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.
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. Thousands of scientists from 20 centres in 6 countries have worked for ten years or more, 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 [2]. "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."
Investment companies were quick to see the implications, as the myth of genetic determinism can no longer be sustained. "Mapping the genome could be route to disaster" [3]. Lehman Brothers and McKinsey predicted that the human genome project could bankrupt the biotech and pharmaceutical industry. The "information overload" will cost much more than previously thought. Genomics "threatens to increase not only the associated research and development costs, but also the average cost per new drug."
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 sinking in even more of our tax money.
The American Museum of Natural History put on a lavish exhibition, "The Genomic Revolution", funded by a corporate-friendly charity [4]. It predicts 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 called "Paradise Now" has gone on tour around the country.
Our genome scientists have distanced themselves from the crude propaganda. Instead, they say the human genome map is just "the end of the beginning", and much more money is needed before the goods can be delivered in cancer cures, eradication of disease, genetic enhancement, gene therapy, personalised medicine and a prescription of lifestyle based on our genetic makeup.
The British government committed some £2.5 billion to genomics over the next five years in 1999 [5]. The Wellcome Trust, a big charity long regarded as friendly to the pharmaceutical industry, is giving £300 million to Cambridge's Sanger Centre for genomics research [6]. 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 [7].
Complete genomic sequence is already available for yeast, fruit fly and nematode; and mouse, rat, zebrafish, chicken and dog are well on the way. Within the next five years, complete genome sequences will be available for all model organisms used in biomedical research.
In addition, the genome of hundreds of viruses and bacteria associated with major infectious diseases are sequenced, with hundreds more to follow. Genomes of many protozoa parasites are available including those associated with malaria, sleeping sickness and Leishmaniasis. And insect vectors, such as the mosquito, Anopheles gambiae, and the Aedes species, will also be sequenced.
Hundreds to tens of thousands of genes will be identified each genome. Then, one needs to find out which genes are transcribed under different conditions, in 'transcriptomics', and what proteins are made and what each protein does, in 'proteomics'. The crystalline 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, 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 website tells us that pharmaceutical companies believe they will get many additional "druggable targets". "Currently, the entire drug cabinet is focussed on just 483 targets", so "enormous possibilities for new therapies exist" [8]. 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 [9].
In reality, the prospects for genomics look bleaker than ever before, and creeping doubt has been developing into full-blown scepticism (Box 1).
Box 1
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 (MEPs) 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 [10], "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, Sir David still believes that the information gained will eventually result in accurate predictive genetics. But will it [11]?
We already know that environmental variables - such as hygiene and living conditions, exposure to toxic substances, social class, poverty, diet and other 'lifestyle' habits - can all significantly influence disease and disease progression across all 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 gene variants, 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, doubts that genomic information will have much impact on human life-span and health [12].
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.
Conversely, recent history of treating cancer and other diseases of the aged through gene-based technology is not reassuring. An earlier report has concluded, "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 an article in Nature, ostensibly to promote 'pharmacogenetics' - the study of how genetic differences influence individual response to drugs [13]. But a different sobering message came across.
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 [14], to identify disease-related susceptibility genes. But susceptibility genes are not drug targets. They "will not be tractable targets or amenable to high throughput screening methods to identify active compounds".
Companies now 'mine' sequences from the human genome, to identify gene families that have sequences similar to one that is known. But, although Roses does not say so, this approach is full of pitfalls, because similar sequences have been found to have entirely different functions, just as completely different sequences can have the same function.
The major challenge remains the validation of the drug target. "Each failure is very expensive in lost time and money". Though in truth, the pharmaceutical industry is still, by a wide margin, the most profitable on earth [15].
The new methods promoted, such as 'genome-wide scans' are generating patterns so complicated and so variable that they defy efforts to interpret or to validate the methods themselves. They have not led to specific targets for drugs.
There are not even experiments demonstrating that the differences in tissue expression of a particular gene are related to the disease. Neither have these screening methods been applied to rare mutational diseases, ie, 'single gene disorder' for "proof of principle" that they give any useful information. Yet these methods are now the major investments in several research programmes on Alzheimer's disease.
Several genes are found to be responsible for rare early-onset form of Alzheimer's disease, and a susceptibility gene has been identified for the common late-onset form. But routine genetic screening is not recommended by consensus groups for either form of the disease, on account of the poor predictive value of the gene tests. Nor have these genes yielded useful targets for drugs (Box 2).
Box 2
Genetics and genomics of Alzheimer's disease
Less than 5% of people with Alzheimer's disease have a strong family history of the disease, with early-onset under 60 years of age. About a fifth to half of these cases are attributed to mutations in three genes coding for the amyloid precursor protein (APP), and presenilin 1 and 2 (PS1 and PS2). The mutations for APP and PS1 are dominant, that is, the presence of one copy of the mutant gene will give the disease. (A person has two copies of each gene, one from mother and the other from father.) However, the severity of the disease is variable and unpredictable.
APP is the precursor of the beta-amyloid which accumulates in the brains of Alzheimer's patients. The function of PS1 and PS2 are not well understood, they appear to be involved in signalling within and between cells, and influence the processing of APP into beta-amyloid.
The more common, late-onset Alzheimer's disease is not linked to APP, PS1 or PS2. A particular variant of the blood protein apolipoprotein E gene, apoE4 has been identified as a 'susceptibility gene'. Case-control studies comparing the genotypes of people with and without Alzheimer's disease suggest that people with the disease are about 3 times more likely to carry a copy of the apoE4 than people without the disease, and 8 to12 times more likely to carry two copies. However, this claim has been contested.
At least one large study failed to confirm the link between apoE4 and late onset Alzheimer's disease. Another study found that the mutation is not predictive of Alzheimer's disease alone as it also occurs in other kinds of dementia. Within the same gene, certain markers may be associated with increased risks while others with decreased risk of disease. It is clear that association alone without knowledge of biological relevance is of no use for the development of drugs.
Although about 34-65% of Alzheimer's patients have at least one copy of apoE4, so do 24-31% of unaffected adults. The association between apoE4 and dementia is not seen in all populations either.
A possible target for drug intervention in Alzheimer's disease are the presenilins, It was thought that by inhibiting presenilin, less beta-amyloid would be produced. Unfortunately, presenilin has other vital functions besides processing APP. And no useful therapeutic treatment has resulted.
On account of the large uncertainty in linkage between the mutant genes identified and disease development and progression, routine gene testing is not recommended by consensus groups in the US and in Britain.
The Public Health Genetics Unit in Cambridge gives the following advice regarding early-onset and late-onset Alzheimer's disease on its webpage:
"If a mutation has been detected in an affected individual, accurate testing is possible for the same mutation in other family members, but a positive test does not necessarily give a good indication of the severity of disease."
"There is no reliable predictive genetic test for late-onset Alzheimer's. The APOE4 allele can be detected easily and rapidly; however, a positive test result does not guarantee that disease will develop, nor does a negative result rule it out."
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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." Doctors already classify diseases according to their differential response to existing drugs.
The SNPs can speed up discovery of susceptibility genes, but as already mentioned, 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. He wrote, "recommendations for patients and relatives with these 'complex' diseases are frequently miss-stated with authority by authors whose only experience is in mutational diseases".
In other words, gene tests based on susceptibility genes and SNPs 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 [14] are in danger of re-igniting those excesses. Those perceived to be 'disabled' or 'defective' are already being treated as objects and denied any voice [16].
There is an urgent need for a sweeping change in direction in biomedical research if we are to truly invest in the health of the nation [15].
Article first published 10/10/00
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