Volume 32 · Number 1 · Fall 2014
Disarming a Trojan horse
James Hildreth trains a new generation of scientists to rein in HIV.
James Hildreth, center, says: "The most fun part of my job is interacting with the undergraduates. I get great joy knowing we’re playing a part in the lives of these individuals.”
(Photo by Karin Higgins/UC Davis)
If there’s a downside of being dean of the College of Biological Sciences, James Hildreth says, it’s this: “I don’t have much time to spend with my ‘kids.’”
As he says that, he’s surrounded by some of those “kids,” or his trainees — undergraduate and graduate students and postdoctoral fellows who work in his lab researching the AIDS virus.
Looking over one student’s lab manual, he shares a tidbit from his own scientific education: As a student he synthesized a biochemical detergent that the lab could not afford to buy from chemical companies.
“I’m a chemist at heart — that was my undergraduate major,” he tells them, then smiles. “I’m just trying to impress you. Things have changed a lot — you guys don’t have to make any detergent.”
They do, however, get to work with a leading HIV authority who is hailed by colleagues as a “scientific hero,” sought after by conference organizers as a speaker, and revered by students from here to Maryland for his mentorship.
Among the many upsides of being dean, Hildreth says, is the opportunity to influence the education of a far bigger brood — thousands of students. “It’s a humbling thing to be responsible for guiding this huge enterprise. But when I think about the wonderful students, faculty and staff here, I get inspired.”
In person, Hildreth comes across as a shy man. He seems uncomfortable trumpeting his many achievements: his undergraduate years at Harvard University, followed by a Rhodes scholarship to Corpus Christ College, at Oxford University, where he earned a doctorate in immunology; his work at Johns Hopkins School of Medicine, as a student and then as a professor of molecular and cellular biology; and his groundbreaking discoveries in AIDS research.
“My life, as important as I like to think it is, pales in comparison to the importance of what I work on,” he once told a TEDx audience in Nashville, Tennessee, where he worked as a professor at Meharry Medical College before joining UC Davis in 2011.
That work involves understanding the biological mechanisms of AIDS, which has killed nearly 30 million people and made orphans of more than 17 million children around the world.
AIDS disproportionately affects Africans and people of African descent. Of the 35 million people afflicted with the virus, more than two-thirds live in sub-Saharan Africa. In the United States, African Americans make up 13 percent of the population but nearly half of all AIDS patients.
Addressing that disparity brings Hildreth back full circle to a promise he made to himself as a young boy.
James Earl Hildreth grew up in the small segregated town of Camden, Arkansas, about 100 miles south of Little Rock, the youngest of seven children of R.J. and Lucy Hildreth.
When he was 11, his father, who was a laborer at the paper mill, was diagnosed with renal cancer but, as a poor, black man in rural Arkansas, received little treatment. “All that we could do was watch him wither away and die,” Hildreth told a group of Howard University students visiting a National Institutes of Health center in 2000.
Deeply angry, the young Hildreth promised himself that he would become a doctor and return, one day, to help his community get equal access to medical care.
Months later, the assassination of his hero, the Rev. Martin Luther King Jr., in Memphis, Tennessee, fueled his rage. Hildreth credits his mother with helping him channel that anger for good. As he was growing up, Lucy Hildreth, a hospital cook, told him, “Your circumstances do not limit your possibilities.”
And so James Hildreth threw himself into his studies. He graduated top of his high school class and was admitted to Harvard, where he majored in chemistry and got research experience in an immunology professor’s lab.
While pursuing his doctorate at Oxford a few years later, he married Phyllis King. He added her surname to his name: James Earl King Hildreth, and in the years following they had two children.
All the while, his focus on biomedical research intensified. As a Johns Hopkins medical student, he insisted on sitting in the same front row seat for class lectures — “I wanted to take it all in.”
Hildreth began researching AIDS during his medical studies and, by the time he graduated in 1987, decided on a career in science instead of realizing his earlier ambition of becoming a transplant surgeon. He joined the faculty at Johns Hopkins and served as an associate dean. In 2005, he moved to Meharry, where he directed the Center for AIDS Health Disparities Research.
Among his many honors, Hildreth has been named a member of the Institute of Medicine (one of the National Academies of Science) and the Johns Hopkins Society of Scholars. This year, he was elected to the Harvard Board of Overseers, one of the university’s two governing boards. In accepting the position, Hildreth said he wanted to help “sustain the availability of a Harvard education for students from disadvantaged backgrounds — as was the case for me back in 1975. I am sure that the experience will help me be a much better leader for my students, faculty and staff.”
A deeply introspective man who loves art and works Shakespeare quotations into his scientific talks, Hildreth is more comfortable immersed in his own thoughts than in making small talk.
On a flight to Zambia several years back, Meharry Medical College colleague Valerie Montgomery Rice had to coax conversation out of him. The two scientists were on their way to set up a study on a vaginal microbicide, or “chemical condom,” that Hildreth believed could inhibit HIV transmission in a country where more than one of every seven adults lives with the virus.
On the plane, Hildreth preferred to listen to his iPod, on which he keeps a huge, eclectic collection of music. Hildreth is a bass guitar player, and some of his friends believe he nurtures a secret fantasy to take his musical skills up to a professional level.
