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

“Although it is difficult to hear a mouse wheeze,” observed Harvard immunologist Laurie Glimcher, “these mice have asthma.” Those animals are stand-ins for human asthma patients, as Glimcher describes in a Science paper dated Jan. 11, 2002, of which she is senior author. Its title: “Development of spontaneous airway changes consistent with human asthma in mice lacking T-bet.”

T-bet is the acronym for a gene that encodes a T-lymphocyte-box transcription factor,” Glimcher told BioWorld Today. “These asthma-modeling mice, in which we knocked out the T-bet gene, have spontaneous asthma at baseline. In vivo veritas! Most in vivo models of human asthma suffer from the fact that you have to induce them with an antigen; they’re not spontaneous.

“Our KO mice,” she continued, “had chronic airway remodeling, inflammatory infiltrates, collagen deposition, airway hyperreactivity. Their lungs showed symptoms of asthma. I think they most closely resemble human asthma of any model that exists. With it,” Glimcher recounted, “we discovered that asthma, which is of growing epidemic proportions nowadays worldwide, is a disease of T-lymphocyte helper cells.”

A back-to-back accompanying article in the same issue of Science, also authored by Glimcher, bears the title: “Distinct effects of T-bet in TH1 lineage commitment and IFN-g production in CD4 and CD8 T cells.”

Harvard, she observed, has filed patent applications on her asthma mouse model and its findings. “I’m working with a company out on the West Coast,” Glimcher disclosed, “called Mannkind Corp., in Valencia, Calif. They have licensed this technology, and I am on the firm’s scientific advisory board. They are using high-throughput screens to look for compounds that will affect T-bet activity either increase it or decrease it. One would want to increase T-bet activity in asthma, and decrease it in autoimmune diseases.” Glimcher concluded: “We’ve got a long way to go to find a compound.”

Allecure, also in Valencia to which the T-bet license is exclusively assigned is a wholly owned subsidiary of Mannkind. Its president and CEO is Stephen McCormack.

“When you take T-bet away from Laurie Glimcher’s knockout mice,” he told BioWorld Today, “what she has shown in these Science papers is that removal of T-bet down to only a single copy results in the features of chronic human asthma, which I find quite amazing.

“The T-box,” McCormack explained, “is a genetic sequence, a binding and promoter element. It directly activates expression of interferon-gamma.

“T-bet,” he continued, “is the only protein that’s been shown to cause a fully polarized TH1 cell to change its phenotype. There are TH1 cells and TH2 cells,” McCormack pointed out. “TH1s are thought to be the inflammatory cells. TH2s are the ones involved in parasitic infections. Also, their overabundance results in allergy, such as asthma, while TH1 can cause the allergy to be eliminated.

“We’ve developed a high-throughput cell-based screen that specifically targets the T-bet gene,” McCormack concluded, “and are well on our way in the process of identifying compounds.”

Gene Mutations In Patients With Xeroderma Pigmentosum Define DNA Repair Mechanisms

People afflicted with the inherited disease xeroderma pigmentosum (XP) have a 1,000-fold increase in the incidence of skin cancers brought on by exposure to the sun’s ultraviolet rays. This eruption of exposed skin usually follows severe sunburn in infancy, marked by freckle-like pigmented spots. XP results from rare, autosomal recessive mutations in which DNA repair processes are defective. Besides skin cancer, XP frequently strikes at eyesight and neurological abnormalities.

An early edition paper in the Proceedings of the National Academy of Sciences (PNAS), released Jan. 1, 2002, is titled: “Molecular analysis of mutations in DNA polymerase h [Greek letter eta] in xeroderma pigmentosum-variant patients.” Its principal authors are at the University of Sussex, UK. They have analyzed the mutations in 21 patients carrying the same variant. The 16 they identified fell mainly into two categories: protein truncations so severe as to nullify function, and five missense alterations. Both prevented repair synthesis past sites of DNA damage. Three other mutations occurred well beyond the catalytic domains on the gene, so those cells were able to perform nucleotide excision repairs.

The gene product, the paper notes, Pol-eta, belongs to a newly discovered family of DNA polymerases.

X-Ray Crystallography Limned Two Proteins Linked to Cancer Caught Interfacing In The Act

Structural analysis has yielded the first-ever detailed picture of two cancer-related proteins interacting. They indicate which areas are essential for development of malignancy. The work was led by biochemists and biophysicists at Memorial Sloan-Kettering Cancer Center in New York. Their report in Nature dated Dec. 20/27, 2001, carries the title: “Crystal structure of an Eph receptor-ephrin complex.”

Eph receptors are tyrosine kinase receptors; ephrin their membrane-anchored ligands. “Given the importance of Eph receptor kinases and ephrin in cardiovascular function, nerve generation and cancer,” predicted the paper’s senior author, Dimitar Nikolov, “the results could be the first step toward the future development of novel therapeutic strategies.”

From Mad Cow To Tainted Sheep To Its Human Meat Eater, 150,00 Deaths Possible

If a sheep in Britain catches mad cow disease (bovine spongiform encephalopathy, or BSE) from a cow, can eating its mutton or lamb chops give variant Creutzfeldt-Jakob Disease (vCJD) to a person?

That grim question is posed by a closely-reasoned paper in Nature released on Jan. 9, 2002. Its title: “Estimating the human health risk from possible BSE infection of the British sheep flock.” Its authors are epidemiologists in the Imperial College of Science, Technology and Medicine in London.

They estimate that if BSE does move from sheep to humans the risk of vCJD posed by sheep could be greater than the threat currently posed by cattle. The study’s worst-case scenario: If BSE spreads freely within a flock, maximum vCJD deaths could reach 150,000.