A Citizen's Guide to the Biotech Revolution

Stanford Geneticist Contemplates Light Side of Genome Research
Unraveling secrets of human inheritance has fun applications 
The imminent completion of the Human Genome Project is heralded as one of the greatest achievements in all of science, but Stanford geneticist David Cox likes to consider the lighter side of this momentous development.

“Researchers always put forward the medical applications as the prime use for human genome information, but what about the fun aspects of genetics?” he wonders aloud.

As co-director of Stanford’s Human Genome Center, part of the federally funded effort to unravel the secrets of human inheritance, Cox has given serious thought to how we are likely to use the genetic knowledge we are rapidly acquiring.

His guiding precept is the observation that inventors often misjudge the usefulness of their inventions. Thomas Edison envisioned his phonograph as a dictation machine. Alexander Graham Bell stumbled onto the telephone while trying to solve the bandwidth problem of the 19th century: how to cram more messages through telegraph wires.

Don’t get me wrong. Cox knows genetic data will expedite drug discovery, disease diagnosis and have other medical uses. He simply thinks we underestimate the potential for a range of whimsical applications.

“I think genetics will be the modern day astrology,” he says.

Cox isn’t sure how personal genetic profiles will be used for predictive purposes. Perhaps newspapers in the future will add a new type of genetic horoscope that will help new couples assess whether their genes dispose them to fight or flourish.

Cox doesn’t think genetic predictions will pigeonhole people for life — leading to the sort of genetic determinism portrayed in the movie “Gattaca.”

“Overall, I think people are smart about how they use information,” Cox said. “Genetics will be just one more type of knowledge they’ll use to navigate through their world.”

Speculations of this sort are a form of mental relaxation for Cox who, when he isn’t cranking out science at Stanford, is wrestling with dilemmas as a member of the National Bioethics Advisory Commission.

This 18-person panel, established by President Clinton in 1995, advises federal agencies on issues like cloning or stem cell research that arise in the course of biomedical experiments.

Cox — and his NBAC colleagues — were in San Francisco last week, grappling with the question of how to make sure that experiments on humans are conducted in an ethical fashion.

Virtually every life-saving advance in medicine today began as an experimental treatment tried first on animals and later on human subjects.

The ethics of human experimentation came into sharp focus last year after it was revealed that researchers at some universities delayed reporting the deaths of several subjects in gene therapy experiments. It turned out some of the professors had ties to biotechnology firms, causing concern that their actions were influenced by financial pressures.

Dr. Bernie Lo, director of medical ethics at the University of California at San Francisco and also an NBAC member, says the commission’s concerns go far deeper than the obvious problems of financial conflicts of interest.

“Our charter is to ask the philosophical questions about how and whether you can properly do research on human beings,” Lo said.

NBAC spent much of its time last week on the issue of informed consent. In short, the subject of an experiment should know precisely the risks and benefits of becoming a human guinea pig, and make a decision freely.

But that is easier said than done. Lo says cancer patients dramatize the difficulty of achieving informed consent. Say the patient has gone through all current treatments to no avail. Their oncologist mentions an experimental therapy. It’s only in Phase I trials, the earliest stage of human testing. Phase I studies have one objective: to determine how much of a drug the human body can safely tolerate.

“But the patients and even the doctors who refer them to the trials think this will help, when there’s very, very little chance that it will,” Lo said.

Is it ethical to let patients grasp at straws? Lo shrugs. Many patients consider the odds and decide that even if they don’t benefit, the experiment may save lives down the line. But in a world where researchers have stock options, or even tenure, riding on the outcome of human experiments, a little ethical hand-wringing seems wise.

The problems of informed consent become even greater when U.S. researchers take experiments into developing nations. This may occur because it may be cheaper to do research abroad, or because the underlying disease may be prevalent there.

Cox says a dilemma in international research is applying U.S. norms to foreign settings. Here, if the subject of an experiment is a woman, the researcher would naturally seek her informed consent.

But what if the research is being done in a country where the cultural norm is that some man — a father or husband — speaks for the woman?

“Do you talk to a woman when, by doing so, you put her in danger of some man beating the crap out of her?” Cox asks.

Ultimately, NBAC answers such questions in long reports that it sends to federal agencies and posts on a Web site (www.bioethics.gov). Whether these ruminations have any effect on the express train that is biomedical research is debatable.

“We’re not the ethics police,” Cox says.

No, but maybe they’re referees watching from the sidelines.

GENOME SPECIAL ON TV: The ethical questions arising from human genome research will be the subject of a PBS special that will air on KQED Sunday at 2:30 p.m.

Hosted by former NBC newsman Bob Abernethy, the show will discuss the patenting of human genes, the prospect that parents might genetically alter their children, and the questions of genetic privacy.

by ARTHUR B. CODY

New York, June 2000

 

  GENETICS IS the new science. Every day, something fascinating appears in the newspapers or on television, in magazines or books, in connection with the genetic engineering of crops and animals, the Human Genome Project and all that it portends for our future, or the imminent conquest of human disease through gene therapy. The last-named of these has become especially salient lately with the report from France of success in treating an immune disorder by adding working genes to cells. But whatever the specific subject may be, the cornerstone of almost every story about the science of genetics is the central significance of the DNA molecule-the genome-that contains the complete set of instructions for making an organism.

  The concept is, indeed, astounding. No matter how many times you encounter the notion that from a small set of chromosomes-tiny objects that can be seen only under extreme magnification-a fly or a whale is constructed, it remains staggeringly hard to take in. But you would not know this from reading the journalists and researchers who interpret the new science for us. To them, there is little that is incomprehensible about the process. We may be ignorant of details, to be sure, but our ignorance, we are assured, is rapidly evaporating. The theory is sound and proved, the research proceeds apace, the authorities have spoken. And what they have told us is that, though the information contained in the genome is immense, we know how it works, and we stand on the verge of controlling it.

  Item: In early April, the papers carry a story about the Monsanto Corporation’s having arrived at “a working draft” of the genetic code of the rice plant. Obviously, if rice, which is eaten regularly by most people in the world, can be redesigned in ways to make it hardier, healthier, or tastier, it will do a lot of people good (in addition to making Monsanto a lot of money). What does a “working draft” involve? “By analogy,” a researcher is quoted as saying, “think of an encyclopedia of how to construct a rice plant made up of 100 volumes, each with 1,000 pages and with 1,000 words to a page.” Monsanto printed out all these pages, albeit with some errors and gaps. The volumes contain the information, the information is vast, and this information constructs the rice plant. Q.E.D.

  Item: The lead story in the October 1999 National Geographic is entitled “Secrets of the Gene.” It mainly concerns the potential (for both good and evil) that we will have to deal with when the results of the Human Genome Project come in. In it, the director of the Sanger Center, a major research laboratory, asserts: “All the information required to make a human being is written into our DNA.” And he goes on: “We can even put an upper limit on the size of it-about one gigabyte [a billion characters] of data. Your entire genome will easily fit on the hard disk of your desktop.” Again: the informational capacity of the genome is huge; being “written,” the information is readable; and it is all that is required to construct an organism.

  Item: In The Origins of Life, a book published last year, the evolutionary biologists John Maynard Smith and Eors Szathmary declare that, when it comes to making an elephant, “what we can say . . . is approximately how many base pairs”-the chemical bases in the DNA that carry the gene code-”are actually used.” True, there are lots of unused stretches of DNA; true, too, the base pairs do not always combine with maximum mathematical efficiency. But the genome of elephants, like that of all mammals, is about one gigabyte of data in size, and it does the job.

  Item: In Genome,* the most recent of his three books on evolution and human nature, the science writer Matt Ridley proclaims ours to be a lucky generation, for we will be the first “to read the book that is our genome.” Just how abundant is that genome? As long, Ridley writes, as 800 bible-”a gigantic document, an immense book, a recipe of extravagant length.” (This is another way of saying: one gigabyte.) Reading the book of our genome, moreover, “will tell us more about our origins, our evolution, our nature, and our minds than all the efforts of science to date.”

  Why so much stress on the size of the genome? Clearly, building an organism requires a tremendous amount of information, and that information must come from somewhere. As Ridley puts it: “Something, somewhere must be imposing a pattern of increasing detail upon the egg as it grows and develops. There must be a plan. But unless we are to invoke divine intervention, that imposer of detail must be within the egg itself.”

  Ridley’s “must” expresses the assumption that all of science quite properly rests on-that explanations can appeal only to natural objects and processes. In the present context, what this means is that the capacity of the genome to construct an organism must lie both in the sheer magnitude of the information it contains and in its power to transform that information from “inputs” to “outputs.” How this transformation comes about is precisely what we are told we now know for a virtual certainty. But do we? To address that question properly will require a brief immersion in scientific description.

