Waste is not usually a popular topic for polite conversation. Biochemists also avoided it for many years, thinking of protein degradation as a general process that simply gets rid of unwanted biological waste. It was not until Aaron Ciechanover, Avram Hershko and Irwin Rose discovered the ubiquitin-based protein degradation system that the specificity and centrality of this process in life was recognized. Ubiquitin, as the name indicates, is a small protein that is ubiquitously expressed in eukaryotes. It binds to unwanted and broken down proteins and peptides and labels them for recognition by the proteasome, where they are broken down. Both ubiquitin and the proteasome have emerged as key features of living systems. They underscore the notion that death is as important as life. Not only have both of these become important in the study of biological processes but the proteasome has also emerged as a possible target for drugs.
9:04 A.M. Aaron Ciechanover was supposed to talk about protein degradation. The title “Why our proteins must die so that we can live” was changed to “Drug Discovery and Biomedical Research in the 21st century”.
Ciechanover emphasizes the last century of medical research, noting that most drugs that been used for hundreds of years have been used without knowledge of their mechanism of action. He talks about several revolutions in medicine in the last century. The first revolution largely emerged from serendipitous observation of the biological action of many substances related to natural products, or natural products themselves. Aspirin whose mechanism is being investigated even today is a prime example. Ciechanover briefly traces the history of aspirin, from the accidental observation of its anti-inflammatory and painkilling properties discovered by the natives to the “clinical trial” by Felix Hoffman who gave the drug to his father to mitigate his arthritic pains. It was not until the 70s that John Vane and others discovered the close connection between aspirin and prostaglandin synthesis. Today aspirin is prescribed as a preventive measure for heart disease, and recently discovered relationships between inflammation and cancer have cast a new light on aspirin’s role in possibly treating or preventing cancer. The point about aspirin is that all this research was conducted or decades without really knowing how the drug works.
The next example Ciechanover talks about is penicillin and there is hardly a fact about its discovery that is not known. Suffice it to say that its mechanism too was discovered relatively recently, and tremendous effort has been expended in developing other ß-lactam antibiotics of the penicillin class that have improved metabolic characteristics and activity against gram-negative bacteria.
The second revolution has occurred from about 1970 to the turn of the last century. This revolution involved brute force, high-throughput approaches to screening large libraries of compounds. Millions of compounds are tested against cells or proteins using automated techniques . Even in the last thirty years there have been examples of intuition and knowledge-based approaches to treating disease. Ciechanover examined the discovery of H. pylori by Barry Marshall and Robin Warren. I remember reading Barry Marshall’s story in a Readers Digest issue a few years after it was made. Marshall wanted to challenge the conventional wisdom of the medical community which believed that peptic ulcers have a non-infectious cause. Marshall wanted to prove the medical establishment wrong about ulcers and thought that a bacterium, H. pylori, caused them. Since nobody believed that a simple bacterium could cause such a widespread medical condition, Marshall took the drastic step of drinking a concoction of H. pylori himself and developed acute ulcers. The cause-effect relationship has seldom been better demonstrated in medicine.
As an example of high-throughput screening Ciechanover talked about statins, the best-selling drugs of all time used to treat and prevent heart disease. Akiro Endo in Japan discovered statins in fungal extracts. After a lot of effort by major pharmaceutical company, many important statins were discovered, including atorvastatin which is the best-selling drug in the world (I personally think that there is a Nobel Prize for Endo waiting in the wings).
According to Ciechanover, the third revolution in the twenty-first century will consist of personalized medicine. Personalized medicine involves molecular studies of the same disease in different individuals who may respond differently to the same treatment because of differences in protein expression and the genetic underpinnings of the disease. A good example is breast cancer. Women who have breast cancer can be either estrogen receptor positive or negative, referring to the expression of the protein that binds estrogen and activates key cancer-causing genes. Depending on this classification, a woman who is estrogen receptor negative may not respond to Tamoxifen, the most widely used drug against breast cancer. Other therapies may be needed for treating her disease. Molecular studies could identify such tiny but vital differences among individuals who superficially seem to have the same disease. Such studies would be important in deciding specific combinations of treatment. Interestingly, personalized medicine is a modern name for an approach that doctors have empirically adopted for centuries when they recognized that every individual reacts differently to the same medicine (My grandfather who was a doctor used to say to two patients with arthritis, “I am going to prescribe different treatments to both of you because your arthritis is not the same as his arthritis”)
Ciechanover then talked about how sequencing of every single individual’s human genome would help to enable such targeted therapies. He identified certain challenges and obstacles in achieving the goal of personalized medicine and better therapies in general. One of the problems is that most diseases are multigenic and multifactorial, and different complex factors may cause the same disease in different individuals. Genomic instability means that targets of drugs are not always stable, and cells such as cancer cells may and do circumvent therapy by adopting different pathways for growth and survival. The lack of animal models is another acknowledged challenge in therapeutic intervention; we still lack good mouse models for several neurological disorders for instance (How do you find out whether a mouse is truly depressed or not? Does the mouse start drinking?)
And then of course there is the quagmire of moral and ethical issues. Plumbing the depth of personal genomic information carries many potential moral hazards. For one thing, do we want to make potentially damaging genetic information available to future employers, family members and spouses? Would it be fair to determine the entire genetic makeup of an individual even before he or she is born, knowledge that could identify many future possible problems resulting from genetic defects or abnormalities? Naturally such information can also be positively used to prevent medical disorders, but as with other scientific information it is a double-edged sword. The moral and ethical problems associated with such scientific knowledge will continue to challenge us long after the scientific problems themselves have been resolved.
