A Humane Agenda for Modern Medical Science

In 1957, the year I entered college, the American Medical Association issued its "Principles of Medical Ethics."  Section 10 stated "The honored ideals of the medical profession imply that the responsibility of the physician extends not only to the individual, but also to society, and these responsibilities deserve his [sic] interest and participation in activities that have the purpose of improving both the health and the well-being of the individual and the community."  Improving the health and well-being of the individual and the community remains an honored ideal of the medical profession, and one that has also served as the guiding principle behind government funding of basic biomedical research. In many ways, though, it has been an ideal more easily articulated than put into practice.

This year, the interlocking worlds of international politics, the stock market, the NIH and the medical profession all joined in celebration of what was widely touted as the most significant -- and possibly the culminating -- creative act of our society, the transfer from molecule to database of one or more DNA sequences, for most or all of the coding sequences in the human genome.  To my eye, the current wave of enthusiasm for genomic research seems to have little to offer in the task of creating a more humane version of medical practice.  Indeed, the practice of medicine by real doctors and the consequences of this practice to real patients -- ever more deeply immersed as they both are in delayed intervention, fiscal crisis and contentious insurance regulation -- seem no closer to meeting these obligations now than it did in 1957.

Whatever the reason for the disjunction between optimism at the lab-bench and pessimism at the bedside, it cannot be that basic biomedical science has no responsibility for bridging the gap, nor can the completion of the first stages of The Human Genome Initiative by itself be allowed to excuse medical scientists from our responsibility to our colleagues' patients. In my book "The Missing Moment," I provided the following brief list of suggested ways in which medical science might work now and in the immediate future to meet those principles of ethical medicine so well stated almost fifty years ago. None require any patents held by Celera, nor any technologies not now available; all do require, however, the will to do the right thing.

1: For the long term, Create a Strategic Vaccine Initiative

Microbes do not respect national boundaries; the strongest ally infectious agents have is the human notion of national sovereignty. International cooperation was a prerequisite to the elimination of smallpox. If every person on the planet could simply be vaccinated with the vaccines we already have, hundreds of millions of people, a good fraction of them babies, would be saved from dying.

Only a few agents of infectious disease - yellow fever, an insect-borne virus; Llasa, viral hemorrhagic disease; smallpox; cholera; diphtheria; tuberculosis; and plague - cause illnesses that must be reported to the United States government today. All others, including malaria and all antibiotic-resistant strains of common infectious microbes, come and go unremarked. Many other diseases used to be reported; the shortsighted decision to save a small amount of CDC money guaranteed the fast and distant spread of any outbreak of antibiotic-resistant infection. It also mistakenly presumed that the United States had no need to worry about tropical diseases like malaria, even though the climate of the southeastern United States would suit the insect vector quite well.

To pay for a more rational and comprehensive defense against microbes, we might consider using a version of the military model which is not based on a fantasy of total victory. There is a pleasing symmetry to extending the notion of subsidy for the sake of security from the production and purchase of lethal weapons to the production and distribution of life-saving vaccines. The underlying logic of a military model for mobilization to assist our immune systems through vaccines is the opposite of the SDI notion of perfection. Instead of SDI we need an SVI - a Strategic Vaccine Initiative. SVI would acknowledge that our best hope is a standoff and that our best strategy is to help our immune systems turn microbial mutability to our advantage by domesticating the microbes that get inside us.

In contrast to SDI, SVI could work only if it were the product of total international cooperation. Political, religious, and ideological differences make no difference to tuberculosis or malaria; they have no place in species-wide SVI. National sovereignty may seem an impermeable barrier to the necessary transnational attitudes and actions, but we have a precedent at our fingertips for the permeability of national borders to new technologies.

Ideas and information that get onto the Internet travel around the planet, crossing national boundaries with impunity. Organized and run from the beginning on the Internet, an internationally funded SVI would not need to have a single location in any one nation. That would be an appropriate organizational strategy for the kind of international effort it will take to respond - as a species - to the invisible species that will always threaten us. Like the immune system in any of our bodies, the Internet is widely distributed, rapidly adaptable, and quick to learn. A new idea that travels through the Web is quite like a new antigen that stimulates a strong immune response. And like the chemicals and cells in a person's immune system, ideas that move through the Web may be what keep our species going, especially if one or more of the microbes we live among gets going in us in a serious new way.

2: For the short term, create Edible Vaccines

The ideal vaccine for any infectious agent should be safe, oral, and effective when given in few doses early in life. The new technologies and insights of molecular biology can and should be brought to the task of creating such vaccines. Only twenty or so vaccines are available in clinics today. Bringing any of them closer to this ideal would be a way to save a lot of young lives.

