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Genetics and human malleability.

Genetics and Human Malleability

Just how much can, and should we change human nature ... by genetic engineering? Our response to that hinges on the answers to three further questions: (1) What can we do now? Or more precisely, what are we doing now in the area of human genetic engineering? (2) What will we be able to do? In other words, what technical advances are we likely to achieve over the next five to ten years? (3) What should we do? I will argue that a line can be drawn and should be drawn to use gene transfer only for the treatment of serious disease, and not for any other purpose. Gene transfer should never be undertaken in an attempt to enhance or "improve" human beings.

What Can We Do?

In 1980 John Fletcher and I published a paper in the New England Journal of Medicine in which we delineated what would be necessary before it would be ethical to carry out human gene therapy. [1] As with any other new therapeutic procedure, the fundamental principle is that it should be determined in advance that the probable benefits outweigh the probable risks. We analyzed the risk/benefit determination for somatic cell gene therapy and proposed three questions that need to have been answered from prior animal experimentation: Can the new gene be inserted stably into the correct target cells? Will the new gene be expressed (that is, function) in the cells at an appropriate level? Will the new gene harm the cell or the animal? These criteria are very similar to those required before use of any new therapeutic procedure, surgical operation, or drug. They simply require that the new treatment should get to the area of disease, correct it, and do more good than harm.

A great deal of scientific progress has occurred in the nine years since that paper was published. The technology does now exist for inserting genes into some types of target cells. [2] The procedure being used is called "retroviral-mediated gene transfer." In brief, a disabled murine retrovirus serves as a delivery vehicle for transporting a gene into a population of cells that have been removed from a patient. The gene-engineered cells are then returned to the patient.

The first clinical application of this procedure was approved by the National Institutes of Health and the Food and Drug Administration on January 19, 1989. [3] Our protocol received the most thorough prior review of any clinical protocol in history: It was approved only after being reviewed fifteen times by seven different regulatory bodies. In the end it received unanimous approval from every one of those committees. But the simple fact that the NIH and FDA, as well as the public, felt that the protocol needed such extensive review demonstrates that the concept of gene therapy raises serious concerns.

We can answer our initial question, "What can we do now in the area of human genetic engineering?," by examining this approved clinical protocol. Gene transfer is used to mark cancer-fighting cells in the body as a way of better understanding a new form of cancer therapy. The cancer-fighting cells are called TIL (tumor-infiltrating-lymphocytes), and are isolated from a patient's own tumor, grown up to a large number, and then given back to the patient along with one of the body's immune growth factors, a molecule called interleukin 2 (IL-2). The procedure, developed by Steven Rosenberg of the NIH, is known to help about half the patients treated. [4]

The difficulty is that there is at present no way to study the TIL once they are returned to the patient to determine why they work when they do work (that is, kill cancer cells), and why they do not work when they do not work. The goal of the gene transfer protocol was to put a label on the infused TIL, that is, to mark these cells so that they could be studied in blood and tumor specimens from the patient over time.

The TIL were marked with a vector (called N2) containing a bacterial gene that could be easily identified through recombinant DNA techniques. Our protocol was called, therefore, the N2-TIL Human Gene Transfer Clinical Protocol. The first patient received gene-marked TIL on May 22, 1989. Five patients have now received marked cells. No side effects or problems have thus far arisen from the gene transfer portion of the therapy. Useful data on the fate of the gene-marked TIL are being obtained.

But what was done that was new? Simply, a single gene was inserted into a population of cells that had been obtained from a patient's body. There are an estimated 100,000 genes in every human cell. Therefore the actual addition of material was extremely minute, nothing to correspond to the fears expressed by some that human beings would be "reengineered." Nonetheless, a functioning piece of genetic material was successfully inserted into human cells and the gene-engineered cells did survive in human patients.

What Will We Be Able to Do?

