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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.