Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
D. Charleton Gajdusek,
Director, NINDS, National Institutes of Health, USA
In human affairs, crass honesty may not always be the cardinal virtue. Truth must, and often should, yield to discretion, kindness and compassion in the usually irrational realm of human affairs. Naked, sheer honesty as applied to such tricky issues as human values, ethics, and human good suffers from the difficulty of discerning, in the human world of noncommensurate values, what truth really is. It may be hard to differentiate honesty of the heart from honesty of the word.
The scientist, however, is expected by his peers and the public to report what nature reveals to him, and his observations and their reporting must in no way be influenced by issues of value, morality, personal or social gain, race, nationality, patriotism, religion or creed. His integrity as a scientist demands that.
When the scientist communicates to the public or layman about the possible social impact of his work and of its moral, religious, economic or political consequences and implications, he is no longer only a scientist. His self-assurance and the certainty of all his assertions must yield, with humility, to the uncertainty of all matters human.
At this moment, I am no longer speaking as a scientist, and as a result, all the authority and certainty of my remarks as they report experimental data are lost. It is the disaster of our times that scientists sometimes forget this. Those scientists have then lost their humility and humanity, and they should be suspect.
I decided to bring up a few issues that I found lacking in all the previous fascinating papers. One that surely involves the realm of ethics, and involves almost all scientists, might best be phrased as patronage.
Almost all modern scientists require patronage. And all patronage requires wealth and power on the part of the patron. Architects, engineers, and many artists of the present and Ancient world, similarly required patronage. We have few examples today of the gentleman scientist from the nobility - Lavoisier, Priestly, Cavendish, who played the game on their own financial resources.
But all accumulations of wealth or power imply to a moralist an underlying evil, an underlying offence to someone. No wealth or power is morally clean at its roots - hence the holiness of saints, Buddha or Christ-like figures who cast off earthly wealth and power. All disturbances of rising entropy which have lead to the accumulation of wealth are suspect and of questionable ethical or moral purity when scrutinised at the level of religious fundamentals or values. This applies whether the patron be:
Church via Pope via the Civil Authority or Prince - the Medici
Government via its source of wealth in war, conquest, taxes from drug lords and industry
Foundations via their wealthy private donors
Academic societies (NAS, APS) via donors, drug companies selling both ethical and unethical drugs, and other industry
Private universities via their financial holdings in stocks and bonds, and wealthy Alumini or corporate donors.
Thus Praxiteles, Leonardo da Vinci, Gieto, Michaelangelo, Mozart, Bach and Beethoven, all had their patrons as did Voltaire, Jean Jacque Rousseau and Goethe. Rarely do we have an Emily Dickinson or a Franz Kafka who apparently did not.
Now, in the modern age , we are being asked by "ethiticians" - and the scientists are themselves asking - to inquire the sources of their patronage. Is it "dirty money"? The hermit, the beggar, the saint, would tell us that all wealth is dirty. We approach this way of thinking when we begin to wonder about the morality and ethics of taking out patents on scientific discoveries which should belong to all mankind. When we try to patent for local gain to ourselves, our companies, our nations, or our institutions, the sequences of the genes of man, or of his domestic animals and cultivated plants, and even of man's enemies, the pathogenic microbes and insect pests like flies, mosquitoes, ticks, mites and commensal rodents, we are surely letting avarice of personal gain cloud out the need of the impoverished and ailing of our world.
It must be admitted that we have been doing this cloning and genetic engineering for centuries with selective breeding and inbreeding in animal husbandry and cross pollination and hybridisation in agriculture, and we have been cloning most of our crops by vegetative propagation, altering the genetics of our cultivars for centuries, and producing polyploidy and homozygosity, which is often very vulnerable in nature uncontrolled by man. Such artificially produced species may alter or influence the genetics of their much faster evolving pathogenic and even previously nonpathogenic microbes. No one has ever forseen these type of possibilities in genetic improvement of stock.
