ISIS Special Series, Jan. 2002 - Inside Human Genetics and Genomics
Part 2 of a 4 part series
Genomics for health?
Human DNA ‘BioBank’ worthless
The silenced targets
The national health crisis and ‘health genomics’
Genomics for Health?
Despite heroic efforts to keep up the hype, prospects for genomics – information gathering around genomes, genes and proteins - look bleaker than ever before, and for good scientific reasons, according to Dr. Mae-Wan Ho.
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A two-day symposium on "The Future of the Pharmaceutical Industry" last December sponsored by the Massachusetts Institute of Technology came at a crucial time. Research released by the Tufts Center for the Study of Drug Development shows that the ‘biotech revolution’ has, so far, greatly slowed drug development cost while increasing cost.
During the last two decades, the average time spent on clinical trials increased from 33 months to 68 months, while the average cost of developing a new prescription drug has jumped to $802 million from $231 million a decade ago. This figure includes the cost of human trials, pre-clinical studies, expenses for product failures, and the impact of long development times on investment costs.
According to an editorial in the December 2001 issue of Nature Biotechnology by David Horrobin, CEO of Laxdale Research, Stirling, Scotland, most of the top 20 multinational pharmaceutical companies are not generating in-house the new products needed to sustain the rates of growth they have enjoyed in the past. "No serious industry onlooker could dispute this depressing picture", he wrote.
The key question is, will genomics help? Anthony Sinskey, a co-director of MIT’s Program on the Pharmaceutical Industry, stressed that the millions of chemicals
sitting on pharma’s shelves need to be investigated. And that it is up to the ‘array makers’, ‘microfluidics developers’, and ‘informatics providers’ to help predict and measure outcomes and bring products to market.
Horrobin points out, however, that combinatorial chemistry has been around for over a decade, but yielded relatively few products considering the extraordinary size of the investment.
"Could it be that there is something wrong with the technology in principle, and that the target choices and the target configurations are fundamentally flawed?" he asked.
The human genome map has cost the public US$3 billion, and hundreds of millions of pounds in Britain alone. Thousands of scientists from 20 centres in 6 countries have worked for ten years, only to be overtaken by Craig Venter’s private company Celera.
Venter came up from behind to finish equal in the human genome race, and to burst the bubble by telling the world that our understanding of the human genome has changed in the most fundamental ways. "The small number of genes - some 30,000 - supports the notion that we are not hard wired. We now know the notion that one gene leads to one protein, and perhaps one disease, is false." There may be ten times as many proteins as genes, that "can change dramatically once they are produced". One simply "cannot define the function of genes without defining the influence of the environment." (See Human genome map spells death of genetic determinism ISIS News 7/8, www.i-sis.org.uk.)
Investment companies were quick to see the implications, as the myth of genetic determinism can no longer be sustained. Lehman Brothers and McKinsey predicted that the human genome project could bankrupt the biotech and pharmaceutical industry. The "information overload" threatens to increase research and development costs.
Instead of cutting the losses and retreating, proponents simply redoubled their effort to keep up the hype, and our governments are set to bail out another ailing industry by throwing away even more of our tax money.
The American Museum of Natural History put on a lavish exhibition last year, "The Genomic Revolution", funded by a corporate-friendly charity. It claims that, "By the year 2020 it is highly possible that the average human life span will be increased by 50 percent; gene therapy will make most common surgery of today obsolete; and we will be able to genetically enhance our capacity for memory". At the same time, an art show promoting genetics, "Paradise Now" toured the country.
Our genome scientists have distanced themselves from the crude propaganda. They say the human genome map is just "the end of the beginning", and much more money is needed before the health goods can be delivered.
The British government committed some £2.5 billion to genomics over the next five years in 1999. The Wellcome Trust, long regarded as friendly to the pharmaceutical industry, is giving £300 million to Cambridge’s Sanger Centre. The centre is changing its name to the Wellcome Trust Sanger Institute.
