1996 - The Genetic Revolution

Topics discussed during this proceeding include The Genetic Revolution, The Human Genome Project: An Overview, Medical Ramifications, Ethical Issues in the Human Genome Project, Legal Aspects, The University of Texas Southwestern Medical Center at Dallas, Sequencing of Genes, What Price Designer Genes? The Genetic Revolution, Ready or Not? Designer Genes and the Genetic Revolution, and more.

Welcome and Introduction Remarks

It's a great pleasure on behalf of the local committee to welcome you to Dallas for this meeting. We hope that you will find it both interesting and thought provoking. Before proceeding, though, I'd like to thank the local arrangements committee. Their names are listed in your program there. The committee was chaired by Margaret McDermott and Bill Seybold.

I'd also like, at this time, to recognize Evelyn Stehling who is seated in the back, as well as her assistant, Melinda Reese. These two ladies are really responsible for all the arrangements, and I'd ask you to join me in expressing our appreciation to them.

We had hoped that Dr. Francis Collins, who is the director of the Human Genome Project, could be with us at this meeting, but, unfortunately, he had a conflict and couldn't join us. I had the good fortune of attending a meeting in San Francisco a couple of weeks ago where Dr. Collins spoke. In his presentation he listed a number of questions that he felt needed to be addressed within the context of the Human Genome Project.

I asked him if I might present some of those same questions to the audience today because I think it would set the stage for this meeting. He graciously agreed and I would suggest that you make a mental note, or even jot down on paper, these questions. I think you'll find that each of them will be touched on in one way or another by our speakers today. The ultimate answers, however, will not be forthcoming until years in the future.

If I could have the first slide, please. I'm not going to elaborate on Dr. Collins's questions for I think they'll be self-explanatory. Will the therapeutic promise of genetics be realized? Will we successfully shepherd new genetic information from research into clinical practice? Can health care providers and the public become genetically literate in time? Will the benefits of advances in genetics be available only to a privileged few? Will we arrive at consensus about the limits of genetic technology for trait enhancement? Will effective legislative solutions to genetic discrimination be found? And finally, will we succumb to genetic determinism?

I don't know how many of you may have read an article in last week's U.S. News and World Report where it was stated that they now have a genetic explanation for everything, including our behavior. And further, will we use that as an excuse to say that we have no control over our future for our genes have determined what we're going to be and how we're going to behave.

So these are the questions that Dr. Collins has posed and, as I stated earlier, each will be touched on in one way or another in today's presentations.

I'd like to close my introductory comments with a quote from Sir William Osler because I think it's appropriate for our program today:
To wrest from nature the secrets which have perplexed philosophers in all ages, to track to their sources the causes of diseases, to correlate the vast stores of knowledge that they may be quickly available for the prevention and cure of disease; these are our ambitions.

Well, if Osler were alive today, I think even he would be surprised at the degree to which we have achieved the ambition he enunciated years ago.

As you know, we select a moderator for the program each year-someone who is not an expert in the field, but who has an understanding and appreciation for the theme, whatever it happens to be. This year we have selected Hans Mark. I think all of you know Hans as well as his background.

Hans is a bit of a Renaissance person. He is not a genetics expert, but by virtue of his own personal experience with NASA in space exploration, he has an appreciation of the importance and relevance of projects of this kind. We're delighted to have Hans serve as our moderator today and, at this point, I would like to turn the program over to him. Please welcome Hans Mark, one of our own.

What Price Designer Genes: The Genetic Revolution

I. Introduction
A few months ago, our distinguished friend and colleague, Charlie Sprague, called me and asked me whether I would serve as the moderator of this meeting of our society. When he told me what the topic would be, I remonstrated and asked him why he thought that a former bureaucrat and ex-engineer could do this job. I told him that I knew next to nothing about genetics or biochemistry or the law or, worse yet, ethics--and all that this loaded word implies. When he told me who else was on the program, I was even more agitated. What on earth could I do to deal with a couple of Nobel laureates? Apparently, Charlie had hit the bottom of the barrel in this search for a moderator so he finally put the arm on me. He reminded me that he was a member of the search committee that brought me to Texas in the first place back in 1984 and that therefore, I owed him one! He had me there, so here I am. And, I am both very honored and pleased to have the opportunity to moderate this session of the Philosophical Society of Texas.

Now, it turns out that my connection with genetics is, in fact, genetic. What I mean here is that it has to do with my father, the late Professor Herman Mark. Many of you here today met him during the years that he lived with us at the Bauer House in Austin so you know who I am talking about. Anyway, let me explain.

II. Family Genetics
In 1925 while working at the Institute for Textile Studies at the University of Berlin, my father and his colleague, J. R. Katz, were the first to use x-ray diffraction to establish the techniques to determine the structures of large molecules of biological origin. People at the Institute were interested in establishing the physical properties of fibers used by the German textile industry. Mark and Katz pioneered the use of the then new physical technique of x-ray diffraction to initiate the determination of the molecular structure of cellulose (Ref.1). They chose cellulose because that compound is the major constituent of cotton, which is the most widely used and versatile textile fiber. Later, when the structure was finally determined by Mark and Meyer, it was found that with this knowledge predictions could be made about the behavior of the fibers and the textiles made from them. It was a useful technique that substantially improved the textiles manufactured in Germany and it led to much wider applications of x-ray diffraction (Ref.2). Hopefully, this begins to establish my genetic credibility but I still have to explain the bit about Nobel laureates.

