Dr. Harold E. Varmus, Director of the National Institutes of Health
104th Landon Lecture
February 5, 1996
Gene Research: A Biological Frontier
Good morning. First let me begin with a note of gratitude to this campus. My first postdoctoral fellow was a graduate of your graduate school. One of my best students, Bruce Bowerman, a native Kansan, was a student in my lab for several years, and now is professor at Oregon University in Eugene, and I'm grateful for the instruction and direction he received here.
Two things make me particularly glad to be giving this lecture, but one thing first is that I learned about this lecture from the student, Bruce Bowerman, who said he got a good deal of direction in life from the lectures themselves. But this occasion is special for a couple of reasons for me. First it allows me to pay public tribute to Nancy Landon Kassebaum, whose intelligent and generous support of medical research have made my current job a lot more easy, and whose gracious friendship has made life in Washington much more pleasant. Kansas should be, I know is, very proud of her.
Secondly, the inclusion of at least two scientists, Carl Sagan and myself, on the Landon Lecture program this year, recognizes the enormous but often overlooked significance of science in the workings of our society. I want to thank the organizers, the organizing committee for featuring science in this way. Now, I learned yesterday that unfortunately Carl Sagan will not be able to speak as scheduled, and so I'd like to begin by usurping a few of his words from his book "Broca's Brain" at the outset.
"There have been astonishing recent findings," he wrote, in 1974, 22 years ago, "on the exploration of the planets, the collision of continents, the evolution of the human species, and the nature of the genetic code, which determines our heredity and makes us cousins to all the other plants and animals on this planet. Recent findings on these questions can be understood by any intelligent person," and there are many of them in this room. "Civilizations can be characterized," he wrote, "by how people approach such questions, how they nurture the mind as well as the body. Many of the problems facing us may be soluble, but only if we are willing to embrace brilliant, daring and complex solutions."
These words provide a useful backdrop for what I have to say today, and presumably for what Carl would have said next week and hopefully will say to you later in the year.
Now, I am here today as the director of the National Institutes of Health, not as an individual scientist, and for that reason I will say very little, but a little bit, about my own scientific work. Instead I will concentrate on one of the overarching themes that makes the work of the NIH so exciting intellectually and so promising for the nation's health. I'll also address aspects of the work that challenge us to adapt as a society, so that we can make use of new truths without abandoning old values.
First I want to tell you a few things about the NIH itself. We are a confederacy with over 20 semi autonomous units, each dedicated to the study of either an organ like the heart or a disease like cancer. With a budget of nearly $12 billion, we have the largest responsibility for federal support of science, outside of defense. We spend our money in two ways. About 10 percent of our budget pays for the work of several thousand scientists and our own clinical and laboratory programs largely on our Bethesda, Md., campus. The rest of our money, over 80 percent, is distributed to academic and research institutions throughout the country as grants, based on competitive review of applications by scientific peers. For example, in Kansas we support a 175 projects at 10 different institutions, at an annual cost of over $30 million. All this activity is based on the beliefs -- two beliefs -- that science can benefit health and that the support of fundamental health promoting science is the responsibility of an enlightened government.
When Franklin Roosevelt dedicated the NIH campus in Bethesda in October 1940, on the eve of World War II, he said, "We cannot be a strong nation unless we are a healthy nation, and so we must recruit not only men and materials, but also knowledge and science in the service of national strengths." Now, I realize there's a mild irony here. The man being honored by this lectureship, your great former Gov. Alf Landon, had to lose his bid for the presidency in 1936 to allow F.D.R. to speak these inspiring words. But I was pleased to learn last night that Mr. Landon, another hero of mine, was also a fan of F.D.R.
My privilege today is not to enumerate the past successes of the NIH, instead I want to describe what I see as a yet more exciting future. I want you to understand why the Congress and the president have agreed to provide a handsome 5.8 percent increase in funding for the NIH this year, a year, as you all know, when many highly valued agencies of government face a still uncertain future. I also hope to encourage some of you -- I gather there are high school students from other towns in Kansas brought in for this event -- to seek careers in biology and related fields. And I want to acquaint all of you with changes that are likely to occur in the practice of medicine over the next 50 years or so.
