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GENOMICS - THE FUTURE RISK
Rainer K. Liedtke, M.D.
 
 
THE PUBLIC IMAGE
As in every new and growing professional scene, some special disciplines of biotechnology also have problems as far as their acceptance and image is concerned. This applies undoubtedly to Genomics, whose medical activities are referred to obliquely as the so-called "gene therapy".
The fact that some of genomics negative aspects have not become public can be put down to a clever information policy on the one hand and to the difficulties to understand this rather abstract matter and its practical effects on the other. As biological processes, unlike mechanical developments, are less obvious and hard to trace, they tend to be quickly underestimated. It looks like a "systematic flaw in the weave" that genomics has been able to praise its medical progress for decades now, although none of this progress has ever been properly identified. Quite the opposite, the unusual risks coming along with it tend to be played down and concealed by a smoke screen. To present public reservations against genomics summarily as a "reactionary ideology" is one such example of a smoke screen, although what it is really about are provable facts. And they do not look positive at all.
The matter is further complicated by the fact that it is increasingly economic arguments which are brought into play, saying that "one will miss the boat", "one will become economically dependent", "one will lose momentum" etc., if nothing is done for genomics. The economic interest in biotechnological methods can be put down to the simple and economical production of important natural medical drugs (such as insulin, erythropoietin etc.) as bio-products with genetically "re-programmed" bacterial strains as well as numerous other substances with a protein or peptide structure, such as enzymes that can be used for other technical processes in a useful way. Some of the genomics companies have benefited from the economic success of the corporate pioneers in this business segment (such as Amgen, Genentech). However, but the objectives of a "human gene therapy" have nothing to do with this "Biotech Pharma".
In fact, large sections of the population do not have reservations against biotechnology at all, their reservations are concentrated on genomics. This reflex-like defensive position has indeed valid scientific reasons. People's reservations refer to everything summarized and announced under the title "genetic corrections", genetic optimization, cloning" etc. The politically insensitive behavior of some representatives of this discipline does not help calm things down.
THE QUALITY OF FACTUAL INFORMATION
The experience gained with the public relation activities of genomics is based on the impression that the less there is substance the more ado is needed. Any result which can possibly be exploited, such as the formal establishment of the DNA sequences of the human genome, will immediately be pronounced as a "historic" step, that will soon and "invariably" lead to the cure of cancer, AIDS and Alzheimer.
The computer printouts of the human genome on the basis of DNA sequences established by using fully automatic chemical routines (machines determining DNA bases) are nothing else but a huge pile of sequences with characters composed of triads that are made up of four different letters with an information volume of some 750 megabytes. In order to speed up the tiring sequential routine processes (determining the individual DNA building stones), a biotech company (Celera) had purchased a large number of high-performance computers with the money of venture capitalists, which added more speed to the process than before. Besides, they employed the so-called "shotgun method" which is scientifically even less exact. And that was all. But if one reads the dramatic reports about this event (from Craig Venter etc.) the impression that a clever rationalization measure of a technical routine process has been described (under business aspects), but that the wheel has been re-invented for scientific purposes.
There is hardly any mention of the missing medical proof whether such statistical printouts reflect a biologically relevant reality. The sequences of letters alone do not make any sense as they do not reveal anything about biological functions. The printouts convey about as much information to those who have created them as an indefinite sequence of zeros and ones can express. It seems to be rather dubious to make a forecast on the basis of a sequence of numbers with an unknown meaning that it will now be possible to heal cancer. Such prognoses are therefore wishful thinking and not substantiated by scientific facts.
But it is not only the speculations and optimistic forecasts, it is also the cultivation of general myths. One of them is that genomics itself is "biology". The truth is quite the opposite - it artificially interferes in natural biological processes by turning these operations into a kind of biological warfare against the biological evolution. Another myth is that genomics works on a natural basis only and creates "natural" substances. Quite the contrary: the artificial genome manipulations generate predominantly new substances, which do not correspond to those produced by the cells with their original genomes. They are therefore neither "natural" nor necessarily agreeable (see below). This applies to all manipulated organisms, and thus to plants ("Green" biotech) as well as to animal and human cells ("Red" biotech).