  II THE PHYSICAL Capacity of the genome-that gigabyte of data-is calculated this way In the case of mammals, there are about three billion base pairs of nucleotides, each one of which forms a rung on the twisted ladder that makes up the DNA molecule. In sets of three, those base pairs participate in a code; in the code, each set, appropriately called a codon and representing one character of data, designates a specific element of the protein eventually to be constructed by the gene. Divide three billion, the physical length of the genome, by three, the biological character called a codon, and you get one gigabyte.

  As for the discrete series of codons that are the genes themselves, there are, in the mammalian genome, only about 100,000 of them, and therefore about 100,000 different kinds of proteins that are used by the body in some capacity or other. In molecular biology there is something called the central dogma: one gene, one protein. This dogma declares what it is genes do, and all they do. Genes, it tells us, do not code for body parts, for processes, for habits, or for instincts. All such organic and temperamental components must somehow be erected out of proteins, or whatever proteins themselves build, and the construction program for those components must be provided for in Ridley’s “egg”-i.e., the genome.

  And how does that construction program work– that is, how do we get from inputs to outputs? The genome seems to function as a vehicle of computation, systematically causing a staggering array of factors to coalesce and thereby leading in an orderly fashion to different structural configurations in an organism’s complex arrangement of proteins. To perform this marvelous function, there are, over and above the somatic genes, regulatory genes that somehow control the formation of organs and appendages. The most notable of these genes are the homeotic ones, and their discovery in 1983 is described by Ridley as “probably the greatest intellectual prize that modern genetics has won since the code itself was cracked.”

  The important thing about regulatory genes is that their protein products do not themselves form parts of the body or join in its metabolic processes. Instead, they switch on other genes, and sometimes they switch them off. Here, for example, is how the early stages of development of a fruit fly might be described in an introductory textbook, with the regulatory genes identified in italics:

  The body formation starts with a gene (actually its protein), a morphogen called bicoid, that establishes the front-rear polarity of the egg; then segmentation genes regulate the origin of segmentation; then gap genes map out the basic subdivision; then pair-rule genes set up modular pair segmentation; then, at last, the homeotic genes come along to specify the type of appendage that belongs at some body segment location.

  As this paraphrase suggests, there is a hierarchy of increasing refinement that culminates in the homeotic genes. There are, in fact, hundreds of these homeotic genes, and they assist in the manufacture of a bewildering range of body and organ structures. One homeotic gene will switch on several other genes, and if they, too, happen to include a homeotic gene, that gene will in turn switch on other genes, and so forth, thus producing a “cascade” effect. In combination, as though by a polynomial formula, the mutual effects of these overlappings are modulated or expanded in an orderly fashion-a fashion that may properly be called computational.

  Ridley observes that once a cell knows where it is in the organism-a feat possibly attributable to the action of earlier regulatory genes-it “looks this up in its guidebook and finds the instruction: `grow a wing,’ or `start to become a kidney cell’ or something like this.” Of course, he does not mean it literally As he proceeds to explain, “There are no computers and no guidebooks, just a series of automatic steps in which gene switches on gene which switches on gene.” Nevertheless, he asserts, there is a virtue to the guidebook analogy:

  [T]he great beauty of embryo development, the bit that human beings find hard to grasp, is that it is a totally decentralized process. Since every cell in the body carries a complete copy of the genome, no cell need wait for instructions from authority; every cell can act on its own information and the signals it receives from its neighbors.

  There is, in short, a sort of solipsism through which each cell conducts itself. Although it is not ignorant of its neighborhood, or indifferent to signals from its neighbors, it receives no instruction from anywhere outside itself. (This is not to exclude influences of the environment, but such influences are influential only according to the rules published in the genome.) Self assembly-the title of Ridley’s chapter on the homeotic gene-is carried out according to each cell’s genomic instructions, instructions that are somehow generally available for each cell to read and decipher.

  The wonder, then, is that the genome operates everywhere and always in the same way “Flies and people are just variations on a theme of how to build a body that was laid down in some worm-like creature in the Cambrian period,” writes Ridley. The genome is the creative machine working always in the identical style, no matter what the organism: yeast, lily, fly, elephant, or human.

  III NOW LET us retrace our steps, and ask again whether the genome does, in fact, possess both sufficient information.and sufficient power to make an organism.

  First, there is a minor correction to be made in the one-gigabyte claim. More than 90 percent of the DNA does not code for proteins, and within each DNA gene there is again another percentage that is unused. Thus, rather than a gigabyte, it may be more correct to say that there are fewer than 300 megabytes of useful data in the genome, an amount that even a vintage hard drive can manage.

  Then there is a curious messiness surrounding the numbers. The number of chromosomes differs among species, and for no apparent reason. Chimpanzees have 24, one more than we do. Sheep have 26 plus the X and Y; the Muntjac, a small deer, has just two, plus an X and two Y’s. Crabs have over 250. Perhaps there is no importance to this fact, but it does shake one’s confidence that everything always, and everywhere, operates in a strict order.

  Another confidence-shaking fact is this: the number of nucleotides in the genome also varies wildly, and again for no perceptible reason. If the human genome has three billion base pairs, the tiger lily has 100 billion, over 30 times as many; the lowly salamander has fewer than the lily, but fifteen times more than the human. How many genes do their genomes divide into, how much junk? The answer is not known exactly, though it is known that the little zebra fish that swims in the Ganges has 100,000 genes, just as we do, and that those genes happen to be very similar to ours.

  Does any of this matter? Perhaps not. What matters, clearly, is that the base pairs, the materials of the genome, function in a way that will build an organism from scratch and without any instructional aid from outside. But consider the stupendous labor to be discharged in this task. Creating enzymes, cells, skeleton, and organs, together with the systems for their regulation; monitoring, metering, repairing, timing, orientating, sensing, and coordinating in movements designed for hunting, fleeing, breeding, seeking shelter, and so on-such a task is quite beyond our ability adequately to describe.

  Nest-building, for example-think what it involves, and remember that, as an instinctual behavior, all of it must be provided for in the genome. A timing event occurs, one coordinated with the season; courtship and mating behavior ensue; a nest must be built. A bird is not equipped with cognitive knowledge of the world: “twig,” “branch,” “cat,” “hawk,” “seed,” “berry” are not given to its understanding as concepts but programmed into modules of the brain. Assuming a certain species of bird, one that eats seeds and berries, builds nests of twigs in branches and flees from cats and hawks, we can see that, without knowing what these things are, the bird is nevertheless able to get nourishment, reproduce, and escape from predators.

  In nest-building, as in its other activities, the bird’s brain modules must be tuned to sensory inputs, so that their vocabulary is one of light and dark, angles and colors, shimmerings, textures, scents, and accrued recollections of these elements. The bird must coordinate its flight movements of wing and tail to land near a twig, then coordinate movements of eye, leg, and beak so as to ascertain that the thing does not wiggle (that would be not a twig but a snake) and then to pick it up. It must have override mechanisms in the program so that if the twig is near a cat, no landing will take place; or so that, if the bird needs nourishment, it will eat first before collecting the twig. Once a twig is picked up, it must be flown back to the nest location, a matter of utilizing acquired memory clues of light and dark and a sense of distance, again completely without cognitive understanding. The first twig must be placed in a suitable branch for security from ground scavengers and for the engineering requirements of further construction. And so forth, and so on, and so forth, and so on again.

  Think of the social behavior of ants, the web– building of spiders, the culture of elephants. Think of the growth of deciduous trees, the elaborateness of a flower’s design, the intricacies of the basal bodies in the cortex of a protozoan. No need to go on: each of us knows enough about life to generate plenty of examples on our own. Even before we ask how it all works, we must confront the ineluctable fact that the labor involved is immense, while the number of genes constructing this immensity and the bytes of information they deploy are quite limited.

  There are some 100 trillion cells in the human body. Inside each cell there are many vital and complex materials; the cells in turn collect in mutually dependent ways into the many organs of the body; each organ has many design components and cell types; and there are different cell stages associated with embryological development and with the mature organism. There are so many possible combinations of cellular assignments that the number quickly becomes astronomical; in fact it becomes superastronomical, to an unmanageable degree.

  It is very difficult, and always artificial,. to attempt to quantify biological processes. It is very difficult because one does not know what to count as units-individual molecules, cells, sets of cells (materials), or some sort of minimum functional constituent such as bone, liver, immune system. It is artificial because we are trying to quantify a living system, and we do not know the essential or permissible parameters of such systems even if we know-which we do not-how many individual elements belong to them. But for illustrative purposes we can take a whack at it.

  We are helped in this regard by the late Walter Elsasser, who after a distinguished career in nuclear physics produced four books in the field of biology. In one of them, Reflections on a Theory of Organisms (1986, new edition 1998), he looks at the numbers. To the question, how many different cells can theoretically be compounded out of the four organic elements already fixed-carbon, oxygen, hydrogen, and nitrogen-his answer is, “the number is always extravagantly large.” What he means by that is a number larger-in the mammalian case, much larger-than ten to the 100th power: a figure already so large as to be virtually infinite. For comparison’s sake, the number of protons in the universe is estimated to be ten to the 70th power.

