 4 years, usually affecting adult cattle at a peak age onset of four to five years, all breeds

being equally susceptible. In the United Kingdom, the country worst affected, more than 179,000 cattle have been infected and 4.4 million slaughtered during the eradication programme.

Tracking down the cause of Mad cow disease:First synthetic prion with an anchor:-The cause of diseases such as BSE in cattle and Creutzfeld–Jakob disease in humans is a prion protein. This protein attaches to cell membranes by way of an anchor made of sugar and lipid components (a glycosylphosphatidylinositol, GPI) anchor. The anchoring of the prions seems to have a strong influence on the transformation of the normal form of the protein into its pathogenic form, which causes scrapie and mad cow disease.

A team headed by Christian F. W. Becker at the TU Munich and Peter H. Seeberger at the ETH Zurich has now “recreated” the first GPI-anchored prion in the laboratory. As they report in the journal Angewandte Chemie, they have been able to develop a new general method for the synthesis of anchored proteins.

The isolation of a complete prion protein that includes the anchor has not yet been achieved, nor has it been possible to produce a synthetic GPI-anchored protein. The function of the GPI anchor has thus remained in the dark. A new synthetic technique has now provided an important breakthrough for the German and Swiss team of researchers.

The sugar component of natural prion GPI anchors consists of five sugar building blocks, to which further sugars are attached through branches. Details of the lipid component have not been determined before. As a synthetic target, the researchers thus chose a construct made of the five sugars and one C18-lipid chain and worked out the corresponding synthetic route. First, the anchor was furnished with the sulfur-containing amino acid cysteine. The prion protein was produced with the use of bacteria and was given an additional thioester (a sulfur-containing group). The centerpiece of the new concept is the linkage of the protein and anchor by means of a native chemical ligation, in which the cysteine group reacts with the thioester. This allowed the prion protein to firmly attach to the vesicle membranes by way of the artificial anchor.

This new concept will allow production of sufficient quantities of proteins modified with GPI anchors for in-depth studies. Experiments with the artificial GPI prion protein should help to clarify the influence of membrane association on conversion of the protein into the pathogenic scrapie form. This should finally make it possible to track down the infectious form of the prion.

Mad Cow Disease also caused by Genetic Mutation:-New findings about the causes of mad cow disease show that sometimes it may be genetic. "We now know it's also in the genes of cattle," said Juergen A. Richt, Regents Distinguished Professor of Diagnostic Medicine and Pathobiology at Kansas State University's College of Veterinary Medicine.

Until several years ago, Richt said, it was thought that the cattle prion disease bovine spongiform encephalopathy -- also called BSE or mad cow disease -- was a foodborne disease. But his team's new findings suggest that mad cow disease also is caused by a genetic mutation within a gene called Prion Protein Gene. Prion proteins are proteins expressed abundantly in the brain and immune cells of mammals.

The research shows, for the first time, that a 10-year-old cow from Alabama with an atypical form of bovine spongiform encephalopathy had the same type of prion protein gene mutation as found in human patients with the genetic form of Creutzfeldt-Jakob disease, also called genetic CJD for short. Besides having a genetic origin, other human forms of prion diseases can be sporadic, as in sporadic CJD, as well as foodborne. That is, they are contracted when people eat products contaminated with mad cow disease. This form of Creutzfeldt-Jakob disease is called variant CJD.

"Our findings that there is a genetic component to BSE are significant because they tell you we can have this disease everywhere in the world, even in so-called BSE-free countries," Richt said.

An article by Richt and colleague Mark Hall of the National Veterinary Services Laboratories in Ames, Iowa, was published online in the journal PLoS Pathogens. Richt conducted the research while working at the National Animal Disease Center operated in Ames, Iowa, by the U.S. Department of Agriculture's Agricultural Research Service.

Richt said that prion diseases including mad cow disease are referred to as "slow diseases."

"It's a slow process for infectious prion proteins to develop," he said. "That's why the disease takes a long time -- as long as several years -- to show up."

Richt said mad cow disease caused by genetics is extremely rare. A recent epidemiological study estimated that the mutation affects less than 1 in 2,000 cattle. The study was done in collaboration with the U.S. Department of Agriculture-U.S. Meat Animal Research Center in Clay Center, Neb., which is operated by the Agricultural Research Service.