THE FUNDAMENTAL PROBLEMS
It is a fundamental fact in molecular genetics that a manipulated genome produces other proteins than the natural ones, when the genome of a cell is artificially modified by introducing a foreign gene from another organism in its own DNA. Consequently, cells manipulated in this way will also produce new types of protein. These new cell products are foreign substances to the (host) organism, and there is not much or nothing at all known about their toxic properties. It is irrelevant in this context, whether these foreign substances have been produced in a modified cell or whether they have been injected into the cell from the outside.
The metabolic mechanism is accustomed to handle only its own substances which it naturally knows, because its original genome has been programmed by this mechanism to do exactly that. One often hears that the new proteins are, more or less, natural substances (because the term "protein" automatically triggers off notions like "protein food"), but one must not forget that e.g. the BSE "prions" are also proteins, although distorted ones. But it is these molecular variations where the difference between natural (healthy) and disagreeable (unhealthy) proteins lies. Also some of the toxic "natural" substances contained in small doses in the poison of snakes, scorpions and jellyfish contain merely "distorted" protein and peptide structures, but they definitely do not agree with us biologically. This is nothing new. Even minute changes in the molecular structure of medical drugs cause considerable changes in their effect and toxicity. This is called the structural interrelationship, which also applies to the complicated structures of proteins. The BSE prions are demonstrating impressively what effect the sediments of "distorted" proteins may have on the organism as a whole.
The fundamental problem of Genomics are its technical objectives, which can be considered as hostile to evolution. This is exactly where the significant risk potential lurks. Researchers in genomics talk about their intention to improve the selective evolutionary process which has been going on for millions of years. But evolution has also been a biochemical process that has been going on for millions of years and during which billions of self-adapting and self-regulating gene reactions have taken place. Our own biological balance and the life functions have solely been created out of these processes. It is therefore unavoidable and predictable that any isolated and artificial interference in this biological balance will destabilize the bio-systems of man, environment and food. This will artificially and irreversibly destroy the functional balance established in the genome, which to build up was difficult enough.
Some genomics specialists consider themselves able to influence this complicated interrelationship with the help of localized/punctual technical manipulations and thus to "improve" or "correct" it. It is predictable that such attacks on complex biosystems (organisms) will destabilize them to such an extent that they are incapable again, wholly or partly, to live. The good intentions possibly connected with such kind of manipulations can be disregarded as irrelevant, because the disastrous result is the same. This can be seen from the experience gained by the practical gene "therapy" (see below).
The consequences of such manipulations are predictable: new toxic substances or viruses will emerge that can have toxic, cancerous or mutagenic properties, to name but a few, and hence the entire potential for the development of new and hitherto unknown diseases. Until recently, people representing the interests of genomics have referred to such events as "highly unlikely", "impossible" or "unforeseeable", when the need arose. They were neither this nor that.
How quickly things can go wrong in genomics can be demonstrated by the example of a publication ( Journal of Virology 2001, 75(3), 1205)*: As a result of manipulating a virus which had been considered controllable until then, a kind of "killer virus" suddenly and "unpredictably" emerged. The only "positive" effect this event had was the realization that it may also be relatively easy for bioterrorists to produce something similar one day as well.
*) It seems to be doubtful whether the title of such a publication would be identified by a layperson as something explosive ("Expression of Mouse Interleukin-4 by a Recombinant Ectromelia Virus Suppresses Cytolytic Lymphocyte Responses and Overcomes Genetic Resistance to Mousepox"). Nor would probably its conclusion in the abstract start the warning lights flashing in the minds of the laypersons when they read kryptic statements like: "These data therefore suggest that virus-encoded IL-4 not only suppresses primary antiviral cell-mediated immune responses but can also inhibit the expression of immune memory responses."
The basic problem connected with such kind of interference also points to some considerable problems those people involved have: “gene therapists” in clinics attempt to treat patients without sufficiently knowing the fundamentals of the cure they apply. This approach can partly be compared with the level of knowledge at the time when people thought animal blood could be used for curing men. It has also taken quite a while at that time (and needed some fatal results) until it was suspected that the assumptions concerning the fundamental biological principle (the different blood groups) may have been wrong. The way of thinking does not seem to have basically changed since. The question, whether the unsuccessful attempts in human genetics are not attributable to a technical but to a fundamental thinking error, has not occurred to the people concerned. Otherwise they would not keep assuming that one can selectively influence a complex biosystem - the dynamically functioning interplay of all genes - by just removing one "wrong chip" in one location of the genome and substitute it by one new and "correct" one. The fact that this has never worked so far is put down to "unforeseen" effects. Given the number of about 25-40,000 genes (even that number is still being disputed), one can imagine the astronomically large number of combinations possible as far as the mutual relationship between them is concerned. The chances are higher that a localized/punctual gene „correction" within a biosystem will only bring about a disturbance in the system (hence a new disease) rather than have a healing effect.