On Rice and Hildreth’s second trip to Zambia, however, Hildreth opened up more. The colleagues played Scrabble together for much of the journey. And they talked about Hildreth’s work in immunology.
The scientist had, in his years at Johns Hopkins and Meharry, established a reputation as one of the country’s leading HIV/AIDS researchers. He believed that the virus was a Trojan horse, a “thief” that, while possessing relatively few genes of its own — normally an indicator of a lack of biological complexity — acquired potency by stealing protein from other cells.
It was, he thought with a mixture of respect and horror, “an awesome example of what can happen when a pathogen has the ability to hijack or steal macromolecules from host cells. This virus appears to have evolved to avoid or neutralize all the mechanisms that deal with it. Or it has a way to escape them. It’s really incredible. It’s just an amazing pathogen.”
Let HIV run rampant and it would, inevitably, find a way to wear down the human immune system, which is capable of dealing with an almost unfathomable number of threats — at least a quintillion, or a billion billions, was Hildreth’s estimate.
Yet, in his years of studying the virus, Hildreth had also come to recognize its Achilles' heel: HIV needs cholesterol in order to fuse with the cytoplasm of a host cell. If you could devise a way to starve it of cholesterol, you could negate much of its fearsomeness.
After years of work, Hildreth and his team found what they were looking for in statins, the medicines prescribed to millions of people to lower their cholesterol. Adding statins to the drug cocktails used to treat HIV could reduce the chance of HIV infection developing into AIDS. Statins also allowed doctors to prescribe lower doses of the powerful and sometimes toxic antiviral drugs that form the backbone of current HIV treatments. And, rounding the achievement out, they reduced the transmission rates for the disease. Moreover, because certain microbicides can block cholesterol from reaching the virus, Hildreth’s team concluded that it would be possible to develop microbicides that could inactivate HIV during sex, in much the same way that spermicidal creams are used to prevent pregnancies. It was this insight that had led Hildreth to travel to Zambia to set up studies. That began what is still an ongoing process — to develop fully effective microbicides as a core part of the anti-HIV arsenal.
Over a number of years, they identified a set of microbicides that could be used this way. (One, beta-cyclodextrin, had long been used as an ingredient in toothpaste.) This was a key development, for while HIV has rapidly evolved to counter the cocktail of drugs used to fight it, Hildreth cannot see a way that it could dodge microbicides that interfere with the absorption of cholesterol. “We have confirmed that HIV that is resistant to all other classes of compounds is still sensitive to this one, and that’s a really important point,” he says. This finding suggests that beta-cyclodextrin may be useful against multi-drug resistant strains of HIV.
Yet Hildreth doesn’t believe that simply developing better medical interventions can end the AIDS epidemic. At the same time as he works to improve treatments for those with HIV, he also works to improve prevention. While at Meharry he obtained a $2 million grant from the federal Centers for Disease Control to bring anti-HIV strategies into at-risk communities with the help of African American ministers throughout the South. “My goal is to form partnerships with the churches and their leaders to embrace HIV prevention. What the black church leaders represent is that they are trusted messengers.”
Postdoctoral researcher Ebony Coleman says that Hildreth “encourages you to think on your own.”
(Karin Higgins/UC Davis)
In August 2011, Hildreth arrived at UC Davis as dean of the College of Biological Sciences, excited to join “one of the strongest units in the country and, I would say, the world.”
The college has 5,500 undergraduates and 450 graduate students, and Hildreth takes pride in getting to know as many of them as possible. “The most fun part of my job is interacting with the undergraduates. I get great joy knowing we’re playing a part in the lives of these individuals.”
Rice, now president and dean of Morehouse School of Medicine, believes that her friend “thrives on developing young scientists. That’s where his passion is.”
In a profile she co-authored last year in the Journal of Health Care for the Poor and Underserved, Rice described Hildreth as a “scientific hero.”
Cathy Will, who works in the Office of Graduate Student Affairs at the Johns Hopkins School of Medicine, recalls Hildreth’s contributions there: “At the time only 4 percent of the student population was from underrepresented minority groups. Hildreth told the dean about recruitment problems.” He persuaded the dean to start a summer internship program for students of color.
Wanting to cultivate students’ participation in the creative work of research, he also helped set up a mentorship program, allowing students to choose their labs and then linking them up with appropriate mentors. “It took a decade,” Will says, “but it changed the culture of Hopkins.”
Hildreth’s students deeply admire the man and his methods. “I don’t think you can survive in his lab without independent thinking,” says Ebony Coleman, a postdoctoral scholar whom he recruited, along with two others, from Meharry when he moved to UC Davis. “He encourages you to think on your own. I had to get comfortable with that; it gives me a profound appreciation and confidence in my own abilities. Science is like art — you need to have your creative space.”
At Davis, Hildreth sees a unique opportunity to set his team of professors and students to work on some of the biggest challenges facing molecular biologists and immunologists today.
“The discovery of new knowledge is the thing that holds us all together,” says Hildreth, “and Davis has a wonderful culture of collaboration. That’s how the big problems are going to be solved.”