The Los Angeles Times from Los Angeles, California • 51

i ISA angtlrt CintfS Sun, August 29, 1976 -Port IV 5 7- III I II -II lit I o- it1 i is y'f itis i i 4 Im gpslfgltifs MfsMs5if A New Genie Is Out of the Bottle Biologists Have Taken Extraordinary Steps to Minimize Risk makes it possible to increase our knowledge of how those components function. Over the long-term, genetic engineering may conceivably yield rather spectacular "practical" benefits. Since a relationship is suspected between cancer and DNA, genetic manipulation might be a way to learn more about coping with that killer. It might be used to "teach" bacteria to produce inexpensive and abundant quantities of vital vitamins and hormones. Much further down the road, direct genetic intervention might be used to circumvent the laborious process of breeding better food-producing plants and animals, or even to repair genetic birth defects in humans.

However, as desirable as these ends may be, recombinant DNA research could involve hazards of uncertain magni-tude. For example, if a disease-causing bacterium receives a piece of genetic material that confers resistance to the agent normally used to control it, the bacterium might become far more dangerous to humans. Similarly, a bacterium that now inhabits the human body without doing harm might receive a genetic fragment that would cause it to begin manufacturing a deadly toxin. Moreover, since bacteria can easily disperse themselves over wide areas, hybrid microorganisms inadvertently imbued with harmful characteristics could spread before their existence is even detected. The molecular biologists involved in recombinant DNA research were the first to recognize the existence of these hazards, and this led them to take an extraordinary step: At a major international conference held last year at Asilomar prominent scientists agreed to halt this sort of experimentation until its inherent risks could be thoughtfully assessed.

Such an assessment has been made. As a result the National Institutes of Health, which support most American research in this field, recently issued a set of guidelines that terminate the voluntary moratorium and impose a form of quasi-regu-lation. These guidelines proscribe, for the time being, certain kinds of recombinant DNA research and classify others according to their, estimated risk. For each level of risk, a specific set of safety requirements is given. In all instances the emphasis is on preventing the spread of potentially dangerous organisms.

Basically, the physical containment measures now required are those which have overwhelmingly, but not invariably, prevented the spread of disease-causing organisms already under study in medical laboratories. Any researcher who receives funds from the NIH must abide by these regulations, and the new guidelines urge all scientists working in the field to observe them. However, the guidelines do not have the force of law within the United States and are obviously uninforce-able beyond its borders. Even so, most informed people have greeted the NIH guidelins as a satisfactory first step in meeting the novel challenges posed by a new technology. Several respected researchers, however, have expressed grave concern about the guidelines' real value, and not long ago the Cambridge city council called upon Harvard to postpone further experimentation in this area, pending three months of further study.

Some critics contend that public participation in the debate has been inadequate, and that those who had the greatest voice in formulating the guidelines were scientists committed to continuing recombinant DNA research. While the initial questions were raised by involved scientists, subsequent assessments included the views of some other scientists and concerned laymen. Once the NIH assumed responsibility as a public agency, it sought to open its proceedings to wider scientific and public reaction. Moreover, other mechanisms designed to review the issues generated by scientific and technological advances are now coming into play. Since the NIH has agreed that the hazards posed by recombinant DNA research constitute an environmental impact, the National Environmental Protection Act requires that a full report on the guidelines be filed.

This document, which should be completed next month, will in turn be open to professional and public comment. The National Commission for Protection of Human Subjects, which is charged with examining the social, legal and ethical implications of biomedical research, is also expected to report on recombinant DNA early next year. There is a disposition in some quarters to impose greater public control over scientific research. In the case of recombinant DNA, scientists have conceded the need for some measure of control and they have invited a government agency to provide it. Even if greater control of recombinant DNA research is desirable, how should it be enforced? What good will it do for Cambridge to control Harvard if New Haven ignores Yale? Should the United States prohibit what the Soviet Union or any other nation may encourage? After all, this is not a technique that requires great sophistication or large amounts of money.

So a new genie has emerged from the bottle of scientific research. Dealing with it demands sophistication and rational analysis. Since quick decisions must be avoided, the NIH guidelines provide a welcome holding operation. Only with a growing understanding of the issues at stake can we realize the potential of this new field and, not incidentally, hold its risks to a minimum. BY CLIFFORD GROBSTEIN Two fundamental advances in human understanding are about to converge and when they do, science and its relation to society may be significantly altered.