Maybe, the following example from the world of computer technology can illustrate the situation better: An engineer carries out his "remedial surgery" on a central processor with millions of integrated circuit elements. He picks one of the millions of transistors at random as the "faulty" component and replaces it by a new one with totally different parameters (the "foreign transistor"). After having accomplished the exchange, he would then claim all functions in the central processor work normally again. As this is predictably impossible and as the computer will function differently (if it has survived the "operation" in the first place), the engineer will refer to the results of his operation as an "unforeseen effect". This is similar to the principle of the current "therapeutic" gene treatment.
SUCCESS SO FAR ?
So far, a few hundred cases of gene „therapeutic" applications have become known, of which some have been fatal. The rate of those cures which proved to be permanent as has been intended is virtually nil. Any pharmaceutical company with a "success rate" of this kind would face criminal proceedings very soon, if it made clinical tests with medical drugs in this way and with the respective level of previous knowledge in this field, and especially if it continued its efforts with a "success rate" like this.
It is quite possible that the rate of negative results in the previous cases of localized/punctual gene manipulations may have been reduced by the ability of the complex organisms to repair themselves. The natural genome resists attempts of individual artificial „corrections" and tries to clear up the mess created by external influences or gene engineers so that things can be put back into its normal order. Gene repairs against detrimental environmental influences (such as against mutations caused by radiation) are well known. This is what natural evolution is all about: the permanent attempt to resist dangerous influences in order to survive in the best possible manner.
The deficit of knowledge that manifests itself in these attempts to affect a „clinical cure" and the sobering, not to say damaging results achieved over the years have obviously not prevented the gene therapists from further experiments. The example of 18-year old Jesse Gelsinger who died after a gene „correction" attempt (although he had no life-threatening disease) may be used for argument's sake: The researchers of the University of Pennsylvania involved in the case eventually admitted after one year had passed that they believed, the adenovirus (or more specifically its protein membrane) used as vector (vehicle) for the target cell may have caused the death of the boy and characterized the incident as a "fatal chain of events". Such fundamental evidence of the presence of risks casts considerable doubt on the safety of other gene experiments*).
*) As a result of this disaster, the US health authority FDA has suspended this team of scientists from gene experiments for an indefinite period of time and threatened to exclude the team leader from gene experiments with humans in the US forever.
A mixture of fear and hope is used in order to obtain the funding for further experiments and the permit to continue with them. Facts are not always interpreted exactly and sometimes half-truths are used. Genomics has tried to make the general public believe that it is mainly (if not altogether) the genes which are responsible for the development of cancer, although serious epidemiological studies have proved that in more than 60% of the cases not the genome but environmental factors have caused the growth of tumors.
*) One of the DNA pioneers (Chargaff, who discovered the DNA base complementarity without which the genome sequencing would have been impossible) wondered: "The human geneticists advertise themselves with the promise that incurable diseases can now be cured at last. This is an old pretext of bio-research, although nothing has happened so far. If they have really read the genome I would like to know what that has got to do with cancer."
Another field of Genomics is gerontology. Although improvements have undoubtedly been achieved in the quality of life during old age as a result of medical progress, nothing of that has come from genomics. Not only has the prognosis of a genetically engineered extension of the life span not come true, it has alternatively been found out that the formation of tumors can be triggered off when the cell cycle during the phase of the cell division is manipulated.
It is understandable on the background of such "success rates" that the genomics industry reacts rather sensitively to the publication of such data. The US Biotechnology Industry Organization (BIO) has voiced its "concerns" about a regulation the FDA is about to issue and that is aimed at publishing more information about gene therapy experiments*).