  What does this tell us? It tells us that until we know the range of permissible cell constitutions, and the method by which that permissible range is disciplined, the alternatives the genome must control will lie on a scale whose extent is impossible to stipulate.

  IV HOW, AGAIN, does it control them? To capture the constructive power of the genome, three metaphors have been commonly invoked.

  In the first, the genome is described as defining or actually making an organism’s “building blocks.” In a quite straightforward sense, this is correct. The genome delineates and, with the associated apparatus in the cell, makes all the proteins used in an organism. Some proteins have duties of their own-hemoglobin carries oxygen in the blood; enzymes promote chemical reactions in the cell; Titin, a 30,000-amino-acid-long protein, ties muscle fibers together-while some merge with others and with molecules of different kinds from fats to metals to become the substance of the organism’s structures: fibers, leaves, fruit, skin, bone, brain.

  In the sense that building blocks are what buildings are made of, the genome makes building blocks. But the trouble with the building-block metaphor is that it suggests nothing about the dynamics of construction, or of use. It is not a bad metaphor as far as it goes, but it does not go very far.

  The second metaphor is that of a blueprint. This figures regularly in many popularized renditions of contemporary genetics (as in Newsweek’s April 10 cover story about the Human Genome Project). The image of a blueprint seems fitting because blueprints prefigure the object pictured and in so doing specify the relationships of its elements. More importantly, the design is read as a set of instructions: make it come to pass that the object looks like this. Ridley, however, forswears the use of this metaphor because blueprints are two-dimensional maps, not one-dimensional codes, and because “each part of a blueprint makes an equivalent part of the machine or building; each sentence of a recipe book does not make a different mouthful of cake.” These are trenchant criticisms.

  And there is a more fundamental difficulty with the blueprint metaphor. In the genome, there is no reader, no agent to be instructed and to follow directions. It is the machinist who knows his mill and drilling machines, who knows his materials and how they can be cut and shaped; it is the carpenter or electrician who knows wood and wire and how to cut them to the proper lengths and fasten them correctly together. A blueprint presupposes this kind of intelligence, but that is exactly the kind of intelligence that, in the genome, we need to explain.

  Ridley, and he is hardly alone in this, prefers a third metaphor: that of an instruction book or guidebook of some kind, a book carrying the instructions that direct each cell in the self arrangement routine appropriate for its particular place in the organism, and that then call for the cells to fit themselves together so as to form first parts of the organism and then the whole.

  ”The genome is a very clever book,” Ridley writes, “because in the right conditions it can both photocopy itself and read itself. The photocopying is known as replication, and the reading as translation.” These are the only two functions ascribed to the book, but he thinks they are enough. By means of replication (from one DNA molecule to another), every cell can have its own book to read. By means of translation, proteins are made.

  But does this take us where we need to go? Making proteins is important, but we still do not have a metaphor that captures the genome’s presumed power to design and construct an entire organism. That power, if it is to be found anywhere, must reside in the computation-al role I described earlier, and that is played by the proteins that are expressed by the homeotic genes.

  IT IS a remarkable thing that the genome is never described as a computer, especially since the computer is a standard metaphor for the brain. Indeed, one kind of computer design-the “neural network”bears a name that reflects the apparent affinity between brains and machines, being a parallel-processing design rather than the serial processing of the standard computer.

  One trillion of the body’s 100 trillion cells are involved in the human brain, and 10 percent of that number, 100 billion, are neurons of various types. Those neurons in most cases put out thousands of connections (called dendrites) that hook up to one another in the millions, forming vast interconnected networks that are very precisely wired to one another. The brain’s system uses chemical and electrical signals that are weighed, balanced, and processed in very elaborate and complex, massively parallel ways. And yet, still and all, the brain is an inferior in the chain of command, for the genome is credited with making the entire organism, including, as one of its parts, the brain.

  So, does the genome itself resemble a computer? Not in the least. It is not just that computers do not make anything. After all, sometimes they do: a powerful computer hooked up to an assembly line might very well make an automobile, a washing machine, or (when the day comes) a household robot; and it might replicate itself to boot. At some ultimate echelon of mechanical achievement, where intelligence itself is fully computerized, we might even have a system that begins to approximate the economy within an organism’s genome. No, the real reason the genome does not resemble a computer is that, so far as we understand it, anything having to do with cognition, or simulating cognition, is foreign to the genome and what it does.

  Consider a few facts about the marvelous homeotic gene. In an embryo, a very small portion of the protein produced by this gene (according to the usual formula, only 60 amino acids in length) insinuates itself into one of the chromosomes in a small set of cells at some definite regional location at an appropriate time and stage of development; there it switches on a small group of genes, usually between eight and thirteen. But in so doing it is (metaphorically) quite mindless-a very minor trigger, like a stick one might use to prod a herd of cows toward the barn.

  What triggers the triggerer? Nobody knows. More than that, nobody has any theoretical proposal to suggest. It is the farmer who picks up the stick, and it is the cows that know their way to the milking barn. Nothing in the homeotic story simulates the farmer’s or the cows’ intelligence. “Triggering” is an interesting biological event; it goes nowhere toward explaining construction. What kicks the homeotic gene into action? No answer exists, factual or theoretical.

  And why does a leg or a forebrain form under the prodding of the homeotic gene? This is a somewhat different question from the question that I have just said has no answer. It is like the question, why do the cows come home? The homeotic gene triggers other genes, and genes make proteins. How do the proteins that are expressed by those subordinate genes find their way into a highly structured organization like a leg or an eye? Once again the answer is, no one knows. Not only does no one know, no one has the slightest idea how to look for an answer.

  The flamboyant images Ridley uses, based on cognitive metaphors like reading, understanding, knowledge, intention, and so forth, are utterly irreducible to biological mechanics, and there is also no analogy in mechanical or computer technology to help us. The homeotic recital is somewhat like a tale of components for a Boeing 747 coming together to form a landing gear or tail assembly when the shipping crates in which their parts have arrived at the plant are opened by a crowbar. In a way, the crowbar is essential to the landing gear, and, in a way, the crowbar also controls the downstream pathway of the nuts, bolts, struts, wheels, tires, and so forth: for unless the crates are opened, the parts cannot be assembled. But in the genome, the parts themselves know where they belong. Moreover, they go where they belong by themselves, without any help from the crowbar, or anyone wielding it.

  V AT LAST we are able to observe something very clearly: it is not ignorance that befuddles us, but what we know. We know, to repeat, that the mammalian genome contains only about 100,000 genes. And we know-we can see all around us– that what the genome must do is immense. From this knowledge we have constructed explanations that do not explain.

  By way of working toward a conclusion, let me introduce a final consideration that is again based on the work of Walter Elsasser. Within a wide range of variation, there seems to be no definable concept of anatomical or metabolic normalcy. The size of a stomach varies greatly from one individual to another, irrespective of the size of the person; similarly, the location of the stomach can be anywhere from about one to about nine inches below the sternum. Biochemical variations among persons are, as Elsasser points out, even greater. In the “normal” range of blood chemistry, the ratios of upper to lower limits can be two, six, or even nine; and there are always some people whose chemistry falls well outside the normal without any deleterious effect, and much farther outside without fatal consequences. Bone density, which most people tend to think is fairly uniform, has been shown to vary by almost sixfold among young males. Since the body’s chemistry and its organs are functionally interdependent (though to what degree we do not know, and cannot measure) the possible viable combinations are, as before, “extravagantly large.”

  This flexibility of design is, of course, what enables life and evolution to proceed. One interesting, even exhilarating, possibility arising from it is that individuality itself may be a feature of living systems, and that this individuality becomes most striking when we look at details rather than at crude summations. If the genome is the sole cause of organic development and maintenance, then in each case, rather than in the general case, it not only makes the component parts but adapts the entire system to itself. This takes us back to the point about solipsism I raised earlier; but what it suggests is not that (as Ridley would have it) the genome works always in the identical style but rather that it operates in an environment of such freedom that, at every point, its alternative viable courses are virtually infinite.

  Two sets of conclusions follow from this, the one intellectual and the other practical.

  Obviously, incontestably, the fertilization of a single egg by a single sperm cell is materially sufficient to make an organism. As has been proved by the successful cloning of goats and cows from differentiated cells, the “information” to make an organism remains within every collection of chromosomes. The genome does it; it makes the organism. But we do not know how it makes the organism, and what we do know, as we presently know it, offers us no theory, no model, of how an explanation might be framed to tell us how the thing is done. We can sequence the genome until those cows come home, but that will not instruct us how it works. The genome does too much for the capacity we presently perceive it has, and it does not do what it does in any way that we can faintly understand.

