By David N. Leff
In days of old, when knights were bold, those medieval warriors sallied forth to the Crusades, leaving their wives behind. To forfend spousal cheating, they had their brides fitted with chastity belts ¿ metal or leather girdles that prevented intercourse, while permitting micturition. These devices not only preserved feminine virtue, they guaranteed the legitimacy of any potential male heirs.
Contraception has come a long way from such primitive contrivances, but it still leaves a lot to be desired. That desire is more frequently felt by the female sex partner, who pops pills and inserts vaginal barriers, while trusting that her male consort won¿t omit the condom.
¿Condoms are one method that works well,¿ observed molecular biologist David Clapham at Harvard-affiliated Children¿s Hospital in Boston. ¿Most women, however,¿ he added, ¿use hormonal birth-control pills, which have to be taken daily, and risk side effects.¿
¿Wham-bam-thank-you-ma¿am¿ ¿ meaning quick, casual coitus ¿ entered the American language just over a century ago. While since enriching the locker-room bragging of teen-agers, this self-explanatory expression doesn¿t go beyond the act of sex to the process of reproduction. A quickie may once in a while end up with a pregnancy, but the male-to-female route from sperm to egg is a slow-motion, mutual form of cellular Russian roulette. When a high tide of spermatozoa inundate the vaginal tract, after ejaculation, there¿s still a long road to travel before sperm and ovum meet.
To traverse this reproductive racetrack, each sperm cell is propelled forward by a whiplash motion of its long, thin, contractile tail. From the vaginal tract, it traverses the uterus and fallopian tubes. Fertilization usually takes place upstream at the ovary-fallopian junction. There, the first sperm across the finish line encounters the ovum, enwrapped in its thick, protective zona pellucida (ZP). This fastest-forward sperm transforms its snout from a bullet to a needle, and pierces that ZP.
Clapham, who teaches neurobiology at Harvard, is senior author of a paper in today¿s Nature, dated Oct. 11, 2001. It bears the title: ¿A sperm ion channel required for sperm motility and male fertility.¿
¿We reported finding a gene in mammalian sperm that encodes an ion channel important for fertility,¿ Clapham told BioWorld Today. ¿Mice in which we knocked out this gene are 100 percent infertile. One significance of this finding,¿ he continued, ¿is that it might be a good target for contraceptive drugs that could be taken just before sex, or even shortly after, would block fertility, and wouldn¿t have side effects.¿
Unsought Ion Channel Sets Sex Stage
Clapham and his co-authors discovered this sex-oriented calcium channel almost by serendipity. ¿I work in two departments,¿ he explained, ¿cardiology and neurobiology. There we looked for calcium-selective ion channels in the genome data base. We were not searching for anything related to sperm, but we found an unusual structure ¿ for an ion channel ¿ that looked as if it was calcium-selective.
¿We first got the full-length gene out of that channel, and made sure that it expressed protein. Then we looked for messenger RNA, and found it only in spermatozoa. We made antibodies to show where it was within sperm, and showed that it was located in its plasma membrane. That¿s consistent with an ion channel. Then we knocked it out in mice, and found that they were 100 percent infertile.
¿In vitro fertilization studies revealed low sperm motility. They could not fertilize eggs unless the zona pellucida was removed.¿
The team located its oddball calcium ion channel to a segment of the spermatozoon called the ¿principal piece.¿
¿There¿s the head of the sperm,¿ Clapham pointed out, ¿then the middle piece, the contractile principal piece, and at the very end, the flagellum. The principal piece,¿ he noted, ¿is a fairly long segment next to the contractile apparatus.
¿Probably bringing in calcium increases the contractility of the sperm,¿ he suggested. ¿By analogy, all muscle contraction is initiated by calcium entry from the outside. So we may think of the sperm¿s tail as a tiny muscle, into which this channel brings calcium. That element¿s key role,¿ he surmised, ¿is probably evolutionary. Because calcium is abundant in seawater, and divalent cations have special properties, they often bind and change the conformation of proteins.¿
Cations are positively charged atoms that move toward negative electrodes. Clapham dubbed both his ion channel gene and its protein ¿CatSper¿ ¿ standing for cation and sperm.
¿This protein is the ion channel,¿ he explained. ¿Channels are tunnels that go through the plasma membrane and bring ions into cells. Every cell is a battery, and the ion channel acts as the battery¿s switch.¿
Clapham described his strategy, based on the CatSper ion channel, for designing and realizing male ¿ and female ¿ contraceptives.
Biotech Firm In Running For Commercialization
¿Ion channels,¿ he observed, ¿are common targets for drugs against various cardiac disorders, such as arrhythmias and hypertension. The way such therapeutics are discovered,¿ he added, ¿is by screening a large number of compounds for binding or blocking of an ion channel, then isolating those compounds, and selecting candidates for animal testing that are specific and don¿t have side effects.
¿The way this would work for us,¿ he continued, ¿is if someone found such an ideal blocker that inhibited this channel, it could be taken as a pill by males or by females, because it should reach the sperm also in females after fertilization.¿
Clapham made the point, ¿We ourselves won¿t carry out the drug-discovery steps, because the biotech industry is better suited to do that sort of thing.¿
The Children¿s Hospital has filed a patent application, with Clapham as principal inventor, covering use of this channel for contraceptives in general. He is a founder of a Boston-based start-up called Hydra Biosciences Inc.
¿We¿re mainly dealing with this one company about licensing it to screen for calcium channel blockers,¿ he said. ¿It¿s hard to predict Phase I trials in patients because we don¿t know how easy it will be to screen for a drug. It may be years before it comes into animal testing. If Hydra is lucky, it could happen in one year. If unlucky, it could take many years. Then from animal testing,¿ Clapham concluded, ¿it could take still more years to become a drug.¿