*) BIO even voiced the "concern" that the general public should not be "unnecessarily frightened" by the failed gene experiments the FDA is about to publish. More likely is that they do not like to have its activities to be confronted publicly with its failures, as it rather sees its activities portrayed as beneficial and promising.
THE FUTURE RISK - A SCIENCE FICTION?
Although one should not venture too many prognoses, it can be said in general that all sorts of things might happen in the field of genomics which would have been discarded earlier as a pure science fiction. These risks have a much more lasting and long-term effect than any mechanical techniques hitherto known.
The reason for this is the capacity of biological self-reproduction which escapes any control.
So far, man has never had to fight against artificially generated new biological creations, in other word against self-reproducing external mechanisms (leaving aside bacteriological means of warfare which are legally banned all over the world). Naturally, we are only confronted with bacteria and viruses that cause the infectious diseases we know. In some cases, immunity barriers have been erected against these diseases as part of the natural evolutionary process. Nevertheless, some of the bacteria still have an excellent ability to adapt themselves genetically and to strengthen their own striking power or to become resistant against human defense mechanisms. Applying this to mechanics, a scenario is conceivable where humans have to fight highly intelligent robots who can always re-assemble and adapt themselves to the new situation in an improved and more intelligent way. However, as biological reproduction mechanisms of that kind are concealed and more abstract they quickly tend to be underestimated. The insidious effects of such "new creations" in the field of „green" genomics, e.g. in the food sector, will become slowly visible by changing allergy rates, while the toxic effects curently seem to be less obvious since the percentage of undetected cases cannot be clearly separated from other factors as yet.
The difference between a „Titanic catastrophe" and biogenetic processes is the repetitiveness of the latter. The sinking of the Titanic was a unique mechanical/technical event caused by human incompetence. A ship may be built only once. In the field of genomics, the biogenetic error is irreversible as it is maintained and repeated by the system's self-reproduction capability. Modifications implanted artificially into a biological information structure of a genome will remain more or less resistant and largely defy any attempts of a later correction by developing their own kind of intelligent defense mechanism. This applies both to bacteria and to viruses.*)
*) A surprising example concerning bacteria is how the genome of E. coli was found (well known from some outbreaks after "hamburger" catastrophes that resulted in a number of fatalities). The scientists were "surprised" about their findings to what extent the pathogenic variant had already moved away genetically from the harmless one and became aggressive (Nature, 409, 529-533; 2001: genome sequence of enterohaemorrhagic Escherichia Coli 0157:H7).
Even more devastating is a kind of "stealth bomber tactics" of the viruses, which is known from the spread of virus diseases (such as AIDS), whose manifold facets no therapy has so far been able to contain. The same applies to some particularly dangerous genetic variants of the flu. The US film "Outbreak" (starring Dustin Hoffman) may serve as an illustrative "Science Fiction" scenario of things which could still happen.
The fundamental error in the system of Genomics Gene Therapy is that the individual manipulations as applied by them cannot permanently change complex biosystems, so that the desired effect on the system is not achieved. On the other hand, these manipulations are effective enough to trigger off the isolated production of substances, which include new and toxic or infectious types of substances.
The worst can only be prevented by the strictest possible control of any such attempts to apply “gene therapies" as well as by informing the general public about all activities in this field. The worst as referred to above would be the "unintentional design" of artificial new diseases, very similar to the worst-case scenario in the above mentioned film "Outbreak".
It would be unreasonable both under social and economic aspects not to promote promising new developments with good chances such as e.g. the field of Biotech pharmaceuticals. Unfortunately, the chance/risk ratio of “gene therapy" reveals more risks which are unacceptably high and unjustified as far as the wellbeing of the general public is concerned. This has something to do with fundamental biological facts and not with ideology. It may sound absurd, but there may well be the case in genomics that new pathogenic organisms "unintentionally" designed by a biogenetic error can only be fought with new biotechnical remedies, but the price for this new "therapy" would prove to be very high. Hence, there is no reason to go for new and artificially created pathogenic agents or to contract any such diseases only in exchange for a so-called "progress". We have already enough problems with the old ones. One has to realize that we do not talk about regional but global risks. Biological effects are by no means restricted to any particular social class and neither a selective nor a permanent protection exists for any individual against the biological ghosts thus raised. History shows that everything conceivable under technical aspects has come true sooner or later.
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© 2010 Rainer K. Liedtke