The Impact of Physics on Biology and MedicineHarold Varmus, M.D.
Director, National Institutes of Health
Plenary Talk, Centennial Meeting of the American Physical Society
March 22, 1999
The organizers of your hundredth birthday party have asked me to describe the impact of your field, physics, on the two fields, biology and medicine, that are most obviously identified with the agency I lead, the National Institutes of Health. They have done me this honor not to recognize any knowledge I might have retained from college course work in your field, but to allow me to discuss one of my convictions about medical research, namely, the opinion that the NIH can wage an effective war on disease only if we--as a nation and a scientific community, not just as a single agency--harness the energies of many disciplines, not just biology and medicine. These allied disciplines range from mathematics, engineering, and computer sciences to sociology, anthropology, and behavioral sciences. But the weight of historical evidence and the prospects for the future place physics and chemistry most prominently among them.
I propose to consider the effects of physics on the medical sciences from three perspectives:
- First, I will briefly catalog some of the consequences of a simple and obvious connection between physics and medicine, namely, that the human body and its components are physical objects that can be viewed and measured and altered in ways that resemble what a physicist might do with any physical object.
- Second, I will remind you of an enormously important phase in the history of biology in which physicists transformed the study of living things by helping to discover the principles of heredity.
- Third, I will describe some contemporary problems in the biomedical sciences that I believe should be inviting challenges to physicists, young and old. In the context of doing this, I will also allude to ways in which the NIH is attempting to ease the path from a formal training in physics to an active investigative role in biomedical sciences.
Biological forms as physical objects
I am only the latest in a long list of commentators who have made the really quite obvious point that for at least several hundred years physicists--and especially their principles, methods and machines--have been illuminating our views of the human body and of every other living thing.
This notion was brought home to me very early in life when my father--a general practitioner whose office was directly connected to our house--showed me how X-rays and fluorography could reveal the bones and lungs of our pets and his patients--and make diagnoses of disease. (Figures 1A and 1B illustrate early domestic use of these methods in Roentgen's image of his wife's hand and in a version of fluorography similar to that used by Edison.)
The significance of using the discoveries of physics to perceive biological function was further impressed on me at college, when one of my first independent projects required that I try to explain the repeating peaks and valleys of my electrocardiogram as a record of voltage changes in the salty sea of a human body. And yet again at medical school, when I learned that the doyens of our biochemistry department had become famous by being the first to tag red blood cells with easily detected radioisotopes to learn how long such cells survived in the body.
These few personal memories are just a sampling of the hundreds of physics-based methods that have been applied to view living bodies without the disruption of anatomical dissection or to visualize very small components of living things.
A more systematic rendering of this topic was offered by the distinguished Stanford physicist, Robert Hofstadter, in a talk he delivered to the National Academy of Sciences in 1983 (Table 1).1 I don't want to review this list in too ponderous a manner, but it is instructive to note how many of the methods can be classified as those that permit us to visualize the inner parts of working bodies of humans (and other animals) at successively higher levels of resolution and those that allow us to see smaller and smaller elements of bodily components. The methods of "macro-imaging" include conventional X-radiology, computerized tomography scanning, ultrasound, positron-emission tomography (PET), and magnetic resonance imaging (MRI). The impact of these procedures on medical practice is unquestioned and continues to grow as new methods and new applications appear.
Two recent examples convey the exciting potential for both clinical and investigative work--the use of PET to provide images of the human brain at work (Figure 2) and the use of MRI to analyze both structural and functional characteristics of the human heart in disease states (Figure 3). "Micro-imaging" began with the use of optical principles to devise the light microscope, but has progressed to much higher levels of resolution with electron microscopy, X-ray crystallography, and nuclear magnetic resonance. Sometimes a collection of methods proves important, as in the use of molecular hybridization, fluorochrome chemistry, wave optics, and computer science in spectral karyotyping (Figure 4), a procedure that allows rapid identification of each of the 23 pairs of normal human chromosomes and the origins of recombined chromosomes that often appear in cancer cells. Long-awaited success in using a time-honored technique, X-ray crystallography, to solve the structure of proteins embedded in biological membranes has recently transformed the study of cell function and disease. I used an important example of this progress--Rod McKinnon's analysis2 of potassium channel proteins to understand how the channels can be so efficient and yet so selective for potassium (Figure 5)--in justifying further investments in research to our Congressional Appropriations Subcommittees this year.
