Picturing DNA
Chapter 7:
What is Normal?

Introduction

Chapter 1

Chapter 2

Chapter 3

Chapter 4

Chapter 5

Chapter 6

Epilogue

Babies decanted from bottles instead of delivered from women? Aldous Huxley described this dystopia in his 1932 novel, Brave New World. But he made several errors in his prediction. At the moment, pregnancy is more fashionable than ever, with bellies big to bursting prominent everywhere from the workplace to the Academy Awards ceremony. Yet how these fetuses get into those bellies is not always the old-fashioned way. Increasingly, reproduction is achieved by means closer Huxley's vision of test tubes and petri dishes, what we now call "in vitro" fertilization, and many couples are as happy bragging about this new approach to parenthood as others are enthusiastic about the traditional method.

Huxley's bottle-incubated babies were bred for intelligence and skills, as they were to be placed into a particular rung of society at birth. But he was writing in an era when planned economies, and government planning in general, seemed the political reality most likely to prevail. (Science-fiction writers often take whatever is current to its logical extreme.) Neither Huxley nor his contemporaries foresaw the kind of unimpeded capitalism that greeted the opening of the twenty-first century. It is not government, but the individual parents who carry genes for conditions they do not want to pass on to their offspring who are deciding which embryo leaves the petri dish to spend nine months planted in its mother's womb.

Most parents are concerned with the quality and the quantity of their offspring's life. Most would want to avoid their own anguish and prevent the suffering of an infant afflicted with, for example, Tay-Sachs disease, a painful hereditary condition that causes so much agony during the child's short, heartbreaking life. Those at risk may choose to abort the fetus, though they must wait several months to know the fetal condition, and these can be anxious, painful months indeed. But couples who carry Tay-Sachs genes can now choose to implant a healthy embryo fertilized in vitro rather than wait and undergo abortion. Or perhaps a couple has experienced the constant tension and pressure of raising a child with cystic fibrosis. Life expectancy is lengthening for these children, but it is a life filled with painful treatments almost from the start. For their next pregnancy, parents might choose to select embryos free from this condition as well.

For those willing to bear the costs and physical discomfort, it is now possible to examine, in vitro, the cells of an embryo to search for an increasingly large number of diseases caused by a single gene. But as we become more familiar with the details of the human genome, we will most likely discover that all of us carry genes for the majority of diseases that are caused by a multiplicity of genes. We will be able to predict for ourselves or for our children the susceptibility to heart disease, stroke, different kinds of diabetes and cancers, and the whole gamut of diseases that strike aging brains, including Parkinson's and Alzheimer's. Should be chose, we may eventually be able to ensure that our offspring do not carry genes for these familiar conditions by deciding not to let those embryos develop in the first place.

There may be another option, a technique that already has agreed-upon ethical guidelines, but is not yet biomedically possible. It is called germ-line therapy, and it would eliminate the problematic gene in reproductive cells for inherited conditions such as Huntington's disease and Tay-Sachs. Not only will the child not inherit the condition, neither will his or her offspring. One reason germ-line therapy is now considered unethical is that we do not know the complexities of many medical conditions. What if cystic fibrosis, for instance, were to be linked with qualities that we do not want to eliminate, such as a certain kind of imagination or a sense of humor? It also may be possible that as treatments become increasingly effective, it becomes unnecessary to eliminate the condition altogether.

As the genome releases more secrets, we may find that a small collection of genes contributes to a disposition for violent sociopathic behavior. If we could identify embryos with these genes, would we be obliged to forego implantation? Some governments might require that prospective parents with the hereditary capacity to have such children undergo testing, and then deflect the pregnancy, either by embryo selection or abortion, to make sure that no such people get a chance to live at all. Such a government might also make it difficult for individuals to choose to have children whose medical care will be an economic burden on the entire community. These possibilities and choices, whether individual or societal, are not just about our own lives but about how one generation decides who will be excluded from the next.

There will most likely be another set of choices confronting parents in the near future. Parents who would like a child with their own musical talents, rather than Uncle Jim's tin ear, may be able to make that choice should these genes become identifiable. In this instance, parents could scan a selection of their own embryos and select the one, if there is one, that carries the musical genes. Alternatively, they might opt to select any of their healthy embryos and insert a gene from a stranger, probably one for which they have paid market value and which carries a genius for chess or jazz or cross-country skiing.

