Modeling a B Cell Flash Mob

Thomas Kepler, Director of Duke's Laboratory of Computational Immunology, sure doesn't sound like a physicist, but he is, or rather was. At Friday's Visualization Friday Forum, Kepler shared his group's latest work on modeling immune system behavior in a session called "Vaccines (the Movie)."

It's a collaboration within the Human Vaccine Institute that pulls together statistics and math, computer science, and visualization technology with colleagues from Duke, UC Irvine, Emory and the National Institutes for Allergy and Infectious Disease, a part of the NIH.

The immune system might be thought of as an organ, with several types of specialized cells working together -- but it moves. "That's the coolest thing!" Kepler says. Immune cells flow through the body, and aggregate at the scene of trouble as needed, forming "a semi-solid organ."

After walking the group through some immune system 101 (the macrophage's connected to the dendrite; the dendrite's connected to the T cell; the T cell's connected to the B cell…), Kepler narrowed his focus to the flash mob of B cells that gather in the lymph node to educate each other about an invader. The goal is to understand how B cells and T cells get organized into these tight aggregations inside the lymph, called germinal centers, and figure out ways vaccines might optimize their performance.

(SEE MOVIE: from NIAID, showing B Cells (red) moving throughout a lattice of collagen fibers within the lymph tissue.)

Kepler's group is combining the latest cellular imagery with mathematical models of lymph tissue to better understand how these cells become organized to then go out to the site of infection and wage a carefully calibrated battle against the invaders.

The ultimate goal is to develop swift and effective vaccines with minimal side effects.

Science that breaks the pieces down and figures them out individually has brought this far, Kepler says, but now it's time for the modelers and biostatisticians to try to put the pieces back together and figure how they work in a dynamic system. "So far, we still have a long way to go."

Medical Fiction That Rings True

A guest-post from Andrea Fereshteh, senior writer in Duke's office of news and communications:

Re-reading physician-turned author Abraham Verghese’s first book My Own Country last month, I was struck by his raw, revealing look at treating AIDS in East Tennessee during the late 1980s.

My father went to work with Verghese when I was just seven years old and though I identified them as doctors by their white coats and the stethoscopes draped around their necks, I now appreciate Verghese’s graphic illustration of the daily challenges they faced confronting the space between life and death, witnessing humanity laid bare.

Verghese continues to usher readers into the intimate world between patient and physician with his debut novel Cutting for Stone.

He read excerpts from the book and spoke to an audience of physicians, medical students and local fans at the Searle Center last night. (Read a New York Times review and the first chapter of the book)

The story follows twin brothers born of a secret union between an Indian nun and a British surgeon named Thomas Stone in a hospital in Africa. The circumstances are familiar ground for Verghese; he was born in Ethiopia to Indian parents. The twins in the story later find themselves drawn to the medical profession, as did Verghese.
He read aloud two excerpts from the book, including a humorous exchange between two doctors -- one teaching the other how to do a vasectomy -- that had the audience laughing out loud.

He then spoke candidly to the audience about his journey from medicine into writing, and how he continues to straddle both worlds today as professor of internal medicine at Stanford University

Marking a departure from the two non-fiction books he has written in the past, fiction writing, Verghese commented, was a challenge.

“People have an inherent interest in non-fiction because it actually happened,” he said. “For fiction writing, you have to work harder to make the reader suspend disbelief from the moment they begin reading through the last page of the book.”

Describing how he felt drawn to medicine after reading Of Human Bondage by William Somerset Maugham, Verghese says he writes in order to “find out what I’m thinking.”

Writing this book, he said, reminded him that the most important function of a physician is not just scientific or technical, but Samaritan.

“The act of sitting down to write is important,” he said, noting that he keeps a journal and finds time to write whenever he can. “Writing this novel reaffirmed my faith and love for medicine. It is more than a profession, it’s a calling.”

Sick and Tired

Monday was the 20th World AIDS Day, but "celebration is such an odd word for it," assistant dean Michael Relf told a small brown bag session at the School of Nursing.