Although only one clinical protocol is presently being conducted, it is clear that there are several applications for gene transfer that probably will be carried out over the next five to ten years. Many genetic diseases that are caused by a defect in a single gene should be treatable, such as ADA deficiency (a severe immune deficiency disease of children), sickle cell anemia, hemophilia, and Gaucher disease. Some types of cancer, viral diseases such as AIDS, and some forms of cardiovascular disease are targets for treatment by gene therapy. In addition, germline gene therapy, that is, the insertion of a gene into the reproductive cells of a patient, will probably be technically possible in the foreseeable future. My position on the ethics of germline gene therapy is published elsewhere. [5]

But successful somatic cell gene therapy also opens the door for enhancement genetic engineering, that is, for supplying a specific characteristic that individuals might want for themselves (somatic cell engineering) or their children (germline engineering) which would not involve the treatment of a disease. The most obvious example at the moment would be the insertion of a growth hormone gene into a normal child in the hope that this would make the child grow larger. Should parents be allowed to choose (if the science should ever make it possible) whatever useful characteristics they wish for their children?

What Should We Do?

A line can and should be drawn between somatic cell gene therapy and enhancement genetic engineering. [6] Our society has repeatedly demonstrated that it can draw a line in biomedical research when necessary. The Belmont Report illustrates how guidelines were formulated to delineate ethical from unethical clinical research and to distinguish clinical research from clinical practice. Our responsibility is to determine how and where to draw lines with respect to genetic engineering.

Somatic cell gene therapy for the treatment of severe disease is considered ethical because it can be supported by the fundamental moral principle of beneficence: It would relieve human suffering. Gene therapy would be, therefore, a moral good. Under what circumstances would human genetic engineering not be a moral good? In the broadest sense, when it detracts from, rather than contributes to, the dignity of man. Whether viewed from a theological perspective or a secular humanist one, the justification for drawing a line is founded on the argument that, beyond the line, human values that our society considers important for the dignity of man would be significantly threatened.

Somatic cell enhancement engineering would threaten important human values in two ways: It could be medically hazardous, in that the risks could exceed the potential benefits and the procedure therefore cause harm. And it would be morally precarious, in that it would require moral decisions our society is not now prepared to make, and it could lead to an increase in inequality and discriminatory practices.

Medicine is a very inexact science. We understand roughly how a simple gene works and that there are many thousands of housekeeping genes, that is, genes that do the job of running a cell. We predict that there are genes which make regulatory messages that are involved in the overall control and regulation of the many housekeeping genes. Yet we have only limited understanding of how a body organ develops into the size and shape it does. We know many things about how the central nervous system works - for example, we are beginning to comprehend how molecules are involved in electric circuits, in memory storage, in transmission of signals. But we are a long way from understanding thought and consciousness. And we are even further from understanding the spiritual side of our existence.

Even though we do not understand how a thinking, loving, interacting organism can be derived from its molecules, we are approaching the time when we can change some of those molecules. Might there be genes that influence the brain's organization or structure or metabolism or circuitry in some way so as to allow abstract thinking, contemplation of good and evil, fear of death, awe of a `God'? What if in our innocent attempts to improve our genetic make-up we alter one or more of those genes? Could we test for the alteration? Certainly not at present. If we caused a problem that would affect the individual or his or her offspring, could we repair the damage? Certainly not at present. Every parent who has several children knows that some babies accept and give more affection than others, in the same environment. Do genes control this? What if these genes were accidentally altered? How would we even know if such a gene were altered?

My concern is that, at this point in the development of our culture's scientific expertise, we might be like the young boy who loves to take things apart. He is bright enough to disassemble a watch, and maybe even bright enough to get it back together again so that it works. But what if he tries to "improve" it? Maybe put on bigger hands so that the time can be read more easily. But if the hands are too heavy for the mechanism, the watch will run slowly, erratically, or not at all. The boy can understand what is visible, but he cannot comprehend the precise engineering calculations that determined exactly how strong each spring should be, why the gears interact in the ways that they do, etc. Attempts on his part to improve the watch will probably only harm it. We are now able to provide a new gene so that a property involved in a human life would be changed, for example, a growth hormone gene. If we were to do so simply because we could, I fear we would be like that young boy who changed the watch's hands. We, too, do not really understand what makes the object we are tinkering with tick.

In summary, it could be harmful to insert a gene into humans. In somatic cell gene therapy for an already existing disease the potential benefits could outweigh the risks. In enhancement engineering, however, the risks would be greater while the benefits would be considerably less clear.

