A 2011 study in the United States reported that 49% of pregnancies were unintended in 2006 . Across the globe, this type of trend has contributed directly to maternal mortality, as well as the ethical, social, and financial costs associated with abortions and deliveries to single mothers. The high rate of unplanned pregnancies, especially in teenagers, is, in part, due to the lack of contraceptive alternatives for men. Male contraceptive options are limited, at best, with the most prominent and widespread options being condom-use and vasectomies. An effective male contraceptive would undoubtedly help to reduce unplanned pregnancies. Surveys conducted around the world have indicated that, whatever the setting, at least 25% of men would consider using drug-based contraception, even if it meant affecting their own hormone levels . Researchers at Harvard Medical School and the Dana-Farber Cancer Institute have designed a small molecule that dramatically reduces the generation of viable sperm, without affecting hormone levels, potentially providing a new way for men to combat unplanned pregnancy.
The JQ1 molecule targets an aggressive carcinoma
The small molecule JQ1 was developed in the laboratory of James E. Bradner at the Dana-Farber Cancer Institute . JQ1 was originally developed not to serve as a contraceptive but rather to function as a new cancer treatment. Researchers found that JQ1 targets the BRD4 bromodomain . You may be wondering what exactly is a bromodomain? A bromodomain is a portion of some proteins that is involved in regulating whether particular genes are turned on or off in our cells. This regulation is accomplished through the formation of protein complexes with these bromodomain-containing proteins. Bromodomains are critical for making sure that our cells properly synthesize many of the proteins our bodies need to function.
The BRD4 bromodomain that JQ1 targets was of interest to researchers since it had been identified as a component of a chromosomal translocation in an aggressive form of human squamous carcinoma, called NUT midline carcinoma (NMC). In other words, in these cancer cells, the BRD4 bromodomain was found in genomic locations where it wasn’t found in normal cells. These squamous carcinomas are a rare form of epithelial cancer, which means they typically come out of epithelial cells, such as those in the layers of cells that make up our skin. Bromodomains in these locations disrupted normal genes causing them to code for fusion proteins, proteins that had the bromodomain attached to them. Cells with these fusion proteins grow uncontrollably. No wonder the development of a specific BRD4 bromodomain inhibitor was of key interest to investigators!
The Bradner lab tested the effectiveness of JQ1 on the growth of tumor cells obtained from human patients with NMC. Amazingly, the JQ1 molecule caused the immediate and progressive apoptosis, or cell death, of BRD4-dependent human carcinoma cells, without having significant effects on healthy cells without the BRD4 translocation. They also reported that JQ1 was similarly effective in mice transplanted with NMC tumor cells, where JQ1 treatment actually shrank the size of the tumors and prolonged animal survival .
JQ1 is found to be a potent inhibitor of spermatogenesis
As mentioned previously, bromodomains are found in a wide variety of proteins. One very interesting member of the bromodomain-containing protein family is BRDT. BRDT is found specifically in the testis and is essential for turning genes on and off during spermatogenesis, or the formation of sperm. Essentially, BRDT tells early sperm precursor cells that they should grow into mature sperm cells. Since JQ1 targets bromodomain-containing proteins, researchers were interested in seeing whether it had any effects on BRDT and spermatogenesis. Researcher’s tests in mice showed that JQ1 could inhibit BRDT. This lead to reduced testis size, number of sperm, and sperm motility, without affecting hormone levels in the animals [3,6].
Mice treated with JQ1 showed, on average, at least a 90 percent decrease in sperm count and at least a 75 percent decrease in sperm cell motility. Most interesting is that the effects of JQ1 on sperm quality and production were also reversible. This latter point is very important, as other drugs currently in clinical trials as potential male contraceptives are analogs of the male sex hormone, testosterone, and alter hormone levels in patients. Excitingly, no significant side effects were noted in the mice, and overall mating behaviors were not impacted by JQ1 treatment. Ongoing work optimizing the properties of JQ1 for contraceptive use, such as trying to extend the amount of time that the effects of the drug last, is the next direction for researchers. Since human and mouse BRDT are nearly identical, it is hoped that the transition to clinical trials in men will be just as successful as the results seen in mice.
Adoption of a drug like JQ1 across the population may take some time, and will be dependent on numerous factors such as socio-economic status, quality and accessibility of healthcare, and personal sexual education. But looking beyond these limitations, this candidate drug may soon be a critical tool in helping us meet the world-wide need for alternative family planning, and both excitement and media-coverage over these studies will likely increase as clinical trials get underway.
Video from Dana-Farber covering this discovery.
Christian Berrios is a graduate student in the Virology Program at Harvard Medical School.
 Glasier A (2010) Acceptability of contraception for men: a review. Contraception 82: 453-456.
 Filippakopoulos P, Qi J, Picaud S, Shen Y, Smith WB, Fedorov O, Morse EM, Keates T, Hickman TT, Felletar I, Philpott M, Munro S, McKeown MR, Wang Y, Christie AL, West N, Cameron MJ, Schwartz B, Heightman TD, La Thangue N, French CA, West O, Kung AL, Knapp S, Bradner JE (2010) Selective inhibition of BET Bromodomains. Nature 468:1067-1073.
 Matzuk MM, McKeown MR, Filippakopoulus P, Li Q, Ma L, Agno JE, Lemieux ME, Picaud S, Yu RN, Qi J, Knapp S, Bradner JE (2012) Small-Molecule Inhibition of BRDT for Male Contraception. Cell 150:673-684.
 Unintended Pregnancy Prevention (CDC) <http://www.cdc.gov/reproductivehealth/unintendedpregnancy/>
 James E. Bradner Lab Page (DFCI) <http://bradner.dfci.harvard.edu/>
 Advances towards a male birth control pill (Washington Post) <>