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Business: The Rogue Enzyme
Ian Deitch
Statistical evidence has long pointed to a genetic link for schizophrenia. Now Israeli researchers think they�ve identified it -- hailing their discovery as "the first conclusive data ever" regarding the origins of the disease in the coding of a single gene. And the root of the severe mental disease, which involves a diminished ability to think clearly, delusions and hallucinations, they say, is COMT, an enzyme, or protein, that this gene produces. The way their data shows it, COMT is the culprit in 20 percent of all schizophrenia cases, and quite possibly a whole lot more.
Schizophrenia affects 1 percent of the general population worldwide, a figure which increases to 13 percent if one parent is affected, and 35 percent for offspring of two schizophrenic parents. Though its inci-dence in Israel is about the same as the rest of the world, the Jerusalem-based firm IDGene attributes its breakthrough here largely to the fact that it has used Israel�s concentration of 2.8 million Ashkenazim as the base for its research.
"Genes are the body�s instruction manual, and being able to understand the blueprints is the first step towards curing a disease," explains the firm's founder and CEO, Hebrew University geneticist Ariel Dervasi. But it�s only the beginning, he cautions; the transition from raw genetic data collated at a research company like IDGene, to a finished product developed by a pharmaceutical firm, involves many millions of dollars and lots of time for clinical testing.
The gene identified by Chilean Darvasi, 40, who spent several years working on genetic research for the SmithKline Beecham pharmaceutical multinational, produces COMT, which triggers a chemical reaction in the body. The link between COMT variants and schizophrenia has long been suspected; IDGene says its newly released data confirms it.
The discovery is the first major vindication for IDGene�s scientific strategy of concentrating on the hereditary pool of Israeli Ashkenazim. Ashkenazi Jews are a classic "founder population," a term geneticists use to describe a modern population descended from a relatively small group of common ancestors which over the centuries has had minimal mixing with outside groups.
Conventional wisdom traces most of the world�s 10 million or so Ashkenazi Jews
to 1,500 families who lived in Germany and Eastern Europe in the 14th century; Darvasi says the original pool may be even smaller -- "about 500 families." Israel, with a large concentration of Ashkenazim in one relatively small area and a well-developed medical system, offers an ideal opportunity to track down links between gene abnormalities and disease.
The homogeneity is important because it minimizes extraneous genetic variations, which geneticists call "noise," when they search for the common signals connecting a specific gene with a specific malady. "Gene discovery is a signal-to-noise problem," says Darvasi, who founded IDGene in 1999. "Using isolated populations reduces the genetic noise."
Israel isn't the only place with a homogenous founder population. Researchers have also studied a subgroup of 18,000 people in northeastern Finland, which traces its ancestry back to 40 families who settled in that remote area in the 17th century. Studies of the Mormons in the U.S. have unveiled links to hereditary cancer of the colon, and people with extra digits among the Amish in Lancaster, Pennsylvania, have been traced back to one common ancestor. One company, Reykjavik-based deCODE, has begun a study of gene-disease links in Iceland�s population of about 300,000 -- which it claims has changed little genetically since the Vikings arrived on the northern island in the ninth and 10th centuries.
Darvasi is skeptical about the assumed purity of the Icelandic gene pool, noting studies that point to substantial Norwegian and Celtic migrations. The Ashkenazi gene poll is preferable, he maintains, because it's small enough to be studied intensively, and big enough to contain significant variations.
There are also differences in research technique; the Icelandic firm uses public health and population records to search for people to test for genetic-linked disease, while IDGene -- which now has about 30 employees, mostly at its HQ in Jerusalem's Givat Shaul industrial area -- bases its research on 10,000 voluntary blood samples collected in seven Israeli medical centers from Ashkenazi Jews suffering schizophrenia, asthma, diabetes, Parkinson�s, Alzheimer�s, breast cancer and colon cancer. Genetic profiles of the victims in each disease category are compared with the profiles of healthy Ashkenazim, in the hope of isolating variations that lead to the needle in the genetic haystack. The analysis, Darvasi says, employs molecular biol-ogy techniques that allow for the testing of large pools of genes simultaneously, and proprietary algorithms that speed the process of sifting through the data.
Darvasi shies away from discussing the status of research currently in progress, but IDGene�s website lists 15 diseases, including arteriosclerosis and hypertension, migraine and multiple sclerosis, as areas in which it has a research interest.
At least in the first stage, IDGene�s business plan does not contemplate drug development on its own. Instead the company and its investors -- Israel Seed Partners, Apax Partners and Britain�s Wellcome Trust, the venture capitalists who have put in about $10 million so far -- aim to market its knowledge to pharmaceutical firms, and earn its keep by collecting "milestone payments" for its basic research and royalties if and when finished products reach the market. It is currently in the process, Darvasi says, without going into details, of negotiating its first sale.
At the same time, he admits that while confirmation of the COMT connection "is an important step" in the development of a new schizophrenia drug, there may still be other genetic connections to explore. "All of the common diseases are polygenic -- associated with more than one gene," he says. "It will probably take around 15 years for the knowledge to be transformed into medi-cation to combat schizophrenia."
January 13, 2003
Business
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