Given David Lawrence’s educational background—a bachelor’s degree in biology and a PhD in chemistry—it only seems natural that his research would encompass both disciplines.

Getting others to see it that way, however, wasn’t always easy.

“One of the people on my thesis committee thought I was nuts,” Lawrence says. “I had mentioned to him that I wanted to take the biology background that I had as an undergraduate, couple it with my synthesis background as a graduate student and do something that would interface between chemistry and biology. His response was, ‘Well, time will tell whether it’s a good idea or not.’ But you could tell that he was just really not convinced.”

Two-and-a-half decades later, time has told: Lawrence is a leading expert in the field of chemical biology, and he has found like-minded colleagues, first at the Albert Einstein College of Medicine at Yeshiva University, and more recently in Chapel Hill. In the summer of 2007, he joined the Division of Chemical Biology and Medicinal Chemistry at the UNC School of Pharmacy, the Department of Chemistry in the School of Arts and Sciences, the Department of Pharmacology in the School of Medicine, and the Lineberger Cancer Center. Just as Lawrence’s work spans several areas of research, UNC’s effort to recruit him was a joint venture involving all of these programs.

Lawrence says the opportunity to work with researchers from each of these areas was an important factor in his decision to come to Chapel Hill.

“The medicinal chemistry program is really uniquely positioned to interface between the chemistry department and the medical school on campus,” he says. “It serves as an intellectual bridge between the more chemical world and the more biological world.

“There are universities out there that have great chemistry departments and there are those that have great medical schools. There are even a handful that have both. But there are very few, like UNC, that also have an existing school of pharmacy, and in particular an existing medicinal chemistry program, which can serve as that bridge. In that sense, Carolina is quite unique. That’s one thing I found really appealing.”

What Happens in the Cell Stays in the Cell

Lawrence’s research focuses on the biochemical processes of the cell. Traditionally, scientists study these processes by cracking open the cell, purifying its enzymes, and observing their reactions in an artificial environment in a cuvette. Lawrence’s approach, however, aims to study the enzymes without removing them from the cell. To do that, one must overcome a series of hurdles.

“Biochemical sensors are an exciting way to look inside a cell and visualize the chemistry as it’s taking place,” Lawrence says. “However, one needs to design these sensors, synthesize them, and figure out how to deliver them into cells. The sensor has to be selective for a particular chemical transformation. The sensor then needs to report back to the investigator what’s actually going on inside this little bag that contains thousands of different proteins, nucleic acids, and carbohydrates. Sometimes, you don’t want the sensor working until the cell reaches a particular stage. The latter can be a real problem, because once a probe is placed inside a cell, you lose control over that probe.”

Lawrence has devised a way for researchers to retain some of that control, even after the probe has entered the cell. His group has developed light-activated sensors, inhibitors, and enzymes. These molecules are inert when they enter the cell, and scientists can switch them on by exposing them to varying wavelengths of light.

“The beauty of the light is that we have control over not only when we switch the sensor or enzyme on, but where we switch it on inside the cell as well,” Lawrence says. “So if we want to activate an enzyme near the cell membrane, we can do that and see how the cell responds. This allows us to correlate the activities of a particular protein with the subsequent cellular response.”

The idea of light-activated molecules isn’t new—it was developed in the 1970s. However, the approach had been applied generally to only in vitro systems. More recently, Lawrence and other researchers have recognized the usefulness of the method for cell-based studies.

While part of Lawrence’s research focuses on understanding the chemistry of the cell, other aspects of his work have potential therapeutic applications. For instance, his group has developed molecules that can activate the insulin and leptin signaling pathways, which could be useful for treating diabetes and obesity. In addition, his group has developed other agents that may prove useful for treating various forms or cancer as well as certain rare genetic disorders.

Lawrence has also used light-activated molecules to control gene expression to study cancer development in cells. Commonly, in order to study carcinogenesis in animals, researchers have to inject cancerous cells into healthy subjects or create a transgenic animal that is designed to develop cancer as it grows up.

Lawrence says neither of those approaches simulates the environment in which cancer typically develops in humans. He is working on technology that would feed a molecule to healthy animals. The molecule remains inert until researchers trigger it with light, at which point it switches on the gene of interest in cells in the affected area, allowing researchers to observe the consequences. The procedure has been successful in experiments with cell cultures, and Lawrence is collaborating with two former colleagues at the Albert Einstein College of Medicine on the next step.

Breaking down Barriers

Given the multi-disciplinary nature of his research, it is little wonder that Lawrence places a strong emphasis on working with experts in various areas of science. He abhors the barriers that impede collaboration across departments at many universities.