Now, nearly everyone has heard or read that great discoveries are being made frequently, almost daily in the health sciences. These discoveries concern many different medical problems, but most of them are based on work with genes. The concept of a gene has been around for a long time, serving to describe the inheritance of observable traits, like the colors of eyes or of plants. But in the new biology the gene is more than a concept, it is a physical thing, touchable, that can be isolated from cells in pure form, analyzed in full detail, multiplied a million-fold in a test tube, changed at will, and even used as medical treatment. Among our 23 sets of chromosomes present in the nucleus of each of our cells, there reside nearly 100,000 genes. Each gene is part of an extremely long chemical chain called DNA, the now familiar two-stranded or double helix, which I hope you're able to see. The strands are composed of only four chemical constituents, which are along the bottom of the slide, perhaps a little difficult to observe. These constituents are referred to as bases, and we abbreviate them by the initials, A, C, T and G. Now, despite this apparent simplicity, the order of the three billion -- yes, billion -- A, C, Ts and Gs in human DNA has enormous information content. In a language that is essentially universal, DNA provides to all kinds of cells in animals, in plants, in bacteria, the instructions for making proteins, the enzymatic work horses and the building blocks of cells. To make protein the DNA is first read out in the form of a related chemical called RNA in the same code, and the RNA is then translated to make protein. For those familiar with computers, DNA is like the information on a hard disk. RNA is like the same information on a floppy disk and protein is like the product of that information displayed in readable form on the screen.
All of you who have had elementary biology know that reproduction is an essential property of life forms. When DNA itself is reproduced mistakes occasionally occur. This isn't surprising, since each of the cells in our body contains the same three billion A, C, Ts and Gs. Our cells are equipped with tools to proofread and correct such typographical errors, but nevertheless, error correction is not perfect. The changes that remain known as mutations sometimes have very little consequence and may even have some benefit. But as shown here, mutations may also cause ineffective proteins to be made, and furthermore, mutations may be transmitted when cells divide. If those mutations have occurred in germ cells, eggs or sperm, they can be transmitted to future generations. For all these reasons the changes that occur in our DNA are the source of our joys and our sorrows. They are the origins of our diversity as a species and as individuals. They are the causes of many of the diseases that we suffer or our predispositions to disease, and they are the instruments of cancer and other disorders that arise during our lifetimes. The study of life's great molecules, DNA, RNA and protein, has been gradually transforming biology and medicine for the past 40 years, but in the past few years that transformation has been accelerated exponentially by international efforts to determine the placement and the sequence of all the genes in the human chromosomes. That is to decipher the order of all the bases in human DNA, the totality of which is known as the genome. To give you some idea of the enormity of that task, if we imagine each of the letters in DNA to be roughly a millimeter in size, just large enough to read with the naked eye, a complete sequence would stretch from here in Manhattan to San Diego.
Our country plays a leading role in this effort through a program funded by the NIH and by the Department of Energy, a program known as the Human Genome Project. By the year 2005, and perhaps earlier, we'll have a complete map of each of our 23 chromosomes, knowing the position of each gene, knowing the position of each sequence, knowing the order of the bases in and between each gene. Already several thousands of genes have been partially deciphered, including at least 50 that are known to govern major inherited diseases, like cystic fibrosis, Huntington's disease, other neurological disorders, some forms of cancer and Alzheimer's disease. Families with such inherited diseases, families in which are very high risk of serious illness is determined by a single misspelling of one of these genes, provides some of the most compelling stories from this biological frontier.
I will soon consider a couple of these stories, but before I do so, I want to make a more general point about disease. All disease represents a complex interplay between environmental and genetic factors. Some environmental factors are obvious, invading microbes, for example. But others are subtle, complex, clearly understood. Conversely, the influence of genes on disease can be much more complex and subtle than the examples of genetic disease I'll discuss in more detail in a moment, and there are at least three reasons for saying that genetic factors may have very subtle effects.
First of all, each of us brings into our lives susceptibilities of different kinds to environmental causes of disease, and that susceptibility is determined by the genes we inherit from our parents. In fact, in each case, the susceptibility is likely to be determined by multiple genes. So high blood pressure, addictive and other psychiatric disorders, diabetes, coronary artery disease, are common conditions influenced by multiple genes in combination with diet, behavior, economic status and other environmental factors.
Secondly, some diseases, most generally cancers, are caused by mutations that occur during our lifetimes, not by inherited mutations. Third, genes proteins that govern the behavior, the physiology of healthy and diseased tissues and cells, hence knowing genes helps us to understand and to counter disease.
Now, I want to take a liberty here to illustrate this last important point with a brief, somewhat self-indulgent anecdote from my own area of research. This will be as scientific as the talk gets; it will get back into a less scientific mode in a moment. Over 20 years ago my colleagues and I at the University of California, San Francisco, identified a normal gene called SRC, S-R-C, as the source of a viral gene capable of causing tumors in infected chickens. The SRC gene was the first of a large group of genes now known as oncogenes, some of which are actively involved in the development of human cancers.
The point I want to make here though is not about cancer. The normal functions of oncogenes, the reason we have oncogenes in our chromosomes was obscured for many years. Recently scientists have learned to alter the chromosomes of mice, to change or eliminate individual genes. When mice were deprived of their normal SRC gene, they were found to have a dramatic surprising disease called osteopetrosis. Their bones are abnormally thick, there is too much bone. Now ordinarily bone is continually being made, even in adults, by one cell type and being continually removed by another. In mice without a SRC gene the bone removing cell called an osteoclast doesn't work properly.