During his academic career, my father supervised two Ph.D. students who later were awarded Nobel prizes. One was Eugene Wigner, whose Ph.D. work had to do with the use of x-ray diffraction to establish the crystal structure of rhombic sulfur (Ref.3). He received his Nobel Prize for the application of group theory to the solution of problems in quantum mechanics, a theory he learned while analyzing the x-ray diffraction patterns produced by the Sulfur crystals he examined to earn his Ph.D. The other student was Max Perutz, and he is the one who is important for our discussion today because he was the one who developed the techniques that were later used by James Watson, Francis Crick, Maurice Wilkins, and Rosalind Franklin to determine the structure of deoxyribonucleic acid (DNA). In that sense, Max might be called the grandfather of the genetic revolution! In any event, I knew both of these gentlemen quite well because of my father, so I have at least some experience in talking to Nobel laureates.

Max Perutz finished his Ph.D. thesis in 1937 doing research on a problem in classic organic chemistry at the University of Vienna. Unfortunately, the thesis was never published because both Perutz and my father left Vienna shortly after the work was completed. My father saw the danger posed by the Nazis at that time since he was himself planning to leave Austria. Thus, he urged his young protÈgÈ to leave Austria as well, preferably sooner rather than later. There was a vacancy in the laboratory of Sir William Lawrence Bragg at Cambridge University. At the time, Bragg was the world's leading expert on x-ray diffraction. Perutz was worried that he knew nothing about x-rays whereupon my father said: "You will learn," and learn he did! After a painstaking series of experiments using much trial and error, Perutz succeeded in determining the molecular structure of myoglobin and later of hemoglobin, a feat for which he was awarded the Nobel Prize in 1962 (Ref. 4). Hemoglobin was a much more difficult proposition than cellulose. It is a very complex three dimensional structure and Perutz had to go far beyond what was done with cellulose, which is a relatively simple structure that has cylindrical symmetry. Perutz completed this work a few years before the structure of DNA was established using the same techniques in 1954 (Ref. 5).

III. Computers and Their Limits
The realization that DNA was the template that determines the properties of all living things using a three-digit code was the intellectual breakthrough that brings us here today. You will hear both about the promise and the problems raised by the new insights that have been gained. The prospects are truly as mind boggling as they are varied. Instead of making lists, let me talk about what interested me most about the genetic revolution. Not surprisingly, it is related to engineering. In 1979, when I was serving as Secretary of the Air Force, we began to wonder how much computer capacity we could put on the Airborne Warning and Control System (AWACS) aircraft. I called my old friend Walt Morrow, who was director of the MIT Lincoln Lab at the time, and asked him what he thought about the question. He replied that it has to do with the size of switching elements. Transistors that control the flow of electrons cannot be smaller than a certain size. They depend for their operation on the establishment of energy levels called Brillouin zones and, if the transistor becomes too small, then these zones can no longer exist. By doing some elementary quantum mechanics, Walt estimated that the smallest transistors must have at least 1012 atoms to work--that is one thousand billion. We are today about a factor of 50 away from this limit, the smallest current switches today contain about 5 x 1013 atoms. From a practical viewpoint, there is still lots of room for improvement. Every factor of two is worth lots of money so don't sell your computer company stocks! However, from a scientific viewpoint, Walt could foresee even twenty years ago that at some point, we would come up against a fundamental limit.

IV. Biological Switches
The final question that I asked Walt was what he thought could be done to overcome that limit and he then told me a most interesting story. He said that there were people in the biological departments at MIT who were beginning to learn how the switching elements in our nervous system worked. He told me that these switches were molecules containing about ten thousand atoms that are impregnated on the membranes enclosing nerve cells and that these molecules control the flow of ions (and hence electric currents) in our nervous system. If we could learn how to use and control these biological switches, Walt told me, we could build computers that are smaller by many orders of magnitude than the ones we have today. To be more precise, biological switches are eight orders of magnitude smaller than electronic switches. They are much slower since they operate on currents of relatively slowly moving ions rather than on rapidly moving electrons. However, we have since learned that it is relatively easy to overcome this problem by introducing what we call parallel computer architecture (Ref. 6). We have made much progress in learning about biological switches and what my computer friends call neural networks since I had my conversation with Walt Morrow almost twenty years ago. Walt will very probably turn out to be right that we will overcome the quantum mechanical limit imposed by size on transistors by the use of biological switches.

V. A Speculation
It is this last point that leads me to the speculation with which I want to wind up this introduction. The human mind is by far the most complex and sophisticated computer we know about. It has about 1011 (one hundred billion) synapses and each of these may contain hundreds of thousands of switching molecules, so astronomical numbers of switches exist in the brain-- approaching say 1016. Compare this to our best current computers which have about a hundred million (109) switches. The point of all this is that the way in which the switches in the human mind are wired up is contained in the genetic code. The architecture of the computer that is the human mind is hidden somewhere in the three plus billion units of the DNA molecule. By knowing the complete sequence of human DNA, will it become possible to build computers that approach the capability of the human mind? Can we understand how the architecture of the brain is encoded in the DNA molecule? If so, can we replicate the principles and use them to build artificial brains? Can we put a bunch of nerve cells in a Petri dish and then, by somehow introducing the information contained in the DNA, wire them up in such a way that they become a computer more capable than anything we now possess? My own judgement is that all of these things will eventually become possible. I believe that this is the prospect before us and the things we will discuss today only represent the first step in the Genetic Revolution.

1. J.R. Katz and H. Mark, Z. Electrochem, vol. 31, p. 105 (1925).
2. K. H. Meyer and H. Mark, Ber. Deut. Chem. Ges., vol. 61B, p. 593 (1928).
3. H. Mark and E. Wigner, Z. Phys. Chem., vol. 111, p. 398 (1924).
4. M.F. Perutz, Proc. Roy. Soc. A, 195, p. 474 (1949).
5. J.D. Watson and F.H.C. Crick, Nature, 171, p. 737 (1953).
6. R. Michael Hord, The Illiac IV, The First Supercomputer, Computer Science Press, Rockville, MD (1982).