  Will we ever understand it? At the risk of sounding reckless, or mystical, I would say: perhaps not. But at the very least it should be clear that until some profound new idea, some tremendous leap in human understanding, comes upon us, well beyond anything we now comprehend, the genome will indeed remain a mystery. In my own judgment, this new explanatory idea, if and when it arrives, is likely to take us very far from anything that is intuitively comfortable, farther than relativity theory or quantum mechanics ever took us in physics. Explanation awaits a genius, and probably a long developmental period thereafter; it will not come into the world full-blown.

  But if, in the end, we come back to the genome after all, though by a means as yet undreamt of, will we not be returning to what we are being told by our experts that we already know for a certainty? No, we will not-any more than, after relativity theory, we came back to the same three dimensions. It is not a matter of a detail here or there that remains to be cleared up, or of a small and rapidly receding area of ignorance. Rather, everything truly essential about the process is utterly and even radically incomprehensible. Until the moment of illumination arrives, we should, in the name of scientific and intellectual honesty, acknowledge as much.

  BUT THERE is an urgent practical and indeed moral consideration here as well.* Gene therapy, for example, is premised on the idea that we are in fact confident about which genes do what, and (crucially) how, and that by locating and replacing a faulty or missing gene in an organism we can thereby effect a cure. This, after all, is what has happened recently in France, where working genes were added to cells in bone marrow to save the lives of infants who might otherwise have died of a particular immune disorder. Human genetic engineering, for its part, goes still further than this, manipulating genes in the germline itself-that is, at or before the sperm– and-egg stage-and hence affecting not just a single living organism but its heirs unto all eternity

  The promise held out by these enterprises is nothing short of breathtaking. But they are, to put it gently, inherently dangerous, and not just because they can mislead ill people into entertaining false hopes-although they can certainly do that. As has been pointed out in the more thoughtful news stories about the recent French breakthrough, the therapy in this one case is itself highly limited in nature, as is the disease being treated, and its implications for other diseases and other therapies are quite uncertain. More important, this achievement comes after a decade of gene-therapy research characterized by the most grandiose and sweeping promises of imminent cures for everything from cystic fibrosis to Alzheimer’s to all forms of cancer. In practice, there has been one crushing failure after another, including, last year, the death of a teenage boy in a clinical trial at the University of Pennsylvania.

  ”There were a lot of people going around grandstanding” in the past decade, one honest medical researcher has acknowledged in the New York Times, citing the large numbers of trials that have been approved “without extraordinary oversight in terms of scientific or clinical benefit.” This “awful history,” he went on, indicts not just the companies that have stood to benefit commercially from successful trials, and therefore have an interest in hyping the potential of gene therapy. “Some of it, unfortunately,” is the fault of “the investigators and the academic institutions.”

  This is very bad, and it sheds a rather lurid light on academic and scientific pretensions to probity and cautiousness. But there is real cause of alarm when one considers just what all the “grandstanding” has been about. Genes are not machines, and we ourselves do not work like computers. Unless and until we know how collections of genes go together, how they combine to form organisms, whether plants or animals or human beings, we will not know what, really, we are doing when we add a gene to an existing organism, or manipulate the genes in a germline in such a way as to affect future generations. If the process of forming an organism possesses, as I have argued, an element of freedom, and is fraught with an infinite number of choices along the path, each of them setting in train numerous complex and far from predetermined actions and reactions, it is terrible to contemplate the responsibility that lies upon us when, profoundly ignorant as we remain, we make bold to add to, subtract from, or alter the pages in the book of life.

By BILL TAMMEUS 
Date: 07/29/00 22:00

LOS ALAMOS, N.M. — Since the announcement earlier this summer that

scientists have produced a rough draft of the human genome, enough time has

elapsed to allow a reasonably calm and measured analysis.

To help with that, I’ve come here to the birth place of the atomic bomb to hear from a man who has been thinking about the astonishing new world of genetics for more than a decade.

He’s Michael Yesley, a Los Alamos lawyer who has been part of the Human Genome Project’s effort to think through the ethical, legal and social implications of knowing the genetic recipe for human life.

In fact, I’ve brought with me 15 or so people who’ve been taking a weeklong seminar on science and religion that I’m helping to lead at Ghost Ranch, a national Presbyterian conference center in Abiquiu, about an hour from Los Alamos.

(By the way, it feels almost off the point to be here focusing on the human genome, even though the Los Alamos National Laboratory has been engaged in some of that work for years. This is, after all, a doubly traumatized community at the moment. In mid-May, some 410 families lost their homes in a stunning forest fire. And allegations of security breeches have affected the national lab. In all, this is a wounded community that seems to feel a bit like a modern-day Job.)

Yesley has been part of a laudable effort to anticipate the moral, legal and social questions that knowing the human genome inevitably raises. The Department of Energy and the National Institutes of Health, which have directed the genome project, have wisely invested a portion of their genome budgets researching these sticky matters.

And Yesley is convinced that, on the whole, social-science researchers have done an adequate job identifying areas we’d all do well to worry about. He thinks, however, that genetic scientists aren’t worrying enough about ethics and that ethicists aren’t up to speed on the science. As a result, he says, they aren’t communicating well.

But Yesley is realistic about how well we can anticipate the problems before the science of genetics begins to have more direct applications in our lives. The major issue to be faced, he says with a sense of realistic resignation, “won’t be the things we’re now worried about.” Rather, he says, it will be something that may now seem trivial.

For sure, Yesley says, the coming availability of gene therapies to treat and prevent diseases will lead to a wider gap between the haves and the have-nots under our current health insurance and health-care delivery systems.

Unless there’s some sort of “single-payer” insurance system that’s universal in scope, he says, people with the financial resources will benefit most from the knowledge the Human Genome Project is producing. And yet Yesley readily acknowledges that such single-payer plans (you can find them in Canada and England, among other places) have inherent problems of their own.

What Yesley is talking about is not so much an ethical, legal or social issue as a political one, and it’s one we’ll all need to demand that our politicians solve fairly.

Otherwise, as Washington Post columnist William Raspberry wrote

recently, “The rich will have their lives improved and extended. The poor

won’t.”

The Human Genome Project raises countless other issues, too, from human cloning to whether people will be able to design their own babies before they’re born.

But all those difficult questions, it seems to me, need to be seen in

the context of the rich-poor question to which Yesley points.

In our Ghost Ranch seminar, I’ve been trying to encourage participants to think about how people in religious communities can be part of this whole debate on genetics. It’s a key question that goes to the very heart of what it means to be human. If we are simply biological structures whose genome fully defines us, then worrying about the moral questions associated with genetic research seems almost pointless.

But if we are also — however defined — spiritual beings, as I believe we are, then people with spiritual values must articulate their sense of boundaries and imperatives in this and every other area of science. If Albert Einstein was right that science without religion is lame and religion without science is blind, silence cannot be an option.

by Francis S. Collins, Lowell Weiss, and Kathy Hudson

Issue Date: 06.25.01
Post Date: 06.20.01

Forty-eight years ago, James Watson and Francis Crick introduced DNA’s elegant double helix to the world in the pages of Nature. With extravagant understatement, they began their report by noting that DNA’s “structure has novel features which are of considerable biological interest.” Four months ago, with the publication of the sequence and the analysis of the human genome, scientists offered further evidence of just how considerable. Researchers gained a wealth of fresh insights into the miracle of life, and uncovered new mysteries that will occupy biomedical researchers for years to come.

Unfortunately, the new focus on the genome has left some people with the impression that DNA’s power is perhaps too considerable–that is, that genes are too great a factor in defining who we are. This fear is understandable. It seems that every morning we awake to a news story presenting yet another way in which our genes appear to be controlling us, like the proverbial tail that wags the dog: “Scientists Zero in on `Genius Gene’”; “Kennedy Tragedies Linked to `Risk-Taking Gene’”; “Diabetes Gene Poses Risk for Latinos”; “Scientists Say a Study of Brothers Proves Existence of a `Gay Gene.’”

With a torrent of headlines such as these, reasonable people have come to fear that the more we learn about the human genome, the more we will see that every aspect of the human condition–from illness to intelligence to fear itself–is just the inevitable product of an unyielding, unfeeling genetic code. For this reason, they worry that our new genomic knowledge represents not a giant leap for humankind but rather a giant demotion. Perhaps we are just marionettes being tugged along by the strands of our DNA. Perhaps our lives are nothing more than a formulaic drama, with a plot line that was finalized before our birth.

Fortunately, ten years of intensive study of the human genome have provided ample evidence that these fears of genetic determinism are unwarranted. It has shown us definitively that we human beings are far more than the sum of our genetic parts. Needless to say, our genes play a major, formative role in human development–and in many of the processes of human disease; but high-tech molecular studies as well as low-tech (but still eminently useful) studies of identical and fraternal twins make it perfectly evident that our genes are not all-determining factors in the human experience.