“Unfortunately, the way most universities are set up—with divisions and departments that were created more than 100 years ago—impede both scientific progress as well as the mission of education itself,” he says. “There generally isn’t such a thing as pure chemistry, pure medicinal chemistry, or pure biology anymore.

“Barriers between departments can prevent or preclude the sort of interactions that allow science to move forward. In addition, graduate students and postdocs in departments suffer from lack of exposure to other disciplines. Undergraduates suffer in coursework if the impact that one area of science has on another is not discussed. So it’s unfortunate that these divisions and barriers exist, but they’ve existed for a long time. Now we have to work really hard to break them down.”

Lawrence practices what he preaches. To make sure that he gets the perspectives of both biologists and chemists, he has split his lab into two, half in the Lineberger Comprehensive Cancer Center and the other half in the Department of Chemistry.

“This will force me to go back-and-forth on a day-to-day basis between these two parts of campus and interact with both chemists and biologists,” he says.

Lawrence is also trying something different to facilitate strong communication between his two labs. Each lab will be equipped with video-conferencing equipment, including giant plasma screens. This setup will allow for continuous, real-time communication rather than limit conversations between the labs to scheduled meetings.

"I wish I thought of this way of connecting my labs, but to be honest, Bob Blouin, the dean of the School of Pharmacy, immediately recognized the potential problems a split lab could encounter and suggested an innovative technological solution," Lawrence says.

“I think that’s something unique that will keep the chemists, medicinal chemists, biochemists, and biologists in my labs talking with one another and perhaps it will serve as a starting point for other labs that have collaborations with the other side of campus. I wanted something where group members can talk on an informal basis.”

“They Just Didn’t Know What to Make of Me”

Lawrence works at the interface between chemistry and biology, but he didn’t take the most direct route to get there. He started out as a math major at the University of California-Irvine, but switched to biology when he felt that the math courses beyond calculus were too abstract for his taste.

A course in organic chemistry whetted his appetite for chemical biology.

“Organic chemistry was so easy and so exciting,” he says. “Organic chemists are architects and engineers who design and manipulate nature at the molecular level. You can do whatever you want to make new forms of matter. What gets more exciting than that?”

He credits his undergraduate adviser, Hal Moore, with driving home the importance of the correlation between biology and chemistry.

“Hal once said to me, ‘If my colleagues over in the Department of Biology knew a little bit more chemistry, they could really do great things.’” Lawrence says. “That comment really struck me. It just made a tremendous impression upon me.”

Lawrence’s interest in biology made him a bit of an oddity in the chemistry department at the State University of New York at Buffalo, his first stop after his postdoctoral fellowship.

“It was a very traditional chemistry department at the time,” he says. “My work was very biological relative to everyone else’s in the department. I made things called peptides.

“They just didn’t know what to make of me. My primary saving grace was that I got my PhD in the area of organic synthesis. I knew all the standard ‘organic name reactions’, so I was considered an OK guy. But I also did some really bizarre things in terms of research and published in some bizarre places that chemists ordinarily didn’t publish in, such as the Journal of Biological Chemistry. I look back upon this now and it’s amusing. Times have really changed.”

Lawrence says the department was nonetheless very supportive, and he rose to full professor before moving on to the Albert Einstein College of Medicine at Yeshiva University. There, he enjoyed a collaborative atmosphere and an opportunity to work more closely with colleagues from the biology side.

Not surprisingly, when UNC came calling, it took a campus-wide effort to convince Lawrence that he would have a similarly collaborative environment in Chapel Hill. Aside from his endowed professorship in the UNC Eshelman School of Pharmacy, Lawrence has a salaried joint appointment in the Department of Chemistry and nonsalaried joint appointments in the Department of Pharmacology and at Lineberger.

Even Mother Nature lent a hand in bringing Lawrence to UNC. On his second campus visit, in early January 2007, he was treated to a rare sight in Chapel Hill—a light flurry that turned out to be the only snow in the area that winter.

“I had already mentioned to my two younger children, who are twelve and fourteen, that there was a possibility that we might move to Chapel Hill,” he says. “Not surprisingly, they said, ‘No way, we don’t want to move.’ I asked for reasons why, and in addition to leaving their friends behind, they both agreed that the absence of snow days would be a real negative.

“When I got here in January, it must’ve been sixty-five degrees out and it was absolutely beautiful. My idea of a winter day! However, when I got up the next morning, I looked outside and there was snow on the ground. All the schools in the area were canceled. Of course, it was only half an inch, but that was all it took. I was able to report back that there would, in fact, be snow days.”