Medical Ramifications

Michael Brown has just presented an overview of the Human Genome Project, which is a technological effort to obtain the DNA sequence of all the human genes. This project officially began in 1986 and is expected to reach completion by year 2005. In my remarks today, I will discuss the Human Biology Project, which is an experimental effort to understand the function of all of the genes identified in the Human Genome Project. The Human Biology Project will become the dominant activity of biomedical science during the next century.
To understand the function of the genes, which are composed of DNA, we must discover the function of the products produced by these genes, which are called proteins. The genes are the blueprint of life. But it's the products of the genes-the proteins-that are the bricks and mortar that carry out all the business of the body. The proteins determine how muscles contract, how the stomach digests food, and when the heart beats.

When we talk about 100,000 genes in the human genome, we are talking about 100,000 different proteins in the body that are encoded by these genes. The big question for the next century is how do these proteins assemble to make the human body work. What are the interactions and interconnections of each of these proteins with each other? How many proteins does it take to
product a heart? How many proteins does it take to produce a liver? And how do they all fit together? This will be the most gigantic jigsaw puzzle that has ever been put together once it is completed-much more complex than creating a map of the city of London, which is a maze of 30,000 streets.

In 1936 there was no map of London. An enterprising individual named Phyllis Pearsall took it upon herself sixty years ago to make the first map of London, the famous A to Z map. She got up every morning at 5 o'clock, walked sixteen to eighteen hours a day for a year-and-a-half, covered over 3,500 miles, and made an alphabetical list of all 30,000 streets in London. This was before the era of computers so Pearsall had to sort all her data in 500 shoe boxes. Her first A to Z listing (before she made the map) did not include Trafalgar Square because the shoe box that began with TR was lost!

Assembling the list of the 30,000 streets of London without an accompanying map that showed all the interconnections and all the interactions-how every street was related to each other street-would be analogous to obtaining the sequence of the 100,000 genes. Having this alphabetical list of 30,000 streets without a street map would be essentially useless to a Texas tourist who comes to London for the first time.

The next one hundred years of biology will be analogous to assembling the first functional street map of London from the alphabetical listing of the 30,000 streets, i.e., taking the gene sequences and the proteins that they encode and figuring out how these proteins interact with each other to form different parts of the body and how these 100,000 proteins relate to each other to orchestrate human life.
So the challenge for biologists of the future will be to learn the structure and the function of these 100,000 proteins. We now know the function and structure of about 4,000 proteins. So we have a long way to go.

When the sequence of the DNA in our genome is completed, we'll have three billion code words, which is equivalent to the information contained in forty Manhattan phone directories. The job of the scientist is to look at all of this information and figure out which regions of this DNA are translated into the proteins that are the workhorses of the body. The challenge to decode and decipher the human genome is truly enormous and approaches the surreal. One has to live in a world of dreams and fantasy to comprehend the enormity of this challenge.

And this brings me to a famous Belgian artist, RenÈ Magritte, our greatest surrealist painter. His paintings, which were done about 60 years ago, capture the style and spirit of the genome revolution. In his painting called Clairvoyance, the artist-this is a self-portrait of Magritte-is looking at an egg and painting a bird. By analogy, the scientist must do exactly what the artist does. He must look at some ill-defined phenomenon of nature (studying the DNA sequence of a gene) and create a thing of beauty (discovering how the protein encoded by the gene works).

Let's assume that scientists have clairvoyance and can look at all 100,000 of these DNA sequences and discover the function of their encoded proteins. This will allow us to answer four central questions of biology.

The first question is how do humans develop from a single egg? This question leads us to ask a sub-question: How is the heart formed from the genes and the proteins that are encoded in our genome? And once you know the answer to this question, then you can begin to say: How can we grow a new heart and transplant it into individuals? And how is the liver formed? Can we grow a new liver and transplant it?

We're beginning to understand how humans develop from a single egg by studying simple organisms like baker's yeast, round worms, and fruit flies. The genomes of these organisms, which are much smaller than that of humans, are being sequenced at the same time that the human genome is being sequenced. Baker's yeast is the first organism whose genome has been completely sequenced. A yeast cell has 6,000 genes compared to 100,000 in the human, and nearly one-half of these yeast genes have an evolutionary counterpart in the human genome.

What we're learning is that the metabolic pathways inside the cell are basically the same in all organisms, whether you're a yeast, a round worm, a fruit fly, an elephant, or a human. What makes a human different from a fruit fly appears to be the regulatory signals at the beginning of a gene that instruct the gene when to turn on and how much of the protein to make. An exciting area in the future is to understand these regulatory signals that instruct the same gene in elephants to express itself differently from its counterpart in humans and fruit flies.

The second question is how do humans differ from one another. Michael Brown has already talked about this topic. Learning about individual genetic differences will lead us to early diagnosis of disease and ultimately to the development of medicines that are tailored to the individual-medicines without side effects, the wonder drugs of the future. The side effects of many drugs that we take today are caused by different responses of individuals to the same drug because different individuals have different genetic makeups that influence the metabolism of the same drug once it gets into the body.

Today we all take the same penicillin. When we get a prescription for penicillin, every one of us will receive the exact same chemical form of penicillin. It will have the same atomic structure. Patients with AIDS all get the same AZT. These are medicines of identity. In the future we will have medicines of variation. Once we understand the genetic differences in the way the body metabolizes the same drug in different individuals, we will then be able to take advantage of that information and design these medicines of variation.

Now to the third question: How do our brains work? The human brain is a small organ with an astonishing complexity, the most complicated machine that exists in nature. No Boeing or General Motors has ever produced a machine that can match the human brain. It contains 100 billion neurons or nerve cells-1011. Each neuron is capable of making 1,000 synapses or connections with a different neuron. And that adds up to be 100 trillion synaptic connections in the brain-1014. That's 100,000 times more synapses in each human brain than code words for DNA in our genome. Counting synapses at a rate of 1,000 per second would take an individual 30,000 years to count them all!