Genomics is a huge undertaking. ‘Health genomics’ alone includes information gathering, not just on the human genome, but the genomes of ultimately all animals, plants, fungi, bacteria and viruses that ‘serve as disease models’ or cause or transmit diseases of one form or another.
Hundreds of genomes have been sequenced, and thousands more will be available down the line. Hundreds to tens of thousands of genes will be identified in each genome. Then, one needs to find out which genes are transcribed under different conditions, and what proteins are made and what each protein does. The structure of each protein will have to be determined in big synchrotron X-ray facilities. That’s not all.
Each gene exists in hundreds of variants, and any two human individuals will differ by one in every 500 bases in their genome. These single nucleotide polymorphisms (SNPs), millions of them, account for most of the genetic differences between individuals, and are the great white hope to ‘personalised’ medicines. A public-private consortium of the Wellcome Trust and 13 pharmaceutical companies is supporting mapping and analysis of SNPs in the Sanger Institute plus four other centres in the United States. In addition, ‘genome-wide’ scans for patterns of genes expressed and proteins synthesized are made with gene chips and protein chips to find out what happens in different diseases under different conditions. Endless reams of data will be generated, demanding ever bigger and faster computers to compile and analyse, and much more efficient and compact means of data storage.
The databases will be owned by companies and available to paid-up subscribers only. And of course, the genes, the proteins, ten times as many as genes, and millions of SNPs identified will all be patented.
Only a fool would think any useful knowledge could automatically emerge from this vast graveyard of information. More seriously, genuine scientific research will cease as patents and proprietary databases place severe restrictions on the use of material and information.
The Wellcome Trust’s website tells us that pharmaceutical companies believe they will get many additional "druggable targets". The SNPs are even better. Pharmaceutical companies are "eagerly awaiting this flood of new information about human variability" to accelerate the development of drugs based on individual differences.
In reality, the prospects look bleak, and creeping doubt about genomics is developing into full-blown scepticism (see Box).
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Creeping doubt on genomics developing into full-blown scepticism
A row has broken out in the European Parliament over the European Commission’s proposal for its sixth framework for research funding, which covers public research funding within EU countries for the next 6 years. Members of the European Parliament and researchers criticise the proposal for focussing too much on genomics and biotechnology, and not enough on individual diseases like cancer, diabetes and Alzheimer’s.
Plans to build a new genomics facility in Grenoble is reported to be in jeopardy because of a lack of funding. The project is a joint venture between the European Synchrontron Radiation Facility, the Institut Laue-Langevin and the European Molecular Biology Laboratory, and was due to be finance in large part by an industrial consortium.
Russia is cutting its spending on genomics research through its 12 year old national Human Genome Program by 50%, and putting the money into a general pot for basic research.
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Sir David Weatherall, one of UK’s most eminent geneticists, has warned, "the remarkable complexity of the genotype-phenotype relationship has undoubtedly been underestimated.... It has led to many statements being made about the imminence of accurate predictive genetics that are simply not true". Nevertheless, he still believes that more information will eventually result in accurate predictive genetics. But will it?
We already know that environmental variables - such as hygiene and living conditions, exposure to toxic substances, social class, diet and other ‘lifestyle’ habits - can all significantly influence disease and disease progression across ethnic groups and major genetic differences. For the vast majority of diseases, the environmental variables will swamp the effects of ‘susceptibility genes’.
‘Susceptibility’, by definition, denotes weak linkage, and can never give firm predictions. Moreover, it describes the population attribute of certain genes, and says nothing at all about the susceptibility of individual human beings. Thus, ‘personalised’ medicine based on susceptibility genes or SNPs is scientific nonsense at best. At worst, it can be an excuse for genetic discrimination and eugenics.
Dr. Richard Strohman, Emeritus Professor of University of California, Berkeley, expressed doubts that genomic information will have much impact on human life-span and health in a commentary published in Nature biotechnology last year.
Genes influencing general health and longevity are numerous, perhaps hundreds or even thousands, but their effects are confounded by interaction with the environment. It is simply impossible to pin them down. Scientists face a ‘computational barrier’ because the possible number of interactions that have to be taken into account far exceeds our ability to cope with them, even with the fastest, biggest computer.