The first advance has occurred in biology, where new knowledge of the molecular basis of heredity has given scientists an enhanced ability to manipulate consciously genetic material that determines the physical destiny of every living organism.The result is a new process called "recombinant DNA technology" or "genetic To cope with the enormous implications of this emerging field, a social innovation is being brought to bear. This is the developing ability of officials to employ formal analysis and planning in establishing public policy. Thus, it may be possible to smooth the integration of a major scientific advance into the social fabric. This is particularly important in the case of recom-bi nant DNA, which seems to hold the potential for creating great benefits and, possibly, apocalyptic perils. Greatly simplified, the scientific process is this: Every living cell contains at least one chromosome whose essential component is DNA.

The DNA molecule is in the form of a double spiral or spring and is composed of smaller segments called genes. These genes de- Clifford Grobstein is a professor of biology and vice chancellor of university relations at UC-SD. termine the organism's hereditary properties. In addition to chromosomal DNA, bacterial cells may also contain, smaller circular DNA arrangements called plasmids. These entities, which are relatively easy to handle in a laboratory, are also capable of entering other bacterial cells.

By using a substance called a restriction enzyme, scientists can split a plasmid into specific fragments, which have an important property: They will adhere to other DNA fragments with which they come in contact. Thus, if plasmids from two different organisms are split and the resulting fragments mixed, they may "recom-bine" into a hybrid plasmid, bearing some of the characteristics of both the original organisms. To propogate quantities of this hybrid, scientists can mix it with bacterial cells, which will absorb the new plasmid and duplicate it at an enormous rate. For the moment, the chief value of this technique is that it provides an opportunity to learn more about the way in which genetic molecules function. While biologists already know a great deal about the operation of DNA in bacteria, they understand much less about its activity in higher organisms such as man.

Obviously, the ability to exchange the components of living organisms More Stringent Guidelines Are Vitally Needed BY L. DOUGLAS DENIKE When the world's leading molecular biologists agreed to impose a voluntary moratorium on their research into recombinant DNA, it was indeed an "unprecedented" step in the history of scientific exploration. The scientists, however, were moved by what many of them recognized as the novel hazards posed by a radically new biological technology. Genetic manipulation, they felt, could conceivably result in the creation of entirely new diseases or an increased resistence to antibiotics in existing pathogens. Therefore, the researchers resolved to halt experimentation until the real hazards inherent in their work could be identified and appropriate safety measures prescribed.

On June 23 of this year, the National Institutes of Health issued a set of guidelines intended to regulate recombinant DNA research supported by its grants. Though the requisite environmental impact report needed to evaluate these guidelines will not be released until next month, the NIH's action had the effect of immediately ending the voluntary moratorium. Unfortunately, the NIH guidelines are per-vasirely inadequate. L. Douglas DeNike is a psychologist who specializes in the study of scientific hazards.

It would be tragic if the inadvertent creation of dangerous new microorganisms caused biology to repeat the sad history of nuclear physics with its radioisotopes or organic chemistry with pesticides. Under the proper set of circumstances, recombinant DNA techniques could produce microbes at least as dangerous as the radioactive substance, stron-tium-90, or the dioxin that recently created such havoc in Seveso, Italy. As living entities, these microbes would not only be more mobile than other toxins, but also able to reproduce themselves. Yet the NIH guidelines fail to address a number of obvious hazards: The regulations permit continued experimentation with so-called "crippled" forms of Echerichia coli, which in its normal states is found in humans, animals, plants and soil. Many concerned biologists fear that even "crippled" forms of this microbe might transmit dangerous characteristics to ordinary Escherichia coli if they were accidentally released.

The guidelines list six categories of recombinant DNA which are too dangerous to handle even with the best possible containment. Yet the only penalty for violating these regulations is withdrawal of NIH funding. No reccomendations are made for legislation to completely ban work with these particularly hazardous recombinations. In their descriptions of measures required to physically contain the recombinant DNA experiments, the guidelines say nothing about designing research facilities to withstand natural disasters such as earthquakes and tornadoes. Federal regulations routinely require that the nuclear industry build structures incorporating such safeguards.

The guidelines specify no particular precautions against the possible actions of criminals or deranged individuals. Much has been made in recent years of the possibility that nuclear materials might be stolen and used for blackmail or terror. Hybrid bacteria might provide an even more inviting and potentially more accessible target. Nicholas Wade of Science magazine has noted that 'the emerging recombinant DNA technology has "enormous manipulative power (giving) it an obvious application for biological warfare, for example by inserting the genes for deadly or incapacitating products into highly infective host bacteria." Yet the basic apparatus and materials needed to carry on this technique are commercially available. The NIH guidelines are silent as to what, if any, steps can be taken to remedy this situation.

The halfway measures incorporated in the NIH guidelines create the potential for great harm. If, as the molecular biologists tell us, the this new field holds the potential for great benefit as well as great harm perhaps extraordinary measures are in order. It has been suggested that all recombinant DNA research be confined to a single, suitable remote site under international suprvision. 'Caution May Be an Essential Scientific Virtue organism such as man, the consequences may be profound. New diseases could evolve or existing diseases might be transmitted in unexpected ways.