Prometheus set the pattern for the modern scientist-technologist, in stealing fire from the gods - and in the myth he was punished for it. Let us ask one question that is directly related to our discussion: Is it ethically permissible to tell the public, to imply to the public, that genetic engineering is the best way to control even genetic susceptibility to disease?
In accepting patronage the individual scientist may be diverting support from other possible uses - even within biomedical research community. Thus the molecular biological approach to malaria, influenca and also to an HIV (AIDS) vaccine have cost hundreds of millions of dollars. Many now contend that it would have been better spent on other approaches to the control of all of these diseases. Poliomyelitis, yellow fever, diptheria, measles, mumps, varicella, pertusis and tetanus have been well controlled, and smallpox eliminated, without any recourse to molecular genetics. Whether vector control or other control of exposure to the pathogen may not be more reasonable than genetically engineered subunit vaccines is questionable, and reasonably questionable. What I mean by vector control, we can list the ailments of humanity: malaria; Japanese B encephilitis, where in Japan you don't even use your own commercially made vaccine but you control exposure to the mosquitoes from pigs; rabies, where we control exposure to dogs and wild rabid animals; Hemologic adrenal syndrome, which causes no trouble in America and Europe although it is in all the ports, but a devastating infection only because of problems of rodent control in China, Eastern Siberia and Korea; hantaviruses; Tsutsugamushi (Tick typhus), which is in South East Asia, wouldn't mite control have been far simpler than engineered vaccines that don't work and were an absolute fiasco because every field has a genetically variant dominant epitope; typhus, spread by mites; or plague, which needs rat and flea control. And you think whether environmental control of exposure is not more reasonable than genetically engineered vaccines to other things like: enteric pathogens (cholera, typhoid, dysentery), tuberculosis, leprosy, syphilis, gonorrhea, AIDS or sepsis, by water purification, pasteurization, sewage disposal, refrigeration, condoms and safe sex and viricidal compounds, sterilisation and disinfection, which would have been far cheaper and more effective for both the developed and nondeveloped world.
Let me go into an example of high technology research that me, my students, and my colleagues have been very involved in. One of the great triumphs of DNA research has been the demonstration of the neurotropic loop on poliomyelitis virus, and our ability to predict exactly what makes it neurotropic and what amino acids changes control its neurotrope. All done expostfacto, after the real tool for polio elimination from the world was discovered and used in much of the world, with no recourse to this biotechnology. It satisfies our demand for reductionist understanding of how things work, it has nothing to do with the practical control of polio. With epitopic structural analysis of the polio virus, not only with polyclonal but hybridoma produced monoclonal antibodies against various epitopes, discovering the major and dominant neutralising antibodies, we can split the polio viruses into 5,000 different viruses, and it would take an Einstein in the 21st century to discover that they work in three groups of evolutionary significance. All of which we learnt before we knew about DNA, RNA, or epitopes.
In most infections only a rare individual becomes ill or suffers rare complications, and that individual may be genetically predetermined, it usually is. For example, HTLV-1 infects 1-2 million Japanese, but only one in over a thousand gets adult advanced T cell leukemia after 40 years, and fortunately only about one in a thousand gets HAM, HTLV-1 associated myolopophy. Those unfortunate rare individuals are the problem, not the problem of the innocuous, or carriers, the other one thousand who die without ever knowing that they had it, and having no ill effect. The same can be said for poliomyelitis, where it takes 1,000 infected cases in order to induce a paralysis, the others don't know they were infected. Japanese B encephelitis only produces a clinical disease in a rare infection. Syphilis, untreated will allow in old age, two thirds of such people to go to the grave from other causes. But certainly, what concerns us is the control of those unfortunates who get a rupture of an aorta, general parasis of the insane, or any of the thousands of syndromes that the great imitator can cause. Tuberculosis is almost the same. Staphylococcal complications of acute glomeral nephritis, rheumatic fever and other autoimmune syndromes are all rare complications perhaps under remote genetic control. But for these we will not be looking for somatic cell gene therapy to control these, since it is much cheaper and much easier to control the quantity and extent of exposure by the methods that each of these pathogens, along with leprosy, require.
