17—
Science and Society—
Toward Wider Horizons

We are at a hinge point in evolution. Some two hundred thousand years ago, Homo sapiens emerged on this planet—out of a panoply of life—mostly mute, unself-aware, living, multiplying, dying. We emerged with this body, this frame, these hands, this mind, unaware of any past, ignorant of our inner selves, innocent of the future.

Somehow we found our way. We invented language, writing, agriculture, industry, social organization, and science and only in the last hundred years or so have we begun to learn about the physics and chemistry of our inner selves and consequently about our long ago past; about our intricate machinery and why it can go awry; about the inheritance that makes worms become worms, birds birds, and us humans.

What a wonderful time to be a biologist.

The mysteries fade in the light of knowledge, but with knowledge and understanding can come the urge to intervene, to change, to modify. But the human mind, which is so good at the analysis of what is, falters before what ought to be. This is hardly surprising. Our mind did not evolve to cope with such questions. Evolution has not confronted such issues until now.

Curiously, my conscious reflection on this profound change in the human condition all began with a request to give a Monday Night Lecture. The invitation seemed to tap a previously unconscious, unexpressed vein of interest and concern. By 1965, I had been immersed in science for nearly three decades—a student, a researcher, a teacher, I

had rather singlemindedly pursued a scientific career, interacting with other scientists, teaching future scientists. Now several events were to change my path in the coming decades toward much wider and hazier horizons.

The Monday Night Lectures (now called the Watson Lectures) were a Caltech tradition. On most Monday evenings during the academic year, a Caltech faculty member would attempt to describe his or her research—methods, objectives, results—in terms understandable to an "educated" public. The lectures were one hour, followed by a question-and-answer period. Most made considerable use of visual aids. Over the years, a considerable audience of five hundred to one thousand persons had developed for these lectures, including many of the Caltech faculty. They were a successful means to reduce possible estrangement or tension between the institute and the resident community.

Having never before attempted to present my research program to a nonscientific audience, I took the "challenge" seriously. My title was "The Book of Life." I endeavored to compare the genetic information to the information in a book—like a book of recipes or a manual of flower arranging—written in an unknown language, like a Mayan codex, and I sought to explain how far we had come in deciphering this text and what it meant and what it would mean when the knowledge was more complete. I had made many diagrams for the purpose.

The night of the lecture arrived during one of the torrential downpours Pasadena can have in the winter. I anticipated minuscule attendance, but the audience was loyal and a good crowd appeared. To my pleasure and surprise the lecture was well received. Indeed, the substance was later printed by Addison-Wesley as a "separate" and sold many thousands of copies.

The lecture had another consequence. In the fall of 1966, Caltech was celebrating its seventy-fifth anniversary in Pasadena. A major symposium was planned on the subject of the future of science. Because of my Monday Night Lecture, I was asked to present a lead address on the future of molecular biology and its potential implications. I had never given this larger theme much thought. Scientists are generally immersed in their scientific questions, in daily research and the planning—invention, really—of the next experiment. The larger, more cumulative impacts of scientific knowledge are not often within their ken, and in any case seem rather speculative and remote.

But for the next six months my mind kept returning to these questions and I found I would jot down notes for this talk at all times—

early in the morning, during a car ride, at a concert intermission. It was during this time that I came to realize that the advances continually being made in genetics would before long have the most profound social consequences. I could not foresee the specific pattern of scientific advance that would lead to the potential for genetic intervention. But nature clearly had developed means for genetic modification and recombination and we would surely, in time, and sooner rather than later, unravel these mechanisms and have this capability at our disposal.

We were at an epochal moment, not only for our society or for Homo sapiens but for all of life on earth. For the first time in the long course of evolution, for the first time in all time, a species was coming to understand its origins and its inheritance, and with that knowledge would come the ability to alter its inheritance, to determine its own genetic destiny, as well as that of other living species. Through DNA, biology was moving beyond analysis to synthesis.

This was a transformation without precedent. The issues that would be raised far exceeded the boundaries of our historical morality born of human experience. A few novelists, Aldous Huxley for one, had jousted with the issues, but now fiction could become reality. What principles should guide us? How should decisions be made, how could agreement be reached in a fractured world society? In this light, the links between our social structure and the givens—to date—of human existence became evident. Our size, our life span, our numerical equality of male and female, our genetic diversity and accompanying normal range of talents and traits, all are imbedded in our social order. And all now are potentially mutable.

The potential for intervention in human inheritance raises fundamental questions of the meaning of "equality of opportunity," of responsibility (liability?) when genetic chance is replaced by design, and of human dignity when an individual realizes that his or her traits have been programmed.

