By David N. Leff

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

Just as human brain cells were long presumed never to regenerate after injury, a similar dogma posits that cardiac muscle cells cannot stage a comeback following a heart attack. ¿Traditional views have concluded that once the heart is damaged by a heart attack,¿ observed Christopher Reinhard, president and CEO of Collateral Therapeutics in San Diego, ¿functional muscles are replaced by nonfunctioning scar tissue.¿

In September 2000, Collateral exclusively licensed patents from the University of Texas Southwestern Medical Center in Dallas covering certain human genes discovered by molecular biologists at the university. They are co-authors of an article in the journal Cell, dated June 29, 2001, titled: ¿Activation of cardiac gene expression by myocardin, a transcriptional cofactor for serum response factor.¿

Their paper reports preclinical studies showing that myocardin, a novel and potent gene-regulating protein, is expressed specifically in heart and smooth-muscle cells, and can switch on other cardiac-specific genes in nonmuscle cells. It is apparently essential for forming heart cells in embryos of Xenopus laevis, the African clawed frog. The co-authors found that during embryogenesis, myocardin was expressed in heart muscle cells and a subset of smooth-muscle cells. This proceeded in step with expression of muscle genes dependent on SRF ¿ serum response factor ¿ which regulates transcription of many muscle and growth factor-inducible genes.

Specifically, myocardin increased the expression of several cardiac-specific genes in fibroblasts. These are nonmuscle cells involved in the formation of scar tissue after a heart attack. The proprietary protein may potentially act as a gene switch, transforming fibroblasts into cardiomyocytes ¿ functioning, contracting heart muscle cells.

An estimated 1.1 million people a year in the U.S. suffer heart attacks, which kill 40 percent of them. Soon after such an onslaught, white blood cells deployed by the immune system migrate into the area of infarction and remove the dead heart muscle cells. Fibroblasts then proliferate, and form a fibrous collagen scar in the affected region. The injured heart¿s ability to maintain normal function will depend on the site and size of damaged tissue.

Current therapeutic post-attack treatments focus on acute measures, notably clot-dissolving drugs to restore blood flow to the heart. Surviving patients are prescribed medication to forestall future episodes, and advised to adopt lifestyle changes, such as altering diet, increasing exercise and quitting smoking. The Cell paper¿s authors suggest that myocardin up-regulated genes might provide opportunities for converting noncardiac cells into human cardiac muscle cells for heart repair through nonsurgical gene therapy.

Nasopharyngeal Cancer, Rare In U.S., Endemic In China, Linked To Ubiquitous Epstein-Barr Virus

In the U.S. and other First World countries, Epstein-Barr virus (EBV) is rightly blamed for infectious mononucleosis, a mild, self-limiting disorder known as the ¿kissing disease,¿ because it infects young, osculatory adults who swap saliva. In certain Third World populations, notably of Chinese ancestry, EBV is linked to an endemic nose-and-throat cancer, nasopharyngeal carcinoma (NPC), which has a 35 percent mortality rate. It¿s virtually endemic in China, Taiwan and Southeast Asia, but not Japan, and rarely in the Western world. EBV is virtually ubiquitous in the human race, but generally lies low ¿ latent.

EBV genomes are detected in virtually all NPC cases worldwide, and are monoclonal ¿ consistent with a causative role for the disease. Scientists at the University of North Carolina at Chapel Hill make this point in the Proceedings of the National Academy of Sciences (PNAS), dated June 5, 2001. Their paper bears the title: ¿Induction of cyclooxygenase-2 [COX-2] by Epstein-Barr virus latent membrane protein 1 [LMP 1] is involved in vascular endothelial growth factor production in nasopharyngeal carcinoma cells.¿

COX-2¿s latest claim to fame is as a target for nonsteroidal pain killers. On a different tack, the PNAS paper suggests that EBV¿s latent membrane protein may play a role in NPC carcinogenesis by inducing expression of COX-2. That enzyme, they find, also contributes to the invasiveness of cancer cells by promoting angiogenesis ¿ proliferation of blood vessels that feed tumor growth and metastasis.

Mix/Match Analysis Of Gene Diversity In Ethnic Cross-Section Aims At Personalized Medicine

When all the chips were down last winter, at publication of the complete human genome sequence, scientists felt a sense of letdown that Homo sapiens¿ total DNA complement numbered only 30,000 to 35,000 genes. Triple that number had been bandied about for months before that dispiriting bottom line. (See BioWorld Today, Feb. 13, 2001, p. 1.)

Now a paper in Science, released electronically on July 12, 2001, reports that a large-scale gene series from varied human subjects ¿identified an average of approximately 12.5 biallelic SNPs [single nucleotide polymorphisms] per gene.¿ Their paper¿s title: ¿Haplotype variation and linkage disequilibrium in 313 human genes.¿

Those genes came from blood samples provided by 82 unrelated individuals of diverse ancestry ¿ Caucasians, African-Americans, Asians and Hispanic-Latinos. For evolutionary comparisons, the team also sequenced the corresponding genomic regions from a chimpanzee. The article¿s 28 co-authors were all from Genaissance Pharmaceuticals Inc., of New Haven, Conn. The company¿s game plan was to allow tailoring of disease treatments to individual patients by comparing genomic variations. The authors found that variant haplotypes were more useful than SNPs for linking a specific gene with a particular physical trait.

¿A haplotype,¿ they explained, ¿is the specific combination of the nucleotides ¿ one from each of the SNP polymorphic sites ¿ that are present on an individual chromosome.¿ They discovered 3,899 polymorphic sites in nearly 720 kilobases of genomic sequence, or an average of one SNP approximately every 185 bases. Fewer than 2 percent of these sites had been previously described.

The researchers pointed out, ¿Highly frequent population-specific alleles are particularly useful in mapping genes responsible for disease susceptibility and other traits in populations of mixed ancestry. Our observations,¿ they concluded, ¿demonstrate the necessity of understanding patterns of human genomic evolution if genomic variability is to be used as a tool in human health research.¿