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Fear and DNA

The researchers have behaved with unprecedented restraint and caution. Raising the issue themselves; bringing it to public attention; urging the voluntary deferral of various experiments; and debating the hazards in full public view, represents four quite different and thoroughly commendable steps. In addition, most have, quite surprisingly, been able to come to agreement on a set of guidelines that have grown steadily more stringent—even while many of the researchers have grown more sanguine about the dangers. This is a tribute to the statesmanship of their leaders. It is no surprise that now they want to go ahead with research which all observers agree is filled with promise, and which promises tremendous assistance in understanding biology. They only ask a “yellow” light—the right to proceed with caution.

Among the hazards the FAS calls attention to is the accidental escape of potentially dangerous organisms as yet unknown in nature. The FAS seems to fear that the body’s immunological system would be confounded by such unknown organisms. This fear of the unknown because it is unknown is not really justified. Human beings for example are perfectly capable of mounting immunological reactions against organisms new to them or even against chemical compounds which they have never met before—which, indeed, have not yet been invented. It is a misunderstanding of physiology to suppose that immunological-like neurological reactions depend at least in part on prior experience: there is after all always a first time we are confronted with any disease-causing organism but we do not necessarily succumb to it. The FAS goes on to say:

The basic current hazard is the introduction into bacteria of genes which make the bacteria more dangerous. In the simplest case, such genetic changes might give one strain of bacteria the resistance to antibiotics that exists in other strains; thus some such antibiotic as penicillin might suddenly find that strains of bacteria that cause pneumonia had become resistant to its application.

It is notorious, though, that this process has been going on since penicillin was first introduced into medical practice and used more frequently and in larger doses than immediate needs called for. The appearance of antibiotic resistant strains of formerly susceptible bacteria is a typical evolutionary process. Although the existence of penicillin-resistant strains of bacteria is a major nuisance, it does not portend widespread disaster: rather it puts biologists on their mettle to find ways around the problem.

The FAS draws special attention to and endorses the main conclusions of the Working Party under Lord Ashby of the benefits and possible risks of genetic engineering. The Working Party’s conclusions are worth setting out anew:

We now have to declare our assessment of the potential benefits and practical hazards of using the techniques we have described. We reiterate our unanimous view that the potential benefits are likely to be great. The most substantial (though unpredictable) benefit to be expected from the techniques is that they may lead to a rapid advance in our detailed understanding of gene action. This in turn might add substantially to our understanding of immunology, resistance to antibiotics, cancer, and other medically important subjects.

Furthermore, application of the techniques might enable agricultural scientists to extend the climatic range of crops and to equip plants to secure their nitrogen supply from the air. Another possible application is that segments of DNA, selected because they are templates for valuable products such as hormones, antigens or antibodies, might be produced in bulk by multiplying them in culture of E. coli: this would be of great benefit to medicine. And it is not inconceivable that the technique might ultimately lead to ways to cure some human diseases known to be due to genetic deficiency.

In discussing the hazards of these techniques we have to distinguish between the risk to workers in the laboratory and the risk to the public. Many scientists are engaged on potentially hazardous research (using radioactive materials, or unstable chemicals, or pathogens). They and those who work with them are trained to take precautions; accidents are rare and they do not spread. But if the danger is one which might not be contained within the laboratory, the need for precaution is much greater and the public have a right to seek assurances that they are not at risk.

Fortunately there are precedents for making such assurances. In the production of some vaccines, in public health and hospital laboratories, in research institutes for the study of infectious disease, it is essential to handle pathogenic organisms, some of them extremely dangerous. Accordingly, there is a well developed strategy of containment for these hazardous operations…. The dramatic response to any failure in containment illustrates how rare such failures are. A recent example of this is the enquiry which followed an outbreak of smallpox in London in 1973.

In short, the potential benefits of recombinant DNA research are great and the precautions the experiments call for must be commensurate with the magnitude of the risks involved.

I once had the pleasure of a lengthy formal discussion with the late Jacques Monod, at that time the Director of the Institut Pasteur, about a number of biological problems having to do with the threat and promise of genetical engineering—a subject upon which he was as well qualified as anybody in the world to express an authoritative opinion. We agreed that both the threats and the promises were greatly exaggerated and that the realization of both good and bad dreams was a very much more difficult exercise than it was commonly assumed to be, but at the same time Monod made an exception of cloning—the production of an indefinitely large number of replicas of some chosen human type.

