"In everyday language the talk is about a gene for this and a gene for that. We are now finding that that is rarely so. The number of genes that work in that way can almost be counted on your fingers, because we are just not hard-wired in that way." Craig Venter, Celera Genomics, 12 February 2001
Although few may have yet noticed, the primitive scientific model on which the foundations of genetic engineering have been constructed was dealt a quiet but earth-shattering blow this week with the formal publication of the base pair sequence of the human genome. That at least must be the ultimate conclusion to be drawn from what has now been revealed (see press reports below).
Although the human genome project is nominally specific to our own genetic code, the "surprising" nature of its results have much broader implications relating to science's understanding of the genome functioning of all species. The project graphically demonstrates that organism biochemistry is driven as much (if not considerably more so) by the multi-dimensional relationships between the thousands of genes involved (which are in turn symbiotically linked to the functioning of the organism as a whole in its environment), as it is by the previously assumed linear influence of individual genes which has largely dominated scientific thinking up until now.
This realisation is one which has been anticipated and highlighted by critics of genetic engineering from the outset, but which (for reasons best known to itself) large portions of the biotechnology community have chosen to ignore. It represents an implicit acknowledgement of why genetic engineering is inherently risk laden, and it is a dramatic illustration of the old common sense adage that "a little knowledge is a dangerous thing".
Current methods of modern biotechnology predominately rely on an out-of-date model of the way genes influence biological processes within an organism. Although the model espouses some limited embellishments beyond this, it has been largely a simplistic 'one-for-one' component-based model of biochemical processes. Even though this model now has no option but to surrender to the concept of the multi-dimensional genome - where relationships rather than components predominate - there is little corrective action that genetic engineers can now take to limit the inherently large risk quotient associated with the use of recombinant DNA that has been exposed by this new understanding. This is simply because almost nothing is currently known about such relationships, despite the fact that they are ultimately responsible for the way in which all proteins in an organism (250,000 in the case of a human) are generated.
Developing a proper understanding of those relationships (not only within individual organisms but beyond them in the overall context of their environment) is now the principal challenge facing the biotechnology community. It is an awesome, and in practical terms, a hugely expensive one. To quote from an earlier press interview with Craig Venter, the American scientist who lays claim to having been the first to produce the 'complete' sequence of the human genome: "We know shit about biology." [*]
Ultimately what the human genome project is beginning to demonstrate is that the 'core' objections to genetic engineering voiced by its critics are proving to reflect a more complete scientific understanding of genetics than that of the genetic engineers themselves. Meanwhile the genetic engineers continue to operate on a predominately linear model of genetic function and influence which is now demonstrably obsolete. This linear fantasy was, of course, always an extremely naive concept even at the time of its conception.
Perhaps what is most encouraging, however, is that journalists from quarters which otherwise have previously been willing to sing the praises of genetic engineering are now apparently ready to report on the new understanding that is emerging from the discovery of the multi-dimensional nature of the genome and its relationship with the environment. Of course the implications of this understanding are not yet fully articulated - but clearly that is now something to be looked forward to in the not-too-distant future. Essentially a new more holistic understanding of the nature of the genome is starting to form, and under whose penetrating light the primitive interventions of recombinant DNA techniques can only shrivel and die.
In this respect the publication of the human genetic sequence does indeed represent a huge breakthrough in scientific understanding - and it may have come just in the nick of time. The only real "surprise" in all of this is that the scientists and journalists charged with informing the public on such things should themselves be surprised to have found only what to many was the obvious in the first place. It is clearly very difficult to see the biological 'wood for the trees' when you spend too much time peering down a microscope or listening only to those who do so.
Particular credit therefore goes to Craig Venter for the forthright way in which he has been willing to stand back from the mind-numbing detail of the genomic sequence that he himself has helped reveal, and to simultaneously disabuse both the scientific and journalistic communities of the misplaced understanding that has been derived from their own conceptual myopias.
In the end the whole is more than the sum of the parts; it is the totality of the relationships. At its most complete, organism health is exclusively the state of being 'whole'.
In effect, if not by intention, genetic engineering through the use of recombinant DNA is principally concerned with the disintegration of the whole into a collection of unrelated parts. It is the product of an age of ignorance and reductionist superstition which, as from this week, now belongs firmly to the primitive past.
Why you can't judge a man by his genes [extracts]
Times, MONDAY FEBRUARY 12 2001
The two completed maps of the human genetic code reveal a treasure trove of information about the essence of mankind. They include the discovery that human beings have many fewer genes than expected.... ....researchers now believe that the complex ways in which genes operate in the body, and the environmental factors that influence every individual in unique fashion, may be more important than raw genetic material. The debate about the balance between nature and nurture is back on the agenda.... Craig Venter, president of Celera, said that the findings proved that while genes were vital to human development, they could not be the only, or even the major, factor in the behaviour or in many diseases. "There are two fallacies to be avoided: determinism, the idea that all characteristics of a person are hard-wired by the genome; and reductionism, that now the human genome is completely known it is just a matter of time before our understanding of gene functions and interactions will provide a complete causal description of human variability. "In everyday language the talk is about a gene for this and a gene for that. We are now finding that that is rarely so. The number of genes that work in that way can almost be counted on your fingers, because we are just not hard-wired in that way.".... "You cannot define the function of genes without defining the influence of the environment. The notion that one gene equals one disease, or that one gene produces one key protein, is flying out of the window." Sir John Sulston, former director of the Sanger Centre, near Cambridge, which sequenced a third of the genome for the public project, said that the key to the complexity of human beings was the way in which human genes had many different functions. "We know that as we move up the ladder of complexity from the single-cell creatures, through small animals like worms and flies, and up to us, what we are adding on is control genes," he said. "We are not adding so many genes performing new functions, what we are doing is to increase the variety and subtlety of genes that control other genes."
