Professor
Thomas C. Jenkins Department of Biophysics
Krieger School of Arts & Sciences

cone@jhu.edu

320 Jenkins Hall
3400 N. Charles Street
Baltimore, MD 21218

Office: 410-516-7259
Lab: 410-516-6596

Our “Mucosal Protection Laboratory” is developing barrier methods for protecting against sexually transmitted diseases (STDs) and unwanted pregnancy, methods more appealing to use than condoms. Microbicides for this purpose must not only block the infectious entry of STD pathogens, they must also be very safe to use repeatedly on mucosal surfaces, and they must not disturb the healthy microflora of the vagina (lactobacilli). Research in the Mucosal Protection Laboratory helped clarify how secreted antibodies work in concert with mucins to trap pathogens in mucus secretions, thereby preventing pathogens from contacting target cells. More recently, research in this laboratory helped create “BufferGel”, a spermicidal microbicide now in a major clinical efficacy trial (funded by NIH) for preventing HIV infections. BufferGel has recently successfully completed a Phase III contraceptive efficacy trial - by stopping sperm with protons (in press, Obstet. Gynecol., 2007).   BufferGel’s basic mechanism of protection is quite simple: The vagina is mildly acidic (~pH 4), sufficiently acidic to protect against many types of pathogens. But sperm are acid-sensitive, so semen is alkaline and the ejaculate abolishes the protective acidity of the vagina for many hours after intercourse. Otherwise sperm would be killed within seconds by vaginal acidity. Unfortunately the alkalinizing action of semen helps acid-sensitive STD pathogens, not just sperm, to survive in the vagina. Acid-sensitive STD pathogens include HIV, HSV, syphilis, and chlamydia. Since BufferGel can rapidly acidify semen it not only protects against sperm it is also expected to protect against acid-sensitive pathogens while not disturbing acid-tolerant vaginal lactobacilli. Research on BufferGel and other microbicides is being performed in part through an ongoing Research Agreement with ReProtect, Inc, the JHU-associated company that is pursuing commercial development of BufferGel.

What is the most common vaginal infection? (It’s more common than yeast infections.) Answer: Bacterial Vaginosis (“BV”). Most people have never heard of it, and it is asymptomatic in most women. Worldwide, about 1 out of 4 women have BV. Even though most people don’t know about it, recent epidemiological studies reveal that BV is a major health problem: Women with BV are at greatly increased risk of HIV and many other STD infections, and BV greatly increases the risk of stillbirths, premature births, and pelvic and perinatal infections. During a BV infection, the lactobacilli die off, the protective acidity of the vagina is lost, and a marked polymicrobial overgrowth occurs, coating every epithelial cell with a carpet of bacteria. Our research suggests that BufferGel will help prevent BV, and the ongoing clinical trials will determine whether or not it does. In the meantime our lab is investigating what causes BV and the mechanisms by which BV might increase the risk of HIV and other STD infections. Little is known about what causes BV, and no one knows how it is transmitted, so we are pursuing foundation-building research projects that use simple microbiology techniques.

The first graduate student to pursue research on BV in the Mucosal Protection Lab, Elizabeth Boskey, chose to investigate the question: “What makes the vagina acidic?” For over 100 years many clinicians have thought that the vagina is probably acidified by the lactic acid produced by lactobacilli, but no one actually tested whether or not this hypothesis was correct. More recently, some clinicians suggested the reasonable alternative hypothesis that since the vagina is anaerobic, anaerobic metabolism by the epithelial cells produces most of the lactic acid. Boskey’s thesis research provided the first definitive evidence that vaginal acidity is in fact produced primarily by lactobacilli since vaginal lactic acid is mostly the d-isomer and human metabolism produces only the l-isomer (see Boskey et al, 2001). We are now investigating how lactobacilli, by producing large amounts of lactic acid, fend off BV-associated microbes.

Selected Publications
Cone, R.A., T. Hoen, X. Wong, R. Abusuwwa, D.J. Anderson, and T.R. Moench. (2006) Vaginal Microbicides: Detecting toxicities in vivo that paradoxically increase pathogen transmission. BMC Infect. Dis. 6:90.

Olmsted, S.S., K.V. Khanna, E.M. Ng, S.T. Whitten, O.N. Johnson 3rd, R.B. Markham, R.A. Cone, and T.R. Moench. (2005) Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model. BMC Infect. Dis. 5:79.

Cone, R.A. (2005) Mucus. In Handbook of Mucosal Immunology, Third Edition, ed. by Mestecky, Lamm, Strober, Bienenstock, and McGhee, 49-72. London: Academic Press.

Boskey, E.R., T.R. Moench, P.S. Hees and R.A. Cone. (2003) A self-sampling method to obtain large volumes of undiluted cervicovaginal secretions. Sex. Transm. Dis. 30:107-109.

Castle, P.E., D.A. Karp, L. Zeitlin, B. Garcia-Moreno E., T.R. Moench, K.J. Whaley and R.A. Cone. (2002) Human monoclonal antibody stability and activity at vaginal pH. J. Reprod. Immunol. 56:61-76.

Achilles, S.L., P.B. Shete, K.J. Whaley, T.R. Moench and R.A. Cone. (2002) Microbicide efficacy and toxicity tests in a mouse model for vaginal transmission of Chlamydia trachomatis. Sex. Transm. Dis. 29:655-664.

Khanna, K.V., K.J. Whaley, L. Zeitlin, T.R. Moench, K. Mehrazar, R.A. Cone, Z. Liao, J.E. Hildreth, T.E. Hoen, L. Shultz and R.B. Markham. (2002) Vaginal transmission of cell-associated HIV-1 in the mouse is blocked by a topical, membrane-modifying agent. J. Clin. Invest. 109:205-211.

Olmsted, S.S., J.L. Padgett, A.I. Yudin, K.J. Whaley, T.R. Moench, and R.A. Cone. (2001) Diffusion of macromolecules and virus-sized-particles in human cervical mucus. Biophys. J. 81:1930-1937.

Boskey E.R., R.A. Cone, K.J. Whaley, and T.R. Moench. (2001) Origin of vaginal acidity: High D/L lactate ratio is consistent with bacteria being the primary source. Hum. Reprod. 16:1809-1813.

Castle, P.E., K.J. Whaley, T.E. Hoen, T.R. Moench, and R.A. Cone. (1997) Contraceptive effect of sperm-agglutinating monoclonal antibodies in rabbits. Biol. of Reprod. 56:153-159.

Cone, R.A., and K.J. Whaley. (1994) Monoclonal antibodies for reproductive health: Preventing sexual transmission of disease and pregnancy with topically applied antibodies. Am. J. Reprod. Immunol. 32/2:114-131.