9:30 A.M. There’s a slight change in the schedule. John Walker who discovered the structure and mechanism of ATPase is unable to attend the meeting. Instead his time slot has been given to Mario Molina. Thus in this Lindau meeting we have all three of the Nobel laureates who were recognized for their work on the destruction of the ozone layer.
Molina begins with the basics of climate change and acknowledges the work of the IPCC in establishing a consensus on anthropomorphic climate change. He talks about the common objections of skeptics who point to changes in the climate throughout earth’s history and make this an argument for challenging the concern about recent changes in climate. The complex answer to this skepticism is…complex. The simple answer concerns dozens of computer models coupled with meticulous inclusion of field data from multiple sources that demonstrate the anomalous nature of the current drastic changes in climate. Perhaps the single most authoritative source is NASA’s James Hansen (see here for a recent profile of Hansen in the New Yorker).
Molina also emphasized the fallacy of attributing single weather events (like Hurricane Katrina or the European heat wave of a few years back) to man-made global warming. Climate is necessarily an average phenomenon. Thus, while single hurricanes cannot be attributed to global warming, studies clearly indicate a relationship between the mean surface sea temperatures and the increase in the severity, not necessarily the frequency, of hurricanes, a relationship that has been validated by recent observations (for more information you can see Chris Mooney’s “Storm World”).
Molina then talks about data from the Stern report which was commissioned by then Chancellor of the Exchequer Gordon Brown. I have read the summary of the Stern report and both it and the executive summary of the latest IPCC assessment are worth checking out. Both provide probably the most up to date and objective evaluation of the causes and effects of global climate change, along with assignment of probabilities to every effect. However Stern is not an economist and some of his economic proposals for mitigating climate change have been challenged, for instance by economist William Nordhouse (for an interesting analysis of Nordhaus’s proposals and writings, see Freeman Dyson’s review in the New York Review of Books). At this point, Molina emphasizes that scientists who work on climate change are careful not to make policy judgments and always try to stick to the science. This is admirable and should be how science is done. But scientists are human beings with moral senses, and sometimes it is difficult to stay uninvolved. An example again is NASA’s James Hansen who for many years stuck to the science, thinking that its truth would convince policy officials. But after the science was consistently ignored, Hansen has reluctantly adopted the responsibility of becoming a public spokesperson and activist.
So as usual, the cardinal question; what are the solutions? As Molina and many others have noted, at least some drastic changes in our personal and global habits would be necessary to deal with climate change. Alternative energies are key in mitigating CO2 emissions, as is also carbon capture. Gratifyingly Molina also notes the inclusion of nuclear power in future energy options and especially notes the safety and efficiency of the new generation of nuclear reactors.
Molina finally moves on to possible climate policies for the future and discusses their specific values. The point was illustrated by two roulette wheels which involve different sacrifices that people are willing to pay in order for further climate mitigation. We don’t have a lot of time to make the choice of Roulette wheels. One of the reasons is that the situation has turned out to be much more serious than previously thought. Molina discusses various climate forcings including cooling influences which act as negative forcings. Some studies indicate that climate models have possibly underestimated the effect of the positive forcings. In general climate may be much more sensitive to forcings than we thought. Such sensitivity may quickly lead us past a tipping point. What constitutes a tipping point is not completely clear, but Molina cites a 2008 PNAS paper which notes several metrics of climate change (sea ice melting, thermohaline circulation etc.) and indicates that a tipping point has been passed with respect to several of these metrics.
Molina concludes with a list of solutions to mitigating climate change. These include pricing or taxing carbon emissions and further research in energy technology. Molina notes that it is possible to battle climate change, and again points to the Montreal Protocol emerging from his own prize-winning research which showed that cooperation between nations for the betterment of humanity is indeed possible. In the end, unless we inculcate personal habits and social responsibilities, use energy more efficiently, control population and reach out to others in improving the state of our world, we may indeed end up playing the proverbial Russian roulette with our planet, and that we don’t want to do.
10:16 A.M. Erwin Neher’s talk is about applying chemistry to neuroscience. Neher was awarded the 1991 Nobel for Medicine or Physiology along with Bert Sakmann for their development of patch-clamp techniques.
Neher starts by reviewing Spanish histologist Ramon y Cajal’s pioneering work on signal propagation through neurons through studies of their basic structure. Synaptic transmission is essentially a three-step process involving release of neurotransmitter, diffusion of the neurotransmitter across the postsynaptic membrane and reuptake of neurotransmitter. Neurotransmitters are stored in vesicles which fuse with membranes. Calcium and calcium channels are key components in the entire process, as in many other processes crucial for life.
Neher’s work addresses one of the thorny technical problems of studying neurotransmission; in general, he says, the presynaptic terminals are very small and the study of neurotransmitter release is thus difficult. To address these issues, Neher has developed caged compounds which enclose calcium and then release it when zapped by a pulse of UV light. Neher uses these compounds to modulate the levels of calcium in cells using precise timing through light pulses. The ensuing neurotransmission can then be studied using voltage patch clamp techniques.
10:45 A.M. There is now a break before a panel discussion on the future of energy and chemistry. During the break, it is encouraging to hear so many students from so many different countries enthusiastically talking to each other about their interests and research. The international nature of science is well underscored.
|» Ashutosh Jogalekar studied chemistry and is currently a postdoctoral fellow.|