In the early 1940s, as war raged over the continent, the British mathematician Freeman Dyson and the Indian physicist Harish Chandra were taking a walk in Cambridge. Harish Chandra was studying theoretical physics under the legendary Paul Dirac while Dyson was getting ready to spend a depressing time calculating bombing statistics at Bomber Command.
“I have decided to leave physics for mathematics”, quipped Harish Chandra. “I find physics messy, unrigorous, elusive”. “That’s interesting”, replied Dyson. “I am planning to leave mathematics for physics for exactly the same reason.” Leave their respective disciplines the two did, and both of them had highly distinguished careers in their new fields at the Institute for Advanced Study in Princeton.
I narrate this story because I can imagine almost exactly the same conversation taking place today between a biomedical researcher and any other kind of natural scientist. In fact it’s interesting to compare the status of medicine today with the status of physics when Dyson and Harish Chandra had their conversation. By 1940 physics had underwent a great revolution in the form of quantum mechanics and relativity. Yet there was much to be done and the “second revolution” was in the making. In retrospect it’s clear that very little was known about the strong and weak nuclear forces and nothing was known about the particle “zoo” that would be uncovered in the next few years. It took the efforts of many brilliant individuals to unify crucial concepts and make the whole structure look more consistent and complete.
Medicine in the year 2011 is like physics in the year 1940. Just like physics it has had a recent revolutionary past in the advent of molecular biology. Just like physics there is much of it that is “messy, unrigorous, elusive”. And it’s exactly these qualities that make it a field ripe for another revolution. The future beckons for medicine and biology today as it did for physics in 1940.
What will this future look like? In Niels Bohr’s memorable words, “Prediction is difficult…especially about the future”. Yet prediction is not so much about being able to chart the objective course of events as it is about discussing the promises, possibilities and pitfalls of the future. We do not predict in order to be right, we predict in order to be interesting. This year at Lindau we have the opportunity to witness the collision of ideas between 20 Nobel laureates and more than 500 students. The Nobel laureates have achieved great things, yet the future does not belong to them. It belongs to the young researchers attending the meeting. But the young researchers can only try their wings by perching on the edifice erected by their illustrious forefathers. The question we wish to contemplate is “How would these promising young scientists contribute to the future of medicine and how will their work be related to that done by their Nobel predecessors?”
As fraught with uncertainty as the answer to this question is, one thing seems to be clear; the study of life and disease at the molecular level will continue to play a foundational role in the future development of medicine. As we indicated above, medicine has been revolutionized in the last fifty years by the development of molecular biology. The discovery of the structure of DNA was a watershed that made it possible to ask questions about paradigms as grand as cancer, neuroscience, aging and evolution at the molecular level. Today no fundamental question about metabolism, growth, illness and even interactions between species and individuals goes unanswered without at least a cursory look at molecular level events. However, the great achievement of the 20th century was not just to understand life but to try to control and recreate it, most recently exemplified by Craig Venter’s creation of a “synthetic cell”. Now a high-school student can easily extract, purify, splice and insert DNA into other organisms using standard kits and cheap equipment. The “domestication of biotechnology” is on the horizon and we will have to deal with its inevitable wonders and worries. Molecular origami will continue to be an elemental force in medicine’s future development.
This year’s Nobel laureates have laid the foundation for the work that will be done by Lindau’s young guests. They have contributed tools, insights and unifying concepts ranging from man’s perpetual struggle with microorganisms to the elucidation of key biomolecular structures and pathways to the invention of new tools to illuminate the workings of living systems. It’s also worth noting that about half of this year’s laureates have been awarded the Nobel Prize in chemistry. This is not surprising since of all the basic sciences, chemistry is closest to medicine in being able to provide explanations at a molecular level.
How will specific discoveries by these prize winners inspire those to whom the baton is being passed? Let’s look at scientists who have deciphered the structures of key biological molecules; these include the laureates who have cracked open the workings of the ribosome (Yonath and Steitz), the photosynthetic reaction center (Michel, Huber) and aquaporin (Agre). Without structure there is no understanding of function, so the business of structure elucidation will keep the next generation as busy as it did the previous one. Last year I compared structure determination of biomolecules, especially through x-ray crystallography, to climbing mountains beyond mountains. The peaks that crystallographers and structural biologists have scaled will be footstools on which the young people can stand tall. Structure determination of complex molecules provide a fitting example of science as the “endless frontier”; as molecules which were thought to be impenetrable thirty years ago yielded to intellect and effort, new structures of great complexity beckon the intrepid explorers of the future.
The second class of laureates this year concerns those who have developed new tools to explore biological systems. In science, the value of craftsmen who build tools has sometimes been relegated to that of the deep thinkers, yet today’s biomedical science would be completely diminished if it were not for the discovery of green fluorescent protein (Tsien, Chalfie), recombinant DNA (Smith, Arber) and gene knockouts (Smithies, Evans). All these scientists have provided tools of inestimable value which will supply powerful basic utility to the young generation; they in turn will continue to refine and generalize. The development of the tools provides one of the best examples of how science builds on itself, of how today’s novel discovery turns into tomorrow’s common laboratory protocol.
Another kind of discovery made by some of this year’s prize winners relates to the study of basic physiological pathways mediated by key molecules. If others have shed light on structure, scientists like Fischer (phosphorylation), Blackburn (telomerase), Ciechanover and Hershko (ubiquitin) and Murad (nitric oxide) have illuminated function. Not only have these discoveries led to practical benefits (such as the development of drugs blocking these processes in cancer cells), but they also reinforce one of the perpetual wonders of chemistry and biology; the fact that molecules both maddeningly simple in structure like nitric oxide and more complex ones such as kinases can have such a profound effect on human physiology. Given the staggering multitude of small organic molecules and proteins involved in biological events, one can be sure that there are molecular gems hidden away in caves, waiting to be discovered, polished and held up as further marvels of chemical and biological organization.
