And you thought this was old...

What do you own that is 600 million years old? Your old suit? That little league baseball glove? Your cologne? In fact, every man possesses something that old, and believe it or not, it’s a gene. Not the clothing kind, but the kind you keep in your genome, in your chromosomes. We’ve talked about the Y chromosome in this space but lets take a moment to focus on a single tiny gene.

Tucked away in every cell of your body is a gene called Boule, a piece of DNA critical for sperm production. A colleague of mine just announced that the Boule gene is present in every organism from insects like fruit flies, to sea urchins, roosters, fish and man. It is in invertebrates and vertebrates alike. That is, this tiny bit of DNA has remained essential for making sperm through 600 million years of evolution. Surely the oldest treasure you own.

But what’s really impressive about the Boule gene is that is has not changed over time. And change is the rule with every other known gene involved with reproduction in every species. In fact, evolution of reproductive traits is how a species diverges from other species. It gives each species its identity. And this change can be very rapid: in some fish, reproductive traits are observed to change in fewer than a dozen generations. So why would this one gene stay the same?

We think that the Boule gene has remained true over 600 million years because it is essential for reproduction. Boule is a “quality control” gene that ensures all goes well as sperm are made. Just as you would want your new car to be well inspected so it is safe to drive when you buy it, you want your sperm to be reproductively fit. In fact, if the Boule gene is removed, sperm production stops entirely. Not a single sperm is made in its absence. Now that’s control.

What’s also impressive about the Boule gene is that since it is linked to sperm production, it means that sperm are very, very ancient cells. Seems that nature sticks with what is tried and true and feels no need to experiment with magic potions or fairy dust to get the job done. Reminds me of what Einstein once said while reflecting on relativity and physics: “God does not play dice.” When it comes to reproduction, the Boule gene phenomenon suggests that he may take even fewer chances.

The spine: OK for shivers and tingling, but that's it.

I have a lot of patients in my practice who have broken their backs. Not figuratively by working so hard, but literally, by having spinal cord injuries. Some have been crushed by rolling logs, fallen from tall heights, been victims of shooting, dived into shallow pools or took an untoward jump while skiing or skateboarding. As a group, these men are impressive: imbibed with fortitude, perseverance, decisiveness and joie de vivre, they take nothing in life for granted. Live it hard, wring it dry, no regrets.

Their numbers are not insignificant either. Roughly 5,000-10,000 individuals experience spinal cord injury annually in the U.S. alone. And although you may think that cars have plenty of safety measures, they don’t, as the biggest cause of cord injury is motor vehicle accidents. Violence, recreational activities and workplace-related injuries round out the top four causes. And, of course, single, reproductive age men (ages 20-34 years old) are by far the most commonly affected.

I am reminded of these patients after a good friend, Dr. Stephen Seager, came over for dinner last week. A true Irish gentleman (“blended scotch before dinner and single malt after, no ice”) and world famous veterinarian, Dr. Seager invented the rectal probe electroejaculator in the early 1980s. I will leave it up to your imagination to wonder how this device works. But realize that this one doctor, through his invention and its popularization worldwide among male fertility specialists, has touched every spinal cord injured father from around the world over the past 30 years.

Seriously, the Seager Electroejaculator has revolutionized our ability to help men with spinal cord injury to conceive and become fathers. It takes advantage of the fact that ejaculation is governed by a spinal reflex (like sneezing) and it stimulates that reflex to happen. In fact, probably the only biological function that is not seriously affected in men who have broken their necks and cannot move any of their limbs (quadriplegic) is reproduction as this reflex generally remains intact.

By his innovative thinking, Dr. Seager brings hope to every spinal cord injured patient who dreams of being a father. Personally, seeing my patients with their little children running around their wheelchairs, and the wide, grateful smiles on their faces is easily one of the most satisfying experiences I have had in my medical career.

China: 5000 years old and on the move.

Just got back from China, from Beijing and Hong Kong to be exact. I lectured to several medical and academic institutions on where I believe men’s health is headed in the future. What I found was an audience eager to push the research frontiers in this field, however I also a sensed a lack of sufficient infrastructure to do this at the highest level. I paused for a moment to think about what was possible, since a monumental tidal wave of increased industrial productivity and change is occurring in China. For example, there are 1000 new cars being put on the road daily in Beijing alone! I sensed that when the might of China’s intellectual potential directs its energy toward medical research and innovation, the world will stand in utter awe at the prodigious output that will result.

Despite the fact that China’s culture is endowed with 5000 years of evolution and is responsible for helping to define human civilization, one thing really surprised me: its decision in 1979 to control its population by mandating a “One Child Only” policy. In the rest of the world, human reproduction is a basic right and for the most part, entirely unregulated. Under China law, families are allowed to have one child. After that, a vasectomy is performed on the male partner. Like it or not.

In addition to great control of population growth, the “One Child Only” policy has also led to the development of the wildly successful “No Scalpel Vasectomy” procedure. Now relatively common in the U.S., the “No Scalpel Vasectomy” is a quicker (10 minute), cleaner, less invasive and more comfortable innovation on a 100-year old American procedure.