To put it starkly, we have seen nothing in recent studies to suggest that nature’s role in development is larger, or nurture’s role smaller, than we previously thought. This is certainly an exciting time in genetic research; but if nature were to take advantage of this klieg-lights moment and boldly declare that it is in charge, history would remember it the same way we remember Alexander Haig.
n large measure, the fear of genetic determinism stems from misconceptions of how genetics works. As high school students, our first exposure to genetics came through the story of Gregor Mendel’s experiments with his garden peas. First, we learned that each parent pea plant contributed one copy of each of its genes to its offspring. Second, we learned that certain genes were “dominant” and others “recessive.” (The gene for white flowers [W] is dominant, while the gene for purple flowers [w] is recessive.) And third, we learned that a plant would need to inherit two copies of a recessive gene to manifest a recessive trait, but only one copy of a dominant gene to manifest a dominant trait. Offspring–to use the example of flower color–would grow white flowers if they inherited any of the following gene patterns: Ww, wW, or WW. Purple flowers, in contrast, result only from one combination: ww.

All of the above is correct–for flowers and for pea plants. But when it comes to the study of complex human beings, we must take Mendel’s peas with a giant shake of salt. Despite what your high school biology teacher told you, Mendelian rules do not apply even to eye color or hair color. Truth be told, they do not apply to most characteristics of peas or other plants, either. As Robin Marantz Henig documented in her wonderful book The Monk in the Garden, Mendel himself came to question the validity of his work on peas when he turned to the study of the hawkweed and got much more complex and confusing results.

This is not to say that deterministic Mendelian rules never apply to human traits and disorders. One classic case in which they certainly apply is sicklecell anemia, a painful and often life-threatening disease that is caused by the presence of an abnormal form of hemoglobin (hemoglobin S) and that disproportionately afflicts families of African descent. Like purple flowers in pea plants, sickle-cell anemia is a recessive trait; it manifests itself in those who inherit two copies of the hemoglobin S gene.
nd yet even in this case, human genetics proves far more complicated, and far less deterministic, than Mendel’s pea flowers. It turns out that every case of sickle-cell anemia is not created equal. Even when patients have the same two copies of the hemoglobin S gene, the disease may manifest itself in different ways. This is in part because a separate set of genes in the genome–genes that code for fetal hemoglobin–can counteract some of the ill effects of the adult hemoglobin S genes. In most people, fetal hemoglobin genes turn off a few months after birth and the adult hemoglobin genes take over; but sometimes the fetal hemoglobin genes are “leaky,” and they continue to produce fetal hemoglobin even into adulthood. When people with two copies of the hemoglobin S gene also inherit leaky fetal hemoglobin genes, their sickle-cell symptoms are usually much less severe. So sickle-cell anemia, widely considered to be the classic single-gene Mendelian disease, is not so clear-cut after all.

Phenylketonuria (PKU), a rare disorder that can cause severe mental retardation, is an even better example of how the most deterministic of genes may not determine much in real life. Like sickle-cell anemia, PKU is a recessive trait. If a child inherits two copies of the PKU gene, then he will get the disease. And yet, thanks to the newborn screening program now in place in all fifty states, the child will never experience mental retardation or the other devastating effects of PKU. Since the illness results from an inability to metabolize the amino acid phenylalanine, if you simply remove foods with phenylalanine from the child’s diet, he or she will live a normal and healthy life. PKU is one hundred percent hard-wired in the genes. Yet it can be effectively cured with a one hundred percent environmental intervention.

Keep in mind also that sickle-cell anemia and PKU are about the closest people come to following Mendel’s rules. When we look at other human diseases, the picture is far more complicated, with many more genes involved and an even greater involvement of environmental factors. Consider the case of juvenile (or type I) diabetes. Despite what researchers and reporters may have projected to the public over the past two years, there is no single “gene for diabetes.” Instead, there are fifteen or more genes that may team up in an array of combinations to produce diabetes. In one person, having variants in five of these genes might be enough to cause symptoms, while in another it might take nine variants.

These gene-gene interactions represent just one layer of complexity. Geneenvironment interactions represent an entirely different story. We now believe that type I cases require not only a series of gene variants but also an external environmental trigger–probably a childhood viral infection. If that is the case, it is entirely possible that in the near future researchers will identify the viral offender, produce a childhood vaccine against it for those who are genetically at risk, and ease the fears of parents all over the world.

It follows from all this that the common use of the shorthand term “the gene for illness X” by scientists and journalists is deeply misleading. If illness X is not one of the rare single-gene Mendelian diseases, then the so-called “gene for illness X” is more correctly described as “a gene variant that may, in combination with other genetic and environmental factors, increase the risk of developing illness X.” Just think of how many times in recent years we have heard the inherently deterministic label “the gene for breast cancer” in reference to the genes BRCA1 and BRCA2. For starters, BRCA1 and BRCA2 are actually anti-cancer genes. It is when someone inherits an abnormality in these genes that she can develop breast cancer or ovarian cancer.

But the larger point is that not everyone who has abnormalities in the BRCA1 or BRCA2 genes develops breast cancer, and not everyone who develops breast cancer has BRCA1 or BRCA2 abnormalities. Calling them “the genes for breast cancer” hopelessly confuses a correlation with a cause. And recall also the case of PKU: despite the fact that it is a single-gene Mendelian disease, nurture (in the form of a change of diet) still can trump nature. So yes, gene variants can and do increase our risk of developing diseases. But only extremely rarely do they determine our fate.
hy, then, all the fuss about the genomic revolution in medicine? If disease susceptibility is not deterministic, will it be all that revealing to discover the glitches that all of us have within our DNA? It most certainly will. First, identifying our individual predispositions to future illness will allow individualized programs of preventive medicine, in which we modify lifestyle, diet, and medical surveillance to reduce the risk of illness. In most cases, the resulting treatments will not be the all-or-nothing scenario of PKU; they will have much more in common with the steps that many of us are already taking to reduce our serum cholesterol (for which the set point has strong genetic roots) in an effort to lower our risk of heart disease.

More importantly, perhaps, every disease-susceptibility gene that scientists identify will shine a bright light on the molecular pathway by which that illness comes about. The proper understanding of those pathways offers us the best opportunity ever to develop targeted therapies that work. Even if someone’s case of heart disease or cancer has only weak genetic roots, the knowledge of the pathway involved, discerned by the study of genetics, can form the basis of a treatment that may cure his or her disease.

But what about non-disease-related traits, such as intelligence and violent behavior? When it comes to behavioral traits like these, after all, a little genetic determinism can go a long way. The discovery of a prevalent gene variant strongly correlated with violence could have a profound effect upon our millennia-old understanding of free will, and weigh down the scales of justice in two equally dangerous ways. If someone who commits a violent crime has the gene variant, his lawyer could use a DNA defense (“If it’s in the gene, the man is clean!”), and the defendant could well be seen by a judge and jury as not responsible for his actions. Yet it is also possible to imagine a scenario in which someone who has never even contemplated a violent act is found to have the gene variant and then subjected to the presumption of guilt (or even sent away to a postmodern-day leper colony) for the rest of his life.

If genes truly controlled behavior, our justice system and its guiding principle of equal protection would not be the only casualties. How would our concept of equal opportunity survive? What about the idea of merit? Just think of the frightening “genetocracy” depicted in the movie Gattaca (and note the letters that make up its name), a world in which children are assigned to castes at birth, based on an assessment of their intellectual capacity and professional potential as inscribed in their DNA.
hese fears, too, are unwarranted. To be sure, scientists will find many behavioral factors in the genes. Researchers have long known that there is one extremely common genetic factor that confers at least a ten-fold increase in the propensity to exhibit criminally violent behavior. It is called the Y chromosome. No one has suggested that all those who possess this genetic marker–that is, all males–ought to be seen as lacking free will or inherently possessing criminal intent. More to the point, the case of the Y chromosome is an almost absurd extreme. In the vast majority of cases, genetic factors exert a much smaller influence on patterns of behavior and capability.

In 1998, for example, a researcher reported the discovery of the first gene correlated with general cognitive ability. Reports in the press lauded it as the “genius gene.” Given humankind’s history of eugenics (the hard diabolical Hitler kind and the soft insidious Bell Curve kind), the discovery of a gene linked to intelligence was genuinely explosive stuff. In reality, however, the so-called “genius gene” was found to give a boost of exactly two points on IQ tests. That’s right: two points. Valuable science, yes. Society-altering discovery, no.

New findings that flow from the completion of the human genome draft are likely to follow the same complicated and undeterministic pattern. According to the combined wisdom of twin studies and molecular studies, human behaviors appear to be like the most complex diseases: if a particular behavior has a heritable component at all, it involves the interaction of numerous genes and numerous environmental influences. Surely this should come as no surprise. After all, behavior is a product of the brain, which is by far our most complex organ, and one that continues to develop throughout a lifetime of living and learning.