The prospects both exhilarated and sobered. I was exhilarated by this triumph of human intellect yet sobered by the need to use wisely the powers thus unleashed. I have been less innocent ever since.

My lecture was entitled "The End of the Beginning" to connote my perception of this turning point in evolution.

Because this message was ultimately minatory, I was apprehensive that it might not be well received by a Caltech audience, but the audience seemed taken by the revelation of the extraordinary significance, new to them, of the recent advances in genetics, and the talk was very

well received. Indeed, Thomas Watson, Jr., then president of IBM and a Caltech trustee, invited me to Bermuda to present the same talk to his IBM administrative retreat. In the succeeding years, I was invited to present numerous talks expanding on this general theme Some of the titles were a bit pretentious—"Darkly Wise and Rudely Great" (from Alexander Pope); "All Men Are Created Equal?"; "The Brain of Pooh: An Essay on the Limits of Mind"; "An Inquiry into Inquiry"; "Humanism and Science"; "The Galilean Imperative"; "Prospects for Future Scientific Developments Ambush or Opportunity."

One of my lectures, "Science and the Quest for Human Values," was at the Pittsburgh Theological Seminary in connection with the 175th anniversary of their founding. While there, I visited their library and was astonished to find a collection of some eight hundred regularly published journals from all over the world. There were only two I had ever seen. Here was a whole universe of scholarship of which I was completely unaware. At Pittsburgh, I began:

In time it will probably be seen as inevitable that science, which set out simply to explore the universe objectively—without the constraints of, indeed orthogonal to, the concerns of value—should have come to test in the harshest way the fabric of our values Today it takes little vision to see that science is ready to pose to man wholly unprecedented questions of the most fundamental character which will of necessity require a reformulation and a deeper understanding of our basic moral principles.

For us in science, it is frankly still surprising to have come from a new direction upon the oldest of questions. Perhaps, as we reflect, this consequence will tell us something about the geometry of fate and the matrix of the human mind.

We are already confronted with grave dilemmas arising from the only partial triumphs of science, which splinter our older values and often expose their expedience and inconsistency. The Malthusian tide of population mocks our belief in the value of individual man, the flood of factual knowledge overwhelms our faith in the immanent value of truth and thrusts us in the feckless role of the sorcerer's apprentice, the disintegration of death undermines our ancient views of the beneficent role of the healer and the worth of human life. Graver questions yet lie ahead as the biological sciences prepare to change the boundary conditions of man.

These talks brought me into contact with a wide variety of people and I began to appreciate how extremely varied were the reactions to my message, how each sought to incorporate it into his or her frame of reference, with resulting fear, awe, distaste, greed, eagerness, resignation, antipathy, consternation, or dismissal Among scientists, the reaction was most often one of exclusion. "Our mission is to acquire

knowledge. How it is used is not my concern." Or one of temporizing: "These issues may arise at some time in the future but they need not concern us now." Or of apprehension that raising such questions now might jeopardize current research funding. These responses reflect in part the narrow specialization of much scientific education and in part the intense dedication required of an active life in science.

Continued reflection raised broader questions in my mind as to the largely self-directed patterns of scientific exploration, mostly government funded. Scientists, understandably, want to pursue their own research inclinations. And surely at the research project level, who should know better what paths are the most promising? Out of this perception has arisen the "peer review" process in which proposals for research funding are evaluated by panels of scientists expert in each field, ranked in order of promise, and funded as far as available resources permit.

But does the process assure on a more macroscopic level that funds are directed toward research on problems most pressing or crucial to society in general? It seemed to me that this result was not obvious—that, for instance, in a world confronting large and unmanageable increases in population, it might be desirable to place more resources into means of fertility control and less into studies of the aging process. Or more funds might be spent on studies of drug addiction, and less on novel devices for military use. Such issues of science policy should not and could not be resolved solely by scientists, but a forum was needed within science for their discussion. None was, or is, available. I presented many of these thoughts in an article entitled "The Presumptions of Science," published in Daedalus . It did not win me many friends in the scientific community.

As a result of these contacts and cogitations, when the recombinant DNA issue arose in the mid-1970s, I came to it from an atypical perspective.

The development of the recombinant DNA technology provided us with the ability to move genes about from one organism to another almost at will. The universality of the genetic code implied that a gene, a tract of DNA, could engender synthesis of the same protein wherever it was placed, provided of course that it was activated in the host cell. This concept provided the potential to use microorganisms as biochemical factories to produce scarce proteins of pharmaceutical value in medicine, such as human insulin, blood-clotting factors, growth hormones, interferons, and so on.

For molecular biologists, this development provided the means to

generate for study large quantities of any gene of interest, known or unknown. And, of course, it provided the means, by introduction of specific genes, for intervention in the developmental and biochemical processes of plants and animals to alter these for human purposes. In short, genetic engineering was here.