While this method of building a family may seem farfetched as well as arduous, joyless and expensive, it is likely that some people will choose to become parents this way. There already have been women who sought and became impregnated with sperm from a sperm bank specializing in donations from Nobel Prize winners. There will undoubtedly always be people willing to pay for some kind of supposed genetic guarantee as to a child's physical and perhaps mental and emotional makeup. Should the price of such genetic manipulation drop to the level of the middle-class bank account or even be available in the future as a benefit from a national health system, it is hard to predict what proportion of the population would take advantage of the opportunity to manipulate the make-up of their children, rather than rely on faith or fate.

Predicting the future is at best a fool's errand, but it is hard to resist the temptation, especially in the face of genuinely revolutionary scientific knowledge. There was a time in the nineteenth century when slaves who repeatedly tried to escape were said to have inherited an inability to know their place, and early in the twentieth century, a period when Love of the Sea (philothallasimia) was considered hereditary. Today we are more sophisticated about the role of environment in forming character, yet the unraveling of the genetic code has sent the pendulum swinging back. In their enthusiastic endorsement of the Human Genome Project, even some scientists are willing to assign simple genetic causes to complex personality problems. As we become skilled at reading the map that is the human genome, we will probably understand more about which genes, and how many of them, contribute to behavior. If some turn out to be truly predictive, we may consider making some kind of accommodation for dealing with troubling genetic tendencies. It may be that we will have advance warning, as read in the genome, of the potential for violence in fetuses or young people who have not yet done anything wrong. This is a conundrum we do not now have the ethical, moral, or legal tools to resolve.

Q & A with Dr. David Baltimore

Q: What is your time line for actually being able to give genetic therapy?

Baltimore: Simple genetic therapy should be available in the next fifteen years

Q: And where would you think it would begin?

Baltimore: It would begin with simple gene defects that are well-defined defects in which you can easily tell when a defective gene is corrected.

Q: So what is done is inserting somehow a stronger gene to compensate for the bad gene?

Baltimore: I can't tell you what form it will take. For instance, one form of gene therapy is to take cells out of the body, modify them in a test tube, and put them back in. Another form is to take certain generic cells and modify them and implant them.

Q: Where would you implant them? Would it matter?

Baltimore: It matters which cells you have, it matters where you implant them. Yes. Both are very important.

Q: Which brings up the question of germ line therapy, changing the genes that will be carried on into the next generation.

Baltimore: Right. We can certainly modify the germ cells of mice now. We do it quite routinely. So there's no intrinsic reason why we can't do it with humans. The problem is that we take a tremendous loss in the mice, due to all sorts of secondary events that make it inefficient, which you'd never want to do for humans, because you don't want to develop defective humans.

Q: Do you think there is any ethical reason not to work on having a good germ line treatment?

Baltimore: Depends on what you mean by ethical.

Q: Well, it certainly isn't ethical to knowingly have the possibility of producing defective people, right?

Baltimore: Right.

Q: But if, for some reason, you knew this would work, there are people who think that this too is bad.

Baltimore: Yes, I know. And I have sympathy with that. Their argument is largely a slippery slope argument. Not that it would be a bad thing to get rid of the sickle cell gene in the modern world. No body really needs it . It is not good for anybody. It just does harm. So you could use germ-line therapy mode replace the sickle cell gene with a normal gene. And then, all the children born of that lineage would be cured. I think most people would say that that would be a great thing to do. People who are worried are worried not about doing that particular process unless there's some very strong religious motive there, like for instance, people who believe that you should not abort a Down's child.

Q: Right. It isn't quite the same.

Baltimore: True: What most people are really worried about is not the replacement of a sickle-cell gene, but the slippery slope-when they can start making people taller, smarter, whiter, and all of those value judgments. And what people are really worried about is gene therapy with the aim of making the child somehow more effective in the world, by some set of values, like taller is better or whiter is better, or something. Those are the things that most people are worried about, because what they're worried about is that those value judgments are going to remove diversity from the population and give us a population which will be poorly suited to actually run the diverse world that we're in.

Q: Do you think that this kind of therapy would ever be so simple to do that millions of ordinary people would choose to have children?

Baltimore: No, I really don't. I don't think it would be simple enough to do that. But I'm always worried about making a judgment that science is not going to be able to do something.