The potential to longevity is equally present in a wide variety of genomes, with environmental factors dominating. And, if through genomics, both of our major diseases, cancer and cardiovascular disease, were eliminated, the total increase in life expectancy is estimated to be less than three years.
But then, it is the quality of life, and not longevity that people rate highly.
The improvement in hygiene, medical care and public health measures in the first half of the 20th century added nearly 30 years of life-expectancy to the populations in the G7 countries, which had little to do with genetics. This must now be the priority for Third World countries. Instead of genomics, let them have decent living conditions, nutrition and hygiene.
An earlier report concluded that "genomics combined with related technologies of computer aided drug design and combinatorial chemistry linked to high throughput screening" have not improved drug discovery, and show little evidence that they will provide the bridge from genome to function even at the level of the protein.
Strohman fears that we are "providing more and more resources for less and less advance in a span of problematic quality of life". And, "as far as HGP is concerned, we are on the road to finding technological miracles for the genomes of the few using resources that could bring substantial benefits to the many if applied as preventive measures to the general population.."
Enthusiasm for genomics from industry has been equally muted. Allen Roses, scientist from the Genetics Directorate of Glaxo Wellcome, wrote a long article in Nature, ostensibly to promote ‘pharmacogenetics’ - the study of how genetic differences influence individual response to drugs. But the article conveys a sobering message.
It is very expensive to validate the new drug targets, so, pharmaceutical companies prefer to make new variants of old drugs. "The best-validated targets are those that have already produced well-tolerated and effective medicines."
Roses distinguished ‘discovery genomics’ from ‘discovery genetics’. The former uses databases of DNA sequence information to identify genes and families of genes for possible drug targets, but these are not known to be associated with any disease. The latter uses human populations, like the human DNA Biobank collection, to identify disease-related susceptibility genes. But susceptibility genes are not drug targets.
Companies now ‘mine’ sequences from the human genome, to identify gene families that have sequences similar to one that is known. But this approach is full of pitfalls, because similar sequences may have entirely different functions, just as completely different sequences can have the same function.
The major challenge remains the validation of the target, which pharmaceutical companies are most reluctant to commit resources to. Though in truth, the pharmaceutical industry is still by far the most profitable on earth, beating the automobile and the oil industries.
The new methods currently promoted such as ‘genome-wide scans’ have not yielded useful information on genetic diseases, let alone drug development.
So where does that leave pharmacogenetics? "Pharmacogenetic approaches will no doubt confirm what clinicians already know - disease diagnosis is not easy nor necessarily homogeneous and accurate." The point is, doctors already classify diseases according to their differential response to existing drugs.
The SNPs can speed up discovery of susceptibility genes, but as said already, these are not automatically suitable drug targets, and problems of validation remain. Could SNPs not be used to select for patients that are more likely to respond positively to new drugs? Roses pointed out that regulatory authorities might justifiable look askance at this practice, and would be concerned that when the drug is sold, those patients who do not have the right SNPs might be sold the drug by mistake.
Most of all, Roses warned that gene tests based on susceptibility genes and SNPs cannot be equated with those used for ‘single gene’ disorders. In other words, they are far less reliable or predictive. But even those based on single genes cannot give accurate prognosis for the individuals concerned.
To sum up, genomics is of no benefit for the health of nations. It is not even of clear benefit for drug development. Genomics is a hangover from the genetic determinist ideology that has driven the human genome project. The most valuable lesson of the human genome map is precisely in exposing the error of this pernicious ideology. That is perhaps worth all the tax money that has been spent. Genetic determinism has misguided the policies of nations and has been responsible for inspiring the worst excesses of genetic discrimination and eugenics. Genomics and the associated human DNA BioBank project are in danger of bringing back those excesses. Already, those perceived to be ‘disabled’ or ‘defective’ are being treated as objects and denied any voice.
There is an urgent need for a sweeping change in direction in biomedical research if we are to truly invest in the health of nations.
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