While many of this year’s scientists have provided insight into the inner lives of our cells, others have also accomplished the crucial task of delving deep into the inner lives of our oldest companions and enemies: bacteria and viruses. The fortunes of human wars wax and wane, but we will possibly be fighting the microbe wars until the end of time. Several of this year’s Nobel laureates have discovered the identities and strategies of some of our most dreaded adversaries, including HIV (Montagnier) and HPV (zur Hausen). The practical utility of these discoveries is obvious, but they are also furthering our understanding of the fascinating tactics used by these simplest of organisms to hijack our bodies and turn them into their personal replication factories. The fact that something as simple as the HIV virus can today kill 2 million human beings a year is a testament both to the fragility of seemingly infallible human life as well as the terrifying beauty of evolution and nature’s enduring creations. In addition, the discovery that human papilloma virus causes cervical cancer- a disease which for decades was thought to have non-infectious causes- opens the door to what is one of the most fascinating ares of future medical research: the relationship between chronic diseases likes diabetes, heart disease, Alzheimer’s disease and cancer, and infection. Yet most who boldly first ventured into postulating infectious causes for disease like cancer and ulcers were harshly criticized and shunned. The young researchers at Lindau who wish to explore the relationship between infection and disease will, in addition to scientific imagination, need a healthy dose of tenacity, spirit and conviction. It seems that their scientific heroes have much more to offer them than just innovative ideas. If they are willing to pick up the gauntlet, they will certainly be in august company.
Finally we come to a class of scientists who are underrepresented in this year’s list. There is every possibility that their ilk might dominate in future lists. Edwin Neher and Bert Sakmann received the Nobel Prize for their studies of single ion channels using the patch clamp technique, work that revolutionized neuroscience. Neuroscientists are spread relatively thin among Nobel laureates in medicine. If physics dominated the first half of the twentieth century, many feel that neuroscience will dominate the twenty-first. Very few fields promise as much in terms of startling and revolutionary discoveries as neuroscience. Why? Because put simply, there is still a lot of low-hanging fruit in the field. While great advances were made in understanding the brain in the twentieth century, it is only now that we have begun to make real forays into unraveling this “thin bone vault”, the seat of our thoughts and emotions, at a functional level. New techniques including single-neuron studies and functional magnetic resonance imaging (fMRI) promise unprecedented insights into the working of the most complex biological structure that we know. These studies, for the first time, are allowing us to build bridges between the natural sciences and social sciences like psychology and economics. The ultimate goal is to get a feel of the neural basis of human behavior and consciousness itself, although many caveats exist in establishing such connections. Groundbreaking advances in genetics are also now allowing us to compare brains between different species and postulating what possibly makes us humans special. In addition, because much of the brain is newly accessible virgin territory, the simplest of experiments can still provide the deepest of understanding, something that used to be true of much of science in the nineteenth and twentieth centuries. Finally, just like molecular biology in the last fifty years, neuroscience provides unprecedented opportunity for interdisciplinary contributions, with biologists, psychologists, chemists, biomedical engineers and even computer scientists all being able to contribute. If this year’s young researchers want to pick a field which may well be the most exciting of the new century, they could do no better than to delve into the mysteries of neuroscience.
Let’s return to the conversation between Dyson and Harish Chandra. If medicine is “messy, unrigorous, elusive”, it only means that it is poised on the edge of a new era of understanding. But the other reason why the terms apply is because we have also started to realize some of the limitations of the optimistic pronouncements that have dotted the landscape of medical research in the last twenty years. One is the promise of genomics-based medicine. While the value of genomics in understanding disease is wholly undisputed, some of the starry-eyed expectations about the mapping of the human genome enabling a revolutionary new era in the understanding and treatment of disease seem to have been premature. As we have made leaps in unraveling biological systems, new complexities have emerged. For instance, determining the genome sequence is one thing, but understanding the complex interactions of the signaling networks mediated by proteins and small molecules in the body poses a challenge on a totally different level. As we have also learnt in other sciences over the last few decades, new types of phenomena arising at every level of understanding- dubbed emergent phenomena- challenge us. Knowing the genome is necessary but far from sufficient for knowing signaling cascades in cells. Similarly our understanding of disease has been enriched, but this has also made prospects for treatment more difficult than what they seemed. Cancer, for instance, is now rightly recognized as not just one disease but as a multifaceted series of events that cause a body to rebel against itself.
But as is always the case in science, challenges inherently promise opportunity. The complexities of cancer only mean that we will have to explore the promises of personalized medicine, where every patient gets treatment that is tailored to his or her specific brand of cancer with its specific mutations. The complexity of biological networks only means that we need new approaches from computer science, data analysis and systems biology to fully comprehend living systems. Science may be the only human endeavor where new difficulties and challenges are not only accepted but they are relished. In science, roadblocks almost guarantee new and possibly revolutionary levels of understanding.
This year’s young researchers at Lindau should thus welcome the future of medical science. Building on the work of their predecessors, they have every opportunity to change this future from messy, unrigorous and elusive to clear, rigorous and well-defined. This future beckons and our young scientists are taking the right step to prepare for it by being at Lindau; as Antoine Saint-Exupery would have told them, “As for the future, your task is not to foresee it, but to enable it”.