Understanding synapses is the key to understanding how the brain works. Understanding memory, intelligence, emotion will all come ultimately from knowing the function of all the proteins encoded by our genome and comprehending how these proteins influence all the 1014 synaptic connections in the brain. Nongenetic environmental factors also play a crucial role in influencing the activity of our synaptic connections. This is unquestionably the most challenging problem in biology today. The challenge will be to discover the general principles of the brain that simplify this enormous complexity.

That brings me to a famous quotation by Albert Einstein. In 1920, when confronted with the complexities of quantum mechanics, he said, "Everything should be made as simple as possible, but not simpler."

It seems appropriate to follow this subdued quote from seventy-five years ago with a contemporary quote of a bolder nature, made by Walter Gilbert in 1990. Gilbert received the Nobel Prize in Chemistry in 1980 for teaching us how to sequence DNA. In fact, the whole revolution that we're celebrating today would not be possible if it were not for his major contribution. According to Gilbert: "In the year 2020 you will be able to go into the drug store, have your DNA sequence read in an hour or so, and given back to you on a compact disk so you can analyze it." You would then take the compact disk to your physician, and you and he or she together would analyze it and figure out which one-third of the people in this room will be susceptible to heart attacks because they have a cholesterol problem and therefore should eat a low-cholesterol diet and take drugs that lower their cholesterol, and which two-thirds would be immune to the cholesterol problem and therefore would not have to worry so much about cholesterol in the diet. You would also be able to learn whether you would be susceptible to high blood pressure, diabetes mellitus, schizophrenia, etc.

Is this a realistic possibility?

And that brings me to another famous painting by Magritte, entitled The Human Condition, in the National Gallery of Art in Washington, DC. It's a painting within a painting that exemplifies the essence of surrealism. The distinction between illusion and reality is brilliantly called into question in this painting. The tree in the painting hides the real tree behind it outside the room.

This is the way genomic researchers see the world, as a painted dream. Is the tree really outside the room? Will we really have drugs without side effects? Will each of our genomes really be put on a compact disk? Will we really be able to replace organs with cells produced in the test tube?

Let me now come to the fourth and last question. How do we convert genes into drugs? Of the four central questions of biology, this is the one that is furthest along in development, owing to the successes of the biotechnology industry. Drugs are produced by biotechnology through a sequence of events in which a human gene is cloned and then introduced into a living organism (either a bacteria or a yeast). The bacteria or yeast are then induced to manufacture large amounts of the protein encoded by the introduced human gene. This protein, called a recombinant drug or vaccine, is purified and administered to patients for therapeutic benefit.

The biotechnology industry began twenty years ago. It now consists of 1,311 companies, twenty percent of which are publicly owned. It employs 120,000 people, about one-third of whom are Ph.D. scientists. The industry has a market capitalization of $83 billion, product sales of $11 billion, research and development expenses of $8 billion, and an overall net loss of $4.5 billion. In other words, the entire biotechnology industry is about the size of Merck & Co.-without the profits!

To date, the biotechnology industry has developed seventeen recombinant drugs or vaccines that have been approved by the FDA, including insulin, growth hormone, hepatitis B vaccine, and erythropoietin. Erythropoietin is the leading drug produced by biotechnology and one of the top ten selling drugs in the world today. It is given to patients with kidney disease who have low hemoglobin levels. Like erythropoietin, most of the FDA-approved recombinant drugs and vaccines are major contributions to therapeutic medicine, and in this sense the biotechnology industry is a success.

True to the surrealist spirit, biotechnologists are always cooking up new recipes, and I'll tell you about some of the things that are in the pipeline-that you read about in the Wall Street Journal and The New York Times. For example, there are companies working on new growth factors to treat nerve regeneration and chronic neurological diseases like Alzheimer's disease and Lou Gehring's disease. There are companies working on drugs that will slow aging, on hormones to treat obesity, and on inhibitors to prevent the metastatic spread of cancer. There are also companies working on cures for baldness and on novel approaches of gene therapy for treating cancer, AIDS, and inherited diseases like cystic fibrosis.

But let me now try to put all this information into perspective. Here is how I view the biotechnology industry today-from the surreal to the real. These are the real facts. On average, one new gene is cloned and characterized each day, one new biotechnology company is formed each week, but only one new recombinant drug or vaccine is approved by the FDA each year. So in the twenty-year history of the biotechnology industry, only seventeen new recombinant drugs have been approved by the FDA.

Typically, you will read in the newspaper that a new gene for this or that disease has been cloned and that a new drug will be available soon. This is media hype! The available facts suggest that the creation of a drug from a gene takes about ten to fifteen years if the function of the protein encoded by the gene is already known. But to create a drug from a gene when the function of the protein is not known may take twenty to thirty years.

If Magritte, the surrealist, were alive today, he might represent the situation in biotechnology as shown in his famous painting, The Betrayal of Images, in which he reminds us that the image of the pipe is not the same as the pipe itself (Ceci n'est pas une pipe). A modern version of this painting would replace the image of the pipe with the DNA sequence of a human gene to remind us that a gene sequence is not a drug (Ceci n'est pas un mÈdicament).

Let me conclude by reminding you that the cloning of genes is only the first step in putting together the gigantic jigsaw puzzle of human life. The real clues to the puzzle will emerge from learning the function of each of the 100,000 proteins that are encoded by our genes and how they interact and interconnect with each other. This is the goal of biomedical research for the next century.