Cloning was a definite possibility, he believed, as many others do too. The procedure has nothing to do with the recombinant DNA, however; it is biological engineering in the wider sense discussed above. To get it into perspective I should like to run over the procedure that would have to be adopted if cloning were to succeed. The first step would be to wash out from the fallopian tube a fertilized and therefore activated human egg—an egg developmentally ready to go. The egg would be stored in a cool, sterile nutrient medium outside the body and then manipulation could begin. If toads and newts are anything to go by, the egg’s own nucleus could be replaced by a nucleus from an ordinary body cell (a lymphocyte nucleus, mayhap) from the tissues of the individual chosen for indefinite replication. The egg would then be maintained under conditions which allowed it to undergo a number of successive cell divisions—a process almost exactly analogous to twinning as it may sometimes occur in vivo.

That would only be the beginning of it, however, because for each such daughter egg to develop into a human being it would be necessary to find a woman whose uterus had been prepared by hormones in such a way that the daughter egg transplanted into it would continue with cell division and eventually attach itself to the uterine wall—“implantation” is the technical word. The embryo might or might not go to term; if it did, it would necessarily have the same genetic makeup as the individual whose cell nucleus substituted for the nucleus of the original egg.

Anybody with any experience of experimental pathology—and the rival attraction of less exacting pursuits means that their number is getting less and less—knows that to carry through this program and to overcome all the misadventures that could so easily befall it would require a degree of organization that would make the mobilization and deployment of an army seem like running a Sunday school picnic. Even supposing a grant-giving agency composed mainly of wealthy simpletons could be found to support such a foolish enterprise, the very many misadventures known by all experimentalists to beset such a scheme would almost certainly prevent its being realized. We need not worry then about the difficulty of finding any one human being whose indefinite replication could be thought of with equanimity, for considered as a whole the enterprise is simply not on.

No appraisal of genetic engineering would be fair unless Erwin Chargaff were called upon. Chargaff was one of those who played a leading part in the discoveries that led to our modern understanding of DNA, and his part too, like Avery’s, is not as well known as it ought to be. In writing “On the Dangers of Genetic Meddling”6 Chargaff is very skeptical about the overflowing cornucopia of advances in medicine and human welfare which, it has been alleged, can grow out of the use of genesplicing techniques—benefactions thought to include the repair of human genetic defects (a procedure very far beyond our present competence). Of this project I have said:

It is mentioned in the same spirit as that in which a young biologist seeking funds to study the growth of sea cucumbers in a pleasant seaside resort urges his patrons to believe that such an investigation will throw a flood of light on the transformation from the normal to the malignant cell: it is a harmless form of window dressing that all grant-giving bodies understand and allow for.7

Chargaff declares that the genetic engineers are not nearly so proficient as they are given the credit for being about the splicing of eukaryotic DNA into DNA of microorganisms. (Eukaryotic DNA is the DNA of organisms, such as animals and higher plants, in which genetic material is marshaled and structurally organized in the form of chromosomes, the nucleic acid being combined with a basic protein to form a salt-like compound):

Most of the experimental results published so far in this field are actually quite unconvincing…. It appears that the recombination experiments in which a piece of animal DNA is incorporated into the DNA of a microbial plasmid are being performed without a full appreciation of what is going on.

Chargaff is skeptical of the long-term efficacy of orthodox containment procedures for the possible escape of pathogens, and he asks why molecular geneticists have chosen as the subject of their experiments an organism Escherichia coli, the colon bacillus, which has for so many millennia been living in a state of symbiosis with man. “The answer is that we know so much more about E. Coli than about anything else, including ourselves.” He is right: so much knowledge and know-how is vested in E. coli that there is little likelihood of its being supplanted as a subject of experiment. In any event, so the patrons of E. coli argue, the laboratory organism has now been so modified in the course of prolonged culture outside the body that it no longer qualifies to be considered a regular member of the flora in our gut.

Clifford Grobstein,8 well known for his sensible and temperate views, deplores the polarization of the recombinant DNA debate into an antithesis between “best-case” and “worst-case scenarios.” The worst-case scenario he envisages comprises: worldwide epidemics caused by newly created pathogens; the triggering of catastrophic ecological imbalances; the power to dominate and control the human spirit.

  1. 6

    On the Dangers of Genetic Meddling,” Erwin Chargaff, Science, Vol. 192, June 4, 1976, pp. 938-940.

  2. 7

    The Scientific Conscience,” P.B. Medawar, Hospital Practice, July 1976, p. 17.

  3. 8

    The Recombinant-DNA Debate,” Clifford Grobstein. Scientific American, Vol. 237, No. 1, July 1977, pp. 22-33; “Recombinant DNA Research: Beyond the NIH Guidelines,” Science, Vol. 194, December 10, 1976, pp. 1133-1135.

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