Now, in patients with osteoporosis, an important human disease especially common in older women, there is too little bone, the bone is too thin. If the bone removing osteoclast in these patients could be slowed down, for example, by inhibiting the SRC protein, bones might be strengthened. Now, biotechnology companies are vigorously pursuing such ideas. Now, inhibitors of osteoclast to treat osteoporosis are still in the future, but the impact of genetic knowledge on health is already accelerating.
Readers of the New York Times Sunday magazine were recently taught this lesson by Charles Siebert, the author of an emotionally wrenching article about a genetic disease affecting his own family. Siebert was approaching the age at which his father died prematurely of an uncommon heart condition called hypertrophic cardiomyopathy. It's a mouthful, but it's a fancy term for a sick heart that's too big.
As Siebert consulted Doctor Fanetta Dizere at the NIH Clinical Center to find out whether he had inherited his father's condition, during the quest he confronted some important and troubling questions. "Do I want to know the answer? Will it help me to know?" "Or would," in his words, "a gene predisposing me to an incurable condition only hobble rather than help my existence.?" In other words, could such knowledge be toxic?
Along the way of thinking about these questions he learned many interesting things about the disease. First he learned that it was called by a variety of different mutations that changed the shape and the function of the proteins shown in this diagram, like myosin, that work as a coordinated unit, a kind of machine to allow the heart muscle to pump blood. Now we know a lot about some of the proteins in this contractile machine. For example, we have three-dimensional precise picture of the myosin component, and the mutational changes that weaken the myosin part of the heart's pump. Now, when the heart muscle is weak, blood is less effectively pumped to the rest of the body. The heart tries to compensate by making more heart muscle, and in these thickened walls the electrical impulses that govern the heart's rhythm may fail. This is probably the most common explanation for the sudden deaths of young athletes you occasionally read about in the paper.
Siebert also learned that the disease is quite unpredictable. In some families people who inherit the same mutant myosin gene have very different consequences for reasons still unknown. It is not necessarily useless to diagnose this disease. When a young boy was brought to the hospital with a bruised forehead, fainting spells were suspected. The electrocardiogram shown here showed in the middle panel interruptions in his heart rhythm, some interruptions total lack of contraction long enough to cause blackouts. His DNA was later shown to harbor a mutant myosin gene, inherited from one of his parents. Outfitted with a new cardiac pacemaker, he now plays ball for Jay's Restaurant.
Before deciding whether to test his DNA for myosin gene mutation, the author, Siebert, traveled to a farm town in the Midwest to meet a large family affected with this uncommon disease. It is an encounter that makes the disease real for the reader as it did for Siebert. In Siebert's story we're told only that the family lives in the Midwest, not told whether it's in Kansas or Missouri, and we're not told that information for a single important reason. Most affected members of the family have lost their medical insurance, and the few who still have it are afraid of losing it. That's another reason for Siebert to think that genetic knowledge may be toxic.
Now, Siebert has decided to postpone any further efforts to learn whether he has inherited his father's bad gene. Without symptoms he might not have much to gain from being certain about the mutation and he might have a lot to lose.
Breast cancer can give us another more highly publicized perspective on genetic diseases. Cancer of the breast is a common disease among women in the industrialized world. Nearly 200,000 cases of breast cancer will be diagnosed in this country this year, and over 40,000 women will die of the disease. In the vast majority of these women there is no reason to implicate an inherited mutant gene, but in the families of roughly 5 to 10 percent of women with breast cancer, a simple pattern of inheritance could be discerned.
In about half of these families the mutant gene is called BRCA, for Breast Cancer 1, located on Chromosome 17. Most of the other families have mutations of another gene called BRCA 2 on a different chromosome. Unlike the situation of the myosin gene, we have very little idea what these two genes do. Firstly, nothing is known about the proteins they make. Yet women who inherit a mutant form of BRCA 1 have a much greater likelihood of developing breast cancer than do other women.
Roughly 85 to 90 percent of these women develop breast cancer by the age of 60 to 70, and the cancers tend to appear quite early in life, frequently between the ages of 30 and 50.
Knowing so little about these genes, is it useful to test women for mutations in them? Should all women, after all, be using mammography to try to detect breast cancers early anyway? A woman came to visit my NIH colleague, Frances Collins, the head of the Human Genome Project, because her two sisters, her mother and her mother's sister had all developed breast cancer at an early age. As a result she had decided to have her breasts removed surgically as a preventive measure against what she assumed to be a certain fate. When her DNA was tested, however, she was found not to carry the BRCA mutation present in her affected relatives. She canceled her surgery, she cheered up considerably, very positive effects of a negative test.