Gene code scientists face fresh challenge [extracts]
Times, TUESDAY FEBRUARY 13 2001 http://www.thetimes.co.uk/article/0,,2-82856,00.html
While a handful of diseases are caused by defects in single genes, many more, including the biggest killers such as heart disease, are influenced by a combination of many genes and proteins, as well as by environmental factors.... Much of the next stage of research will focus on the 98 per cent of human DNA that does not form a part of any genes. This so-called "junk DNA" is nothing of the kind, but instead plays a crucial role in controlling gene function, the genome analysis has revealed. Other research will examine the complex ways in which proteins are "folded" from combinations of the 20 different amino acids in the body. A protein's function is affected not only by its amino acid content, but also by the shape in which it is made. The prion proteins that cause BSE and CJD, for example, are dangerous because they are folded in abnormal fashion....
Nature beats nurture [extracts]
Times, TUESDAY FEBRUARY 13 2001 http://www.thetimes.co.uk/article/0,,7-82727,00.html
The genome project has discovered that we have only 10,000 more genes than a worm. Does this mean that our environment is more important than our genetic make-up?
So long-awaited has been the publication of the human genome that it might easily have lost all power to surprise. Yet at the very last minute it has thrown us a curve ball. Instead of the 100,000 genes that most scientists had been expecting, the two rival versions of the genome published yesterday show that there are a mere 30,000. Such a modest parts list is a real shock
- "the single most surprising fact" to emerge from the double publication, says Dr Craig Venter of Celera Genomics, who led the privately funded initiative.....
It means, says Venter, that it takes only another third as many genes to make a human being as it does to make a worm....
Ever since the breaking of the genetic code in the 1960s, we have known that all living things are cut from the same cloth. That cloth is DNA - deoxyribonucleic acid - whose long molecules spell out in the sequence of their bases the recipe for making particular proteins.
The code is the simple way in which the bases, in groups of three, identify particular amino acids, which are then assembled in the right order to make a protein. The discovery that all creatures share the same code was a profound one, for it instantly made sense of evolution and reminded us that all life is one.....
If there is a qualitative difference between our brains and those of animals, it must lie in the proteins, not the genes. Most likely there is no qualitative difference at all, but simply a difference of size and the complexity of cross-links.
As happens so often in science, a peak is conquered only to reveal a still more daunting one ahead. Those who believed that elucidating the genome would provide the key to understanding everything will have to think again..... In the wake of yesterday’s publication, both teams were playing down the importance of the genes in human affairs — as if passing the winning post has made the race seem almost an irrelevance.....
The fact that the human body needs so few genes is likely to have some worrying implications for medicine, which had hoped to find easy genetic answers to disease, and simple explanations for the different ways people respond to the same drug.
"The drug industry has been saying 'one gene, one patent, one drug'," says Venter. "But the uses for this approach can be counted on the fingers." ..... "Because of the relatively low number of genes, Celera scientists believe it will be necessary to look elsewhere for the mechanisms that generate the complexities inherent in human development," the company said in a statement yesterday.
"It's kind of humbling, isn't it?" says Ari Patrinos, of the US Department of Energy, which funded much of the public effort. "There are very, very few traits or diseases that are monogenic (caused by a single gene). It has been an emerging consciousness over the past five years - the recognition that our genes don't control everything."
..... According to Sir John Sulston, a former director of the Sanger Centre near Cambridge and a leading player in the publicly funded genome initiative, the difference lies not in the number of the genes, but in their mode of action. Higher creatures have more control genes, enabling them to play subtler tunes on the basic set of ordinary genes which are universally shared.
According to the historian and philosopher Thomas Kuhn, science advances when a new revolution, or paradigm, takes hold of the scientific consciousness. Such paradigms are often great simplifications, such as plate tectonics, which instantly made the whole of geophysics comprehensible.
But between these shifts of scenery, science advances by the accumulation of detail. The discovery of the structure of DNA and the genetic code was a paradigm shift that had the effect of making the whole of genetics seem simple. Now we are learning what we always do: that it was not as simple as that after all. The never-ending fascination of science is that every question raises another, and that nature always has fresh complexities to throw at us. The unveiling of the genome is not an end, but a beginning.
"These findings demonstrate the fragmentary nature of current knowledge of genome structure and function and regulation of gene expression in general, and the limited understanding of several physiological, ecological, agronomical and toxicological aspects relevant to present-day and planned genetic modifications of crops." Visser et al. Plant Research International (No. 12) 70 pp, 2000 Or "We don't know shit about biology." Craig Venter, the scientist whose company completed the sequencing of the human genome in 2000
("Decoding the genome" Ralph Brave, Jan. 9, 2001)