The Human Genome Project, An Overview

Three days from now in Stockholm, Sweden, two more Texans will receive the Nobel Prize: Smalley and Curl of Rice University. And this will make the sixth Nobel Prize earned by a Texan in the last eleven years. That is really a remarkable achievement for any state. It may be the most for any state in the last eleven years, and it's a tribute to what Texas has become.

All of these people came to Texas before they received their Nobel Prizes. We used to import them afterwards. Now, we're actually growing our own. And that is a tremendous achievement. Of course, the first four of those six were earned here at UT Southwestern, by Joe Goldstein and me, and by Al Gilman and Hans Diesenhofer, and I'm pleased to report that all of us are still on the faculty and still working away actively at science. So our school is a very exciting place to do science.

The subject for today is revolution. You've heard something about it already. It's a revolution in genetics that will change the world in the twenty-first century, just as physics changed it in the twentieth. The physics revolution revealed the nature of space and time and the atom, and gave us atomic energy, computers, space exploration, but it also gave us the atom bomb. The lesson is clear. Scientific revolutions give us power, and power demands responsibility. We must use scientific power for good and not for evil. Physics gave us the power over the external world. Genetics gives us power over our own bodies.

Up to now we've had to make lifestyle recommendations that are one-size-fits-all. Genetic predictions will allow us to adopt a customized lifestyle that takes maximum advantage of each individual's potential. It will help us decide what to eat, how much to exercise, what medicines to take, what career to choose, who to mate with, and what type of children to have. Achievement will be maximized. Death and disability will be postponed.

But at what price? Will the genetics revolution produce a new rationalization for prejudice, discrimination, and loss of freedom? These evils will be avoided only if the population is educated about the powers and the limits of genetics. And that's the topic of today's program.
The genetics revolution began at the mid-point of this century with two fundamental discoveries. The first you've heard about from Hans Mark. The discovery was that genes are simply chemicals. They can be isolated and studied in a test tube. They're somewhat complicated chemicals, but they're nothing more than chemicals.

The second discovery was the deciphering of the genetic code, the working out of how these chemicals actually determine physical and chemical processes in our body. Once the code was deciphered we learned how to read genes, just like we read a recipe book. Only the genetic recipe book is the mother of all recipe books. The genetics book contains complete instructions to make a human being, including the marvelous brain that Hans Mark was referring to. And we've just begun to read this book. We're like children who sneaked into the attic and found their parents' love letters. We're learning how we came to be.

Each of us began life as a single cell, a fertilized egg. Women produce only a few thousand eggs in their lifetime, and men produce trillions of sperm. Each egg and sperm is unique, because each one contains a different assortment of genes from the parent. And the moment that a particular sperm fertilizes a particular egg a unique individual is created.

Immediately, the genes issue orders. First, the egg is instructed to divide to produce two cells, and then four, and then so on. Within nine months the single cell produces more than a trillion daughter cells. Each of these cells contains a complete copy of the genetic instruction book.

The genetic instructions direct some cells to become kidney cells and others to become liver cells or heart cells or brain cells. They direct some cells to form the right index finger and others to form the left thumb. And it manages to get a fingernail in the correct place on each one.

But genes don't only control our body's shape. They also control our metabolism. Let me give you an example that occurred in your body after that delicious dinner at the museum last night.

If you didn't have caffeinated coffee, as I did, and you happened to fall asleep, your blood sugar began to fall because you had already absorbed the food into your system. The fall was detected by cells in the pancreas gland, and they turned on a gene. The gene produced a hormone called glucagon. The hormone was released by these cells and went to your liver. In the liver, glucagon turned on other genes that made the liver into a sugar factory that resupplied your blood. Your blood sugar rose, and you slept peacefully, totally unaware of the drama that was being played out by your genes.

Now, the important thing is that everybody's blood sugar last night didn't reach the same level. Some people's blood sugar had to fall quite a bit before their genes became activated. Their genes were a little sluggish. Other people's genes were turned on very early, and they had very high blood sugars all night.

That is the individuality of the genes-the common features of genes dictate the pattern of metabolism. But the absolute levels of various chemicals in our blood are dictated by differences in our genes. And that's why all of us differ, one from the other.
Each human being has about 100,000 genes, each of which controls a different bodily process. When the sperm fertilizes the egg, the 100,000 genes are selected.

About 80,000 of these genes are the same in all of us. So 80,000 out of the 100,000 are pretty much standard for the human species. And this explains why we all have the same general body plan and the same general patterns of metabolism.

But 20,000 of the 100,000 are variable. They exist in different forms in different people. These variable genes explain why we're not all the same height and why we don't have the same color eyes, hair, or skin. The 20,000 variable genes are the ones that make each human being unique, interesting, and vital. Without them, we'd all be as similar as three billion identical twins. Imagine three billion identical people in the world. What a dull world. Of course, it would simplify the task of choosing a mate.

To appreciate the power of genetic instructions, we need only examine a pair of identical twins. The slide shows two men who were born as identical twins. They were separated at birth and raised entirely independently of each other. In fact, each one didn't know that he had a twin until they were reunited by a scientist at the University of Minnesota who makes a habit of chasing down these pairs of twins that were separated at birth. And when they were reunited it turned out that both of them happened to have mustaches, and both of them happened to be volunteer firemen in their communities.

When you look at these men you see how similar they are, despite their different environments. You realize the enormous power that genes have to dictate a certain level of determinism. Identical twins are extremely close in height, within a half-of-an-inch of each other, but they're not the same in weight. If we think about the weight of identical twins we can learn something about the power and the limit of genetics. People's height doesn't change very much from one year to the next, but their weight changes dramatically, as I can attest. My weight goes up and down by forty pounds, depending on how hard I work at it.