Richt said the upside of knowing that mad cow disease has a genetic component is that it offers ways of stamping out the disease through selective breeding and culling of genetically affected animals. Therefore, Richt and his colleagues developed high throughput assays to offer the possibility for genetic surveillance of cattle for this rare pathogenic mutation.

"Genetic BSE we can combat," Richt said. "We have submitted a patent for a test system that can assess all bulls and cows before they're bred to see whether they have this mutation."

Nano-sensor For betetr detection of Mad Cow Disease Agent:-In an advance in food safety,researchers in New York are reporting development of a nano-sized sensor that detects record lowlwvels of the deadly poisonous prion proteins that cause Mad Cow Disease and other so-called prion diseases.

The sensor, which detects binding of prion proteins by detecting frequency changes of a micromechanical oscillator, could lead to a reliable blood test for prion diseases in both animals and humans, the researchers say.

Prions are infectious proteins that can cause deadly nerve-damaging diseases such as Mad Cow Disease in cattle, scrapie in sheep, and a human form of Mad Cow Disease called variant Creutzfeldt-Jakob Disease. Conventional tests are designed to detect the proteins only upon autopsy and the tests are time-consuming and unreliable.

In the new study, Harold G. Craighead and colleagues describe a high-tech, nano-sized device called a nanomechanical resonator array. The device includes a silicon sensor, which resembles a tiny tuning fork, that changes vibrational resonant frequency when prions bind. Its vibration patterns are then measured by a special detector. In experimental trials, the sensor detected prions at concentrations as low as 2 nanograms per milliliter, the smallest levels measured to date, the researchers say.

The article "Prion Protein Detection Using Nanomechanical Resonator Arrays and Secondary Mass Labeling" is scheduled for the April 1 issue of ACS' Analytical Chemistry.

Protein involved in Mad Cow Disease:-The scientific magazine Brain Research has recently published the results of research work by scientists from the University of Navarra. The work describes the presence and location of the cellular prion protein (PrPC) in the brain of the rat and characterises the neurones expressed therein, above all within the cerebral cortex of this rodent. The authors are José Luis Velayos and Francisco José Moleres, research scientists at the Department of Anatomy at the University of Navarra.

The PrPC is a normal physiological protein, especially present in the central nervous system, including that of the human, with functions that are little known as yet. Altered prionic proteins, pathogens, infectants, i.e. prions, are responsible for spongiform encephalopathies, amongst these being bovine spongiform encephalopathy (BSE or mad cow disease). In order to operate, prions require the presence of the PrPC. Thus, the importance of this investigation for the location of the PrPC in the central nervous system.

Knowing where in the central nervous system the prions operate

Locating the PrPC meant being able to identify which places in the central nervous system the prions operate. The findings enabled the research team to establish that the PrPC is a protein involved in the neuronal metabolism of calcium. Moreover, the existence of neurones without PrPC and surrounded by perineuronal nests breaks with the hypothesis, to date, that the disappearance of such nests – a special form of extracellular matrix – is a primary event in the course of spongiform encephalopathies; rather it is secondary event.

According to the researchers’ observations, the loss of these nests and consequent neuronal death are due to the damage produced after the appearance of the prions in the brain, where they act upon such perineuronal nests, amongst other structures.

According to the researchers’ comments, extrapolating these results from the rat to the human is valid, given that similar results had been obtained after carrying out the study on human brains. Moreover, this work and others carried out on the brains of the autochthonous Pyrenees breed of cow will help to explain the operating mechanisms of the prions in bovine spongiform encephalopathy.

This study, published in Brain Research, is an addition to the work of the Department of Pathological Histology and Anatomy at the University of Navarra regarding the manner in which prions enter the digestive tube of bovine animals, from which organ they enter the central nervous system, causing the mad cow disease or bovine spongiform encephalopathy.

Identifying the variation in the U.S. Bovine Prion Gene:-Do genes affect bovine spongiform encephalopathy--also known as BSE, or "mad cow" disease? Are some cattle more susceptible than others?

