Many are culled; one is chosen.

This is the numbers game that spermatozoa face on their way tofertilize a human egg.

A healthy fertile man releases from 200 million to 300 million spermin a single ejaculation of semen into his mate's vagina. This hyper-swarm of male cells, each propelled by a flagellum, beats its way intothe uterus and on up the fallopian tubes.

There the by-now-diminished population of sperm meets up with asingle ovum, which has worked its tortuous way down from an ovary.When one spermatozoon, selected either by chance or faster, strongermotility, contacts the egg's zona pelludica (the outer layer), a little-understood feedback process shuts off access by the remaining hordeof sperm, and fertilization begins.

One in 1,000 otherwise healthy men are infertile because ofazoospermia _ they make no sperm at all in their testes. And one in30 men have low sperm counts per emission. If this figure falls below10 million to 15 million per milliliter, the man has severeoligozoospermia, which defines clinical infertility.

About one in six American couples cannot conceive a child, and20,000 of them a year seek help from fertility clinics. A defect insperm production is a key factor in a fifth of the couples. Thisdysfunction may result from infection or other illness, but only latelyhave reproductive researchers begun to consider a possible geneticrole.

Inherited Infertility _ An Oxymoron?

The notion of inheriting a gene for infertility sounds like acontradiction in terms, but a seminal paper in the latest issue of TheLancet, dated May 11, 1996, explains the apparent paradox. Its title:"Severe oligozoospermia [very low sperm count] resulting fromdeletions of azoospermia [no sperm at all] factor gene on Ychromosome."

Obviously, such a deletion can't very well be inherited, if the fatherhasn't enough sperm to fertilize the mother's ovum. The authors ofthe Lancet paper concluded from their experiments that the defectmust arise as a de novo mutation.

Molecular geneticist David Page, the article's principal author, headsthe mammalian genetics laboratory of the Whitehead Institute forBiomedical Research at the Massachusetts Institute of Technology."This study," he said, "is the first to definitively show that geneticdefects can cause low sperm counts in some males." Moreover, "itsuggests that intracytoplasmic sperm injection [ICSI] _ the nowpopular technology of injecting a single sperm into an egg tocircumvent low sperm counts _ may cause the sons of these men toinherit infertility."

ICSI, introduced only four years ago, in 1992, achieves a 35-percentpregnancy rate. "It's spread like wildfire," Page told BioWorldToday. He estimates its ballpark cost at "$10,000 per attempt." Afterinjection of the single sperm into a mature oocyte, the fertilizedembryo is implanted into the uterus by standard in vitro fertilization.

Page and his co-authors began their experiment by extracting DNAfrom the white blood cells of 35 men with extremely low spermcounts. These samples came from co-author Pasquale Patrizio at theFertility Center of San Antonio, Texas.

Using PCR, they explored for 118 genomic "landmarks _ sequence-tagged sites _ scattered throughout the Y chromosome, which bydefinition controls all men-only attributes."

Two of the 35 men, they found, lacked a small genomic sequencecontaining the azoospermia factor (AZF) on the long arm of thechromosome. Both of their fathers (who obviously were fertile) hadintact DNA in this chromosomal region. Ergo, a newly arisenmutation must have caused the deletion.

The first subject had sperm counts of 50,000 to 100,000 per mL withonly 20 to 33 percent of them motile; the second, 40,000 to 90,000,with 30 to 40 percent motility.

Turning from blood to semen, they examined the sperm of one of thetwo affected men, and discovered the identical mutation on it.

This clinched a caveat in the back of their minds that ICSI mostlikely would transmit the defect to the offspring.

Hence, their Lancet paper's last words: "In cases of severeoligozoospermia . . . physicians and couples may want to considergenetic counseling and Y-DNA testing before intracytoplasmic sperminjection."

Since submitting their paper early this year, Page and his colleagueshave been exploring the elusive question of whether AZF, theazoospermia factor and DAZ _ a candidate gene he discovered thatis deleted in azoospermia _ are or are not one and the same.

"The answers aren't in there yet," he observed, and explained:

"If DAZ is AZF, then its importance would be that at this point intime we don't know the molecular identities of any genes or proteinsthat are responsible for spermatogenic failure in humans. If we knewthat was AZF, we would know at least one example now of aparticular molecule whose deficiency causes sperm failure.

"We know so little about the etiology of infertility in either sex thathaving a first molecular toehold would be a substantial advance. Itwould also put the whole notion of genetic infertility on a solidmolecular foundation for the first time."

Page concluded: "Maybe the importance from the point of view ofyour biotech readership is that there certainly is a great deal ofinterest these days in using the fruits of the genomic project as a toolto understand common human diseases _ cancer, heart disease,diabetes, hypertension, asthma, and so on.

"Bringing some attention to the possibility of genetic factors in thisvery common young-adult disease category is exactly what'sneeded." n

-- David N. Leff Science Editor

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