Stepping Up

By Mika Ono

For some people, receiving their doctoral degree marks the beginning of a career. For Scripps Research Staff Scientist Ann Hessell, her doctorate falls squarely in the middle—more of an acknowledgement than the launch of a full life in science.

Hessell, who has been working in the Scripps Research laboratory of Professor Dennis Burton since 1996, graduated this spring with a Ph.D. from the Netherlands' Utrecht University.

"I've been very lucky," she said. "I work in one of the best and most exciting labs in the world. On a day-to-day basis, I really enjoy being in the lab and doing experiments."

Hessell continued to work in the Burton lab—which specializes in the field of human immunodeficiency (HIV) research—while completing work for the degree. For her dissertation, she was told her thesis committee would accept two new first author papers. Hessell published three.

The thesis committee, led by Utrecht University Professor Jan van de Winkel, called the dissertation "one of the finest theses they had received."

Full Circle

Hessell's path to earning a doctorate was a non-traditional one.

As a child in Mississippi in the 1950s and 1960s, she took an early liking to scientific subjects. By the time she reached high school, she was excelling in biology, chemistry, and physics.

"I think I liked to show up the boys," she said, laughing.

But her plans to become a science teacher were soon derailed by the demands of family life. Married to her high school boyfriend, soon a mom, and later divorced, she found herself in the workforce, helping to support herself and her son.

While Hessell worked in a variety of jobs, including as office manager of a law firm, she never gave up her goal of getting an education. Whenever she could, she would sign up for a class at the local university or college, class by class chipping away at the requirements for an undergraduate degree.

By the time Hessell met her second husband and moved with their two children to California for his job as a bond lawyer in a Del Mar firm, she had accumulated some college credits, but not enough to complete a bachelor's. When the couple's youngest child entered kindergarten, the time had come, the family decided, for Hessell to complete that long-sought degree.

Knowing of the University of California (UC) San Diego's stellar reputation in the sciences, Hessell set her sights on finishing her undergraduate work there.

"The other moms in my children's playgroups would tell me there was no way," she recalled, "because of the level of competition. That just made me more determined to get in."

Lab Work at the Next Level

Hessell proved her friends wrong when she was accepted into UC San Diego in 1993. She even received a modest scholarship as a first-generation college student with an excellent academic record. At UC San Diego, though, she found for the first time that her classmates grasped the concepts in biology as easily as she did.

"I was like a little mustang in a thoroughbred race," she said. "The kids were so bright and so well prepared!"

She also found, however, that she had a niche where she consistently excelled—lab classes.

"When I'm at the bench doing experiments, it's very much like cooking to me," she said. "I can always get the results."

She took every lab class she could, including an internship at Burnham Institute for Medical Research for course credit. In 1996, Hessell graduated with a B.S. in molecular biology.

While considering whether to pursue a master's degree, Hessell became aware of an open position for a research technician working for Assistant Professor Paul Parren, then a member of the Burton lab. Seizing the opportunity to work in the dynamic field of AIDS research at an internationally renowned institution, Hessell applied for and received the job.

From the beginning, Hessell decided she would conduct as much independent research and participate in as many scientific discussions as permitted, despite the fact that these duties were not a required part of the job.

Observing her enthusiasm and diligence, members of the Burton lab recognized a good thing when they saw it. Fifteen months after she began, Hessell was asked to manage the laboratory and assume the role of lead technician.

Hessell found that running a research lab came naturally to her. But even better, she was also able to sink her teeth into some important scientific problems.

A Tricky Virus

The focus of much of the research in the Burton lab has been on laying the groundwork for the creation of an AIDS vaccine.

To do so, members of the team have been investigating antibodies against the virus that a vaccine might elicit in a person's body. Antibodies are produced by the body's immune system, circulate through the blood, and track down and kill a specific virus.

Most of the antibodies that the body produces to fight HIV, however, are ineffective. The surface of the virus is cloaked with sugar molecules that prevent antibodies from slipping in and blocking the proteins the virus uses to latch onto a cell and infect it. To make matters more complicated, HIV is constantly mutating, so an antibody that neutralizes one strain of the virus won't necessarily work against another.

Nonetheless, while rare, broadly neutralizing antibodies against HIV do exist. In 1994, Burton, Scripps Research Professor Carlos Barbas III, and colleagues identified the broadly neutralizing antibody b12. The antibody came from the bone marrow of a 31-year-old male who had been HIV positive without symptoms for six years.