Identical twins, therefore, don't necessarily have the same weight because each one might have variable weight during his or her lifetime. But there is one thing that they do share. I am unaware of a pair of identical twins, one of whom is habitually thin and has to work to gain weight, and the other is habitually overweight and has to work to keep weight under control. If that happens, it must be rare.
So genes don't determine our body weight, but they determine how hard we have to fight to maintain our body weight. We have a will that can overcome our genetic tendencies, but the genetic tendencies are there, and they create a different background against which each of us must operate.

In the broader sense we approach all environmental challenges equipped with a unique, and highly personal, set of genes. The environment plays upon these genes like a pianist plays upon a keyboard. And all of our keyboards are not the same. Some of us have defective keys here and there. Agents in the environment may exploit those defective keys to produce disease.
The next slide illustrates the other side of the coin-that is, how genetic differences can be. This slide is taken from an American Express advertisement that appeared several ago. The caption was, "Both of these men use the American Express card." But they don't have very much else in common. The short fellow is Willie Shoemaker, the great jockey, and the tall man is Wilt Chamberlain, one of the greatest basketball players in the history of the National Basketball Association.

These are two normal human beings. The physical differences between them were dictated when a single sperm fertilized a single egg. We've known about these genetic differences between people for a long time, and we've long since learned begun to modify our lives to account for our genetic differences and to exploit our genetic potential. It would have been absolutely ridiculous if Wilt Chamberlain had come home in fifth grade and said, "Mom, I want to be a jockey," and if Willie Shoemaker had tried out for the NBA.

Genes aren't everything. For all I know, Willie Shoemaker might have had the drive, and maybe springs in his legs, so that he could train himself to become a basketball star. There are some short players in the NBA, but they have to work a lot harder than the tall players. On the other hand, it would be technically impossible for Chamberlain to become a professional jockey. Fortunately, these two men picked careers that were consistent with their genetic makeup, and this made their life's work easier.

We've been able to make simple genetic predictions with athletes because you can look at people and decide whether they're likely to become an offensive guard of the Dallas Cowboys or a fencing champion.

But we haven't been able, up to now, to make chemical predictions-for example, to decide which person has a genetic tendency to a heart attack, and, therefore, must avoid cholesterol like the plague, or which person has a tendency to cancer, and, therefore, must avoid cigarette smoking.

The genetic revolution is going to allow us to examine the genes directly and to make recommendations for optimum lifestyles just like the recommendations that led these two men to their genetically-appropriate careers.

All diseases result from the environment playing upon the genetic keyboard. In some cases, the genetic problem is predominant. For example, in Down Syndrome, a child inherits an extra copy of a whole chromosome. That child has a very severe problem, which doesn't require an extraordinary challenge from the environment.

But if you look at another "genetic" disease, hemophilia, it's not so clear. These boys are born with a problem in their blood clotting. If they lived in a hermetically-sealed environment, they might never have a problem. But when they run outside and fall down they have bleeding into their knee joint, which causes severe problems. So this is a disease where the defect is genetic, but it requires something in the environment, like falling down, to bring it out.

At the other extreme are diseases that are thought to be completely environmental, like auto accidents and fractures and sunburn. But I would say that all of these environmental diseases have a genetic component. Let me use sunburn as an example.

Wilt Chamberlain has a natural suntan lotion with a protective value of four. That is, if you have dark skin it requires four times as much sun exposure to develop a sunburn as it does for a fair-skinned person.

If Wilt Chamberlain and Willie Shoemaker spend fifteen minutes on the beach on a bright sunny day, Shoemaker will have sunburn and Chamberlain won't. Sunburn is clearly a genetic disease!

We don't need fancy genetic tools to tell us whether we're genetically predisposed to sunburn. Experience teaches us whether we're genetically predisposed and, if so, we put on suntan lotion.

Not all genetic predispositions are so simple to detect. Let's go back to cholesterol. Only about a third of people will ever die of a cholesterol problem. A third is a lot, but it's only one in three. That means that two-thirds of people will never have a cholesterol problem. And yet every one of you here worries, I hope, about the cholesterol in your diet, even though two-thirds of you have no reason to worry.
The problem is we don't know how to pick out the one-third that is at risk and the two-thirds that are immune. We can't look at your arteries the way we can look at your skin and decide whether you need suntan lotion. So we have to make a one-size-fits-all recommendation. That is, everybody should have a low-cholesterol diet.

It may be that a low-cholesterol diet is actually not optimum for some people. For example, women need calcium to prevent osteoporosis. Women are going off of milk in droves because of the fat content. There may well be women who give up milk and develop osteoporosis even though they were in no danger of developing heart disease in the first place.

If we can learn which women can tolerate milk and which ones should avoid milk, and which ones need more calcium and which ones need less calcium, we'll be able to make recommendations that make sense for everybody.

Let me finish by saying something about the chemical nature of genes as an introduction to some of the later talks. Each gene is a long string of chemicals called bases. There are four different bases and they are abbreviated T, A, G, and C. They're lined up in long strings like beads on a string.

A typical gene has about 30,000 of these bases lined up on a string. There are 100,000 genes, and each one has 30,000 of these bases in it. So there are a total of three billion bases in the human genome.

The genes are lined up on chromosomes, which are long strings of DNA. The chromosomes differ in size, and some have more genes than others. But there are, in general, many thousands of genes on each chromosome in the nucleus of every cell.
Each cell has twenty-three pairs of chromosomes. Every gene has a particular home on a particular chromosome, which is always the same in all humans.

If we want to find a defective gene that's causing a disease, we have to map the gene, which means we must find out where it resides. Several years ago the United States government, and several other countries around the world, announced the goal of identifying the chromosomal location of all 100,000 genes. The second goal is to actually determine code letters for each one of the genes-to figure out the 30,000 bases that specify each gene.

The mapping has gone rapidly, even faster than people imagined. And the field is now at the point where they are about to determine the DNA sequence of most of those genes.

