OK

A new article (Matzuk et. al., 2012; open access) just published in the scientific journal Cell documents the discovery of a new contraceptive - a small molecule named JQ1 that binds to the protein BRDT.

What makes this contraceptive very unique is who it's targeted for - males.

Contraceptives have sadly been a hot-button issue lately, especially with the emergence of an emboldened extremist political group known as the Tea Party.  

The overwhelming ignorance of conservatives and religious extremists in regard to the science and medicine of contraceptives has certainly played a major role in suddenly allowing this issue to come up for debate again, even decades after Griswold v. Connecticut.  But despite that, I think the paramount reason that contraceptives are suddenly target number one of the right wing is because of the sex that uses them.  (hint - as of now, 100% women)

Follow me below the Great Orange Croissant for a quick scientific lesson about how current contraceptives work, a summary of this newly discovered contraceptive targeted for males (and why it's such a major scientific discovery), and the implications this new drug has for readjusting the political paradigm in regard to contraceptives and overall reproductive rights.

Attempts at contraception have been around in various forms for over thousands of years.  However, I will focus on the modern era of birth control, which in the United States begins in the 1910s with Margaret Sanger's tireless efforts.  Sanger advocated for the use of contraceptives commonly referred to as "barriers", such as condoms, diaphragms, and cervical caps.  These contraceptives, as their category name suggests, aim to prevent sperm from traveling past the cervix into the fallopian tubes, where sperm encounters and fertilizes the oocyte.

These methods, while extremely pioneering for their time, have quite a high failure rate.  And the barrier method with the lowest fail rate - the condom - is essentially a male-controlled contraceptive; in which I mean that the male decides whether or not to use it, despite any protests his partner may have.

The second breakthrough for contraceptives occurred in the 1960s, when the first hormonal contraceptive was FDA approved and marketed for the general public.

Hormonal contraceptives work by tricking the female's body into thinking it's pregnant, even when it is not.  Since during actual pregnancy no new oocytes are released from the ovary, a woman using hormonal contraceptives will not release oocytes, and thus have no egg to be fertilized, even by sperm that enters the vagina and passes through the cervix.  Additionally, in case an oocyte is still released, hormonal contraceptives prevent implantation of the fertilized zygote into the uterine wall, which is a requirement for pregnancy.

Importantly this type of new medicine, now commonly referred to as "The Pill", finally put the control of contraception into the hands of women.  This was an incredibly empowering development for women and truly began to fulfill the mission of Sanger and others from the 1910s, which was to free poor women from the physical and financial burden of unwanted pregnancy.

This above reason is, I believe, exactly why prominent conservatives and religious fanatics - almost all of whom are male - are adamant about attacking contraceptives.

One of the things that was completely glossed over, in my opinion, during the entire Sandra Fluke attack saga was the type of contraceptives that were being targeted for attack.  Ms. Fluke was verbally assaulted by the likes of Rush Limbaugh and Christian fundamentalist leaders for standing up for "The Pill" (aka "female contraception").  But did you hear a peep from out any of them following reports that 100,000 condoms (aka "male contraception") would be distributed to Olympic athletes during the 2012 Summer Games?

By the way, in case your math is rusty, that's 10 condoms per olympic athlete.  Including females in the total!  So it's actually more like 20 condoms per male athlete.  For a time period of no more than three weeks.

Now who's the sluts?

Before I get back to the political and societal impacts of a small-molecule male contraceptive, I want to quickly talk about the science of such a contraceptive, and why this new discovery is such a big deal.

Pharmaceutical male contraceptives have been desired for a long period of time.  However, the hormonal mechanism of tricking the female body into thinking it's pregnant (which actually is not so difficult) obviously does not exist for males.  One theoretical possibility is to prevent spermatogenesis, but that would involve preventing cell proliferation, and up until this point the pharmaceutical compounds that have such a function act predominantly on a global scale (which means a lot of undesired side effects, most notably a severe depletion of red blood cells and immune cells, which are produced on the order of millions per second).

Enter JQ1, a newly discovered small molecule that specifically targets spermatogenesis.  Here's some background on how it works:

Bromodomain testes-specific protein (BRDT) is a chromatin-associated protein that is expressed only in testes, and only during spermatogenesis.  BRDT is known to modify histone proteins (specifically at acetylated lysine residues), which are proteins that help coil DNA.  Importantly, mice genetically engineered to have no BRDT gene (termed "knock outs") are infertile, which means that BRDT is critical for gamete formation.  As the authors point out in their Introduction section, "These insights establish a compelling rationale to target BRDT for a contraceptive effect."