To build on a metaphor offered by the biologist Johnjoe McFadden, looking for genes that encode our unique behaviors and the other products of our minds is like analyzing the strings of a violin or the keys of a piano in the hope of finding the Emperor Concerto. Indeed, the human genome can be thought of as the grandest of orchestras, with each of our approximately thirty thousand genes representing a unique instrument playing in the wondrous and massive concert that is molecular biology. Each instrument is essential, and each must be in tune to produce the proper (and highly sophisticated) musical sound. Likewise, genes are essential to the development of the brain, and must be “in tune” to produce functioning neurons and neurotransmitters. But this emphatically does not imply that genes make minds any more than a viola or a piccolo makes a sonata.
or many of us, there is still another powerful reason, wholly apart from the mechanics of science, to reject the notion that DNA is the core substance of our humanity. It is the belief that a higher power must also play some role in who we are and what we become. Of course, some scientists and writers dismiss this spiritual notion as pure superstition. Thus Richard Dawkins has observed that “we are machines built by DNA whose purpose is to make copies of the same DNA…. It is every living object’s sole reason for living.” Really? Is there nothing about being human that is different from being a bacterium or a slug?

Can the study of genetics and molecular biology really account for the universal intrinsic knowledge of right and wrong common to all human cultures in all eras (though all of us have trouble acting on this knowledge)? Can it account for the unselfish form of love that the Greeks called agape? Can it account for the experience of feeling called to sacrifice for others even when our own DNA may be placed at risk? While evolutionary biologists proffer various explanations for human behaviors that undermine the efficient propagation of our genes, there is something about those claims that rings hollow to us.

The notion that science alone holds all the secrets of our existence has become a religion of its own. The faith of Dawkins and others in biology seems even greater than the faith of the simple believer in God. Science is the proper way to understand the natural, of course; but science gives us no reason to deny that there are aspects of human identity that fall outside the sphere of nature, and hence outside the sphere of science. For most believers, God has no meaning unless God is more than nature. If God is more than nature, then studying the natural may never reveal the true mystery.

In the end, we must acknowledge that we human beings have only scratched the surface of self-understanding. The structure of DNA does hold considerable interest for this line of inquiry; but it would be the purest form of hubris to take our rudimentary knowledge of our genetic code, craft theories about it with our puny minds, and declare that nature has once and for all trumped nurture and toppled God. This is the kind of arrogance that humans alone seem to possess, and that genes alone could never explain.

 

FRANCIS S. COLLINS is the director of the National Human Genome Research Institute. LOWELL WEISS is an executive at the Morino Institute in Reston, Virginia. KATHY HUDSON is the assistant director of the National Human Genome Research Institute.

By Tuck Wesolowsky

 

Genetically modified foods — known as GMs– are increasingly a part of life both in the United States and in Central and Eastern Europe. They are also increasingly controversial. In a three-part series, RFE/RL correspondent Tuck Wesolowsky explains what GMs are, why they are prevalent in East — but not West — European countries, and what the controversy is all about. This first part looks at what genetic modification does.

Prague, 8 August 2000 (RFE/RL) — Consumers in the United States got their first glimpse — and taste — of the future of food back in 1994. It was called the Flavr-Savr (flavor saver), a tomato whose producer — Calgene — boasted was juicier, bigger, and redder than any others.

The plant’s genes had been spliced together in a laboratory to create a new kind of tomato at once, rather than by the laborious selective breeding process used by traditional farmers. Nothing like it had ever been sold in markets anywhere in the world. The Flavr-Savr was the first global commercial launch of what we now call genetically modified — or bio-engineered — foods or products, commonly known by the abbreviation, GM foods.

To their backers, GMs promise almost incalculable benefits, from healthier food and lower production costs to advantages for the environment. They say GM foods could even stamp out world hunger.

Critics say tampering with genetics could bring an unforeseen backlash from Mother Nature that might harm human health. They also contend genetic modification could give greater control over the world’s food supply to the agro-industry.

Some 40 million hectares of genetically engineered crops were grown throughout the world in 1998. The world’s biggest GM producers are Canada, the United States, and Argentina. In the United States alone, 1,300 companies employ more than 100,000 people in the bio-engineering field. It is believed that about 60 percent of all food produced in the United States now contain GM elements.

What are GM foods? For centuries, man has cultivated plants and bred animals to produce a particular desired trait. Traditional biotechnologies have given us hothouse roses with special colorings and cows with higher meat or milk yields. But today’s bio-engineering is something different, based on taking genes out of an organism’s cells and altering them in some way.

Scientists are now also able to transfer genes among different species to produce genetically engineered organisms with new characteristics. For example, about a quarter of most GM crops are created by inserting a synthetic version of a gene from a naturally occurring soil bacterium — known by its Latin name bacillus thuringiensis, or BT. It enables the plants to produce their own BT toxins to destroy pests.

Isabelle Meister is the head of an anti-genetic engineering campaign for the international environmental group Greenpeace. Like other critics of GMs, she is wary of mixing genes from different species.

“You can only cross closely-related species. For example, maize can cross with maize or with this tirocide, [a] closely related wild plant you find in Mexico. But you definitely [should] not cross maize with chickens. However, genetic engineering enables to put chicken genes into maize.”

But Vivian Moses, the chairman of the British-based bio-engineering institute CroGen, says that one gene is just like another.

“A gene is a gene, a gene is a piece of information. It doesn’t come with a signature on it which says, I belong to such and such a species. You’ve heard the stories that people share about 98 percent of their genes with chimpanzees. So how do you decide what is a human gene and what is a chimpanzee gene.”

One of the biggest arguments made by biotech industry supporters is that GM foods will help meet a growing food shortage. They note that the world’s population is expected to rise by one-third in the next 20 years, and that little more arable land is available. Bio-engineered foods can meet the increased demand, they say.

But the argument that world population growth will outpace food production in the near future has taken a knock from a recent study from the UN’s Food and Agriculture Organization, the FAO. The study said the estimated world population of around 8 billion by 2030 will be better fed than the current population.

FAO economist Josef Schmidhuber says warnings of a coming food shortage are not warranted.

“Overall, I think that we can be very optimistic — or relatively optimistic — as far as global food production is concerned. We expect that food production will continue to outpace population growth and we will have more people better fed, and fewer people undernourished.”

In our the next part we’ll look at the controversy over bio-engineered food and at one scientist who says his critical report on GMs led to him to lose his job.

Daughter of poor immigrants in the US, she made ‘spectacularly good’ as a biologist and physicist. But she has attacked male domination of science and has now produced a controversial book arguing that the concept of the gene is obsolete. Andrew Brown on a fearless feminist who likes to paddle her own kayak

Andrew Brown
Saturday November 4, 2000

 

Professor Evelyn Fox Keller lounges in a swivel chair in her office at Massachusetts Institute of Technology , with her sockless feet in battered Reeboks on the desk in front of her; from time to time, when agitated, she spins round and rests them on the desk behind her, as sturdy and cluttered as the other one. It’s a nice metaphor for the way she fits into the angular world of professional science. She is on top of several subjects, as a pioneering feminist critic and philosopher of science, who has also been a working biologist, but ostentatiously comfortable only on her own terms.

Tom Wilkie, adviser in bio-medical ethics at the Wellcome Trust, says that her kind of criticism of science is something that this country badly needs: “As the BSE crisis shows, we tend to treat scientists as disembodied experts in this culture, but her stuff fills out a fuller picture of the relationship between science and the world around it.”

Her honours as a scientist are numerous: she has been a fellow at the Institute of Advanced Study, where Einstein worked, and has won a MacArthur “genius” award. But she is also famous for an attack on Harvard (where she gained a doctorate in theoretical physics in 1963) and as a feminist scholar of science. To find her in the splendour of MIT – Nerd Central itself and just up the road from Harvard – is something of a surprise.

It is as a feminist critic of science that she is best known. According to the American writer Pamela Weintraub, Keller’s work has “cast a pall on science and its glorious priesthood, whose powerful political bias affects the ‘description of nature’ emerging from the lab”.

Keller was born in 1936, one of three children in a poor Jewish New York City family, first-generation immigrants from Russia. Her father worked in a delicatessen. The children “made spectacularly good,” she says: her sister Frances Fox Piven is a political scientist and poverty campaigner; her elder brother Maurice is a biologist at MIT. Evelyn attributes some of their success to the New York public school system – “It was wonderful. It really was.”

Her original ambition was to be a psychoanalyst: “I heard about the unconscious when I was 12 from my older sister, and I thought it was the neatest thing I had ever heard.” It’s a big swerve from there to theoretical physics, especially as psychoanalysis is now discredited as about the most unscientific theory that could ever have existed. But she retains a huge admiration for Freud.