Was it possible, however, that these experiments might, by design or inadvertence, produce an organism of undesirable properties, one that could be a danger to man or to the ecosystem? In the long course of evolution, genetic exchange among unrelated species is a great rarity. The evolutionary pattern is a branching tree, not an interlaced network. We would be creating novel genetic combinations never before seen on earth.

Much of this work would be performed, initially at least, on the bacterium E. coli simply because its genetics was so well understood after thirty years of intensive exploration. But our laboratory E. coli strains had originally been derived from strains found living in human intestines. While undoubtedly attenuated, after decades of laboratory existence, might they still retain the ability to colonize the human gut, now bringing with them all manner of exotic gene combinations? A popular form of experiment at the time was the "shotgun" experiment in which quite random fragments of DNA from higher organisms were inserted into E. coli . The genes borne by such fragments were completely unknown. Might some, by accident, be toxic? And, of course, the potential for deliberate insertion of toxic genes, for the purposes of biological warfare or terrorism, was evident.

I was further perturbed by another class of experiments then underway. At this time, tumor viruses from various animal species—birds, cats, baboons—were being mutated, recombined, and so on. At that time, no virus causing tumors in humans had been discovered and it seemed evident that viruses were not a major cause of cancer in man. But viruses were a major cause of cancer in other species and we might "inadvertently" in our experiments generate a human tumor-inducing virus. I was also concerned by the fact that the new forms—viruses, cells, organisms—were living, self-reproducing creatures that, should they be inimical and should they escape from the laboratory to find a suitable ecological niche, could multiply indefinitely. They could not be recalled, nor would it suffice to halt their manufacture. The generation of new living organisms was qualitatively different than the generation of new inanimate objects or chemicals.

Some of these concerns had been raised within the biological com-

munity. A "moratorium" had been suggested for recombinant DNA experiments and a conference to discuss these issues and potential hazards was convened at Asilomar in February 1975. I attended this extraordinary, unprecedented, and unrepeated event. About 120 of the leading molecular biologists attended. The sessions were divided between those in which the most recent scientific developments obtained with the new techniques were discussed with great enthusiasm (what moratorium?), and those in which the conceivable hazards were described and means considered to mitigate them.

Molecular biologists, including myself, trained mostly in biochemistry and biophysics rather than pathology, had largely treated viruses and bacteria as we would any other chemical, taking enough precautions of sterility to accomplish our own experiments but otherwise exposing products to the air, pouring used cultures into the sewers, and so on. Without much data, a wide range of opinions was expressed with regard to the conceivable hazard of various genetic introductions. A discussion by a panel of lawyers informed the audience as to the liabilities to which they might conceivably be subject.

Means for the containment of recombinant organisms within the laboratory were discussed. Physical containment in sterile rooms with air locks was feasible but costly and troublesome. The concept of biological containment, the use of strains of E. coli deliberately weakened so as to reduce their likelihood of survival outside of carefully controlled laboratory conditions, gained favor. Such strains were not available but could plausibly be made within a few months. (This was an erroneous assumption—it proved to be much more difficult to create and work with such strains.)

Clearly, there was far less interest in the discussion of hazards than of new science. Any means to cope with such potential hazards would inevitably hinder research. Opinions ranged from fear of possible epidemic to cavalier statements that if a pathogen should result and a few persons die, it would only cost a few million dollars. In the end, a compromise was reached in which various conceivable experiments would be graded as to their potential hazard. Combinations of physical and biological containment would be proposed, commensurate to the perceived hazard of each experiment. The restrictions would range from minimal on the most innocuous experiments to bans on the most dangerous. The details would be worked out by an NIH committee.

It was all plausible; however, since no one knew the absolute level of hazard, no one was sure just where to "float" this entire matrix of

regulation. To nobody's surprise, it was in fact adjusted so that the experiments that most scientists wanted to do at once could be done with minimal precautions, thus buying time to provide more elaborate and safer facilities for experiments to be done in the future. Science could go forward in good conscience.

In the year or two after Asilomar, I became increasingly uneasy with the safety of the regulatory mechanisms developed. They seemed to me to be token. If the problem was to be taken seriously, quite other approaches would be desirable. Instead of using an organism such as E. coli derived initially from human waste and capable of exchanging genes with other organisms known to reside in the human intestine, a host organism such as a thermophilic bacterium—which could only survive at very high and uncommon temperatures—might be used. Sophisticated, high-containment facilities might be established at ten or twelve centers around the country at which the more hazardous experiments could be performed.

Others shared this view, but few were willing to speak out against the biological establishment. Because my position was secure, I felt an obligation to do so. On almost every occasion that I did, others, often junior faculty, would let me know that they agreed with my position but dared not to speak out. They feared reprisals from more senior and powerful colleagues who controlled funds and advancements.