Q: Or be able to at a price that is within the reach of everyone.[ Baltimore: Price is the issue here. And effectiveness. If you could do it swiftly, cheaply, safely-through an injection or something-sure. Then we'd really have a problem.

Baltimore: Well, soon we're going to soon have a catalog of all of the human genes. And in particular, we'll find the really bad genes-genes that predispose one to cancer And we're going to have to then find a way to carry the effects of those genes. And I don't believe gene therapy is going to be the right answer for all of them-not for even very many of them. For instance, if we knew somebody had a gene for cancer and we had really good imaging diagnostic methods for finding early tendencies, then what we would do if we knew somebody was in that situation is probably monitor more often, like we do for people with polyps.

The expression of some genes, like the gene for Huntington's disease, are impervious to the environment. Others, including those that may be linked to sociopathic behavior or those that suggest we may be susceptible to colon or breast cancer, are not like little triggers that indicate that at some point we will fly off the handle and gun down our colleagues or succumb to rapidly multiplying tumors. All they indicate is a predisposition for the behavior or the cancer. Knowing that the genes are there may enable us to take steps to forestall the eventuality. As scientists familiarize themselves with the newly completed map of the genome, it is likely we will discover that everyone has a susceptibility to certain diseases and behaviors.

Conditions such as multiple sclerosis or Parkinson's disease, which can prove devastating today, may be ameliorated in the future because knowledge of the genetic cause may pinpoint the physiologic problem and lead to treatment. In that event, the conditions may be controlled, and those living with them may see them as offering a unique way of looking at the world. In other words, conditions that are life-limiting today might, if treatable, be desirable tomorrow. Genes are only the template of conditions that may present themselves in ways that people choose to live with. Rather than eliminating, or "selecting out," people with divergent physical conditions, we may be en route to redefining and expanding what it means to be normal.

Every ailment, every disease that causes pain, can be traced to malfunctions in at least one vital organ or the circulatory or immune systems. Some conditions are a response to the failure of a single organ like the kidney or liver or to the deterioration of the brain. The organs or systems may be in battle with malignancy. They may, on the other hand, be succumbing to normal aging-or what has been considered normal aging. Perhaps the most startling spin-off of the anticipated benefits of the decoding of the human genome, is the redefinition of what it means to age.

An English king at the end of the seventeenth century decided to poll the oldest people in his realm to discover what they recalled as the most outstanding change during their lifetime. The overwhelming response had nothing to do with the Civil Wars that had raged or the decapitation of Charles I. What the old folks remembered best was the introduction of a fireplace into their humble homes. Suddenly families could cook indoors and heat their homes without being choked by smoke. A similar poll of centenarians recalling life in the twentieth century might describe an even more profound change. Not only has the world population increased from 1.5 billion in 1900 to 6 billion in 2000, the age distribution in developed countries has changed remarkably. So many people now reach the age of one hundred that neurologists who study the brains of long-lived people have enough subjects to form a statistically useful data set. There are, correspondingly, more people over eighty, sixty and forty, leaving children and younger adults a minority for the first time since records were kept.

The increase in longevity can be seen by contrasting life expectancy in 1880 and 1990. Of the 70 million people alive in the United States in 1900, only 4.1 percent were over the age of sixty-five, and a mere one hundred twenty two people were over eighty-five. In contrast, by 1990 the percentage of the population over

Q & A with Dr. Eric Lander

Q: What do you expect could realistically occur in the next ten years in terms of improved medical care through knowing the map of the genome.

Lander: Oh, I think the most important consequence will be tremendously improved understanding of the cause of disease. You know, we don't actually know what causes heart disease, asthma, [or] diabetes at all. By finding the genetic risk factors and understanding what those genes do, for the first time we'll understand the etiology. It's not a guarantee that by understanding the etiology you will be able to fashion therapies, but knowledge sure beats ignorance.

Q: It's certainly a first step, right?

Lander: It's a first step.

sixty-five had tripled to 12.5 percent, and there were now 3 million people who had already celebrated their eighty-fifth birthday. The Census Bureau projects that in 2050, these figures will jump to 20 percent and 18 million, respectively.

The scientific study of longevity, the how and why of aging, has prompted research into the life expectancies of mice and fruit flies in search of the "Methuselah" gene-or perhaps the Methuselah diet.