But the curse of the “No Scalpel Vasectomy” is now being felt in China. Currently, it is difficult to find enough youth to fill jobs in urban areas within the massive and burgeoning Chinese economy. As a consequence, there has been a softening of the law such that couples that are both products of “one child” parents can now have two children. So can farmers, handicapped couples, and couples who work in “high risk” occupations like coal mining, heavy equipment operations and the like.

Even more fascinating is that infertile couples have a real reproductive edge over fertile couples under this law. How? Well, if they need assisted reproduction to help them conceive and they happen to have twins or triplets as a result (a 30-40% chance), they are not penalized for bearing “extra” children. Can’t help but think that this little known fact may partly contribute to the size of the massive, bustling IVF clinics that I visited in China last week. many of which are 4-10 times the size of U.S. clinics.

How about being happy and hopeful as well as healthy?

The couple had been trying to conceive for 5 years unsuccessfully. The tension and anxiety in the relationship was palpable and strained. They had spent well into the 5 digits to have a child with test tube baby technology (IVF) and yet were still not pregnant. His vasectomy reversal had also failed them. And they were going to try one more time, just once, with me, before calling it quits.

When he came to me for care, he was frankly depressed. Out of money and full of debt, close to losing his job in this economy and in a strained relationship hanging on by a thread, he sat across from me. He looked terrible. “Can you help?” he asked me.

Well I did help. I reversed his vasectomy again and it worked. Fast-forward 9 months and a birth announcement arrives in the office from the couple with a long personal note of thanks on the back. But one line really struck me:

”Looking at her, sleeping quietly, I see her future as an astronaut, the President, a doctor, a lawyer or anything else that she wants to be. She can be or do anything!”

Absolutely unbridled hope and enthusiasm was infusing a mind once filled with almost unfathomable despair. All this change, nine months and one baby ago. Wow!

Talk about a biological drive. Reproduction easily ranks up there with breathing and eating. Not for everyone of course, but for many. I am quite sure that if you surveyed infertile couples about their quality of life with infertility, as has been done in patients with cancer, you would find these diagnoses equally impactful. I have no doubt many of my patients would give up five healthy years of their life to have a child. Maybe even 10. Just because it cannot be assessed by a blood pressure cuff, a blood test, or a scar does not make infertility any less important an affliction.

And yet, despite its profound impact, its ability to tear apart relationships, crush self-esteem and slow down an otherwise productive couple to a grinding halt, infertility is not really considered a disease in many societies, including ours.

Want a more productive and healthier society? Cure infertility. And what about something else that this world could use a lot more of, as expressed by my patient: the resurrection of those elemental feelings that lead us to live good lives and to make the world a better place for those who will follow us.

Cellular metabolites: woven together like a rug

Call me a nerd, but I have to admit that I am pretty excited about metabolomic technology. Uh, what? Metabolomics is the study of the chemical fingerprints that cells leave behind. It does not look at genes, DNA, RNA or proteins, but is a peek into the products or metabolites that result from all this genetic orchestration. It is a “physiological snapshot” of a living cell.

This past week, we published a study that applies metabolomics to male infertility. If you have been reading this column, you are well aware of my interest in helping sterile men become fathers. Over the last decade, it has become clear that many men with azoospermia (no ejaculated sperm) may have small pockets of sperm in the testicle. The question is how to safely find that sperm without causing undo harm to the testicle. Current methods for evaluating whether sperm are present include somewhat invasive techniques such as testicular biopsy and microdissection and less invasive ones such as FNA Sperm Mapping that I invented 13 years ago. However, as I always say, there is always room for improvement.

Wouldn’t it be nice to find the “pockets” of sperm in the testis through a simple scan and avoid a biopsy? Maybe even a scan that involves no radiation exposure, like an MRI? Well, that is precisely what we have developed in this study.

We showed that magnetic resonance (MR) spectroscopy can measure metabolic activity in the testis. And given that most metabolic activity in the testis is concentrated on building sperm (remember, normally men produce 1200 sperm/heartbeat!), metabolic measurements in the testis generally reflect sperm production. The study showed that the metabolomic scanning is as accurate as a more invasive testis biopsy in reading several abnormal patterns of sperm production typically associated with infertility. It also showed that testes that contain sperm carry a distinct chemical “signature” that can be distinguished by MR Spectroscopy.

How does it work? Essentially, the scan looks for chemicals in the testis that are the building blocks for sperm production. The theory is if you see a pile of bricks in the yard, then there is a good chance that a house is being built. In the study, phosphocholine was observed as one of the building-block chemicals in the testis. The more there is, the more likely sperm are being made.

Not only that, MR Spectroscopy can evaluate for sperm in as many as 100-200 areas within the testis, significantly increasing the ability to sample for sperm well beyond any of the more invasive techniques commonly used today.

Are we ready to replace a testis biopsy with an MRI scan? Not yet, but give me some time to tweak the system a bit and perform clinical trials comparing it to current approaches. My motivation runs deep, as I know that men would rather have their picture taken than have a surgical procedure to understand whether they can be fathers.

