Who doesn’t like a story? Remember telling stories of each of your scars to your friends as a kid? Or listening to the classic, “remember when…” You also know that if they make no sense, it’s either because of sex or money. Stories are good; they shape the world. More than informational, they reliably tweak the imagination. And, when we go underground, it’s the tales that live on.
Life and Love
Here’s a story about men, sex and babies. Got ya now! It’s really about my deep interest (read obsession) in figuring out why infertile men are less healthy than their fertile peers. It’s a tale of chance meetings, quirky personalities, off-the-cuff thinking, and simple circumstance.
Long ago, early in my career as a surgeon and professor at UCSF, it quickly became clear that most male infertility cases eluded explanation. We were simply unable to define the reason for low or zero sperm counts in men with no definable medical risk. Something else was going on. It must be genetic.
Then I met (and helped hire) Renee Reijo Pera, a brilliant scientist and geneticist. She had just discovered that the Y chromosome caused genetic infertility. In one fell swoop, Y chromosome deletions became the second most common identifiable cause of male infertility, after the inimitable varicocele. Not a bad start.
In close collaboration, even scribbling our ideas on napkins in a Cole Valley wine bar on Friday afternoons, we began to think of ways to find the estimated 2000 genes involved with male fertility. In one fun study with Mark Fox PhD, we subtracted the expressed DNA from testicles without sperm from those with sperm (you know: [A+B]-B=A), hoping to be left with the genes of sperm production. This produced 682 candidate genes. In another cool project, we wanted to identify male infertility “hotspots” in our chromosomes. With the help of Dr. Howard Kim, a budding urologist, we culled all of the reported chromosome breaks associated with male infertility in the world’s literature over the last half century. Then, one evening, we had a “pin the tail on the donkey” party, pizza and all, and placed a pin for each patient on a huge foam board chromosomal map. Low and behold, some “hotspots” were identified.
Life is a Path
As the work progressed, we noted that not only single genes, but also related groups of genes…gene pathways…were left standing when the scientific dust settled. This led to the study of a key genetic pathway for sperm production, meiotic recombination, with Renee Martin PhD and Joanna Gonsalves PhD. Lo and behold, unlike fertile men, infertile men harbored faults this pathway.
Then, one day during Journal Club, we were discussing yet another pathway, one in which critical genes that normally correct errors in the making of new DNA were “knocked out” in mice. These mice knock outs developed cancers, which was expected; but they were also infertile, which was not. Looking at the photos of mouse testicles in the papers, I exclaimed: “I have infertile men whose testicles look just like this!” Odd but true.
That “Aha!” moment led one of us, Dr. David Nudell (another urologist) to examine what could be called “fingerprint” evidence (i.e. microsatellite instability) of faulty DNA mismatch repair in infertile men. And the evidence was unmistakable. Now this lit things up. If infertile mice with faulty gene repair pathways develop cancers, might this also be true for infertile men?
The Road Less Travelled
Taking a different scientific tack, we surmised that a really good population study could shed precious light on this issue. It took several years to put together the perfect team, but in the capable hands of epidemiologists Dr. Thomas Walsh and Mary Croughan PhD, the science bore fruit. Examining the lives of over 22,000 California men for the development of cancer after a prior diagnosis of infertility revealed higher rates of both testicular and prostate cancer relative to the general population and to men without male infertility. Wow! A scientific unicorn was spotted: population science and molecular genetics actually agreed on something. Since then, researchers including Andrea Salonia MD and Michael Eisenberg MD have drawn similar conclusions about the health of infertile men.
But after all of this, how fertility is linked to health is still a big question. Clearly, genes and gene pathways are involved. But what about the environment; how does it fit in the picture? Could the link between nature and nurture reside in epigenetics, a nifty new biological universe that has its fingers in both pies? Ah, I hope that there is wisdom in such wonder.