Karen Smith-McCune, the John Kerner Distinguished Professor of Obstetrics, Gynecology and Reproductive Sciences at UCSF, spends many hours in the clinic, not only performing surgery, but also talking with women about facts and fictions related to the sexually transmitted human papilloma virus (HPV), Pap smears and cervical cancer.

From patient education to surgery may suggest a generalist's range, but Smith-McCune insists that she is highly specialized. Smith-McCune's expertise is in "cervical dysplasia," a condition in which cells of the cervix grow abnormally. Cervical dysplasia is almost always due to long-term infection with certain strains of HPV, and in some cases it eventually leads to cancer.

"In the developing world, cervical cancer is the leading cause of cancer mortality in women; in this country, it's number eight," says Smith-McCune, director of the Dysplasia Clinic at the UCSF Medical Center.

As a medical student at Stanford, Smith-McCune favored academic medicine as a career, and she worked in two different immunology research laboratories. Later, her resolve wavered briefly. "I enjoyed my residency in ob-gyn so much that I thought about a full-time medical practice."

Nonetheless, while she was pregnant with her first child (she is married to another MD/PhD, Joseph McCune, a UCSF professor of medicine; they met in graduate school), Smith-McCune began a three-year postdoctoral research fellowship in the laboratory of Nobel laureate (now UCSF Chancellor) J. Michael Bishop. She took some time off when her second child was born and then joined the UCSF faculty in 1994, sacrificing neither her research interests nor her desire to have a social impact.

In the clinic, Smith-McCune sees women, mostly in their late twenties and thirties, who have had abnormal Pap smears, meaning that some cells that were scraped from the cervix appeared abnormal. When a Pap smear is positive or ambiguous, Smith-McCune examines the cervix under magnification with an instrument called a colposcope to search for dysplastic cervical cells at the source. If she finds areas on the cervix that look abnormal, she performs a biopsy, and if the biopsy confirms the presence of cells that appear to be on their way to becoming cancerous, she conducts electrosurgery, using a loop of wire charged with high current to cut through and excise a button of tissue.

Drugs and diagnostic tests

"There are no pharmacologically based therapies for this disease, which I think is shocking," Smith-McCune says. One of her research goals is to identify drugs that merit clinical testing for treatment of cervical dysplasia or cancer. Another is to develop improved diagnostic tests, based on new molecular indicators, that can be used to help clinicians more quickly and accurately distinguish low-grade cervical dysplasias (which usually disappear on their own) from high-grade dysplasias (which are more likely to eventually turn into cancer).

"The problem with Pap is that it detects the whole spectrum of disease very well." Smith-McCune says. "I'm looking for molecular markers that are present at late stages in the disease progression, in what we consider to be true precancerous lesions. I am going to exclude from the test any markers that appear in abnormal cells at earlier stages." New markers that Smith-McCune identifies may also shed more light on how cervical cancer develops.

"We have shown that angiogenesis -- new blood vessel growth -- is up-regulated during the disease process, and that certain molecular factors known to regulate angiogenesis are measurable in clinical Pap samples," Smith-McCune says. She is trying to determine whether any of these markers can be used to distinguish high-grade dysplasia from low-grade abnormal cells. Working with Doug Hanahan, a UCSF professor of biochemistry who studies blood vessel growth and inflammation in mouse models of cervical cancer, she also will determine whether any anti-angiogenic drugs warrant clinical testing as a topical treatment.

Pap screening and medical follow-up on abnormal tests clearly make a huge difference in the US, but in developing nations most women rarely have access to medical services, let alone to follow-up care. Smith-McCune would like to use the molecular markers she identifies not only to make tests for US women better at identifying later-stage disease, but also to develop a simpler, cheaper alternative to Pap testing for women in poor nations.

Research and vaccines

Such a test would have an instant readout, similar to dipstick urine tests for pregnancy, so that a woman could be diagnosed and treated in a single visit. An example of a low-tech treatment recently tested and shown to be promising by researchers working in Zimbabwe is to wash the cervix with vinegar, which causes abnormally growing cells to appear white. Abnormal areas can then be treated by freezing and destroying the white patch with liquid carbon dioxide.

Tests for infection with cancer-causing strains of HPV have recently become available, but Smith-McCune wonders whether they actually offer any advantage over standard Pap tests. HPV tests are less specific than Pap smears, she says. The majority of women who test positive for HPV have normal cells, and more than 90 percent of infected women get rid of the virus. Even so, when the results of Pap smears are unclear, many physicians reflexively order the HPV test, according to Smith-McCune.

"I can't think of any other instance where you would test for a sexually transmitted infection without discussing it with the patient beforehand," she says.

A more promising advance is the development of HPV vaccines. Early clinical trials have shown one such vaccine to be 100 percent effective in preventing infection with the HPV16 strain responsible for more than half of all cervical cancers worldwide. Evaluation of another vaccine that targets three additional HPV strains is ongoing. Eight strains of HPV account for about 95 percent of cervical cancers, Smith-McCune notes.

"Vaccines could have a huge impact," she says, although it will still be years before any vaccine is available commercially, and longer still before enough people are vaccinated to have a large effect. A vaccine does not eliminate HPV infection, so women who already are chronically infected or who are sexually active today will not benefit.

"Someday," Smith-McCune says, "there will be no screening for cervical cancer. It will no longer be cost-effective. Unfortunately, none of us believe that is going to happen soon enough to put us out of business."