Yet even aside from the medical risks, somatic cell enhancement engineering should not be performed because it would be morally precarious. Let us assume that there were no medical risks at all from somatic cell enhancement engineering. There would still be reasons for objecting to this procedure. To illustrate, let us consider some examples. What if a human gene were cloned that could produce a brain chemical resulting in markedly increased memory capacity in monkeys after gene transfer? Should a person be allowed to receive such a gene on request? Should a pubescent adolescent whose parents are both five feet tall be provided with a growth hormone gene on request? Should a worker who is continually exposed to an industrial toxin receive a gene to give him resistance on his, or his employer's request?

These scenarios suggest three problems that would be difficult to resolve: What genes should be provided; who should receive a gene; and, how to prevent discrimination against individuals who do or do not receive a gene.

We allow that it would be ethically appropriate to use somatic cell gene therapy for treatment of serious disease. But what distinguishes a serious disease from a "minor" disease from cultural "discomfort"? What is suffering? What is significant suffering? Does the absence of growth hormone that results in a growth limitation to two feet in height represent a genetic disease? What about a limitation to a height of four feet, to five feet? Each observer might draw the lines between serious disease, minor disease, and genetic variation differently. But all can agree that there are extreme cases that produce significant suffering and premature death. Here then is where an initial line should be drawn for determining what genes should be provided: treatment of serious disease.

If the position is established that only patients suffering from serious diseases are candidates for gene insertion, then the issues of patient selection are no different than in other medical situations the determination is based on medical need within a supply and demand framework. But if the use of gene transfer extends to allow a normal individual to acquire, for example, a memory-enhancing gene, profound problems would result. On what basis is the decision made to allow one individual to receive the gene but not another: Should it go to those best able to benefit society (the smartest already?) To those most in need (those with low intelligence? But how low? Will enhancing memory help a mentally retarded child?)? To those chosen by a lottery? To those who can afford to pay? As long as our society lacks a significant consensus about these answers, the best way to make equitable decisions in this case should be to base them on the seriousness of the objective medical need, rather than on the personal wishes or resources of an individual.

Discrimination can occur in many forms. If individuals are carriers of a disease (for example, sickle cell anemia), would they be pressured to be treated? Would they have difficulty in obtaining health insurance unless they agreed to be treated? These are ethical issues raised also by genetic screening and by the Human Genome project. But the concerns would become even more troublesome if there were the possibility for "correction" by the use of human genetic engineering.

Finally, we must face the issue of eugenics, the attempt to make hereditary "improvements." The abuse of power that societies have historically demonstrated in the pursuit of eugenic goals is well documented. [7] Might we slide into a new age of eugenic thinking by starting with small "improvements"? It would be difficult, if not impossible, to determine where to draw a line once enhancement engineering had begun. Therefore, gene transfer should be used only for the treatment of serious disease and not for putative improvements.

Our society is comfortable with the use of genetic engineering to treat individuals with serious disease. On medical and ethical grounds we should draw line excluding any form of enhancement engineering. We should not step over the line that delineates treatment from enhancement.


[1] W. French Anderson and John C. Fletcher,

"Gene Therapy in Human Beings: When

Is It Ethical to Begin?," New England Journal

of Medicine 303:22 (1980), 1293-97. [2] See also W. French Anderson, "Prospects for

Human Gene Therapy," Science, 26 October

1984, 401-409; T. Friedman, "Progress

towards Human Gene Therapy," Science, 16

June 1989, 1275-81. [3] J. Wyngaarden, "Human Gene Transfer

Protocol," Federal Register (1989) vol. 54 no.

47, pp. 10508-10510. [4] Steven A. Rosenberg et al., "Use of Tumor-Infiltrating

Lymphocytes and Interleukin-2

in the Immunotherapy of Patients with

Metastatic Melanoma," New England Journal

of Medicine 319:25 (1988), 1676-80. [5] W. French Anderson, "Human Gene Therapy:

Scientific and Ethical Considerations,"

Journal of Medicine and Philosophy 10 (1985):

275-01. [6] W. French Anderson, "Human Gene Therapy:

Why Draw a Line?," Journal of Medicine

and Philosophy 14 (1989), 681-93. [7] See, for example, Kenneth M. Ludmerer,

Genetics and American Society (Baltimore, MD:

The Johns Hopkins University Press, 1972),

and Daniel J. Kevles, In the Name of Eugenics

(New York: Alfred A. Knopf, 1985).

W. French Anderson is chief of the Laboratory of Molecular Hematology of the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
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Author:Anderson, W. French
Publication:The Hastings Center Report
Date:Jan 1, 1990
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