Science Editor

Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.

A hallmark of hemophilia is the inability to clot blood. Yet decreased blood clotting protected several dozen mothers of hemophiliac boys and men against ischemic heart disease. This less-than-apparent finding appears in The Lancet, dated Aug. 2, 2003. The paper is titled "Decreased mortality of ischemic heart disease among carriers of hemophilia." Its senior author is Rits Rosendaal, a professor at Leiden University, the Netherlands.

Coagulation plays an important part in ischemic cardiovascular disease (ICD). According to the Lancet article, extremes in hypocoagulability protect against ICD. The co-authors followed up a cohort of 1,012 mothers of all known people with hemophilia in the Netherlands from birth to death. Deaths from ICD were reduced by 36 percent (39 observed deaths; 60 to 53 expected). The study did not note decreased mortality for cerebral stroke (28 observed deaths; 36 to 82 expected).

Patients with hemophilia have concentrations of clotting factor at the extreme lower end of the hematopoietic range and they incur spontaneous hemorrhages. Hemophilia is a genetic recessive X-linked trait. Therefore, although only men are affected, women are heterozygous gene carriers and can transmit the disorder to their sons. Because they have one unaffected allele, carriers have concentrations of clotting Factor VIII or IX of about 50 percent less than normal, hence decreased coagulability

To determine whether asymptomatic, decreased coagulability protects against ischemic cardiovascular events, the co-authors compared mortality in gene carriers with that in the general population. To do so, they assessed death rates of mothers between 1861 and 2001. The women in the study were selected through their offspring. Although hemophilia can arise in some patients from a new mutation - either in women or in men - only about 40 percent of cases are isolated hemophilia cases. That is, they are without a family history of the disease.

"Our results accord with those of other studies," the article observed, "in which decreased coagulability has been associated with a protective effect against myocardial infarction. Such an effect has also been reported in patients with hemophilia and in individuals with blood group O compared with non-O. [Group O accompanied by lower concentrations of Factor VIII.]"

"Results of this investigation," Rosendaal summed up, "show that the mild decrease in blood coagulation that hemophilia carriers have affects the risk of heart attacks. This finding re-emphasizes the role of clotting and changes in clotting in the development of myocardial infarction. In the future it may have implications for prevention of this disease."

Epidermal Growth Factor Receptor Ushers In Highly Infective Cytomegalovirus To Human Target Cells

Virologists are beginning to understand how the human cytomegalovirus (HCMV) exerts its slippery effects. An article in Nature dated July 24, 2003, suggests that the virus binds to a cell receptor. The paper's title: "Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus." Its co-authors are at the University of North Carolina in Chapel Hill. They suggest that the discovery might help microbiologists and immunologists develop antiviral agents against HCMV infection.

HCMV is a widespread opportunistic human herpesvirus that causes severe and fatal diseases in immuno-compromised individuals, such as organ transplant recipients and AIDS patients. It also is a leading cause of virus-associated birth defects, can cause infections of the testes, cervix and salivary glands and is linked to atherosclerosis. About 80 percent of the U.S. population is latently infected with HCMV just waiting to reactivate and infect. The co-authors have shown that HCMV binds to the epidermal growth factor receptor (EGFR). When those same cells are altered to express the protein, they become susceptible to the virus. "Within 5 minutes," the paper reports, "HCMV addition to human embryonic lung fibroblasts transiently activated EGFR. The EGFR itself was downregulated and was undetectable two hours after infection." The finding suggests that EGFR must be present for HCMV to enter a cell and trigger signaling mechanisms inside. Their data indicate that "EGFR is a necessary component for HCMV-triggered signaling and viral entry." The team speculates that other molecules also might be involved.

Discovered: A New Mechanism Involving Multiple Enzymes That De-Silences Genes In Healthy Adults

The human genome numbers some 30,000 to 70,000 genes. In the body's many cell types, most of these genes are switched off - silenced. That is, they are prevented from doing their work of protein production. For example, thousands of genes are active only during embryo development. Their sole purpose is to create a perfectly formed fetus. These genes are found in every cell of the body, but remain silent in healthy adults. However, in many human cancers these embryogenesis-linked genes are inappropriately reactivated, or de-silenced. This causes the explosion of uncoordinated cell growth that marks tumor formation.

Now, researchers at the Wistar Institute in Philadelphia have identified a mechanism by which genes associated with embryogenesis are kept silent. Importantly, their silencing is heritable. That is, when a cell divides, its daughter cells maintain not only copies of its DNA but also the silencing of those genes. The mechanism could lead to new cancer therapies aimed at re-silencing inappropriately activated genes. The research, released online July 17, 2003, appeared in the Aug. 1, 2003, print edition of Genes & Development. Its title: "Regulated recruitment of HP1 [heterochromatin-1] to a euchromatic gene induces mitotically heritable, epigenetic gene silencing: a mammalian cell culture model of gene variegation." Its senior author is cancer molecular geneticist Frank Rauscher, deputy director of the Wistar Cancer Center.

When a gene is silenced, it is stowed away in the tightly coiled structure of chromatin, which makes up chromosomes. Inside the chromatin, the DNA is wound around small proteins called histones, making it unavailable to the cellular machinery that would otherwise read its coded genetic information.

"From the standpoint of drug development," Rauscher told BioWorld Today, "we have got gene silencing down to a set of enzymes. They should be relatively easy to target with drugs."