Today, an estimated 33 million people carry HIV, of which two-thirds are in sub-Saharan Africa, where Relf does much of his research. As the virus spreads most viciously among the poor, the uneducated, the young and the female, "we're seeing the epidemic start over," he said. Completely depressing.

His colleague, associate professor Julie Barroso, is studying the psychic toll HIV infection takes on American patients, many of whom have been living with it for ten years or more. She presented preliminary data from an ambitious NIH-funded study that is measuring a dizzying array of physiologic and psychosocial factors in a cohort of 128 patients over time. What they're looking for is some predictors of the debilitating fatigue that many HIV-positive people experience. So far, the physiology -- liver function, thyroid, testosterone, viral lode, CD4 cell counts, etc. -- doesn't correlate at all with fatigue. But the psychic factors -- experiences of trauma, PTSD, depression, anxiety, lack of social support, etc. -- are ALL correlated with fatigue.

But there it gets tricky: Do HIV patients experience fatigue because they've got this infection (and all that it symbolizes) lurking over them, or does their stressful, traumatic, unsupported past make them feel more poorly?
Relf pointed out that trauma in childhood and adulthood are themselves predictive of HIV-positive status.

Clearly, another case where an ounce of prevention would save untold lives and resources. The other bottom line: Society, here and in Africa, needs to treat more than the HIV patient's symptoms. "Each of us can do something," Relf said. "Even if it's just listening to someone."

Giving Women Control Against HIV

HIV, the AIDS virus, "targets women with Darwinian ferocity," says Patrick Kiser, an assistant biomedical engineering professor at the University of Utah who got his Ph.D. at Duke. In Africa, the HIV infection rate among young women can be three times higher than men.

That's in part because females are at the "receiving end" of HIV-infected semen and partly because of their vulnerable societal status, Kiser said Nov. 6 at a Duke conference on Bioengineering Applications to Address Global Health. So while male use of condoms can prevent transmission, that requires far-from-certain negotiating between sexual partners.

Kiser's lab is working on techniques that would shift control to women by introducing agents called "microbiocides" to stop the virus cold in the vagina. But early experiments by others have not been promising, he said.

While one candidate gel preparation seemed to block the virus in laboratory culture, for example, the salt content of semen interfered with the agent's effectiveness. Also, women did not always follow instructions that called for applications before each sex act.

His group's tactic is to combine advanced microbiocides more attuned to bodily chemistries with better drug delivery techniques. As one example, it is developing flexible plastic intravaginal rings that can be made for pennies and deliver a constant amount of microbiocide for 30 days.

One gel method of action he described would trigger the release of anti-HIV drug when normally acidic vaginal fluids undergo a pH change upon intercourse (sperm is basic rather than acidic). At the same time, the normally free-flowing gel would chemically crosslink into a semi-solid to stop viral particles from reaching vulnerable white blood cells of the immune system.

Kiser is also collaborating with a Duke group headed by biomedical engineering professor David Katz.

WISE Up about HIV/AIDS

Of all the secondary school students in Africa, only 16% are girls.

To raise this number, Dr. Sherryl Broverman of Duke University and Dr. Rose Odhiambo of Egerton University in Kenya collaborated to found the Women’s Institute for Secondary Education and Research (WISER) in Muhuru Bay, Kenya, an area with some of the highest HIV infection rates in the country. The school is an effort to empower women and help them avoid the cycle of early marriage, early childbirth, HIV, and poverty.

Women, their health and their education, are the heart of all of these issues, says Stephen Lewis, former Canadian ambassador to the United Nations and the UN Secretary-General’s Special Envoy for HIV/AIDS in Africa from 2001 to 2006. He spoke at Duke last week as a guest of Duke’s Global Health Institute as a part of WISER week.

“I believe with every fiber of my being that the single most important battle we face on this planet is the struggle for gender equality,” Lewis said.