The controversy over DNA regulations became more intense and, as often regrettably happens, was joined in by less than rational and illinformed nonscientists bent on ideological or political purposes—the Jeremy Rifkins and the religious zealots. This was my first experience with unwanted fellow travelers. It is not always pleasant to be associated, in common cause, with others whose motives one considers suspect or absurd.

Over time, two developments quite changed our perception of the problem. The E. coli strains in laboratory use proved to be considerably more attenuated, less able to compete with indigenous strains outside the laboratory, than might have been supposed. And even more important, the processing of genetic information, of messenger RNA, in higher organisms unexpectedly proved to be much more complex than in bacteria. As a result of the discovery of introns and splicing mechanisms, it became clear that most genes, simply extracted from a higher organism and placed without modification in a bacterium, could not give rise to a functional protein. While complicating genetic engineer-

ing, this discovery greatly reduced concerns about hazards from "shotgun" experiments.

I continue to believe that, with the knowledge available at the time, my concerns over the potential medical and ecological hazards associated with the introduction of the recombinant DNA technologies were fully justified. We lucked out again. But my opposition to the biological establishment in this matter was personally costly. As one of the few opponents who could not be readily dismissed, I became a target for enmity. I think it no accident that since that period I have not been asked to serve on any NAS or NIH committee, although I had previously done so regularly and despite the fact that I have specifically responded to calls by the president of the national academy for its members to become more personally involved. Such is the price of offense to vested interests.

Persistent dissent is treated harshly within the scientific community. Committed to a single truth, scientists tend to dismiss and exclude those who willfully do not "see the light." Empirically based, science is a self-correcting enterprise. There have been few instances in which long-held, seemingly established concepts have been disproved. Thus, the persistent skeptic is viewed as at least eccentric, if not fanatic, and harboring hidden motives.

Throughout this period of engagement with questions of values and issues of controversy, I became increasingly concerned with the perceived failures of our educational system. The bulk of our citizenry is technologically illiterate. We are creating an increasingly technological society in a democracy with a public largely unprepared even to understand the new and complex issues emerging from our enlarged powers. And conversely, the small group of technologically informed citizenry are largely unconcerned with the social implications of their activities. Their education has not prepared them to cope with the vexing questions of social and cultural values. Indeed, many have no doubt deliberate pursued a career in science with its clarity and objectivity so as to escape the complex, ambiguous, sometimes unresolvable questions of public policy.

Scientists are not innately more rigorous or logical, but they face daily the task of comprehending an objective reality. Bias and cant, aesthetic preference and moral conviction are but snares. The natural world is as it is, not as we might wish it or would construct it. Constrained thus to objectivity as a way of life, scientists can only view with

wonder and alarm, even scorn, the self-serving passions that so often pass for argument in most social and political arenas—the hyperbole that contorts logic, the myopia that accompanies self-righteous claims of superiority The limits of evidence are far transcended; the possibility of error seems never admitted.

Scientists, on the whole, wish simply to pursue their investigations of nature—to explore, to discover, to satisfy their curiosity. Nature can be obscure, but nature does not deceive. Yet their investigations are increasingly costly. Because funding is public, the scientifically ignorant public must continually be persuaded that it should, in its best interest, support scientific programs. Thus, the entire enterprise rests on a public confidence that in turn rests more on faith than knowledge. At the policy level, then, the scientific establishment is deeply insecure. It is little wonder that its leadership feels obliged to present a united front and to resist suggestion that any aspects of the scientific endeavor might not be in this society's ultimate best interest.

This state of affairs bears the seeds of future disaster. An ignorant public and a detached yet wary scientific elite could easily be separated by determined political or ideological forces. We have now seen this happen in such diverse areas as nuclear power and animal rights.

By the mid-1970s, it seemed to me that it might be just as important for the future of science for me to devote my efforts to educational reform as to further advance scientific knowledge—to the design of educational patterns producing a more technically literate citizenry and, particularly, a more socially aware scientific cadre.

But where to do this? Caltech, trapped in its own scientific success, dedicated to the most advanced scientific research, was not a promising site for curricular innovation. Nor could the institute be substantially broadened. In the early 1970s, the American Academy of Arts and Sciences was looking for a new academic site in which to establish a center for advanced study in the humanities. I had suggested Caltech. The academy leadership was truly intrigued by this suggestion for possible liaison between a humanities think tank and a small preeminent scientific institution. Conceivably, "two cultures" could produce a dramatically successful synergism.

But the proposal, while not rejected by the Caltech administration, was not pursued with enthusiasm, and the center went to North Carolina instead. A pity!