To address these and other questions, Agricultural Research Service (ARS) scientists at the U.S. Meat Animal Research Center in Clay Center, Neb., have sequenced the bovine prion gene (PRNP) in 192 cattle that represent 16 beef and five dairy breeds common in the United States.

This work, partially funded by a grant from the U.S. Department of Agriculture's Cooperative State Research, Education and Extension Service, is expanding the understanding of how the disease works.

BSE is a fatal neurological disorder characterized by prions--proteins that occur naturally in mammals--that fold irregularly. Molecular biologist Mike Clawson and his Clay Center colleagues are examining PRNP variation in order to learn if and how prions correlate with BSE susceptibility.

From the 192 PRNP sequences, Clawson and his colleagues have identified 388 variations, or polymorphisms, 287 of which were previously unknown. Some of these polymorphisms may influence BSE susceptibility in cattle.

Comparing PRNP sequences from infected and healthy cattle may enable researchers to identify genetic markers in the prion gene that predict BSE susceptibility. In addition to PRNP, the team is currently sequencing several closely related genes, which will also be tested for their association with BSE.

The prevalence of BSE in the United States is extremely low, but this research could improve understanding of the disease and prepare the cattle industry to respond if another prion disease should arise in the future.

Mad Cow Breakthrough? Genetically modified Cattle are Prion Free:- The U.S. Department of Agriculture's Agricultural Research Service (ARS) have announced initial results of a research project involving prion-free cattle. ARS scientists evaluated cattle that have been genetically modified so they do not produce prions, and determined that there were no observable adverse effects on the animals' health.

"These cattle can help in the exploration and improved understanding of how prions function and cause disease, especially with relation to bovine spongiform encephalopathy, or BSE," said Edward B. Knipling, administrator of ARS. "In particular, cattle lacking the gene that produces prions can help scientists test the resistance to prion propagation, not only in the laboratory, but in live animals as well."

Prions are proteins that are naturally produced in animals. An abnormal form of prion is believed to cause devastating illnesses called transmissible spongiform encephalopathies (TSEs), the best known of which is BSE.

ARS studied eight Holstein males that were developed by Hematech Inc., a pharmaceutical research company based in Sioux Falls, S.D. The evaluation of the prion-free cattle was led by veterinary medical officer Juergen Richt of ARS' National Animal Disease Center (NADC) in Ames, Iowa. The evaluation revealed no apparent developmental abnormalities in the prion-free cattle.

Richt said, "The cattle were monitored for growth and general health status from birth up to 19 months of age. Mean birth and daily gain were both within the normal range for Holsteins. General physical examinations, done at monthly intervals by licensed veterinarians, revealed no unusual health problems."

ARS, with assistance from researchers at Hematech and the University of Texas, evaluated the cattle using careful observation, post-mortem examination of two of the animals, and a technology that amplifies abnormal proteins to make them easier to detect. Further testing will take at least three years to complete.

The evaluation was reported today in the online version of the scientific journal Nature Biotechnology. ARS is USDA's chief intramural scientific research agency.

Test to protect food chain from Human Form of Mad Cow Disease:-Scientists are reporting development of the first test for instantly detecting beef that has been contaminated with tissue from a cow's brain or spinal cord during slaughter — an advance in protecting against possible spread of the human form of Mad Cow Disease.

Jürgen A. Richt and colleagues point out that removal of brain, spinal and other central nervous tissue after slaughter is "one of the highest priority tasks to avoid contamination of the human food chain with bovine spongiform encephalopathy," better known as Mad Cow Disease. "No currently available method enables the real-time detection of possible central nervous system (CNS) tissue contamination on carcasses during slaughter," the report states.

They describe a test based on detection of the fluorescent pigment lipofuscin, a substance that appears in high concentrations in the nervous tissue of cattle. The researchers found that it was a dependable indicator for the presence of brain and spinal tissue in bovine carcasses and meat cuts.

"Small quantities of bovine spinal cord were reliably detected in the presence of raw bovine skeletal muscle, fat and vertebrae. The research lays the foundation for development of a prototype device allowing real-time monitoring of CNS tissue contamination on bovine carcasses and meat cuts," the report says.

It was done with colleagues from the National Animal Disease Center of the USDA-Agricultural Research Service and Iowa State University.

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