Effects of this kind should not be overlooked in our debate about genetic testing. Now, the patient had a 39-year-old female cousin. This cousin thought she was not at high risk because her closest relatives with breast cancer were aunts, but she was found to have the mutant gene which she received from her cancer-free father. Informed of this news she had her first mammogram, a test which would not normally be advised for a woman of her age. The mammogram detected an early breast tumor, which was removed with a very high probability of cure.
Do these stories mean that all women with a family history of breast cancer, or even all women, should be tested for mutations in the BRCA 1 and the BRCA 2 genes? This is a hotly debated issue. For a few months after the discovery of the BRCA 1 gene last year, the answer seems moot, because the gene is very large and the mutations occur at many different positions within the gene. Thus the expense and the difficulty of the test added to other problems, the very little that could be done if the tests were positive, the risk of losing insurance, the worry and the damage to self-image.
So only a few tests were being done in experimental settings and with families known to be at high risk, but very recently the situation has changed. It was discovered that about 1 percent -- quite a high number -- of all Jewish women and, of course, men originating from Eastern Europe, so-called Ostra-Nazi Jews, have exactly the same mutation.
Testing specifically for this mutation is easy, it's cheap. The indications are also strong that this mutation, like the others, strongly predisposes women to breast cancer. Now, understandably, given the odds and the expense, many Jewish women want to know yes or no, do I have this mutation, but how do we ensure these tests are accurately performed? At what age is it appropriate to test women to see if they have it? What do we advise those with positive results to do? Could, for example, frequent mammography -- too frequent mammography -- be harmful in such women? Is it advisable to suggest that women have their breasts removed? Is that even fully protected against breast cancer? Women with mutations in this gene also have a high risk of ovarian cancer.
How do we protect the prophecy of the results so that the tested individuals are not discriminated against by employers, insurers or even prospective mates?
Now, this dilemma that I've sketched out for you in the case of BRCA 1, is only a prominent example of the many that are being raised as genetics and molecular biology transform medicine. Although these questions are daunting, they are not, for me, reasons to turn away from the pursuit. New knowledge always raises new problems, but it is almost always proven superior to ignorance.
The genetic revolution I have tried to describe will produce amazing changes in the practice of medicine, at least in the highly developed and more affluent parts of the world. For this to happen, those who would have medical care will have to become much more familiar with genetics than they are at present. People will need to become used to the idea that their prospects for health care can be gauged early in life by genetic tests.
Now, there will still be ample opportunity for more traditional means to predict success in love and business, but DNA tests will be used for the relatively common mutations that predispose to cancer, heart disease and other ills, and from mutations that are suspected to exist in families because of family histories. This information will guide and hopefully even inspire strategies to prevent disease or detect it at early stages.
Within the next 50 years there will likely be many therapies based on some of the genetic discoveries I've been describing. In a few cases genes themselves will be used to replace mutant genes or to treat cancers or infectious illnesses. More commonly there will be potent drugs based on an understanding of disease in genetic and molecular terms, as I suggested earlier when I discussed osteoporosis.
But there will remain serious concerns even within this promising picture. We will not have resolved a thorny issue about the decisions we make to transmit our genes to our progeny. As individuals every one of us in this room will have to accept the idea that we all carry mutant genes we would have preferred not to have received. Many people already use genetic testing of embryos or early fetuses to prevent the rare devastating illnesses caused by some such genes, such as severe anemia, cystic fibrosis or childhood neurological diseases. But soon we'll be able to consider whether to transmit diseases that predispose to the more common adult illnesses, such as early breast cancer or heart disease. These will be difficult decisions for individuals and will present serious dilemmas for our society.
To make any further progress we have an immediate political issue to resolve. We must insist that all states and the federal government pass laws to protect our citizens from abuses of genetic information. Recently the Equal Employment Opportunity Commission ruled that the Americans for Disabilities Act prevents job discrimination based on genetic information. This will help, but strong laws that guarantee the privacy of genetic information and protection from reprisals by insurance companies will be essential, and currently only a few states, Kansas not among them, have such laws. Provisions in Sen. Kassebaum's proposed Health Insurance Reform Act are especially enlightened in this respect.
Now, I have taken this discussion way beyond the scientific arena into politics, law and ethics, to illustrate some ways in which the genetic revolution in biology will affect us all, will require the talents of many who are not scientists, and will compel all of us to understand the principles on which this revolution in biology rests. To reinforce this point let me give you Carl Sagan, the final words, quoting again from his book "Broke His Brain." I quote: "The compassionate application of new technology to human problems requires a deep understanding of human nature and human culture, a general education in the broader sense. We are at a cross roads in human history. Never before has there been a moment so simultaneously perilous and promising." Now, he was speaking about nuclear power, but it could have been genetics, when he says, "We are the first species to have taken our evolution into our own hands. There is not much time to determine which fork of the road to which we are committing our children and our future.