Despite the centrality of such contributions of physics to modern biology and medicine, I recognize the danger that you might interpret my emphasis as limited and perhaps even insulting, because (you might say) I have portrayed physicists as merely the developers of tools of measurement that allow biomedical scientists to do the really important work. There are reasons for my sensitivity to this issue: In a 1967 commentary on the role of physics in biology and medicine, for example, Sergei Feitelberg, a physicist from Mt. Sinai Hospital in New York, noted that while such "spectacular developments created a clear and unequivocal need for physicists and their help, the role of the physicist was that of a glorified technician engaged in methodology and instrumentation, dignified only by the strangeness of his doings and the mysteriousness of his tools."3
I do not accept that interpretation. In fact, I would argue that we need to show our appreciation of physics-based technology by investing NIH funds more aggressively in its development. We have begun to do just that through a new Bioengineering Consortium and a trans-NIH emphasis on technology development. Still, I would like to address a deeper set of contributions that physics makes to biology--through the efforts of physicists who themselves seek to understand the rules of living systems.
Physicists, the physical basis of heredity, and the rise of molecular biology
Exactly 50 years ago, in a speech delivered to the 1000th meeting of the Connecticut Academy of Arts and Sciences, Max Delbruck, a leading physicist who had made a conversion to biology some years earlier, attempted to describe the transition:
"A mature physicist, acquainting himself for the first time with the problems of biology, is puzzled by the circumstance that there are no 'absolute phenomena'.... The animal or plant or micro-organism he is working with is but a link in an evolutionary chain of changing forms, none of which has any permanent validity. Even the molecular species and the chemical reactions which he encounters are the fashions of today to be replaced by others as evolution goes on. The organism he is working with is not a particular expression of an ideal organism, but one thread in the infinite web of all living forms, all interrelated and all interdependent. The physicist has been reared in a different atmosphere. The materials and phenomena he works with are the same here and now as they were at all times and as they are on the most distant star."4
Delbruck (shown in Figure 6 at a more advanced age) had been a student of Niels Bohr; a successful physicist; and then a powerful proselytizer for biology. With the assistance of Bohr's book, Light and Life, and, more importantly, Schrodinger's book, What is Life?, he attracted many other physicists to biology. The effects of his missionary zeal were powerful--not just because some very smart people started to do biology, but because they brought to biological problems a quantitative, analytic approach, an approach that created the atmosphere in which principles of molecular biology were discovered by seeking the physical basis of heredity.
[An instructive example of Delbruck's proselytizing was coincidentally described by Jonathan Weiner in a charming article about Seymour Benzer, another physicist-turned-geneticist, in the April 5, 1999 issue of The New Yorker that appeared a week after this talk was given.]
The leading physicist, Leo Szilard (on the left in Figure 7), was among the converts, and claimed that what physicists brought to biology was "not any skills acquired in physics, but rather an attitude: the conviction which few biologists had at that time, that mysteries can be solved".5
Delbruck and his friends were gripped by some fundamental questions: What is the physical form in which hereditary information is stored? How is it reproduced when a cell divides? Or, even more impressively, when a single virus particle invades a cell and makes hundreds or thousands of copies of itself? How is the information reassorted during sexual reproduction? How does the information change when mutations occur?
Answers to many of these questions came from the so-called "phage school" that he founded, a group of former physicists and some biologists (such as Salvador Luria, shown at the microscope with Delbruck in Figure 8) who shared his passion for reducing the problem of heredity to simple rules, physical entities, and conserved energy by studying the replication and genetic behavior of bacterial viruses (also called bacteriophage or "phage") in their bacterial hosts. The studies culminated in findings that form the pillars of modern molecular biology: the identification of DNA as genetic material, a description of the physical organization of DNA through X-ray crystallography, the deduction of the principles of base pairing and the strategy of replication from the organization of the double helix, and the deciphering of the genetic code as triplets chosen from a set of four nucleotides.
Delbruck and his phage school were important, but there were, in fact, multiple intellectual lineages connected with physics that helped to create the modern world of molecular biology.6 For instance, Warren Weaver was a mathematical physicist turned science administrator, who, in 1932, first used the term "molecular biology". He chose this phrase because he foresaw "that the moment would arrive when the distinction between chemistry and physics and even mathematics on the one hand and biology on the other would be so illusory and in fact so unfortunate" that he didn't want to use the word "biology" to describe the programs he was supporting at the Rockefeller Foundation. British scientists with a strong physical bent, such as Astbury, Bragg, and others, used X-ray diffraction to study the organization of fibers of many kinds, mainly proteins found in textiles, in an intellectual lineage that led to Wilkins and Franklin and, of course, DNA. The American geneticists, T.H. Morgan and H.J. Muller used physical agents, X rays, to induce mutations in fruit flies. Muller's affinity for the principles of physics was especially strong. He was fond of noting the potential similarities of mutation of genes to transmutation of elements, calling the prospect of understanding these events in physical terms "the two keystones of our rainbow bridges to power".7
Bringing physics, not just physicists, to the problems of biology
In the birth of modern molecular genetics, physicists contributed their analytic skills but they were not really doing physics, and many were not even using the computational or imaging tools of physics as many biologists do. (As you have seen in the photo of Luria and Delbruck [Figure 8], they were laboriously counting virus infections by hand and eye, like any other biologist.) But contemporary biology, especially the deciphering of genomes by nucleotide sequencing, is about to change that. Biology is rapidly becoming a science that demands more intense mathematical and physical analysis than biologists have been accustomed to, and such analysis will be required to understand the workings of cells.
