Synthetic cells: true science or fashion vinyl?

Believe it or not, science has now claimed to have made “synthetic life.” Life created from non-living substances. J Craig Venter and colleagues, after a decade of work, produced a man-made version of the entire DNA content (genome) of a bacteria (adding in a couple of harmless “watermarks” to track it) and inserted it into the shell of another bacteria after removing its DNA. And, lo and behold, the artificial genome starting making proteins and the man-made bacteria began to replicate.

You may remember Craig Venter as the man in corporate biotech a decade back who challenged the U.S. government in a race to completely encode the entire human genome. The Human Genome Project was completed in 2003 and jointly announced. This is a beautiful thing but Venter wanted to “own” and patent the human genome and charge others for using it as a resource whereas the U.S. government insisted that it be made publicly available, which it is.

Is this really synthetic life? No. Essentially, Venter performed the equivalent of gutting a computer and then entirely reprogramming it. Is this an important scientific achievement? Absolutely, a tour de force, since technology has been limiting this work for years. Recently, however, there has been a 100-fold increase in the length of genetic material that can be manufactured from raw chemicals in the lab. Without a doubt, science has been dreaming about this kind of work for three decades and recombinant DNA technology is an early product of this movement.

So, an entirely “artificial cell” was not produced by Venter, as the control station was man-made, but the rest of the cell was not. My only hope is that this is not just another “pleather” (plastic and leather) product in our lives. As Lily Tomlin said: “[even] vinyl leopard skin is becoming an endangered synthetic.” On the contrary, this work may have advance science sufficiently to begin the manufacture of designer cells, good or bad, that can clean up oil spills, dynamite and waste water, dispose of nuclear waste and deliver antibiotics, chemotherapy, testosterone or Viagra to hard to reach but important areas of the body.

This Da Vinci fetus is way past the critical window of exposure.

A relatively alarming study was published a couple of years ago that suggested that a pregnant woman’s behavior can determine the fertility of her unborn son. Sperm quality from 387 men was compared to beef consumption their mothers reported while pregnant with them. They found that the sons of “high beef consumers” (>7 beef meals/week) had sperm counts that were 24% lower than in men whose mothers ate less beef. Interestingly, sperm counts in the sons were not related to mother’s consumption of other meat or to the son’s consumption of meat. In essence, the author’s thought that estrogens in beef consumed by women may alter the testis development of their unborn sons and may adversely affect the son’s fertility. Similarly impressive decreases in semen quality have been described in the sons of women who smoked during pregnancy.

Sounds almost biblical, doesn’t it? I bring this up because of a point that I made in last week’s blog. In “The Curse of Women’s Urine,” I mentioned how xenoestrogens or environmental estrogens have been shown in animals to act at a very precise point in the developing male fetus and result in intersex conditions at birth or infertility as adults. Well, as the study of mothers’ beef intake reveals, the same issues may also exist in humans. As Aristotle once said: “At his best, man is the noblest of all animals; separated from law and justice he is the worst.”

Time for a quick lesson in biology. When do testicles develop in humans? Believe it or not, when male fetus in just 4 weeks old, the location where the future testis will be is organized (the urogenital ridge). Two weeks later, the primitive germ cells (sperm precursor cells) migrate to the urogenital ridge and set up what is to later become the testis. About 1-2 weeks after that, “sex cords” develop in the primitive testis, setting up the architecture of the mature organ. So, by 8-12 weeks of pregnancy, the human testis is virtually a complete organ, holding within it all of the potential it will ever have.

So the “critical window” of exposure for the human testis, that period in which even a potentially small exposure could wreak significant developmental and long lasting havoc, is about the time when women actually just realize that they are pregnant. The time of morning sickness and painful breasts.

So, does male infertility begin in the womb? Still not clear, really, as all studies have flaws. For example, in the study of beef eating pregnant women, the cohort of son’s whose sperm counts were so thoroughly examined were ALL fertile. That’s right, their wives were all pregnant. Oscar Wilde couldn’t have said it better when he said: “The pure and simple truth is rarely pure and never simple.”

How damaged is your genetic sheet metal?

Imaging parking your car at home after work and all the nicks and scratches are removed while you sleep, before heading to work the next day. All shiny and new, polished even, while you sleep. Believe it or not, this is normally what happens to your genes and chromosomes on a minute-to-minute basis. DNA mismatch repair is a constant and vigilant process, occurring in all cells of the body. Why the biologic vigilance?  Well, It keeps us whole, healthy and cancer free.

About 11 years ago, we published a paper showing for the first time that infertile men can’t repair the errors normally encountered in their DNA as well as normal men. This was startling news in part because it implied that infertile men may be more likely to develop other problems later in life, including cancer. Why cancer? Because the development of cancer has been associated with the inability to normally repair the frequent daily errors that occur to one’s DNA as the body’s cells divide and renew.