Oral vaccines available today are prepared from infected, cultured cells. Although it is attenuated, the Sabin live polio vaccine can be taken by mouth because it can still infect the lining of the intestines. It is safe because its genome differs from the pathogenic polio virus in enough places to assure that it will not revert to its ancestral capacity to go from there into neural cells. An oral vaccine is by definition edible; another way to make an oral vaccine would be to put a few of a pathogen's genes into the germ line of an edible plant, forcing offspring plants to produce antigenic foreign proteins and thereby make them into edible, even nutritious vaccines. Transgenic plants are now being tested for their ability to serve as cheap, stable oral vaccines against hepatitis and cholera. The main limitation so far seems to be tolerance: the intestinal immune cells that see the foreign protein as part of a digested mass of plant material cannot tell that it is foreign unless it comes in as part of a larger, more obviously microbe-like structure.

If the ideal preventive medicine for infectious diseases would be the delivery of an optimal vaccine for all the major infectious diseases, women of child-bearing age should be the first to receive these vaccines. A baby fed on breast milk winds up with a fiftyfold enrichment of its mother's immune-protective molecules. Milk also carries natural drugs to fight infection, in particular the anti-inflammatory agent lactoferrin and the antibiotic lactoferritin, as well as sugars that trick bacteria into binding to them rather than to the surfaces of a baby's cells. A baby's immune system is set for life by the mother's milk: an organ transplanted from mother to child will take with much greater ease if the child has been breast-fed.

A complete response to microbial disease must begin with the commitment to encourage and assist every mother to nurse her newborn child before it is exposed to any vaccines, let alone any antibiotics. Breast-feeding so enhances the immune system that cultures that do not breast-feed have a tenfold excess of infant mortality over those that do. This difference is due to the absence of similar enhancers of the immune response in any other foods and to the relative contamination of all foods compared to milk from the breast, which is sterilized by the mother's immune system.

3: for the Long Term, Treat Cancer as a preventable disease

A cancer prevention agenda for basic research would begin with a planetary review of differences in the incidence of various cancers, because some regions and cultures are hot spots for some cancers, while in others the same cancers are exceedingly rare. From this international effort, governments and companies worldwide would have the information necessary to plan a planetary strategy for the prevention of cancer: planetwide optima for low-mutagen food, air, and water and clear guidelines for behaviors that would, together, assure the lowest possible frequency of avoidable cancers. In this context, the current emphasis on the genes responsible for a tumor would be seen for what it is: an interesting sidelight to the real problem of cancer, not the main issue.

At present, we search for populations at high risk for inherited cancers only to tell families what their fates will be. We spend relatively little time and money understanding the origins and consequences of the habits that bring on the majority of fatal cancers and reaching out to the entire population with help in avoiding these habits. A 1996 study by the Harvard School of Public Health found that only about ten percent of people who had died of cancer were born with versions of genes that made the disease inevitable. About seventy percent of the lethal cancers were brought on by choices such as smoking, poor diet, and obesity, and most of the remaining twenty percent could be attributed to alcohol, workplace carcinogens, and infectious agents. Smoking is optional, but eating, drinking, and breathing are not: the task of understanding why people act against their own best interest even after they learn how to act prudently is not part of today's agenda for cancer research, but it should be.

4: For the short term, domesticate the tumors that do arise.

Setting prevention aside - not because it is impossible, but because in scientific terms it is so easy that one is embarrassed to say more about it - in the near future cancers are likely to be dealt with by a slowly evolving combination of genetic, immunologic, and antibiotic interventions. The lessons of microbial research apply here: the immune system is the body's first line of defense.

Reports have begun to appear of drugs that renormalize tumor cells and of others designed to force tumor cells to commit suicide. The simplest use of DNA-based information would be to undertake a DNA-based treatment of the problem. If the activity of BRCA1 or BRCA2 were somehow to be returned to the cells of a breast tumor, they ought to revert to quiescence, curing the disease without the side effects of current treatments. However, there is a catch. Most growth-controlling genes work through proteins that switch other genes on or off. These proteins never leave the nuclear sanctum of the cell they keep quiescent. Any drug designed to mimic such a protein would have to get to the tumor cells - every last one of them - get inside each, get to each nucleus, and find the same set of other genes to turn on or off. This seems unlikely, and in fact to date no laboratory has been able to mimic the effect of an absent tumor-suppressing gene except by introducing the gene itself into a tumor cell, a trick unlikely to work in a clinical setting, where even one untreated tumor cell would be able to seed a brand-new tumor.