This change was clearly foreshadowed in Delbruck's 1949 lecture. He first described his awe at the complexity of biology: "The closer one looks at [the] performances of matter in living organisms the more impressive the show becomes. The meanest living cell becomes a magic puzzle box full of elaborate and changing molecules, and far outstrips all chemical laboratories of man in the skill of organic synthesis ...."8 But he also sounded a warning: "Biology is a very interesting field ...[because of] the vastness of its structure and the extraordinary variety of strange facts...but to the physicist it is also a depressing subject, because...the analysis seems to have stalled around in a semidescriptive manner without noticeably progressing towards a radical physical explanation...we are not yet at the point where we are presented with clear paradoxes and this will not happen until the analysisof the behavior of living cells has been carried into far greater detail."9
In the past 50 years, and especially in the past twenty, molecular and cell biologists have moved much closer to the "radical physical explanation" of cell behavior that Delbruck sought. Certainly the chemical elements--especially the genes, the RNAs, and the proteins--and some of their basic functions are coming into view. What is lacking is a sense of how these functions are integrated to allow cells to manifest their physiological traits.
I would like to mention three of the several arenas of biology in which I believe the skills of physicists and their close cousins can be most productively used.
The first is perhaps the most reductionistic. Methods are now available for examining the physical and chemical properties of single macromolecules and single complexes of large molecules. These advances are important because they avoid the need to synchronize a population of molecules to measure function. Several of these methods and their applications are reviewed in a special section on "single molecules" in the issue of Science magazine that appeared last week.10 They include laser traps ("optical tweezers") to study the energetics of molecular motors used for transport, for contraction, and for flagellar motion. (One of the younger stars of your field, the recently decorated Nobel Laureate Steven Chu of Stanford, has made significant contributions to this problem in collaboration with his cell biologist colleague, Jim Spudich.) Laser traps can also be used to measure the force of an enzyme complex, such as the one that copies DNA sequences into RNA. Fluorescence spectroscopy and scanning tunnel microscopy can visualize the conformation of single large molecules, and methods now in development may soon be able to determine the order of bases in single long DNA molecules.
In the second arena, the computational experience of physical scientists is needed to help interpret complex data sets. One of the consequences of projects to sequence the genomes of human beings and many other species is the opportunity to understand the orchestration of expression of all the genes in an organism. New methods, built on the availability of a piece of DNA from each gene, allow measurement of the extent to which genes are read to form RNA (and subsequently protein) in different tissues and under different environmental conditions. These micromethods, called "expression arrays" (Figure 9), are coming into wide use to study bacteria (with several hundred to a few thousand genes), yeast (with about 6200 genes), worms (with about 19,100 genes), and vertebrates (whose still incompletely analyzed genomes are predicted to contain about 80,000 genes). Some progress has been made through computer-based "cluster analysis"11 to begin to interpret the voluminous data that such experiments generate, but biologists are generally unused to such complex data sets. Recently, I spent an evening at the Carnegie Institution's Chilean observatory at La Serena watching astrophysicists gather amazingly similar data sets to search for supernovae and to measure the chemical composition of distant stars. We are all likely to benefit from an interdisciplinary exchange of computational approaches.
The third arena most closely approaches Delbruck's goal of developing a "radical physical explanation" for cell function. In the past twenty years, mainly through efforts to identify the genes and proteins that control cell growth and responses to hormones, biomedical investigators have constructed many so-called "signaling pathways" that link molecular interactions at the cell surface to changes in gene expression in the nucleus. While there is consensus that these linear pathways are over-simplified, the way forward is far from clear. The pathways doubtless have many unrecognized components; the information is certainly flowing between, not just along, the several pathways; and the pathways are probably regulated in complicated ways through feedback mechanisms and others. A few investigators are beginning to grapple with these issues12,13 but there is an obvious need to apply experiences with potentially analogous complex machines.