This true also for many toxins, deficiencies and hypersensitivities, asthma and other allergic reactions like bee sting, food and plant sensitivities and allergies. They are life long for many, and transient for others. We don't know how to predict there life long seriousness or their transience insignificance in advance. Therefore are we really going to go into expensive, complex, and ethically debatable, DNA treatment of those rare individuals who have these sensitivities. Or is it more reasonable to desensitise them, as was being done successfully in the days of Loius Pasteur, and which we can handle pharmacologically, and by avoiding these, far more easily. Neurological complications of pellagra and berriberry as combined system disease, killing with nervous system damage those rare pernicious anemia patients who get it, and others don't. It is the same small molecule, but why does one get it and another not. We used to discuss this in medicine. I wonder whether it isn't cheaper just to give thiamin and riboflavin, folic acid or liver extract, than talk about repairing the gene damage. So we musn't imply to the public that we are going to chase with the genome project, by somatic DNA therapy, all the genetic ills of man. It is surely more ethically acceptable, even in developed nations, and certainly for the underdeveloped world, to tell them that genetic engineering will not provide them with solutions which they can afford in the foreseeable future to many of these kinds of problems.
Does scientific responsibility not demand recognising this and not misleading the public with false promises, and perhaps unattainable hopes. This has happened in several biomedical projects of immense dimension during the past half century. They happened to be in my own field.
The one which has just been discussed at length in a muck-raking volume by Desuwitz is called The Malarial Capers, ending in chapters in muck-racking journalism as malaria "felons", fortunately starts a century ago with a catastrophic scientific premadonaship of contention for the Nobel prize between Grassi in Italy and Ross in England. Among all the chicanery that was going on then in research just reminds us of what the newspapers tell us today. But it goes on to 1991. The molecular biologists promised, and so did the WHO, much too much to the public and the Third World, "the subunit vaccine for malaria was around the corner". One billion dollars went into the project, and we are nowhere near. And no one has loudly and clearly proclaimed to the Third World, it ain't going to happen, and when it does happen, if it ever does, it will be for generals and armies, and CIA, and wealthy tourists, and not you. No one has ever dared to tell them that, it would interfere with the project, and our careers.
It has been a failure, and will continue to be a failure. What we will gain from it is not a Third World vaccine to control malaria in the Third World in our lifetime. It did, however, cause it to be almost politically impossible for any politician or sociologist or engineer who wanted to really put money into civil engineering control of malaria vectors, waiting for the vaccine around the corner, to solve everything. As a result we can't calculate how many people died in the whole and endemic parts of the Third World where nothing was done, and the developed world over use of the medicine and spraying of DDT for agriculture, not for malarial control, made DDT unavailable for them while it was still effective against their insects. So we have a disastrous upsurge of malaria while there has been no further, or very little good research, on keeping up with the necessary anti-malarials, as all around the world the malarial parasite evolving faster than us or our drugs has become mostly resistant to chloroquine. The chances are that each of the others are slipping out the door and we're getting back to the quinine of Joseph Konrad in the nineteenth century.
Well we're going on, we have learnt a lot about the physiology, we've reduced and analysed the antigens, but we have no idea whether in 5, 10, or 50 years we are going to have a vaccine. And if we do it will be for only one of the four Plasmodium which infect man, and not the one that much of the Third World most cares about. Their population problem is enormous, and what they mean by malaria is what knocks the soccer team out, not what kills their babies from encephelitis. So we have mislead them from the start, because even if we cured malaria, we would load their families with more babies than they want, and they never called that malaria, we did. That's not what they think we are working on.
AIDS is the next example. Although HIV has been the most molecularly analysed virus in virology, we are not as far along as the viroid people are with their simple RNA virus loops that cause disease with no RNA transcription or translation in their replication, but we know a hell of a lot about it. We know so much about it that we can characterise most of what we have done in epidemiology as mispend time and effort, and badly done work. We certainly, with our hundreds of millions of dollars of money spent at the molecular laboratory curtailed work on contraceptives, viricidal compounds, actual safe sex practices; the only thing we now have left, and the only thing the Third World will ever have left to meet this epidemic, because any level of imagined success will not be available in our lifetime, or that of our kids, for the Third World in the current economic possibilities.
