SAY `NO!' TO CROSS-SPECIES DONOR ORGANS?Editor's note: Science Scan is a quick round-up of recently publishedbiotechnology related research.

Enthusiasm for xenotransplantation crescendoed in 1995, with majorpharmaceutical firms buying into small biotech companies raisingtransgenic pigs as prospective donors for heart transplants into humanpatients. (See BioWorld Today, Aug. 30, 1995, p. 1.) And lastmonth, an AIDS patient received a baboon's bone marrow in a highlyexperimental last-ditch effort to enhance his anti-HIV-1 resistance.

An article in the Jan. 5, 1996, New York Times cited analysts'estimates that the xenotransplantation market five years hence wouldrack up "more than $1 billion in annual sales."

The voice of one crying in this wilderness of can-do optimism andgung-ho research and development warns in the January issue ofNature Medicine: "Given that the risks from xenotransplantation maybe far greater than those of genetic engineering and therapy, no less[than comparable federal oversight] should be expected for this newand growing enterprise of cross-species medicine."

That caveat comes, not from the likes of a Jeremy Rifkin naysayerbut from virologist and primatologist Jonathan Allan, of SanAntonio's Southwest Foundation for Biomedical Research.

Allan's commentary in Nature Medicine bears the title:"Xenotransplantation at a crossroads: Prevention vs. progress."

Recalling that simian immunodeficiency virus (SIV) crossed intohumans and unleashed AIDS, Allan urges exclusion of baboons asprospective donors. Baboons, he cautioned, "are known carriers ofseveral latent viruses that can infect human cells and might be athreat if they were inoculated into people."

Allan served on the FDA panel that approved the protocol to transferbaboon bone marrow into that AIDS patient. It was influenced, hesuggested "by emotional pleas on the part of the family of therecipient and by the local community."

He suggested that success of that attempt would be more dangerousthan its failure: "If the patient has little chance of long-term survival,"he wrote, "[any] new viral pathogen is unlikely to be transmitted toothers. The real hazard results from the possibility of the recipienttransmitting these viruses to their contacts after leaving the hospital."

Allan is more bullish about pigs as xeno-donors. He stronglyadvocated "limiting donor species to specific-pathogen-free pigs,"while "removing nonhuman primates from the list of acceptableorgan donors."

"Although the pigs the biotech industry is counting on are alreadyspecies-specific pathogen-free," Allan told BioWorld Today, "they'refree of certain, but not all, viral infections. So there is still a risk, butit's reduced compared to baboons. They are unsafe, and will never bemade safe."

Allan said he is uncomfortable with the panel (including the FDA andCenters for Disease Control and Prevention, of Atlanta) that recentlydrew up pending guidelines to address the public health safety riskssurrounding animal-to-human organ donation.

"In spite of those risks," Allan said, "they still believe that it shouldhappen. That's where I disagree. I say, `If you know there's aninfectious-disease risk, and you really can't prevent introduction ofthe virus into the human population, then you are really exposingpublic health.

All You Ever Wanted to Know About Drug Abuse

Neuropsychopharmacologists studying the brain's role in drugdependence will welcome a five-page update on the subject in thecurrent Lancet, dated Jan. 4, 1996, and titled: "Addiction: brainmechanisms and their treatment implications." It's by David Nutt, ofthe U.K.'s University of Bristol School of Medical Sciences, inBristol.

He deals with "drugs of primary concern," the opioids, stimulants(amphetamines, cocaine) and alcohol, but notes that "nicotineaddiction [smoking] is also an important health issue."

The paper draws much of its new knowledge from neuroimaging ofthe brain with positron emission tomography (PET) and singlephoton emission computed tomography (SPECT).

These techniques refine mapping of abused drugs to their specificneurotransmitters, and concomitant potential chemotherapies.

"For most drugs of misuse," McNutt wrote, "the molecular sites ofaction are receptors or transporter sites; many of these have beencloned and sequenced, discoveries which in themselves are importantadvances for molecular biology."

He dwelt in particular on cloning of the dopamine transporter "toexpedite the understanding of cocaine's action," and observed, "Ofclinical relevance is the suggestion that a genetic polymorphism ofthe D2 receptor is strongly linked to drug misuse but this is stillcontroversial." (See BioWorld Today, Dec. 19, 1995, p. 1.)

"Generally, the more efficacious the drug is at producing itspharmacological effect, the greater is the addiction potential andstreet value," McNutt observed.

He made the point that "Many of the developments in drug misusereflect efforts by addicts to speed up the rate of drug delivery," whichled for example from chewing coca leaves to cocaine paste, tosnortable powder "and finally the lipophilic free-base [crack]."

GHRH Receptor Gene Pinpointed

Many children of severely short stature lack human growth hormone(HGH) even though their genes for the hormone are perfectly normal.What's more, there are no mutations in their growth-hormonereleasing hormone (GHRH) either.

Similar stuntedness affects a mouse, which does have an identifiedmutated GHRH receptor gene, labeled lit.

Inspired by this murine genetic anomaly, pediatric endocrinologists atNew York Hospital Cornell Medical Center and The RockefellerUniversity mapped an analogous human GHRH receptor gene to theshort arm of chromosome 7. Its cDNA open reading frame of 1,269base pairs encodes a 423-amino acid protein.

In the receptor's mutant form, a recessively inherited missensemutation swaps an aspartic acid for a glycine. This switch makes itunable to bind its GHRH target, hence leads to the growth hormonedeficiency.

The researchers found this condition, near the site of the mouse litmutation, in two girls from extended families with many dwarfedmembers. Despite injections of exogenous GHRH, their apparentlyhealthy GH genes failed to get the stimulatory message and turn on.

The two patients did, however, respond to standard treatment withrecombinant HGH.

_ Compiled By Science Editor David N. Leff

(c) 1997 American Health Consultants. All rights reserved.