Maurice was a physicist by then, but it was Evelyn’s comparative failure in English composition that tipped the balance. “No matter how I tried, I couldn’t get better than a C in English. I was reading the George Gamow books [popular science of the 50s in which the ordinary hero, bored by physics lectures, falls asleep and understands what is said in the course of vivid dreams] and my older brother was a scientist. So I started to write my English essays about physics topics. All of a sudden I got As.”

She moved into physics, intending to return to psychoanalysis after she had got a degree, but at Brandeis University, something extraordinary happened. Instead of cleverness being a means in itself, or at least a means of escape from the circumstances of her upbringing, it suddenly became something unselfish. She fell in love with theoretical physics.

This is not a metaphor, says Keller, but a literal description of her experience. She once expanded on it in an article: “I fell in love simultaneously and inextricably, with my professors, with a discipline of pure, precise, definitive thought, and with what I conceived of as its ambitions. I fell in love with the life of the mind. I also fell in love, I might add, with the image of myself striving and succeeding in an area where women had rarely ventured. It was a heady experience.” This idealism is part of a fierce romantic quality that friends detect in her. Gillian Beer, president of Clare Hall, Cambridge, says, “She’s full of a sort of dark life: there’s tremendous intensity in her relationships, and even in her laughter. She’s a very loyal friend, though she also has enemies, whom she rather relishes.”

As a young scientist, Keller believed she was part of the greatest adventure that humans had ever embarked on: “I thought it was a cooperative venture in which people wanted to find out what the world was made up of”; and that the people she worked with were, by definition, working for the benefit of humanity – though perhaps, in those days, she would have said “mankind”. Years later she wrote: “I believed not only in the possibility of clear and certain knowledge of the world, but also in the unique and privileged access to this knowledge provided by science in general and physics in particular. I fully accepted science, and scientists, as arbiters of the truth – physicists were, of course, the highest arbiters.”

She graduated in 1957, a year when the prestige of American scientists was as high as it would ever be. She wrote her undergraduate thesis on the work of Richard Feynman [the Nobel Prize winner regarded as the purest example of idiosyncratic genius among all the discoverers of quantum mechanics] and wanted to go to California to study with him. But in the end she went on a state scholarship to Harvard, and almost at once her dreams collapsed.

She had no trouble with the work, but she found the atmosphere unendurable. “Harvard was a disaster,” she says now. “It was a very difficult time to be a woman in a physics department.” There were only three women among the 100 postgraduate physicists. Several months into her first year, a teacher offered her a lift and asked how she was getting on. As she started to tell him, she almost burst into tears; then realised that admitting her feelings filled him with acute discomfort, as if, instead, she had started to take off her clothes. The experience made her even more buttoned up, even more miserable. It is hard to believe now that this confident woman in steel-rimmed spectacles with a huge gleeful smile could ever have been embarrassed about anything. But she was, and she was deeply miserable. She felt persecuted by the faculty and by her fellow students, and bitterly disappointed by the work she was doing.

“I went to graduate school to learn about… the nature of space, time, and matter… I was taught, instead, how to do physics. In place of wisdom, I was offered skills. Furthermore, this substitution was made with moralistic fervour. It was wrong, foolhardy, indeed foolish, to squander precious time asking ‘why?’. Proper humility was to bend to the grindstone and learn techniques.”

She found this narrowing of the boundless horizons of science quite mystifying, and was still more puzzled that the people who did it were proud of their narrowed horizons. “I didn’t fully understand that in addition to the techniques of physics, they were also learning the techniques of arrogance.” She toyed with the idea of going to medical school, but a certain stubbornness kept her going even after she had passed her first set of exams early and felt she had little more to prove.

It was chance and family connections that showed her the way out in the summer of 1960. Her brother Maurice, newly married, was spending the summer at Cold Spring Harbor, a small village on the north shore of Long Island which is one of the capital cities of modern biology; it houses a permanent government funded research laboratory and hosts a series of influential science conferences. “I went there for the summer, because he had a spare room – well, half a spare room, because he had a baby.”

These were the years in which it seemed that all life could be understood by probing at its simplest structures: bacteria and the viruses that prey on them; and most of this work was done by men who had trained as physicists. The structure of DNA had been unravelled by Crick and Watson in 1953, but its code – the syllables spelt out by the letters Crick and Watson had discovered – was not cracked until 1963; and, of course, the task of turning those syllables into intelligible words, and then deciphering the grammar and syntax of their language still continues. Max Delbruck, one of the leaders of this revolution, was working at Cold Spring Harbor, and got her to work in a lab there: “they were all on the lookout for smart young things, especially from physics”, she says with an unselfconscious acceptance of her own smartness.

She switched her attention entirely to biology, and persuaded the physics department to let her take a doctorate in theoretical physics with a dissertation that was in molecular biology: she had thought of a technique which would make it possible to decide whether one or both strands of DNA were used to make proteins: she thought the task would take weeks. It took more than a year in practice, and she left with a doctorate and a conviction that she was not really cut out to be an experimental scientist. “I couldn’t stand it when I’d see three weeks of work go down the tube because someone brushed against the water heater and the temperature went up. There were just so many variables out of control.”

Matt Meselson, the professor under whom she took her PhD, remembers her as a young woman in a hurry. “She just wanted to get her doctorate quickly and get out. Most of the other students were less impatient. She worked hard. But she didn’t really have the patience.”

So she moved to New York, working again as a theoretical physicist at New York University, and in 1964 married her boss, Joseph B Keller, a mathematician of great distinction. Shortly there after, they had two children – a son and a daughter. Jeffrey, now 35, is a software engineer; Sarah, 34, is a university teacher.

Evelyn started work in yet another field, this time mathematical biology. She was happy. Two of the papers she wrote are said to be classics in the field: working with the mathematician Lee Segel, she produced equations to describe an extremely puzzling phenomenon: how it is that some single-celled amoebas can change, when times are hard, into a single, multi-cellular organism, without any one cell being responsible for the transformation. “This was all very nice, but in 1969 I followed my husband to California. [where he still is] Lee was going round the country talking about our work, and he was getting more and more excited, and I was sitting at home getting more and more bored. So I started thinking about women and science.” In fact she started to study her own predicament as a mathematical biologist with the tools of mathematical biology. She got hold of all the data she could find about women scientists: how many there were, and how long they lasted in their profession. “The attrition rate was really shocking.”

Four years later, when she was invited to give a lecture series on mathematical biology, “I felt I could not in good conscience give six lectures without making some reference to my being a woman. So in the last lecture I developed an epidemiological model for women in science using the data I had collected in Stanford in 1970. I showed them the equations, and the birth and death constants” – which predicted the rate at which women scientists would abandon their profession – “and then I devoted the last few minutes to a review of the reasons for these difficulties. I decided that probably the most serious obstacle to the success of women was the widespread belief that science was an inherently masculine endeavour. Where did it come from? What consequences did it have?”

It was the first time she had asked those questions out loud and the consequence was a huge sense of personal liberation. Even telling the story 26 years on, much of her face disappears in a huge grin. “In 1974 these were not polite questions. I went back to the motel that evening and wrote up the talk. It was the first story I ever sold” – she shakes her hand in the air in a jubilant, cheque-waving motion.

That was the beginning of her career as a feminist critic of science. Gillian Beer says, “What’s important is that she asks new questions, and she holds on to them in ways that other people don’t. She will start with very bold, sometimes odd – I’d say maybe absurd, if that wouldn’t be misunderstood – questions, and moves in from there with that great weight of intellect until she carry them through. We met because I wrote a rather mixed review of her Reflections On Gender And Science and she wrote back and we became friends It’s very typical of the way she listens to how people respond to her ideas. But of course it is the sheer intellectual stamina that is most impressive.”

There is certainly a ferocious energy about Keller which the relaxed posture belies. She has a house on the edge of Cape Cod that she loves and where she gardens, and she keeps a kayak for voyages on the chilly Atlantic.

One of her happiest memories is of teaching cross-disciplinary courses with her colleagues in the humanities at a small university town in New York State in the 70s. “Since it was the 70s, you could ask any question you wanted. We were rethinking everything, including a new educational system”; and in the process she caught up on all the things her scientific education had missed out, reading literature, anthropology, and philosophy. She talks as if this period of blossoming radicalism was about the most fun she ever had in her life.

Today, walking through the streets round MIT, once a centre of radicalism, she seems a figure from a long-past era among the hurrying, brightly efficient students, some of whom greet her respectfully. “They are all so entrepreneurial these days” she says. “But when an MIT student goes radical, they really are radical,” and she laughs at the thought.