Within the first few years of the next century we will have that sequence of all of the human genes. When that sequence is obtained it will be like the star map is to the astronomers. It will be the starting point for all future biological and medical research. We will spend the next century deciding how to use all of this genetic information, which bring us back to the beginning of this talk. Hopefully, you are all now sufficiently knowledgeable so that you can appreciate the powers, and the limits of genetic determinism.

Ethical Issues in the Human Genome Project

Mark Pearson, DuPont's Director of Molecular Biology, has claimed that the human genome project will "usher in the Golden Age of Molecular Medicine."1 But even the legendary golden age of ancient Greece had its problems, and a project of the complexity and sensitivity of the human genome initiative will inevitably be accompanied by vast moral and scientific controversy. Officials at NIH have long been sensitive to this possibility. The ELSI (ethical, legal, and social implications) project was included in the human genome initiative almost from the outset, and journalists have long found the ethics-in-medicine theme almost irresistible, as the cover of Time magazine in March 1989 demonstrated, upon the launching of the genome project.

Reflection on ethical issues in genetics may merit this attention, but it needs to be kept in perspective. Many critics of recombinant DNA research in the 1970s and '80s-and now of the human genome initiative-have offered sensational moral problems, many with the character of Brave New World nightmares. We have been told that we are on the edge of genetic engineering that would fashion the human species as a super race, that germ-line gene therapy will have disastrous effects, that we are stigmatizing the disabled through genetics research, that we will graft animal genes into humans and graft human genes into animals, that we are resurfacing discredited eugenic thinking, that we are intimidating women's reproductive decision-making, and that we may even be destroying the human species. A simple example is found in the following 1991 quotation from U.S. News & World Report:

Society's knotty decisions will become even more tangled as the massive Human Genome Project lumbers toward its goal of mapping the location of every human gene, including those that govern such traits as intelligence, coordination and grace. That knowledge will expand the potential of genetic engineering far beyond the correction of disease and push it toward the realm of social engineering.2

It is likely true that eugenic thinking will be difficult to escape in upcoming years; and it will be difficult to distinguish constructive from destructive eugenic thinking. Nonetheless, the highly speculative nightmare accounts of ethical issues in the human genome project have thus far not been very specific or precise. Moreover, even the worst case scenarios do not suggest that the effort to map and sequence the human genome is intrinsically burdened with ethical issues. The problems are not about new scientific knowledge or the procedures used to obtain it, but about the uses to which such knowledge might be put, or not. It is here that the major moral problems are found-both the more speculative and the more practical problems.

From my perspective, the most interesting class of practical issues concerns the ownership and control of genetic information, and the most interesting class of speculative or theoretical problems is about scientific reductionism and causal determinism.
Insurance Implications and Questions of Social Justice

One of the primary problems is that systematic genetic testing will facilitate the exclusion of the genetically destitute from insurance coverage, and potentially from employment. It has been recognized from the beginning of the human genome project that genetic screening (that is, sorting an asymptomatic population to locate persons at elevated risk of genetic problems) would present issues of privacy and confidentiality involving employers, insurers, bankers, credit raters, and many others. Predictive uses of genetic information are not now sufficiently developed to affect a great many underwriting decisions-and they are not yet cost effective-but the human genome initiative will increasingly create a larger volume of predictive information to be added to the genetic information already available. Once obtainable, this information will encourage insurance companies to make genetic tests cost effective. Companies can then deny coverage, increase charges, initiate exclusions, and the like.

Such information is also obtainable by persons at risk of disease, and they are more likely than others to purchase the relevant type of insurance in maximal amounts because they are more likely to experience claims in excess of premiums. This circumstance and the costs of health care generally give employers a reason to avoid hiring those who may get sick and file claims. Many companies already carry limited coverage in the case of diseases such as AIDS. At the present time, so-called group insurance is being restricted by corporate policy to ever-smaller bundles of persons, eliminating those from the larger group who potentially will be most costly.

The private health insurance industry, not surprisingly, views these strategies and adjustments as justifiable, because insurance policies are designed to limit risk as well as to protect the healthy. But there is a morally unsatisfactory feature at the heart of the current American insurance scheme: Insurers want to avoid those most in need of insurance; the more you need, the less you can obtain, or the more you pay. The situation will worsen as genetic information accumulates. Lost in this upheaval is the moral goal of blindly pooling risks for groups in the face of the unknown lotteries of life. Now we each seek to become economically advantaged by being placed in the lowest risk group. However, if we cannot be placed in this group, our economic position is dramatically worsened, which may also affect our health care expectations. If insurance pools continue to be restricted through genetic tests, as they will be under current policies, then such tests will feed rather than alleviate problems of health care coverage, with the potential to become an American tragedy.3
These developments need to be put in a broader perspective of social justice. It would be incoherent to fashion either a public or a private insurance scheme that prohibited insurers from the use of genetic risks without at the same time prohibiting similar predictors of disease that are currently in use. An obvious question to ask about our system of access to health care is whether it is ethical to even allow risks of this sort to be assessed in contracting for insurance policies, and whether health, life, and disability insurance should be distributed more in accordance the luck of the lottery of nature. In a very different health care system than the one we now experience, it would be morally unjustified-a clear act of discrimination-to exclude persons from an insurance pool merely because they were unlucky in the genetic or any other natural lottery.

This would be less of a problem if persons were responsible for their health conditions, but genetics is the paradigm case of being ill or susceptible to illness for reasons beyond one's control. Broad principles of social justice suggest not only that exclusion of the disadvantaged is unwarranted, but that there is a social obligation to correct or prevent certain genetic defects if it is possible to do so. The logic here is that a commitment to equal opportunity requires more than the removal of barriers such as discriminatory policies. It requires positive steps to remove disadvantaging conditions.