When Hessell arrived in the Burton lab, the group had begun their efforts to determine the structure of b12, which would provide important clues to how it worked to inhibit the virus.

But there was a problem. Determining its structure, and then later testing the antibody's effectiveness in preventing AIDS in animal models, required as a first step the production of large quantities of the antibody. But no technique yet existed that could do that in a small research lab setting.

That's when Hessell stepped up to the plate.

A Love of Problem-Solving

With the guidance of her mentors in the Burton lab, Hessell applied herself to the problem of growing quantities of b12 in culture, meticulously changing variables one by one to see how she could engineer the growth of the antibody in large quantities.

Bucking conventional wisdom that antibody cultures should not contain fetal calf serum, Hessell and colleagues found that if they started growing large amounts of the cells in a culture with the serum, they could gradually wean the cells until they grew in a culture containing only a small amount of it. Using this method, they produced large enough quantities of the antibody, in high enough quality, that the rest of the team could proceed with the structural work.

"Nowadays, companies sell serum-free media and low-bovine serum," she said, "but at that time there weren't those products on the market, so we had to make our own. All this was quite labor-intensive. We had to figure out all the parameters."

In August 1998, Erica Ollmann Saphire (now a Scripps Research associate professor, then a graduate student in the laboratory of Professor Ian Wilson) and colleagues cracked another set of technical challenges to find the structure to the antibody. The work was published a year and a half later.

Hessell found she had enjoyed the process and was eager for more challenges.

"Trouble-shooting experiments—I love that," she said.

In Press

In the years that followed, Hessell worked on a number of research studies, resulting in some half dozen publications with her colleagues in the Burton and Wilson labs. Many of them relate to b12.

"Hopefully, we can work backwards towards a vaccine," said Hessell, "using b12 and the very few other broadly neutralizing antibodies against HIV that have been found."

Hessell was part of the team that published an atomic-level picture of a key portion an HIV surface protein, gp120, as it looks when bound to b12 (Nature, 2007, 445: 732-737). The work showed that the b12 antibody has a long finger-like region on its surface that penetrates the surface of gp120 and prevents the virus from causing disease. The research also detailed the precise stepwise engagement between gp120 and CD4, a glycoprotein on the surface of certain cells that acts as a receptor for HIV.

Hessell was first author of a paper that showed the first evidence that the b12 antibody is most effective when it binds not only to the virus, but also to host immune cells (Nature, 2007, 449: 101-105). The findings suggest that antibody efficiency depends on both directly neutralizing the virus and activating the host immune response. Hessell was invited to present the results at an international AIDS Vaccine conference in Amsterdam.

She was also first author of a paper showing that the broadly neutralizing antibody 2G12—which was isolated from such an HIV-positive individual about a 15 years ago by Hermann Katinger, a doctor at the Institute for Applied Microbiology of the University of Agriculture in Vienna, Austria—is effective in protecting against mucosal SHIV challenge even at low concentrations (PLoS Pathogens, 2009, May 15 (5):e1000433).

Hessell is also pursuing an interest in mucosal immunity. More studies are in press.

Proud Mentors

Since Hessell graduated from Utrecht University in June, the newly minted Ph.D. hasn't changed her day-to-day life in the lab much, although she was recently promoted to the position of staff scientist from research assistant. She does, however, appreciate the fact that the degree opens up the possibility that one day she could teach at the university level.

"One of the most rewarding aspects of my position at Scripps Research has been the opportunity to mentor the brightest and best students from local universities," she says. She is proud to know that many of them have gone on to receive Ph.D. and M.D. degrees.

Hessell, however, is not the only proud mentor. Burton is practically beaming.

"Ann has done fantastically well in the lab," he said, "going in no time from a technician fresh from a UCSD undergraduate degree to a position combining lab manager with running some of our most important HIV protection studies. Seeing Ann get her Ph.D. degree at the ancient university of Utrecht in the Netherlands was quite special. I don't know what I would do without her!"

Send comments to: mikaono[at]scripps.edu

Scripps Research Staff Scientist Ann Hessell receives congratulations on her new Ph.D. degree from mentors Dennis Burton (left), professor at Scripps Research, and Paul Parren, now senior vice president for research and pre-clinical development at Genmab.