In Africa, 61% of people infected with the HIV virus are women. Among 15- to 24-year-olds, almost 80% of those infected are women and girls.


Lewis believes that gender inequality is what puts women at risk for HIV. Because African women lack sexual autonomy, they are not in a position to demand safe sex or use of a condom. As a result, they are very vulnerable to the virus, and also to various kinds of abuse. Hundreds of thousands of women are subject to sexual violence. “The turbulence in the society unleashes male behavior of the worst kind ... There is a tremendous sense of entitlement,” Lewis said. And where there is rape and violence, inevitably, there is HIV.

Even more devastating for many HIV positive women is the inaccessibility of drugs to prevent transmission of the disease to their children. Although certain drugs can reduce the chance of transmission by 50-70%, fewer than a third of pregnant women have access to them. “It’s soul-destroying for these women,” Lewis said.

Of the half-million HIV positive babies born in Africa each year, 50% die before age 2, and 80% die before age 5. “It doesn’t happen in the U.S. or Canada or Europe because we provide a full course of retrovirals [to pregnant women],” Lewis said.

Lewis expressed frustration with the lack of international attention to the issues of AIDS and women’s health in Africa. He cited the United States’ government’s ability to spend $3 billion a week for the war in Iraq, yet barely even $10 billion a year for the war against AIDS.

“I don’t understand the way the world works ... I live my life ricocheting between rage on the one hand and despair on the other.”

However, Lewis is hopeful for the future. He repeatedly praised the efforts of WISER and international NGOs and the progress they’ve been able to achieve around the world. His own NGO, Aids-Free World, promotes urgent and effective international responses to the AIDS crisis by focusing on the achievement of gender equality.

Fighting HIV/AIDS in Tanzania

The challenge in great; the need greater.

Working in a hospital clinic in the town of Moshi, situated right at the base of Mt. Kilimanjaro in northeastern Tanzania, researchers from Duke Medical Center are combining science and service to help fight the HIV/AIDS plague that threatens -- and too often cuts short -- the lives of so many people in Africa.

In a Feb. 14 lecture, part of a series of university seminars on global health, John Bartlett (photo) provided a you-are-there look at what his team faced when first arriving in Tanzania -- where roughly half of all hospitals lack even running water -- and how far research efforts have come. Working at Kilimanjaro Christian Medical Center (photo below), the team has built up laboratory capabilities and trained local lab personnel and health care workers to achieve world-class standards.

But of most importance, the researchers are using the power of clinical trials to bring voluntary counseling, testing and advanced treatment to people in Moshi and other areas of the country.

Dr. Bartlett, a Duke professor of medicine and co-director of the AIDS research program in Tanzania, says that in many cases they have been able to provide patients with their first-ever access to the kind of care that people in Western nations take for granted. He also stresses that they work hard to cooperate and coordinate with local health professionals and community members, and that they view their work as a long-term commitment.

"We'd like to go out of business sometime, by training enough local people to meet the area's and the country's needs," Dr. Bartlett said. "But that likely will take awhile, considering where the country started from, and we plan to be here for the long haul."

To this end, he said part of the reason for his lecture was to make an "unabashed pitch" to recruit students and faculty to come to Moshi to study and work. "We offer lots of opportunities to work with good equipment, and with good scientists from a number of nations, to address some vitally important questions," he said.

As an example of their work, Dr. Bartlett described recent promising efforts to develop an accurate, easy-to-use and inexpensive testing method that uses dried blood drops to determine whether a newborn infant is infected with HIV -- an important challenge in locations where many women carry the virus. The idea is for a health worker anywhere to obtain a few drops of dried blood from a newborn and then send the sample, with no need for costly treatment or packaging, to Moshi or some other large medical center to be interpreted.

Dr. Bartlett's lecture will soon be available for viewing on the Duke Global Health Institute's website. He also participated in a shorter discussion of research in Tanzania that can be heard here, and the AIDS center's work in Moshi has been reported in Duke Magazine.