It is morally shocking that so little of the debate about health care reform has turned on these basic moral issues about fair access, while so much of it has turned on purely economic questions of cost-containment and efficiency. Everyone is aware that the large numbers of uninsured and underinsured citizens is a massive problem in the present system. The point that I have been making is that new genetic information has the potential to enlarge the number of medical uninsurables well beyond what we are now experiencing, at the same time making new technologies available only to the wealthy and those lucky enough to have squeezed through our system of screening for coverage. So-called 'fair discrimination' in access to health insurance in the end amounts to a diminished access to desperately needed health care.

Employment, Genetic Screening, and Discrimination in the Workplace
I will now shift from insurance companies to employers and to connected problems of genetic screening. This shift is not a sharp change of direction, because insurance and employment are closely linked in this setting. Insurers may insist that employees undergo testing, and employers may find it advantageous to exclude potentially costly employees and forms of costly coverage. Although relatively few employers currently use genetic testing, this situation will change as the benefits of testing shift and as the market fosters incentives. The genome project will accelerate the process, increasing the use of genetic screening and raising questions about what can be reliably inferred from genetic information.

Lingering worries about genetic discrimination led to a recent study by Paul Billings and associates of our present systems of using genetic information. He considered whether incidents involving genetic discrimination are already occurring in the workplace, thus affecting access to social services, insurance underwriting, and the delivery of health care. 4

The study was eye-opening. Respondents in the study described difficulties they had encountered in obtaining insurance coverage, finding or retaining employment, and the like. Here is a typical example involving the "asymptomatic ill," as Billings calls them-that is, those who have a disease-associated gene, but no identifiable clinical illness. A clinical geneticist treating individuals with PKU wrote:
[Name withheld] is an 8-year-old girl who was diagnosed as having PKU at 14 days of age through the newborn screening program. . . . Growth and development have been completely normal. . . . The circumstances of the discrimination that this child has experienced involve rejection for medical insurance. She was covered by the company that provided group insurance for her father's previous employer. However, when he changed jobs recently, he was told that his daughter was considered to be a high risk patient because of her diagnosis, and therefore ineligible for insurance coverage under their group plan.
This and many other cases reported in the Billings study illustrate instances of discrimination against persons who are completely asymptomatic; their only "abnormality" lies in their genotypes. Though in truth healthy, persons are treated as if disabled or chronically ill.

Problems of Reductionism, Destiny, and Determinism
I turn now to a range of more speculative problems, all of which center on questions of genetic determinism. I begin by explaining why I think such speculation might be of interest to you.

The Causal Conditions of Behavior: Reductionism and Determinism
A vision of genetics that lacks perspective can foster the belief the genes are the primary and perhaps sole causal determinant of human ills and deviant behaviors. The move in various literatures has been rapid from disorders such as Huntington's and hemophilia to schizophrenia and manic depression, and from there to learning disabilities such as dyslexia, attention-deficit disorder, and dysfunction in language development. From there speculation has spread to the possible genetic bases of shyness, inhibition, risk-avoidance, drug abuse, sexual conduct, and all "modern maladies." At this point speculation has begun to get a little out of control. Here is an example from a recent Time magazine story that places its theses in a Darwinian context:
The premise of evolutionary psychology is simple. The human mind, like any
other organ, was designed for the purpose of transmitting genes to the next generation; the feelings and thoughts it creates are best understood in these terms. Thus the feeling of hunger, no less than the stomach, is here because it helped keep our ancestors alive long enough to reproduce and rear their young. Feelings of lust, no less than the sex organs, are here because they aided reproduction directly. Any ancestors who lacked stomachs or hunger or sex organs or lust-well, they wouldn't have become ancestors, would they? Their traits would have been discarded by natural selection.

This logic goes beyond such obviously Darwinian feelings as hunger and lust. According to evolutionary psychologists, our everyday, ever shifting attitudes toward a mate or prospective mate-trust, suspicion, rhapsody, revulsion, warmth, iciness-are the handiwork of natural selection that remain with us today because in the past they led to behaviors that helped spread genes.5

This 1994 story in Time was followed by another cover story in late 1995 that pointed to genetic roots for all modern maladies such as stress, anxiety, and depression.6

Also at stake in these discussions is the idea that human destiny follows from human biology, together with the accompanying theme that what genetic medicine does is to tinker with, and that human properties are therefore the outcomes of our genetic constitution.7

This theme continues to surface in the context of several delicate, ongoing, controversies, the most visible of which have been the homosexuality controversy, with its generally constrained conclusions about biology and destiny, and the IQ controversy-with its generally unconstrained conclusions.8

Conclusions reached in these controversies are often allegedly supported by scientific data, despite significant gaps between the data and the conclusions reached.

So how much of the variation in IQ is linked to genetic factors and how much to environmental ones? The best way to get a direct estimate is to look at people who share all their genes but grow up in separate settings. Four years ago, in the best single study to date, researchers led by University of Minnesota psychologist Thomas Bouchard published data on 100 sets of middle-aged twins who had been raised apart. These twins exhibited IQ correlations of .7, suggesting that genetic factors account for fully 70 percent of the variation in IQ.9

These conclusions are also turned into a broad social agenda that demands the abolition of welfare and affirmative action programs on grounds that they are doomed to failure, that they will do more harm than good, and that many forms of social inequality are the genetically inevitable outcomes of biological differences between the bright and the dull. Opponents of these arguments fear, of course, that a social and political agenda is driving the interpretation of scientific data; it is not science, but the abuse of science. And it functions to replace the idea of the moral worth of persons with that of their biological gifts.

Somewhere in upcoming years the human genome project will encounter at least one massive problem that no one has yet anticipated. Obviously I do not know what it will be. But it will involve some kind of interaction between science, law, and ethics.