There is no need to go into the decades of the poliomyeloma viruses, the decade of the adenoviruses, the decade of the Herpes viruses, the decade of the SV40-Papova virus, and the decade of the retroviruses, for solving cancer. This virology problem, which seems to be maximum for rodents. For man we are not very far along, and we took all the cancer research money in the world for a third of a century in that direction, for modern molecular high technology engineering.
We promised more than we can deliver. The real successes might just as well be answered. How lucky it was that when we contaminated inadvertently the human growth hormone in our high tech neo-cannibilism, or using the pituitary glands of man for profit, admittedly the NIH stuff was not made for profit for 40-50,000 American kids, and equal number of Europeans, and an equal number of Asians, and South Americans, perhaps 150-200,000 people in the world all of whom are on growth hormone, almost all of it contaminated with Creuskof-Yakof infectious amyloid. Which incidentally will resist all autoclaving and all hormone preparation, but fortunately it was hydrophobic enough to be separated largely, so that we have only killed about 35-40 people, in Australia, New Zealand, America, Canada, the USA, Europe and elsewhere. Just fortuitously, not 200,000! Genetic engineering has saved us at least those kids who really need the hormone, because there we have the cloned product ready, fortunately it was not glycosylated.
Hepatitis B cloned vaccine will probably be the first triumph in molecular virology and cancer research: if it works as we hope, in preventing primary CA of the liver, in China, South East Asia and many other parts of the world.
Prof Wikler and Billings have told us elegantly how the public has become aware of any invasion of their human rights in the name of their own, or of public health. Then, they often believe they require protection against the egotistical or power hungry scientist or prolectian, from even their personal physician, or protection from governments, or industrial complexes which would invade their individual rights in the name of scientific, or economic, or natural, or even public health. A beneficent paternalistic animal husbandry of one's human flock is no longer acceptable to Mankind.
What are the dangers to the species or to the individual of our genetic engineering? We do not know and can not predict these! Thus, every responsible scientist is weary of any manipulation of the germ line - of the genetic stock of man. The huge variability of phenotypic expression we have learned to expect even from a single gene in different environmental situations, and the enormous complexity of possible interactions of one gene and its product in the whole function and adaption of a Metazoan species we now appreciate. We should stand with awe and wonder at our ignorance before we tamper with the germ line evolution of man.
We seem less afraid with other species: domestic animals and cultivated plants, and even our pests. It should be admitted that we have been doing this for centuries - ever since the agricultural revolution some 5000 years ago - with cross pollination, selective inbreeding - and we have been cloning most of our crops by vegetative propagation and grafting, and have produced man-made selection to alter their genetics in agriculture for centuries. Thus we have produced polyploidy and homozygosity and selected rare, often fragile mutations which are often very vulnerable in nature uncontrolled by man. As said above, these man-made breeds of plants and animals may influence the genetics of their faster-evolving parasitic microbes.
To bypass natural selection and replace defective genes or supply missing genes to individuals handicapped by their individual genetic defect seems to go, without much possible danger to the species - except for the preservation of the otherwise self-limiting mutation in the human breeding pool. To alter human inheritance as a species, to reduce the genetic variability which may in some environments seem deleterious, may well leave him more vulnerable to the natural selection of social or geophysical catastrophe. Similarly, to select for, or engineer for desired traits which we in contemporary culture value may lead to catastrophe. In evolution, reduction of variability is synonymous with vulnerability. Loss of hybrid vigor may lead to extinction!
I thought I would give you my ideas on just one aspect of the conference that I thought was left out. I don't want to leave in a pessimistic mood. We are all into the DNA of the human genome, and the genomes of our friends in the farmyard, and our enemies outside it, and sometimes inside it and inside our houses. We are all going to be dependent upon work on this for the future. But let us not promise the public more than we can deliver, and ethically misdirect our patronage. We must not, and should not, confuse ourselves with the Gods.