MaleContraceptiveFigure1B

The authors then undertook a small molecule screen of acetylated lysine analogs in an attempt to find a competitive inhibitor for BRDT, and their screen identified a small molecule called JQ1.  After identifying a potent chemical inhibitor for BRDT, the authors investigated whether chemical inhibition of BRDT had any physiological effect.  Since the previous study mentioned above showed that deletion of the BRDT gene renders male mice infertile, the authors were reasonable in hypothesizing that chemical inhibition of BRDT would have the same effects.

The authors then performed several pharmacological assays to assess the physiological effects of JQ1 on spermatogenesis.  JQ1 treatment for 6 weeks reduced the size of the testes by just below 60%, and this significant decrease in testis volume corresponded with a significant decrease in sperm count.  Importantly, male sex hormone levels are unaffected, which would help to reduce any potential side effects that could have been possible.  As the authors state, "Thus, JQ1 effects are specific to germ cells and do not alter hormone-dependent processes."

Matzuk_Fig3

As a brief note, chromatin-associated proteins as usually involved in regulating gene expression.  Thus, the authors performed a gene expression microarray to determine the effect of JQ1-mediated BRDT inhibition on gene expression.  The data show a drastic down-regulation of hundreds of genes, including many expressed during spermatogenesis.  Interestingly, JQ1 has been used as an anti-cancer drug for cancers caused by genetic mutations in BRDT-like proteins; thus, JQ1 has potent anti-mitotic (aka cell division) properties.  In this light, it makes sense that JQ1 can inhibit spermatogenesis so well, considering that gamete formation is one of the most proliferative processes in the male body.

Finally, of utmost importance is the reversibility of JQ1's contraceptive properties.  Thankfully, the authors demonstrate convincingly that things go back to normal after JQ1 is discontinued.  Mice treated with a high dose of JQ1 were able to sire pups after only three months off the drug, and testis mass and sperm count both rebounded back to 100% within two months following stoppage of the contraceptive.  Finally, as you can see from box "K", the little mousies (haha, the one silly term I use) are of normal size and exhibit normal behavior.  As the authors conclude, "Together, these findings indicate that JQ1 did not have any long-term transgenerational effects on testis physiology or reproductive capacity...  These data support JQ1 as the first contraceptive agent that selectively and reversibly targets the male germ cell."

MaleContraceptiveFigure7

Obviously these experiments were done on mice, however, as the authors write in their final sentence, "Because human and mouse BRDT proteins are highly conserved and have nearly identical bromodomain pockets based on our structural predictions, we envision that our discoveries can be completely translated to men, providing a novel and efficacious strategy for a male contraceptive."

As a cell and molecular biologist, I find the science extremely fascinating and thorough.  However, I also understand the hardened reality that politics and religious fanaticism seem to be driving the debate about contraception currently ongoing.

I am very intrigued as to what the responses from conservatives and fundamentalists would be in regard to an FDA approved contraceptive for males.  If I had to guess, I would say their response would be largely muted, similar to the crickets we heard in regard to the Olympic Village making 100,000 condoms available to athletes.  Because like condoms, JQ1 is a male-targeted contraceptive.  And as we all know here, the outrage from conservatives and fundamentalists really isn't about the science or medicine of contraception; we know this because they are consistently wrong about the science, like calling the morning-after pill the "abortion pill", even though it's simply a mega-dose of current hormonal contraceptives that prevent implantation of the fertilized zygote.

Conservatives are against female-controlled birth control because it empowers freedom for women; freedom from unwanted pregnancy that often binds a woman to a devastating financial situation, or worse yet, an abusive partner.  When conservatives talk about "traditional family values", they don't just mean a world free from homosexuality, they also mean a world where women are subservient to men, where we qualify definitions of rape solely for the reason to maintain absolute power for men while simultaneously crushing women beneath the proverbial steel-toed boots.

That is why the fight for Obamacare to cover birth control at 100% is so vital to our national health policy.  It's much more than just sound medical policy.  It's about empowering women to take reproductive rights into their own hands; it's about reprogramming our society to push forward a massive shift of the contraceptive burden toward having men take equal responsibility in their sexual relationships with their partners.  And one that hopefully won't be stigmatized itself and can help reduce the hypocrisy against female hormonal contraceptives.

Thankfully, this "debate" on "The Pill" is thought to be so ludicrous by my fellow mid-20s peers - both women and men - that I feel we just have to hold on through this temporary dark period to get to an enlightened time of sound family planning policy that's good for the planet and good for reaching true equality.

The floor is yours.

Originally posted to mconvente on Mon Aug 20, 2012 at 08:44 PM PDT.

Also republished by Science Matters and Community Spotlight.

EMAIL TO A FRIEND X
Your Email has been sent.