If these diseases have long latent periods as do cancers and the existing slow virus diseases mankind might not even be aware of their existence until they had spread over wide areas of the globe. Given these potential hazards, I advocate extreme caution in the development of research into recombinant DNA. Specifically, I believe that the guidelines recently formulated by the National Institute of Health should be strengthened in two ways: The focus of recombinant DNA research should be shifted from Escherichia coli to microorganisms less intimately associated with man. Escherichia coli is the choice of most researchers only because its characteristics are better known than those of any other bacterial strain. An extensive program of research into the properties of other microbes could provide alternatives within a few years.

To minimize the potential of dangerous error, recombinant DNA research should be restricted to a small number of carefully supervised laboratories. These facilities should be specifically designed to provide maximum physical containment, and their experimental activity should be subject to frequent independent scrutiny. Clearly, it will not be sufficient to apply such restrictions only to American researchers. An effort must be made to secure an international agreement guaranteeing similar precautions wherever research into recombinant DNA is carried out. In any event, mankind has no assurance that science will not transport it into a more dangerous world.

The advent of this new technology makes it clear that we can no longer rely on the resilience of nature to protect us from human follies. We should not underestimate the stakes involved. Vision and a sense of morality must be employed in the search for those limits within which scientists can explore without fear and beyond which they ought to tread most gingerly. In seeking to understand nature, scientists should not unthinkingly disturb it irreversibly. Like curiosity, caution may now become an essential scientific virtue.

BY ROBERT L. SINSHEIMER Troubled scientists and confused laymen may wish that the recombinant DNA issue would go away, but it will not. Mankind is about to extend its dominion by redirecting the course of biological evolution. Inevitably, this must change not only the world in which we live, but also the way in which science functions in it. The spectacular success of science in the last 100 years has ended its pleasant isolation form the strident conflict of interests and clash of values that characterizes most of human society.

Earlier in this century splendid discoveries in physics and chemistry provided Robert L. Sinsheimer is head of Caltech's biology division and chairman of the editorial board of. the Proceedings of the National Academy of Sciences. us with a definitive understanding of the nature of matter. From that new knowledge has eome the technology, to reshape the inanimate world according to human purpose.

Many, however, are less than pleased with the consequences. Now, great advances in molecular and cellular biology have provided the basis of a technology capable of reshaping the living world of restructuring man's fellow life forms into projections of the human will. Naturally, many are profoundly troubled by this prospect. As science pursues this synthetic biology, we will be leaving the secure web of evolutionary nature that, blindly and strangely, has supported all living creatures for some 3 billion years. With each step we will be increasingly on our own.

How do we prevent grievous, inherently irreversible, errors? Can we in truth foresee the ultimate consequences of intervention into this ancient process? Genes, which are composed of DNA, hold the basic molecular blueprints for the design of all organisms. The recombination of genes containing different arrangements of DNA has always been an essential factor in evolution but only within species. The new technology of "recombinant DNA" makes it possible to combine genetic material from different species to mix, say, genes from animals, plants and microorganisms and thereby create forms of life that have never before existed. I suggest that, given man's current knowledge of this area, it is impossible to predict the properties of these new organisms and, therefore, the consequences of their introduction into the biosphere. Most of them would probably be harmless.

Careful design and selection might produce some that would be of great value to mankind. However, some of these new organisms might, inadvertently, pose a considerable peril to human, plant and animal life as it now exists. If these new organisms could be fully contained while they are under study, there would be less cause for concern. But knowing as we do the likelihood of error and accident, we must believe that some of these organisms will escape. The hazards posed by this eventuality are increased by the fact that the recombination of DNA is currently feasible only in microorganisms, particularly Echerichia coli, a microbe indigenous to man, animals, soil and plants.

Obviously, use of a microbe already so widely dispersed magnifies the dangers inherent in any release of a new organism. After all, these dangers are quite novel, since like any other living thing, new organisms will have the capacity to reproduce themselves. Once they are released, there will be no way to recall them or to halt their manufacture. They could very well be with us forever. Moreover, because the recombination of genetic material from different species does not occur in nature, we are ignorant of its probable consequences.

We do know, however, that nature has evolved strong barriers to prevent it. Figuratively speaking, mankind, like all higher organisms, is immersed in a sea of microorganisms. But our intimate and inevitable interactions with these ubiquitous life forms some of which are beneficial, some harmful are on the metabolic, not the genetic level. For example, when a disease-causing baterium enters a human body it may cause a chain of complicated biochemical reactions on the part of the body's cells. It does not, however, exchange genetic material with those cells.

If science artificially stimulates genetic intercourse between microorganisms and the cells of a higher I.