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Johns Hopkins University logoProgram in Molecular Biophysics
Richard ConeCone Lab

Richard Cone

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

B.S. 1958, Massachusetts Institute of Technology
Ph.D. 1963, University of Chicago

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

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


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Our 'Mucosal Protection Laboratory' is investigating methods for protecting against sexually transmitted diseases (STDs) and vaginal infections, especially bacterial vaginosis (BV). Worldwide, at any given time, more than one third of women have BV. The symptoms of BV are usually mild, but BV markedly increases risk of STDs including HIV/AIDS, and markedly increases risk of premature births.

Like all mucosal surfaces, the vagina supports microbial populations (microbiota). In fact, most cells in the human body are not human - our bodies consist of more bacterial cells than human cells. Healthy mucosal surfaces are populated with symbiotic bacteria that help prevent infections; the healthy symbiotic bacteria in the vagina are lactobacilli. Unfortunately, most women most of the time have either BV or 'intermediate' flora that deplete lactobacilli, shifting the microbiota of the vagina from a monoculture of lactobacilli to dense 'overgrowths' of multi-bacterial communities that increase risk of infections. Many women have healthy vaginal lactobacilli all the time, but most women experience frequent episodes of BV and intermediate flora (See Brotman et al, 2010). What causes these frequent fluctuations in vaginal microbiota is unknown. The focus of current research in this laboratory is to determine how lactobacilli help prevent BV, and other infections. Through an ongoing Research Agreement with ReProtect, Inc., we are also developing a method that we hope will prevent BV and thereby help prevent STDs and premature births.

Remarkably little is known about vaginal microbiota and the physiology of the vaginal mucosa, in part because few scientists have been interested despite all the vaginal health problems women experience. It wasn't until 1992 that the NIH 'discovered' the vagina. That was the year NIH first started to fund research on vaginal physiology, vaginal immunology, and vaginal microbicides for protecting against STDs. This 'discovery' was made when women for the first time were made directors of the STD branch of NIAID and the contraceptive development branch of NICHD. Since there has been so little prior research in these areas many of our research projects are the first to explore new hypotheses rather than incrementally advancing mature research fields.

In her PhD thesis, Beth Boskey, a Jenkins biophysics grad student, obtained definitive proof of the long held belief (based on no direct evidence) that the vagina is acidified by lactic acid produced by lactobacilli. Among other crucial tests, Boskey found that most lactic acid in the vagina is the D optical isomer while human metabolism can only produce the L-isomer. Moreover, lactobacilli grown in culture produced essentially the same D/L ratio as in the vaginal secretions from which they were isolated.

In her recent Ph.D. thesis research, Deirdre E. O'Hanlon found that lactic acid potently inactivates a broad range of BV-associated bacteria without affecting lactobacilli. Thus it is likely that monocultures of lactobacilli can fend off BV if the monoculture produces lactic acid at a fast enough rate to fully acidify the vagina. Most surprising, lactic acid inactivates HIV and HSV (herpes virus) far more potently than acidity (pH) alone. This suggests that vaginal lactic acid may help prevent female to male transmission of HIV and genital herpes. This is consistent with the clinical finding that human populations at high risk for both these pathogens also have exceptionally high prevalence of BV. O'Hanlon also found that the L-isomer is more potent viricide than the D-isomer, a clue that may help lead to discovering the viricidal mechanism.

Our ongoing bacteriological research is being pursued in collaboration with Jacques Ravel, Institute for Genome Sciences, University of Maryland School of Medicine.

In addition, in collaboration with Justin Hanes at the Johns Hopkins School of Medicine we are investigating the protective actions of mucus secretions through which STDs are transmitted (cervico-vaginal mucus, BV secretions, semen, and endocervical mucus). Recently, we found that cervico-vaginal mucus, if acidified with lactic acid, traps HIV. (See Lai et al, 2009)

Lastly, in collaboration with Samuel Lai at the University of North Carolina, we are developing the use of human antibodies produced inexpensively in plants ("plantibodies") for passive immune protection of the vagina: we are investigating the mechanisms by which antibodies prevent infections by trapping pathogens in mucus.

Selected Publications
Abdool Karim, S.S., B.A. Richardson, G. Ramjee, I.F. Hoffman, Z.M. Chirenje, T. Taha, M. Kapina, L. Maslankowski, A. Coletti, A. Profy, T.R. Moench, E. Piwowar-Manning, B. Mâsse, S.L. Hillier, L. Soto-Torres; HIV Prevention Trials Network (HPTN) 035 Study Team. (2011) Safety and effectiveness of BufferGel and 0.5% PRO2000 gel for the prevention of HIV infection in women. AIDS. 25:957-966. (Unfortunately neither protected against HIV.)

Brotman, R.M., J. Ravel, R.A. Cone, and J.M.Zenilman. (2010) Rapid fluctuation of the vaginal microbiota measured by Gram stain analysis. Sex. Transm. Infect. 86:297-302. (Many women have ~2 episodes of BV per month.)

O'Hanlon, D.E., B.R. Lanier, T.R. Moench, and R.A. Cone. (2010) Cervicovaginal fluid and semen block the microbicidal activity of hydrogen peroxide produced by vaginal lactobacilli. BMC Infect. Dis. 10:120. (Instead, the lactic acid the lactobacilli secrete is a broad-spectrum microbicide.)

Lai, S.K., Y.Y. Wang, K. Hida, R. Cone, and J. Hanes. (2010) Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses. Proc. Natl. Acad. Sci. USA 107:598-603. (Viruses evolved both size and surface properties that enable them to penetrate mucus.)

Lai, S.K., K. Hida, S. Shukair, Y.Y. Wang, A. Figueiredo, R. Cone, T.J. Hope, and J. Hanes. (2009) Human immunodeficiency virus type 1 is trapped by acidic but not by neutralized human cervicovaginal mucus. J. Virol. 83:11196-11200. (Vaginal lactic acid inactivates HIV.)

Cone, R.A. (2009) Barrier properties of mucus. Adv. Drug Deliv. Rev. 61:75-85. (Review)

Barnhart, K.T., M.J. Rosenberg, H.T. MacKay, D.L. Blithe, J. Higgins, T. Walsh, L. Wan, M. Thomas, M.D. Creinin, C. Westhoff, W. Schlaff, D.F. Archer, C. Ayers, A. Kaunitz, S. Das, and T.R. Moench. (2007) Contraceptive efficacy of a novel spermicidal microbicide used with a diaphragm: a randomized controlled trial. Obstet. Gynecol. 110:577-586. (ReProtect's acidic-buffering "BufferGel" was successful in these Phase II and Phase III contraceptive trials.)

Lai, S.K., D.E. O'Hanlon, S. Harrold, S.T. Man, Y.Y. Wang, R. Cone, and J. Hanes. (2007) Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus. Proc. Natl. Acad. Sci. USA 104:1482-1487. (Engineering virus-like nanoparticles for mucosal drug delivery.)

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.

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. (Demonstrated that large proteins, including antibodies, can diffuse through mucus.)

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. (Strong evidence that the human vagina is acidified by lactobacilli.)

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