Back in the not-so-distant 1990s, hardly a week went by without a news report or announcement of the discovery of genes for some disease. The most sensational one would probably be the1993 report, published in Science, that a gene at Xq28 is linked with male homosexuality, even though no one has ever been able to validate its finding (SCI-IF score worshippers take note: A journal with a high IF score can still publish not-so-great or even non-reproducible papers). Some prominent scientists promised, often when delivering speeches to medical-profession audiences in awe or in top-notch biomedical journals, that within 10 to 15 years major susceptibility genes for complex diseases will be identified and their functions elucidated. Complex disease are mostly common chronic diseases such as asthma, diabetes, and cancer that invariably have an elusive pathogenesis and collectively contribute to the major burdens of health. So when a baby is born, his genome will be completely sequenced and the data will be stored in a compact disc for detailed analysis, and prediction about his risk of developing major complex diseases, and at what age, will be made so that precautionary measures will be taken. Twenty years down the road, targeted gene therapy would be available.

 

Unfortunately, this rosy picture has never been materialized, and probably will not be materialized any time soon. Several papers published in the April 23 issue of the New England Journal of Medicine demonstrated various challenges in the hunt for genes that predispose people to complex diseases such as diabetes and cancer. Nature also reported some broken promises made in the hunting for disease susceptibility genes (1). The news media followed the suit, pointing out that so far the endeavor to hunt down disease susceptibility genes has not made any tangible impact on improving human health (2). The July 13 issue of Newsweek also featured the complexities of our genome, reflecting the prevailing sentiment towards the issue. 

 

The vogue

 

Following on the heels of successful cloning of genes for these mostly rare Mendelian diseases in the early 1990s, there was a nearly universal enthusiasm at the time that similar positional cloning approach can be employed to hunt down susceptibility genes that predispose people to various complex diseases. It was hoped that once a gene or genes are identified, the characterization of their functions would not only help better understand genotype-phenotype relationships but also facilitate the development of specific therapies and/or preventative measures and the identification of those people at increased risk of developing the disease. It was also hoped that once the risk of particular combinations of genotype and environmental exposure is known, medical interventions such as change in life style, could then be targeted at high-risk groups or individuals, with the aim of preventing the disease.

 

Cashing in

Some biotech companies quickly saw the potential of enormous business opportunities and cashed in. Human Genome Sciences, founded in 1992 by William A. Haseltine, a noted Harvard professor and AIDS researcher, partnered with some genomics companies and soon filed patents on 100,000 genes and, in 1999, quadrupled its stock price. Other genomics companies followed the suit.

Yet this practice had one problem: most, if not all, patented “genes”, in fact, RNA transcripts, were merely pieces of cDNA without any known functions at the time of filing, let alone any connection with any human disease. And connecting a gene with a disease is by no means an easy task, even today. Very often, it was a slow, arduous, painstaking, and imprecise process full of roller-coaster experiences. 

Many other biotech companies and academic scientists took a different approach called “positional cloning”. In this approach, one does not need to know anything about the molecular genetic mechanisms underlying the disease of interest. Instead, through the collection of pedigrees enriched with patients having the disease, one could use some existing genetic sign posts (called DNA markers, which are scattered around the human genome with known locations) and localize the responsible gene in a particular region. Then by some careful work, one could zero in the gene, identify it, and ultimately figure out its function and its relationship with the disease through extensive lab work. Thus, by “positioning” the gene, the gene could be cloned and its functions and roles in disease pathogenesis elucidated without any prior knowledge of the possible pathogenesis of the disease. This conceptual simplicity and beauty, coupled with increasingly fast and affordable methods of making genetic signposts (called “genotyping”) attracted many biomedical scientists and even converted many of them to human genetics, who were frustrated by the slow, arduous and often fruitless process of finding the cause(s) for disease. Thus, in the 1990s hardly a week went by without a report or announcement of the discovery of genes for some disease, at least in the U.S.

 

In 1995, Sequana Therapeutics, a start-up biotech company located in La Jolla, California, announced that it has achieved two significant research milestones related to its asthma gene discovery program. It analyzed DNA collected from about 300 people on Tristan da Cunha, an island in the south Atlantic, about 1,500 miles from South Africa. Approximately 30% of the island's residents had asthma, presumably passed on from an original settler. The announcement prompted cash payments of $2 million from Boehringer Ingelheim, Ingelheim, Germany, based on an agreement. Boehringer later paid Sequana an additional $13 million for its exclusive right for marketing the drug derived from the putative asthma gene, while Sequana retained its exclusive right for developing gene-based diagnostics. Sequana announced in late May, 1997, that it has identified a mutated gene that makes people susceptible to asthma, a feat hailed by one clinical investigator as “perhaps this century's most important finding in the etiology of asthma” (3).