Dolly, the cloned sheep, and others like her may be useful in developing new treatments for cancer: the cytoplasm of a mammalian egg is the only place we know of today that will direct the expression of each differentiated pathway necessary to the construction of all our tissues. Adding a nucleus from a cancer patient to a fertilized egg cytoplasm, it might be possible to grow any differentiated tissue in a dish and have it be wholly acceptable to the donor. In this way it might be possible to replace a tissue like the liver after excising the original to rid the body of all traces of a liver tumor. More generally, it ought to be possible to rebuild a person's immune system in a dish this way, and even to stimulate it in advance, to attack the pathogen that is attacking the body, whether microbe or tumor.

Some diseases - alkaptonuria, for example, or cystic fibrosis - are the consequence of a protein's complete absence from the body. Getting the correct gene into even a few cells can mean at least partial success at ameliorating such diseases. In at least one case - the absence of an immune system due to the inherited lack of a protein called ADA - a cure has been at least temporarily achieved. After a decade of living in a germ-free isolation tent, a child suffering from ADA deficiency - whose blood cells had been removed, given DNA encoding the gene, and transfused back - developed a functioning immune system and has been able to leave the tent.

5: Zero-sum financing: If germ-line gene therapy isn't worth doing, it isn't worth doing well

DNA transfer into embryo cells, the line of work that gave rise to Dolly, has tempted some scientists to contemplate a radical solution to the problem of an inherited propensity to develop tumors: implant the missing growth-control gene in the cells of an early human embryo so that a person is born with a functioning version of the gene in all tissues. The procedure is called germ-line gene therapy. It is a hybrid combining the laboratory technology of delivering DNA directly to a tissue that lacks a necessary gene with the clinical skills to bring sperm and egg together in a dish, allowing couples to have a baby when their own bodies cannot support fertilization of the ordinary sort. In vitro fertilization combined with gene therapy works well in animals. Any DNA that successfully inserts itself into a cell of an early embryo will be copied into all the descendants of that cell, so treated embryos will grow into animals born with a new gene in at least some cells of all their tissues. Under conditions where the switches to turn on the gene are also in their proper place, a new gene makes a normal amount of functional protein in just the cells that would normally have it, so that an animal that would otherwise suffer from an inborn genetic defect can be quite normal at birth and live a normal life thereafter. And, since the implanted DNA is copied into the cells that make sperm or eggs - the germ line - such an animal's offspring will also be cured of the genetic illness forever.

In the conservative sort of germ-line gene therapy, a couple susceptible to a disease because of an inherited damaged version of a gene would donate sperm and eggs to a laboratory. The fertilized egg would be allowed to grow for a while in a dish, then it would be injected with the DNA encoding the missing gene, slipped into the mother's womb, and left to grow into a child with, one hopes, a good copy of the gene functioning in each cell. Injecting a growth-control gene into the early embryo formed from sperm and eggs donated by a couple from susceptible families would not be enough, since a child born with even a few cells lacking the injected gene would be at risk for cancer developing in those cells. Instead, germ-line gene therapy for cancer would have to succeed in putting the growth-control gene into every cell of an embryo. This could be done, but only by inserting the growth-control gene either into the single fertilized egg cell before it divides or into the germ cells of both parents. Along these lines, a few laboratories have recently reported the successful addition of a foreign gene to the chromosomes of mouse testicle cells growing in a dish. When these cells were returned to the testicle of a mouse sterilized by irradiation, they produced functional sperm, making the male mouse a donor of the foreign gene to all his offspring.

Germ-line modification has the elegance of a complete solution. Unfortunately, it is a solution that sacrifices the current generation for the next, and as such it does not serve the purpose of medicine, that is, to alleviate or cure the suffering of a person already here among us. Neither parent of the modified embryo is in any way treated by the technology that would introduce a DNA into an embryo's cells; afflicted parents would not be cured, nor would parents at risk of cancer, say, be any the less at risk if they agreed to let their embryos experiment. Instead, at best a baby would be born with no more but no less risk of cancer than anyone else. At worst, the child might be born with another, unrelated form of inherited disease, the result of an inadvertent mutation caused by the insertion of the DNA into one of its cells.

The creation of any child with a changed genome would be a Promethean grasp at the human germ line. It would also be an act of enormous hubris, risking inadvertent chromosomal damage that might not show itself in the growing child for many years. This line of research has already raised some new social and legal problems. It has obliged us to decide if we are willing to pay the price of converting kinship and childhood into commodities in order to find out whether these techniques will work properly; it has given us the task - as yet unfulfilled - of setting a proper boundary on the freedom to initiate genetic novelties in our own species.

Robert Pollack, Ph.D.
Professor of Biological Sciences
Director, Center for the Study of Science and Religion
Columbia University New York, NY 1002

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