Population Council Research that makes a difference

When sperm leave the testis, they can neither swim nor fertilize an egg. However, they acquire these abilities during their transit through the epididymis, the organ through which they pass immediately after leaving the testis (Figure 1).

The Population Council conducts research on how sperm become activated within the epididymis. If scientists can understand how the activator switch gets turned on in the epididymis, they may be able to turn it back off or prevent it from being turned on at all. This would result in a male contraceptive that would allow for normal ejaculation but with infertile sperm. There are several advantages to this approach: production of hundreds of millions of sperm would not have to be blocked, the sperm would simply be inactivated; manipulation of hormone levels within men would not be required; and the method would be relatively quick and reversible.

Sperm not only encounter a number of environments in the male reproductive tract, they also are exposed to a host of environments in the female reproductive tract. In order to function in these different environments, they have developed the ability to segregate proteins into distinct membrane domains. However, if sperm were unable to maintain this segregation, or if they mistargeted their proteins to incorrect domains, they would not function properly, and infertility would be the result.

During epididymal passage, this dramatic polarization takes place: Many proteins found over the entire head of the sperm when just out of the testis segregate into the anterior head domain (AHD) or the posterior head domain (PHD) (Figure 2). Population Council scientists have identified the discrete region (segments II–IV in Figure 1) of the epididymis where this polarization takes place and hypothesize that the triggering event may be the action of one or more proteases acting on the surface of the sperm. 

In vitro studies support this hypothesis, because if the protease trypsin is added to testicular sperm it will induce the surface to undergo polarization that mimics what is seen in vivo. Council staff members have also shown that there is an active protease(s) within the discrete area of the epididymis where surface redistribution occurs, and that it directly works on at least one of the proteins (fertilin) that undergoes polarization into the PHD. The researchers are interested in identifying this protease to test whether it is indeed responsible for initiating the reorganization of the sperm proteins.

Moving proteins into a specific domain is only the first step in polarization; retaining the proteins within the domain is the next. Keeping proteins polarized to a specific membrane domain can be accomplished by two methods: proteins can be immobilized within the membrane so that they physically cannot diffuse away, or barriers at the domain boundaries can prevent the proteins from leaving the area. Barriers at the domain boundaries could range from physical blockades, such as tightly clustered proteins, to thermodynamically unfavorable conditions.

Anchoring the proteins could be accomplished by any of three basic mechanisms: (1) an interaction with the cytoskeleton; (2) an interaction with an extracellular matrix; or (3) an alteration of the fluidity of the lipid bilayer so that proteins could not diffuse. Population Council scientists are investigating the anchoring mechanisms used by various proteins on the sperm surface to understand this process. Unlocking the mechanisms that initiate the polarization of the sperm surface and that ensure the retention of sperm within the domain once segregated there should help in understanding problems of infertility. This knowledge should also allow researchers to identify targets of action for a new generation of male contraceptives.

Former Council senior scientist Gary Hunnicutt was the lead researcher on this project from 2002 to 2009. In 2010, senior scientist Patricia Morris took over responsibility.