By David N. Leff

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

Eugen von Hippel was a German ophthalmologist who lived from 1867 to 1939. Arvid Lindau was a Swedish pathologist (1892-1958). Both contributed their hyphenated surnames to a rare but horrendous hereditary disease, acronymically called von-Hippel-Lindau syndrome (VHL).

Although VHL affects only one in 36,000 newborns directly - with highly vascularized tumors of the retina, brain and spine - about 70 percent of sporadic (non-inherited) kidney cancers are caused by germline mutations in the VHL tumor-suppressor gene. An affected kidney may harbor up to 600 independent tumors and 1,100 cysts.

Renal clear-cell carcinoma is the seventh or eighth highest cancer killer in the U.S., with deaths estimated at 8,000 to 15,000 a year.

Victims of the syndrome inherit one copy of the VHL gene, but develop tumors only when a mutation occurs in the second gene copy. Like so many such afflictions, its mode of action is poorly understood. Now a paper in the Oct. 24, 1999, Proceedings of the National Academy of Sciences (PNAS) reports: "Identification of the von Hippel-Lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex." Its senior author is Richard Klausner, director of the National Cancer Institute.

Ubiquitin, as its name implies, is a small polypeptide that occurs in virtually every cell of the mammalian body. Its job is to set up redundant or worn-out proteins earmarked for breakdown and recycling. This ubiquitin-managed toxic-waste system of protein degradation involves a wide variety of cellular functions, including cell-cycle progression. "Our results suggest," the PNAS co-authors conclude, "that the pathological consequences of VHL mutations may be caused by the lack of E3 ubiquitin ligase activity toward specific substrates for ubiquitination."

Prenatally Mutated Sex-Hormone Gene Caused Ambiguous Male Genitalia, Fixed By Topical Gel

When a baby boy is born with ambiguous genitalia, the pediatrician faces two equally urgent perinatal tasks, one medical, the other social. Applying hormonal and/or surgical therapy to correct the aberrant condition is obvious. But deciding whether the infant is to be reared as a boy or a girl involves not only the obvious well-being of the growing child but its crucial relationship to parents, other family members and society.

The distinguishing features of male or female genitalia form during the first three months of pregnancy, determined by whether the fetus is equipped with two X chromosomes, dictating females, or a Y for males. The gender-guiding genes in these chromosomes then turn on the steroid hormones that carry out the actual construction of the sex-determined tissues and organs.

At the National University of Singapore, obstetricians received for treatment an infant with the normal male complement of chromosomes, 46XY, but a mutation in his androgen receptor, which blocked cells from responding to testosterone - the premier hormonal honcho of masculinity. In consequence, the baby's external genital organs resembled those of a female, despite his distinctly male chromosomal karyotype.

In vitro, a nanodose of dihydrotestosterone (DHT) restored the mutant receptor to nearly normal levels of binding testosterone. This suggested to the Singapore clinicians that exogenous supplementation of DHT might be of therapeutic value. It was, as they reported in The Lancet dated Oct. 23, 1999, under the title: "Directed pharmacological therapy of ambiguous genitalia due to an androgen receptor gene mutation."

Topical treatment with a DHT gel for five weeks "resulted in improved male genital development. The shaft and corpus of the penis were now clearly palpable, and the stretched width of the penile folds increased to 2.3 centimeters from 1.2 cm previously."

Experimenting On Each Other, Dermatologists Transplant Hair Follicles Across Sex Barriers

Further to the topic of masculinity, two blockbuster prescription drugs launched in this decade treat maladies specific to men only. Namely, Viagra for penile erectile dysfunction and Rogaine for male pattern baldness.

Hair transplants are famously ineffectual, because hair follicles reject immunologically foreign tissue. Now a team of dermatologists at Britain's Durham University have performed a do-it-to-yourself experiment in which human hair follicles from a man were induced to grow in an immune-incompatible woman. Their report, in Nature dated Nov. 4, 1999, bears the title: "Trans-gender induction of hair follicles."

"We microdissected dermal sheath tissue," their article recounts, "from the base of scalp skin follicles of one of us [senior author Colin Jahoda], a male. We implanted this tissue into shallow skin wounds on the inner forearm of another one of us [Amanda Reynolds, lead author], a genetically unrelated and incompatible female recipient."

Result? "Remarkably, each of the sites of dermal sheath implantation produced new follicles and fibers 3 to 5 weeks after the graft. Unlike the tiny, unpigmented vellus hairs of the arm, the newly induced hairs were larger and thicker, mostly pigmented, and grew in various directions, with no evidence of immune rejection."

The co-authors conclude that their approach "might be used in tissue and organ engineering and, more immediately, in new treatments for hair loss."

At Life's Beginning, Rank The Players In Order Of Appearance: RNA? DNA? Protein?

"Do proteins predate DNA?"

That's the title of a Perspective commentary in Science dated Oct. 22, 1999. Its lead author is evolutionary biologist Stephen Freeland at Princeton University. That's no Trivial Pursuit question, and broader than the chicken-or-egg puzzle. Its answer - if ever found - "will define the context of genetic code evolution," the co-authors observe, "and allow predictions to be made about the distribution of DNA within the fundamental machinery of life."

To begin at the beginning, the notion of an "RNA World" has gained a lot of ground lately. But which came next, DNA (a more stable information storage medium) or protein (a more versatile catalyst)?

Read all about it!