 

A reality check

 

Aside from numerous reports of association of diabetes, asthma, and other complex diseases with certain genetic polymorphisms, so far not a single gene has been proven to be chiefly responsible for any of these diseases. Most genetic loci identified to be associated with the disease risk confer only miniscule relative risks, ranging from 1.02 to 1.5 (4). Even when genetic polymorphisms that are associated with a modest increase in risk are combined, they generally have a low discriminatory and predictive ability (5). For human height, a trait that is known to be mostly hereditary, it is calculated that approximately 93,000 single nucleotide polymorphisms that are required to explain 80% of the population variation (6). This nearly astronomical number certainly is not going to inspire any enthusiasm for conducting large-scale gene hunting projects, and questions their value in genetic screening, genetic testing, and the possibility of developing gene-derived therapy (2). The idea that disease genes can be quickly identified, patented, and then quick profits can be made now seems to be too naïve.

 

For Sequana Therapeutics, despite its public announcement of the discovery of the asthma gene in 1997, so far there has been no publication from the company regarding the gene. The claim was never independently verified. The prospect of making diagnostics or therapeutics derived from the putative gene is never materialized. It was acquired by Arris Pharmaceuticals, forming Axys Pharmaceuticals. Axys went on to form Axys Advanced Technologies, which was later bought by ChemRx. The remains of Axys were bought by Celera. What used to be Sequana Therapeutics no longer exists any more.

Human Genome Sciences’ stock price reached its peak at $109 on January 31, 2000 and went through two splits in 2000. Its president and founder Haseltine said that his work “speeds up biological discovery a hundredfold, easily.” He talked of finding in genes “the fountain of youth” in the form of “cellular replacement” therapies. The company raised more than $2 billion in investments by 1999-2000. In September 2000, the company reported that it had found a way to treat large, painful sores that often plague elderly patients, using a protein spray called repifermin, made by a human gene called keratinocyte growth factor-2. In February 2004, however, the company said that it was ending the development of repifermin because it showed no more benefit than a placebo in clinical trials. Another initial drug also failed in clinical trials. In late 2004, the company announced Haseltine's retirement and named H. Thomas Watkins the new President and CEO.

In 2000, the first draft version of the human genome was published, thanks to collaborative work among geneticists from China, France, Germany, Japan, United Kingdom and United States. Celebrating this “stunning and humbling achievement”, the US President Bill Clinton declared the decipherment of the human genome “the most important, most wondrous map ever produced by mankind”. “With this profound new knowledge, humankind is on the verge of gaining immense, new power to heal.” In 2003, the completed version of the human genome was published, marking the completion of the HGP, two years ahead of the schedule.

 

From the first draft of the human genome, it was quickly learned that there are about 23,000 genes, less than one quarter of 100,000 “genes” patented by the Human Genome Sciences. Mirroring the shrinkage in the number of genes, the company stock price also shrank dramatically: the closing price on July 14, 2009, was $2.50, a reduction of 97.7% from its historical high.

 

Other genomics companies do not fare much better. Iceland-based DeCODE Genetics, for example, was founded in 1996 to identify human genes associated with common diseases using population studies. Its stock price reached $28.75 on September 11, 2000, but plummeted to $0.53 on July 14, 2009, a reduction of 98.2% in value. Its stock was removed from the NASDAQ Biotechnology Index in November, 2008. The company 2006 annual report reveals that its net losses were in excess of 530 million US dollars, and that they have never turned a profit. Its 2009 annual report says that “deCODE has recorded substantial operating and net losses over the past three years” (http://www.decode.com/Investors/DCGN-SEC-Filings.php).

 

Life’s complexities

 

People now realize that the full bounty of the genome revolution is apparently further off than originally expected. In retrospect, indeed, the notion that once a baby is born his genome data can be quickly analyzed and stored in a CD and the predictions as what kind of diseases he is predisposed to based on the data can be made is naïve. As biomedical research is revealing more complexities of our genome, some branches of science are revitalized. Epigenetics, once a backwater in research, has now led to many startling discoveries and is holding promises for better treatment of cancer and other diseases. Regardless, the failed predictions remind us humbly just how complex our genome is.

 

References

 

1.             Maher, B. Personal genomes: The case of the missing heritability. Nature, 456: 18-21, 2008.

2.             Wade, N. Genes show limited value in predicting diseases. New York Times. New York, 2009.

3.             Asthma gene discovered. Gene Therapy Weekly. Atlanta, 1997.

4.             Kraft, P. and Hunter, D. J. Genetic risk prediction--are we there yet? N Engl J Med, 360: 1701-1703, 2009.

5.             Janssens, A. C. and van Duijn, C. M. Genome-based prediction of common diseases: advances and prospects. Hum Mol Genet, 17: R166-173, 2008.

6.             Goldstein, D. B. Common genetic variation and human traits. N Engl J Med, 360: 1696-1698, 2009.

 

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