Throwing a wrench in the machinery of sperm production...

I have to admit, the testis “mapping” procedure that I developed some years ago has truly been a workhorse technique for my male infertility practice. And for the practices of other male reproductive specialists around the world as well. Creating fertility from sterility. I bring it up again because it is gathering more attention in the press as this week we recently published another paper that highlights its utility—this time in cancer survivors.

In a related study from 2002, we published that the majority of men who had been exposed to chemotherapy for cancerous or non-cancerous disease and who were “sterile” afterwards have sperm in the testis that can be safely used for fatherhood with assisted reproduction. Fine needle aspiration (FNA) mapping was employed in this study and its potential to help cancer survivors to conceive was convincingly demonstrated. The recent paper expands that group of men to include those who received not only chemotherapy and radiation therapy but also a relatively extreme treatment for certain cancers termed bone marrow transplantation.

Let’s back up a minute for a biology lesson. How does chemotherapy affect a man’s fertility? Well, the basis of its effectiveness in curing cancer is that chemotherapy preferentially kills rapidly dividing cells more than slowly dividing cells. In general, cancer cells divide more rapidly than do normal body cells. The term for this difference in cell susceptibility is “therapeutic index”. Unfortunately, sperm are also produced very rapidly (about 1200 sperm are made every heartbeat) and therefore sperm precursor cells are also very sensitive to the effects of chemotherapy. Think of sperm production as a rapidly turning set of gears and chemotherapy as a wrench being thrown into them. Ka-chunk! Machine comes to a loud and crashing halt. Sperm production is over, or tremendously slowed down. The same action is true for radiation therapy treatment.

Now, imagine not just one small wrench being thrown into the gears, but a huge wrench (or many wrenches) being suddenly thrown into the machine of sperm production. The result? More damage to the sperm-making machinery and a much higher chance of sterility. This is the essential difference between the patients from the 2002 paper on mapping and the most recent one. The cancer survivors in this week’s paper got blasted with the heaviest doses of chemotherapy imaginable, and topped off with a dollop of radiation therapy just to be sure. Hard to believe, but they also had usable pockets of sperm in their testicles. And normal babies as a result.

So, with techniques like FNA sperm mapping, there continues to be hope and good news about fertility after the storm of cancer treatment has passed.

Heirlooms for the species.

As a living, breathing being on this good earth, we tend to take things for granted. The ability to have offspring can be one of them. That is, until the day that a serious medical condition like cancer rears it ugly head and puts childbearing at risk. In addition to the sterilizing effect of cancer treatments, the mad rush to treat the disease often marginalizes efforts to preserve fertility. Fire all the canons and check for collateral damage later.

Fertility preservation seeks to protect men, adolescents and children from a common, serious and impactful side effect of cancer treatment: infertility. The goal of fertility restoration is to empower patients who are cured and potentially infertile to bear children. These related fields have burgeoned recently because medical care is now shifting from curing cancer to improving the quality of life among survivors. And without a doubt, for many, fertility is a key quality of life issue at some point. Thankfully, exciting new methods of restoring fertility have already been developed and even newer technologies are under study.

Classic techniques for fertility preservation in men include gonadal shielding and sperm banking. Gonadal shielding uses lead-based devices to protect the testicles from being struck directly by sterilizing radiation treatment. Sperm banking is the process of freezing healthy sperm before cancer treatment begins for later use to conceive. But there is more. For patients who are too young to bank sperm, for those who have precious little time to bank sperm, or for those who have no ejaculated sperm to bank, testis sperm retrieval by biopsy (TESE) or needle aspiration (TESA) for banking is now possible before cancer treatment. In fact, in some cases of testis cancer, it is possible to remove only the cancerous nodule instead of the whole testis, or to freeze sperm from the testicle after it is surgically removed. These are now routine ways to preserve fertility in men.

Fertility restoration for men has also seen real advances lately. Sperm “mapping” is an innovation that I developed for men who survive cancer treatment but have no sperm in the ejaculate. It non-invasively and non-surgically deciphers whether there are small numbers of mature sperm in the testis, too few to get into the ejaculate, but usable nonetheless. In men who sustain nerve injury from cancer surgery and who are unable to ejaculate, a special medical instrument can produce an ejaculate for fertility purposes in a process termed electroejaculation. Techniques such as these are valuable tools to help men deemed “sterile” after cancer treatment to become fathers.

One of the most exciting areas of fertility restoration involves stem cell technology. Yes, the “promise” that we have all heard about stem cells curing disease will likely find its way into the fertility field as well. In pre-pubertal boys with cancer, ejaculated sperm is not present. Despite this, it may be possible to freeze the early stem cells from the testicles of boys before sterilizing treatment. After thawing, these “adult” stem cells may later be used to create sperm after further growth in a Petri dish or after transplantation back into the same individual. Also on the horizon is our ability to take skin cells from a sterile man, convert them into an embryonic-like stem cells and then “drive” these cells to become mature sperm in a dish–a true “artificial testicle.” So, with the belief that hope can cure misery, the world of science has taken fertility research from science fiction to reality. Not convinced? Stay tuned!