Finale: Moving between disciplines
In talking about the effects of one field on others, I have generally ignored the "boundary problem"---how do we distinguish among fields? We do this now, in part, by self-identification, just as we deal with ambiguity about race, ethnicity, and religion. Self-identification in science is commonly linked to the source of one's graduate degree, and departmental names on diplomas can become limits to exploration in adjacent fields. But many of us in biology expect that, as studies of cells and molecules become more obviously in need of several disciplinary approaches, it will become increasingly difficult to label the science and to predict the kinds of degrees people doing it should have. At the NIH, we have become concerned about how people should be trained in college and in graduate studies to pursue biological problems over the next fifty years, and we are discussing the need to study this issue with the National Research Council. I also agree with Leon Lederman, who has been leading the movement to establish a more logical order of sciences---physics, chemistry, and then biology---in high school curricula. But these activities will come to fruition only after many years, and it is important to consider as well the more immediate need to transport intellects across artificial disciplinary boundaries.
I sense increasing interest in attempting to open borders that have been traditionally hard to cross. Workshops on computational biology and approaches to complex systems have recently been organized by the National Institute of General Medical Sciences and the Department of Energy. New funding opportunities for interdisciplinary work are available through our Bioengineering Consortium (BECON) and other programs advertised in the NIH Guide for Grants and Contracts and described in the Blue Sheet.14 (At present, total NIH funding of physics projects is estimated to be about $287 million.) There are many anecdotal accounts of successful interdisciplinary training programs. Within our intramural research program at the NIH, physicists and physics trainees from the United States and abroad do graduate thesis work, take courses in biological topics, and engage in post-doctoral training that promotes interactions with biologists and clinicians. Much of this activity occurs under the direction of some of our most prestigious scientists, such as Ad Bax, Bob Balaban, Bill Eaton, and Adrian Parsegian, and includes work on small-molecule- and protein-NMR, brain- and cardiac-MRI, and other topics, leading to good job prospects for trainees.
On the occasion of the 100th anniversary of the APS, I thank you and your colleagues for your many contributions to biology and medicine--for providing the tools that allow us to see and probe living things and for training great minds that have uncovered some of the most fundamental principles of biology. I now encourage you to work collaboratively with us as we strive to achieve Delbruck's "radical physical explanation" for biological systems.
1. Hofstadter, R. Cross Strands Linking Physics and Medicine. In: National Conference on Biological Imaging. Washington, D.C.: National Academy Press, 1984; 1-38.
2. Doyle, D.A. et al. The Structure of the Potassium Channel: Molecular Basis of K+ Conduction and Selectivity. Science 1998; 280:69-77.
3. Feitelberg, S. Disciplines: Physics, Biology, and Medicine. J Mt Sinai Hosp NY 1967; 34(4):378-381.
4. Delbruck, M. A Physicist Looks at Biology. Trans of Conn Acad Arts and Sci 1949; 38:173-190.
5. Quoted in Fleming, D. "Emigre Physicists and the Biological Revolution", Perspect Amer Hist 1968; 2:161.
6. Keller, E.F. Physics and the Emergence of Molecular Biology: A History of Cognitive and Political Synergy. J Hist Biol 1990; 23(3):389- 409.
7. Quoted in Elof Axel Carlson. "An Unacknowledged Founding of Molecular Biology: H.J.Muller's Contributions to Gene Theory,1910- 1936." J Hist Biol 1971;4:160-161.
8. Delbruck, M. A Physicist Looks at Biology.
10. Science 1999; 283 (5408).
11. Eisen, B. et al. Cluster analysis and display of genome-wide expression patterns. Proc Natl Acad Sci USA 1998; 95:14863-14868.
12. Bhalla, U.S. and Iyengar,R. Emergent Properties of Networks of Biological Signaling Pathways. Science 1999; 283:381-387.
13. Weng, G. et al. Complexity in Biolgical Signaling Systems. Science, in press.
14. "The Blue Sheet" on health policy and biomedical research is published weekly by F-D-C Reports, Inc., Chevy Chase, MD.
Citations for Figures
Figures 1A and 1B: Kevles, B. H. Naked to the Bone. Reading, Massachusetts: Helix Books, 1997.
Figure 2: Rosen, B.R. et al. Proc Natl Acad Sci USA 1998; 95: 773-780.
Figure 3: Courtesy of Robert S. Balaban, NHLBI
Figure 4: Schrock, E., et al. Science 1996; 273:494-497.
Figure 5: Doyle, D.A. et al. Science 1998; 280:69-77.
Figure 6: Cairns J, et al. eds. Phage and the Origins of Molecular Biology. Plainview, New York: Cold Spring Harbor Laboratory of Quantitative Biology, 1966.
Figure 7: Ibid.
Figure 8: Ibid.
Figure 9: Duggan, D.J. et al. Nat Genet 1999; 21(1 Suppl):10-14.