Today, however, we know much more. We know that testis cancer is 3-fold more likely to occur in previously infertile men than in fertile men as they age. And our latest research has shown that prostate cancer, thought to be a disease exclusive to older men, occurs more seriously and more commonly in previously infertile men.

So what does this mean? Is male infertility the first sign of a larger problem in our species? It is the ultimate medical problem of a species trying to reproduce?  Well, honestly it isn’t entirely clear. However, to me it indicates that male infertility should certainly be considered an insurable and real medical condition that should be taken as seriously as a heart attack. Even more worrisome is the issue of whether the use of sperm from severely infertile men is putting their offspring at even higher risk of medical issues than that experienced by their fathers.

So do not ignore the infertility issue when it strikes and get that male partner evaluated by a specialist. Teach him to perform testicular self-examination, a simple maneuver performed once monthly in the shower that has far more potential to extend his life than even exercising or weight control. Educate him about prostate cancer so that he does not ignore the powerful screening tools available to find it early. The age of innocence is over. The warning signs are now clear; get men the care that they deserve.

Can we be DNA barcoded like a soup can in a grocery store?

How many of you would take a blood test to learn exactly how long you will live? How about whether or not you will become demented? Since the Human Genome Project ended, the genes and mutations associated with a vast array of diseases are being discovered daily and it is pretty easy to just put them on “chip” and make them available to the public.

Don’t get me wrong; gene testing already has already improved our lives. Such tests can clarify a diagnosis and better direct care, while others allow families to avoid having children with life-threatening or disabling conditions. They can be used to prevent disease before it happens, as with monitoring and removal of colon growths among those who have a gene for familial polyposis, and can diagnose common iron-storage diseases early enough to treat them and prevent them from becoming fatal. They can also help to positively identify murderers two decades after the crime.

One real problem is that many commercialized gene tests are targeted to healthy people who might be at high risk because of a strong family medical history for a disorder. Unfortunately, because of how complex we are as biological organisms, the tests give only a “probability” for developing the disorder. That means that some people who carry a mutation may never develop the disease. Another limitation is the possibility of laboratory errors. What this means is that the tests are not perfect and could be wrong.

And what happens to your job prospects and health (or life) insurance rates when it is learned through genetic testing that you might develop a significant disease? Well…nothing. Because of the federal GINA Law (Genetic Information Nondiscrimination Act) passed in May 2008, insurance companies and employers cannot discriminate on the basis of information derived from genetic tests. So, genetics has now been added to the list of characteristics first embodied by the Civil Rights Act of 1964, that states that U.S. employers cannot discriminate according to race, color, national origin, sex, or religion. And this is good.

So, go ahead and take the “23 and Me” “DeCode” or “Navigenics” genomic screens if you so desire. Get to know your DNA barcode. Maybe you will get an idea of what may be around the corner for you. And maybe, just maybe, you will take better care of yourself knowing more about your genes. Just understand that many in the medical community feel that uncertainties surrounding test results, the current lack of available treatment options, the tests’ potential for provoking anxiety and social stigmatization could outweigh the benefits of testing. You know the saying: “Too much information…”

The Y chromosome: diminutive but cool.

Among the many chromosomes in a man’s body, the smallest one with the largest personality has to be the Y chromosome. With it, you are a male; without it, you are a female, with few exceptions. More than any other chromosome, it really defines who you are.

The Y chromosome controls other traits as well: hairy ears, tooth enamel, and stature to name a few. But for the longest time, the Y chromosome was also considered home to a lot of “junk DNA” that we thought had no purpose. We now know that much of this DNA has a purpose and that the Y is the home of many important male fertility genes.

Before its association with male fertility, the Y chromosome was widely considered a genetic black hole, a chromosome that evolved as a broken remnant of the X chromosome. We knew that the “maleness” gene was on the Y and a few other genes. However, since the Y chromosome has been fully undressed as a result of the human genome project, we now know that it is very unique, even special, and that it evolves in its own special way to keep men men.

The Y chromosome, and its neighbor the X chromosome, evolved into “sex” chromosomes hundreds of millions of years ago. This is important because many species do not have a chromosome for each sex like we do. Some species become male or female based simply on the environment in which they find themselves. Imagine that! A boy in the Artic but a girl in the Caribbean. At first, the original sex chromosomes probably evolved as a pair of two X chromosomes. Then, 150 million years ago, the Y chromosome made its break from the X chromosome. Basically, it stopped associating with it and this led to our current X-Y system of sex determination. I guess this is when men really became men.

As it works now, the single Y chromosome has no partner with which to swap genes when sperm are made (at a normal rate of 1200 sperm/heartbeat!) This “swap meet” of genes that occurs when new sperm are formed is an important repair process for the 22 other chromosomes and is absolutely critical for our evolution as a species. In fact, this is the source of our evolution. So, now that the Y chromosome has become isolated and less of a team player, is it doomed to extinction? More importantly, are men are doomed to extinction?  