In studies of rats, those forced to live on a diet of a few well-selected calories lived twice as long a control group that ate normal rat diet. While no one has done such a controlled experiment with people, studies of individuals as well as patients recovering from heart disease suggest that a very low-calorie vegetarian diet combined with regular exercise can diminish the degenerative aspects of aging like dementia, arthritis and disorders of the digestive track. But it cannot hurt to pick the right set of parents, say the scientists who study aging. Good habits can help, but may not be enough to compensate for inheriting a bad set of genes.

For those not lucky enough to have picked the right parents, an increasing understanding of the human genome may give us insight into strategies for longevity in addition to those based on modified diet and exercise. We may be able to figure out why our cells stop replicating, why we age and how to do something about it.

Biologists knew for most of the twentieth century that there is a limit to the number of times a cell can replicate. After a certain number of divisions, most human cells die and our vital organs wear out. The mechanism inside the cells that stops them from replicating is part of the mechanism that prevents healthy cells from becoming cancer cells. Cancer cells are runaway replicators. They keep making more of themselves, growing into tumors without inhibition, invading healthy parts of the body.

In the 1930s, biologists discovered that tissue from human cells doubles about once a day for about sixty days, and then stops growing. They called this limit "cell mortality." It took some time to understand the mechanism for the cells' ability to "remember" how many generations they had been through so as to know when to stop. This process was explored by American geneticists studying very different kinds of organisms-corn and fruit flies. Scientists in both fields independently observed that the string of chromosomes of their organisms had ends that are protected by shields, like the plastic tips at the ends of shoe laces. These tips act to protect the ends of the chromosomes from fusing with one another, or from wearing away. They called these ends telomeres.

At about this time, a French biologist claimed that human cells could be maintained alive in tissue culture indefinitely, and that he had ancient human tissue culture to prove it. His sample was so valuable and, indeed, unique, that his laboratory maintained it for years, even after he died. No one challenged his claim until twenty years after his death when two American biologists decided to prove the French lab wrong. In the early 1960s, they performed his original experiment again and found that contrary to his claim, there was a limit to how often the cells could divide. This natural limit, called the Hayflick Limit, is named for one of the researchers, Leonard Hayflick, who also suggested that this limit might have something to do with the aging process.

By the mid-1970s, the double helix of DNA was widely accepted as the mechanism that governs the reproduction of the genetic code for all living organisms and maintains each organism by continuously making exact copies of its cells. Then an exception was discovered. The extreme ends of most chromosomes are never copied perfectly. Instead, the ends, or telomeres, get shorter with each replication.

That was the state of knowledge until a few years later when a geneticist working on paramecia, a single-celled protozoa, made a discovery. Paramecia do not lose telomeres; instead they divide and reproduce indefinitely. They are essentially immortal because they have a specialized enzyme called telomerase that regenerates the ends of their telomeres.

Alas, most human cells are not like paramecia; after a set number of replications, they die. However, there is an exception. Human germ cells-sperm and eggs-keep on replicating, because, like the paramecia, they contain telomerase enzymes, and they keep this enzyme even as they become embryos, at least for a few cell divisions. Then the telomerase disappears, its extinction a powerful barrier to runaway cell replication, which is an operative description of cancer.

A paradox that teases molecular biologists is how to harness telomerase so that it can be killed when it permits cancer cells to replicate, while at the same time encouraging it to maintain the cells that have reached the limit of their life expectancy, allowing them-and of course the person in whose body they exist-to live longer. The search for the reason that some cells live and some cells die is a search for, if not immortality, a vast extension to human lives.

The search is now moving on at least two paths. On one, researchers seek to extend the shelf life of organs that are wearing out. On the other, researchers focus on understanding cancer. Both searchers are confident that in the next few decades, an increasing familiarity with the map of the human genome will lead to an understanding of most kinds of human cancers.

Postponing aging, and thus postponing death, may lead to the ultimate reconception of what it means to be normal. But this will only be true if society figures out a way to distribute the advantages of the knowledge gleaned from the human genome project equitably. There remains the possibility that private interests will price the access to the benefits of the biomedical spin-offs of the Human Genome Project beyond the reach of most people in affluent nations and certainly beyond that of the overwhelming majority of people in the developing world. If that comes to pass, Huxley's Brave New World may seem a pastoral idyll.

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Picturing DNA by Bettyann Holtzmann Kevles & Marilyn Nissenson
Copyright © 2000 Bettyann Holtzmann Kevles & Marilyn Nissenson
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