But even though it is a powerhouse of capitalism now, the atmosphere at MIT remains extraordinarily informal, in ways she fits right into. The faculty lunchroom is a kind of 50s cafeteria, with some of the smartest people in the world eating off paper plates at plain deal tables; after lunch she took a cardboard mug of coffee outside and sat on a bench to enjoy the autumn sunlight, asking a student to move up and make room for her. This mixture of sensual relish and intellectual stringency makes her company rather disconcerting; it would not be very pleasant to be a student who she decided was not trying.

The trouble is that like so many revolutionaries she sees her followers going further than she thinks they should. For she still believes in science. It’s no use saying , as some do, that science is a purely cultural construct, like art or fashion, because that does nothing to explain why it works and helps us change the world with a precision and power that no other human activity can approach. She doesn’t even think there is any special way that women do science differently from men. On the other hand, she believes it is grossly misleading to pretend that science has no cultural element in a way that actually holds back scientific progress.

Language which is seen as transparent becomes impervious, she says, and holds people back from the complexity of the phenomena they are trying to understand. The consequence is that both men and women do science less well than they might. These arguments came together, in a huge stroke of good luck, in her study of the maverick geneticist Barbara McClintock, who won the Nobel Prize for physiology and medicine in 1983, whom she had seen, as from a great distance, in her lab at Cold Spring Harbor in the summer of 1960, when Keller was converted to molecular biology.

McClintock had worked there, solitary among the crowds, since 1945. Her speciality was the genetics of maize, a plant to which she remained faithful throughout the decades when almost every other geneticist had moved on to simpler and faster-growing organisms. But, by the detailed and patient study of patterns in individual plants as they grew, McClintock had been able to discover, on her own, two hugely important parts of the genetic mechanism: she identified genes which controlled the activity of others, placed further along the chromosome; and she saw how these regulated genes could “jump” from one part of a chromosome to another. She called this “transposition”.

It took her six years to work it all out, and when she presented her results to her peers, no-one understood them. Nearly 15 years later, they were independently rediscovered in bacteria by molecular biologists, and McClintock was acknowledged as a pioneer; but by this time the habit of solitude was well entrenched and she continued to feel isolated by her interests and understanding of the world.

Keller’s biography of her, A Feeling For The Organism, started off as a study for the New Yorker. But it grew into a full-scale biography, which appeared five months before McClintock won her Nobel Prize (she died in 1992). The moral seemed simple: that women could only succeed in science, as McClintock had, by sacrificing everything else in their lives.

Keller says: “By her own account, even as a child, McClintock neither had nor felt any need of emotional intimacy in any of her personal relationships. The world of nature… became the principle focus of both her intellectual and emotional energies. From reading the text of nature, McClintock reaps the kind of understanding and fulfilment that others acquire from personal intimacy.” But Keller was also interested in whether McClintock gained a deeper intellectual understanding of the world through this emotional connection. This is sometimes also a plea for a more holistic understanding of the world, not because it is spiritually improving, but because it is in some respects scientifically enlightening. It can make our knowledge of the world more precise and reliable, which is, of course, the opposite of what holistic normally means – fuzzy and new age.

Keller’s latest book, The Century Of The Gene, argues that the idea of the gene, which carried science through to such huge advances in the last century, will not do so well in this one, as more and more is learnt about the ways in which strings of DNA actually work in the world, and the complexities of their interactions with surrounding cells.

On one level it is a beautifully illustrated examination of the arcane ways in which particular, meaningful stretches of DNA are pulled out of a chromosome which is, so far as we know, 97% meaningless “junk”, and assembled into the kind of genes that actually specify the proteins that build people and every other living thing. On another, it is an attack on the view that genes are agents which do things to the passive world around them and are solely responsible for changing it. Lewis Wolpert, professor of biology at London University, a conspicuous opponent of Keller, attacks her for talking “junk” and “bullshit”; but at the same time says her thesis is “what everybody knows” and cries “So what!” when specific points are raised.

The row between Wolpert and Keller is a wonderful example of the kind of antler-locking into which academics of all sexes naturally fall in a world where simply agreeing with someone can seem an unforgivable insult. One of Wolpert’s themes is that the philosophy of science has absolutely nothing to teach working scientists. So when he gave a talk to this effect in Cambridge, England, and cited all the wonderful work which was going on in the laboratory without any help from philosophers, Keller rose at the end and said she agreed entirely with the importance and interest of this work – but why had he left his own laboratory to join in the science wars? The consequence was, first, that he heckled her next lecture in London, and then wrote a pamphlet attacking it.

“I suppose she wants a feminist interpretation of the gene,” says Wolpert.

But the only thing feminist about Century Of The Gene is that she works in the territory familiar to another woman philosopher, Mary Midgley, an admirer of her work, where the metaphors that scientists use are taken seriously. These are dangerous borderlands; metaphors such as “selfish genes” can take on a life of their own among non-scientists, who take them to meant things that their creators never intended. But Keller, as a scientist herself, is more interested in the effect that metaphors have on the way that scientists see the world, and the sort of possibilities that they lead them to explore, or to exclude.

This is, if anything, even more unpopular among working scientists than are questions about the effects of their language on the outside world. It’s quite easy to come to terms with the idea that stupid, ignorant people – non-scientists – might misinterpret the language that scientists use. It is more threatening to suppose that scientists themselves might be misled. Yet this has been the thrust of all Keller’s recent work; and in The Century Of The Gene, she looks at the possibility that the word “gene” itself has outlived its usefulness. For the century she has in mind is not the one just opening, with its promise that genetic engineering will transform the world and our understanding of it, but the 20th century, just over, when all the theoretical discoveries were made.

“At the very moment in which gene-talk has come to so powerfully dominate our biological discourse, the prowess of new analytic techniques in molecular biology and the sheer weight of the findings they have enabled have bought the concept of the gene to the verge of collapse,” she says. “It’s been a growing conviction of mine that biologists have a whole other way of talking to each other in the lab than they do to the public.”

All the information in a cell is contained in its genes, or at least in its DNA. But this begs the question of what exactly information is, and whether it can exist on its own, self-sufficient as God. Keller believes that without a context, it is meaningless. Because genes are switched on and off in response to the circumstances of the cell around them, a “genetic program” cannot reside solely in the genes.

She is certain to make more enemies by challenging the view popularised by Daniel Dennett and Richard Dawkins that the gene is the motor of evolution. “Before you can talk about natural selection, evolution had to arrive at a system that would endure for long enough for natural selection to operate on,” she says. But she has never worried about voyaging alone through uncharted seas of thought. Her self-confidence remains extraordinary: a woman with a big laugh happily paddling her own kayak through the ocean, just because she thinks it fun and interesting.

Saturday, July 15, 2000

By RICHARD SALTUS

The race to map the human genome reached fruition last month, with promises of a revolution in medicine spurred by reading out the genetic scripts in our own DNA.

Which makes the timing of Robin Marantz Henig’s excellent book about the “father of genetics” just about perfect. The work of Gregor Mendel, who lived from 1822 to 1884, was rediscovered just a century ago this year: It had lain ignored for 35 years after he reported his revelations about heredity, which ultimately galvanized a new generation of biologists who went on to discover genes, chromosomes and DNA — all unknown to Mendel.

Mendel’s story, as delightfully told in “The Monk in the Garden,” is miles away from Big Science. It’s the tale of a solitary researcher, a rotund, cigar-loving (as many as 20 a day) cleric who carried out his experiments while leading a simple life in a monastery in Brno, now in the Czech Republic. He had, and needed, little equipment except pen and paper, seeds and a sunny garden, and penetrating intelligence — as well as immense patience.

In tediously systematic breeding experiments between 1857 and 1863, Mendel examined 28,000 pea plants in an effort to understand how individual traits such as height, seed shape, seed pod color and so forth were passed along from one generation to another.

The going theory was that if you crossed (bred) strains of plants or animals with differing traits, the offspring would display “blended” or intermediate traits.

Mendel disproved this. His hard-won insightswould point the way toward the discovery that chromosomes and genes for the traits are inherited as pure units — not blended — and that the traits reappear in successive generations in mathematically predictable ratios.

In addition, said Mendel, the two units of each trait, one from the father and one from the mother, are passed randomly to the offspring. He showed that some “factors” — what we now call genes — are dominant and determine the offsprings’ appearance, even though recessive factors persist and will show up in future generations.

But his work, conveyed in two reports to a local society and in a few letters, was virtually ignored. Some 35years later, when several scientists made similar findings, they discovered they had been beaten to them by Mendel.

Henig’s account of Mendel and the conflicting scientific currents of his time is rich, clear, and filled with wonderful evocations of Mendel’s world. In her research, she gleaned so many details of place, weather, sounds, and sights that the book has an unexpectedly sensual texture, making it as pleasurable to read as a superbly written travelogue.

Nor is she afraid to speculate about many unresolved issues surrounding this “gentle revolutionary,” most of whose papers were burned.