The working group identified "few scenarios where there was no alternative to [germ-line] modification for couples to minimize their prospect that their offspring will have a specific genetic disorder," Chapman said. In certain situations—for example, when both parents have the same autosomal recessive disease, such as sickle-cell anemia or phenylketonuria—germ-line therapy could apply, Cook-Deegan conceded. In such cases, each parent has two copies of the defective gene and cannot have a child who doesn't have the disease, he explained. The AAAS report defines inheritable genetic modification (IGM) "as any biomedical intervention that can be expected to modify the genome that a person can transfer to his or her offspring." Chapman contended that interventions that fall within the scope of that definition are already taking place without stringent oversight. An example is in vitro fertilization to treat mitochondrial diseases, which are passed from mother to child through defective mitochondria in the cytoplasm in the egg cell.
In current approaches to treat the diseases, the cytoplasm of the affected egg is replaced with that from a donor egg. As a result, all children inherit the donor's mitochondrial genes, with daughters passing that DNA to their children, Cook-Deegan pointed out. It's an example of technology that brings about genetic change and that wasn't "fully anticipated," he added. Cook-Deegan believes the independent IGM oversight committee could be modeled after the National Institutes of Health's Recombinant DNA Advisory Committee that supervised the introduction of somatic gene therapy from the mid-1980s to the late 1990s. The IGM committee, however, would have the authority to regulate IGM applications in both the public and private sectors and would be separate from the agency funding the research. NIH's current mechanisms for protecting participants in gene therapy studies can be accessed on the Internet (http://www.nih.gov/about/director/ 07122000.htm). Mairin Brennan
New Pathway Found To Type 2 Diabetes A new pathway to type 2 diabetes has been discovered by researchers who have identified a major susceptibility gene for this disease. When fully understood, the pathway could lead to new approaches to prevention, diagnosis, and treatment. Meanwhile, the approach used to identify the gene could be applied to other genetically complex disorders. Type 2, or non-insulin-dependent diabetes mellitus, is the most common form of diabetes. Like asthma, hypertension, cardiovascular disease, and schizophrenia, it is a multifactorial disorder, with multiple genes playing a role. The contribution of any one gene is not very great, however. Identifying
Cox: a lot of resources went Into effort
um-activated neutral proteases), which are regulatory proteins found in all human cells. Their functions are still not fully understood, but calpains are being investigated for their role in nerve damage in the brain. In humans, at least eight versions of calpain-10 are expressed in different tissues. One form is found only in insulinproducing pancreatic islets. In related work, Bell and others show that variations in calpain-10 affect the rate of insulin-stimulated glucose oxidation \J. Clin. Invest, 106, R69 (2000)]. "We're trying to uncover the details" of the diabetes-inducing pathway in which calpain-10 operates, Bell says. "What molecules it is interacting with in the cells that affect insulin action is undetermined yet. As we learn more about this pathway and how it leads to diabetes, there may be opportunities to develop new drugs. But that's just speculation at this point." The work is a landmark in human genetics. "People who are studying asthma will be excited," Bell tells C&EN, "not because they're interested in type 2 diabetes genes but because the approach we've used is relevant to their disease." With single-gene diseases, localizing the gene, identifying it, and correlating mutations with the disease is straightforward. With genetically complex diseases,
the genes involved in such diseases is one of the biggest challenges facing geneticists. In a pioneering effort, a multidisciplinary team led by the University of Chicago's Graeme I. Bell, a professor of biochemistry, molecular biology, and medicine, and Nancy J. Cox, an associate professor of human genetics, has identified a gene that affects susceptibility to type 2 diabetes in some diabetes-prone populations [Nat. Genet, 2 6 , 163 (2000)]. The gene encodes calpain-10, a protein that has never before been associated with type 2 diabetes. Bell: opportunity to develop new drugs The team found that variations in the gene are associated with up correlating genetic variations with the to a threefold increase in the risk of disease is far more difficult, Cox says. developing type 2 diabetes among With the success of the Bell-Cox team, Mexican Americans. 'This is just a groups that already have linked certain single gene that seems to be very parts of the genome to specific complex important in Mexican Americans," diseases might be encouraged to take the he says. "As we identify more genes next steps to identify the genes. But they in Mexican Americans, as well as in should be warned: "We put a lot of reother groups, we will be able to sources into this effort," Cox says. "We generate genetic risk profiles for in- collaborated and worked like dogs. We dividuals in those populations." almost did nothing else" since 1995, Calpain-10 is one member of the when the work began. protein family called calpains (calciMaureen Rouhi OCTOBER 9,2000 C&EN
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