So how does the Y chromosome survive and repair itself, living alone in isolation while the world is changing around it? Well, we now know that it manages very well on its own, thank you. And this has probably been true for about 5 million years. Although it no longer swaps genes with the X chromosome, from which it came, the human Y chromosome is able to swap genes with itself to discard bad genes. It’s called gene conversion and no other chromosome does it. Just the Y. How uniquely male.

Basically, essential Y chromosome genes are arranged in a series of eight “palindromes,” or mirror image sequences, each of which folds like a hairpin in which its two arms come together. Then the “DNA checkers” compare the two arms for any differences and convert a mutation back to the correct sequence, thus saving the Y’s genes from mutational decay. So, the older “junk DNA” thought to exist on the Y chromosome is now known to represent DNA that it critical for its survival. One man’s junk is another man’s treasure. And so it goes, the Y lives on, and men do too.

Stem cells are past the snake oil stage of medical treatment

True stem cells are “pluripotent.” That is, they have the ability to become all of the different types of cells in the body. They could be used to rebuild or replace damaged tissue that is difficult or impossible for our own bodies to repair. Take nerves for example. If nerve cells degenerate, as occurs say with multiple sclerosis, one could apply stem cells to replace those degenerated nerve cells. These same stem cells could also replace damaged tissue associated with lung cancer, or Parkinson’s disease, or diabetes. Many conditions, including these, can currently be medically controlled, and made easier to live with, but they can’t be cured. Stem cells may change all that. For example, if eyesight has been lost due to corneal damage, we may be able to use stem cells to grow a new cornea, and restore lost vision.

There are many hurdles to overcome, some of them highly technical problems dealing with how to get from point A to point B. And cells that come from someone else can potentially be rejected. Even still, there are questions that may never be satisfactorily answered, ethical and cultural questions. Truly pluripotent stem cells are currently taken from embryos. When embryos get older, we call them fetuses, and when they are born, we call them children. The meaning of taking basically the seedling of a human being to treat another isn’t easy for some people to swallow. For others, the idea of cell-based therapy goes against deeply rooted notions of what is natural on this good earth. How you feel about this reaches into the most sacrosanct places in the heart and mind.

But there are other possibilities besides taking stem cells from embryos. “Adult” stem cells are stem cells made not from embryos, but from the tissues of fully grown adults. Bone marrow is a good example. Within bone marrow, special cells exist that can create all the cells within your blood. It could be that almost every tissue in the adult body has some kind of adult stem cell within it. Such cells might be able to be harvested from the same patient who needs treatment. Manipulated in a dish, they could be coaxed into other tissues, just like embryonic stem cells. This would avoid the issue of rejection discussed earlier, as well as the ethical questions raised from using embryonic stem cells. Currently, this coaxing is only possible with the help of viruses that introduce specific pluripotency genes into the adult cells and transform them into embryonic like cells. But who knows what tomorrow will bring? As I said, I have seen the potential already in a petri dish. More on that in my next posting.

The genetic complexity of sperm and precursor cells when the chromosomes are painted is similar to that of constellations of planets and stars, and look very similar.

So what did we find?

The study showed that men who are infertile have a much higher risk (3 times) of developing testis cancer later in life than the average citizen. And this was based on some serious number crunching. We worked from a huge database of over 51,000 infertile couples who sought care over a 22 year period in California.  The male partners were cross referenced with a California cancer registry to figure out who among them developed testis cancer as they got older. Among infertile couples in whom the male partner was not the reason for infertility, the future risk of testis cancer was the same as in the general population. However, among infertile men who were themselves the cause of the infertility, the risk of future testis cancer was 3 times higher.

So what does this really mean? Well, first of all, it confirms studies from Europe that have suggested the same thing is happening there. This confirmation in a U.S. based study is important, because the rate of testis cancer in many European countries is much higher than it is in the U.S. It also implies that there may be a connection of some kind between male infertility and testis cancer.

But what kind of connection could exist between male infertility and testis cancer? Well, environmental exposures might link these two conditions. However, the kinds of substances that could do this are still unclear. Estrogenic compounds such as bisphenol A, phthalates and pesticides have garnered much press lately as they alter sexual development in animals, but have not been definitively linked either to testis cancer or human infertility.

The connect, I think, may be even more basic: it probably involves genes and gene mutations. About 10 years ago, we and others reported that severely infertile men have more trouble than other men in properly repairing the daily breaks and kinks that occur in everyone’s DNA with daily use. Because faulty DNA repair is clearly associated with cancer in humans, this led us to surmise back then that infertile men with faulty DNA repair might have a higher risk of cancer later in life.  And voila! The results from the recent research appear to support this idea. 

For the time being, the risk holds only for testis cancer, but who know what future research will show? Based on this, I recommend that all infertile men certainly be evaluated by a urologist with a good history and physical examination. They should also be taught testicular self examination as a screening tool to detect testis cancer.

Infertility as a window into men’s health?  As a shift in thinking, it certainly does shine a new light on the problem.