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SPRING 2004
Sweet Dreams
by Kathleen Cason

What started as a small idea between two friends has grown into one of the most successful research collaborations in the entire country.

On a fall day in 1983, Peter Albersheim and Alan Darvill met for afternoon tea at London’s exquisite Goring Hotel. The scientists welcomed the quiet break from hectic days on a consulting job.

They knew they were on to something — maybe something big.

Their research group had identified naturally occurring molecules that switched on an immune-like response in plants. Could this lead to new, environmentally friendly pesticides? That seemed to be an obvious possibility. But the discovery had much broader significance.

The molecular “on button” was a piece of complex carbohydrate. Unlike the carbohydrates in their scones, complex carbohydrates are large molecules made of sugars joined together as strings and complicated branches. It turned out that enzymes released in the heat of battle between plant and microbe snipped off a molecule from the cell walls that acted like a plant hormone, chemically alerting the plant to protect itself.

Signaling plant defenses was certainly an unexpected role for a carbohydrate and ran counter to scientific knowledge of the day. Until fairly recently, most scientists believed that carbohydrates only had two functions: to store energy (as starch in plants; as glycogen in animals) or provide structure (in the form of cellulose, connective tissue or fluid in eyeballs).

The idea that chemical messages were encrypted in complex carbohydrates seemed nearly unthinkable then. Some scientists even thought that Albersheim and Darvill’s results were anomalies. Little was known about other roles for carbohydrates in biology because few scientists dared tackle the subject, research methods were relatively primitive and the chemistry was difficult.

But Albersheim and Darvill trusted their findings. They predicted that similar carbohydrate molecules might regulate other biological processes in plants. Heparin, which prevents blood clotting, was one of the few known examples of a complex carbohydrate that controls a biological event. So perhaps, they reasoned, complex carbohydrates also carried messages for animal cells.

In 1983, Albersheim and Darvill could not have foreseen that studying complex carbohydrates would become one of biology’s hottest emerging research topics two decades later.

“I don’t know if Albersheim’s group was ahead of its time,” said Martha Krebs, former director of the U.S. Department of Energy’s Office of Science. “But I do know that they were on the leading edge of the discovery curve.”

Today, glycobiologists (“glyco-” means sugar) are deciphering the astonishing roles of carbohydrates in plants, microbes, and humans and other animals. Cell-surface carbohydrates inhibit or promote invading microbes, dictate the success of organ transplants and blood transfusions, and determine whether a bacterium infects pigs but not humans. The roles of carbohydrates in human health — from bacterial and viral infections to cancer, diabetes and autoimmune diseases — promise to lead to new vaccines, diagnostics and medicines.

Albersheim and Darvill knew that unlocking secrets of these molecules was going to take equipment and expertise that the pair did not have. So as the tea grew cold, the two talked about creating a research center devoted to understanding complex carbohydrates in biology.

They would need a team of scientists from diverse disciplines, free from the artificial boundaries that might pigeonhole researchers as chemists or botanists or cell biologists. The pair imagined that melding ideas and approaches would lead to discoveries no single scientist could have envisaged or would have been able to accomplish alone. Plus, a critical mass of carbohydrate researchers assembled in one place would give them a competitive advantage for funding, especially to purchase and operate expensive equipment out of reach for an individual scientist.

Albersheim and Darvill had considered creating such a center at the University of Colorado where administrators’ enthusiasm was apparent but the financial backing wasn’t forthcoming.

So in the Goring Hotel’s elegantly appointed sitting room, the twosome decided the time had come to devise a new plan. They knew they were on to something — maybe something big.

Charting the course

For Albersheim, 1983 was a watershed year. He had been on the Colorado faculty for nearly two decades. At 49 years old, he was a well-established plant biochemist; in fact, that year he was named a Fellow of the American Academy for the Advancement of Sciences. His laboratory had an international reputation for its studies on plant cell wall structure and on the fate of cell walls under attack by disease-causing microbes.

Albersheim spent most of his boyhood in Interlaken, N.J., near Asbury Park and the Jersey shore. In those days, the town of 900 was situated in the nation’s third-largest agricultural-producing county, supplying New York City with fresh vegetables and dairy products. His mother had a law degree, although she didn’t practice law after marrying. His father, a German immigrant with a doctorate in electrical engineering, contributed to development of radar and sonar at Bell Labs during World War II. While his parents may have molded his intellect and stimulated a passion for science, it was the rural setting that kindled his interest in agriculture.

“I wanted to become a farmer,” Albersheim said, “but after my first year working on a farm, I realized I’d always be working for somebody else.”

So he decided on a career in agricultural research, studying chemistry and plant pathology at Cornell University.

While cultivating corn fields for local farmers, Albersheim had noticed that healthy and sick plants grew side by side. He wondered why the healthy ones didn’t get sick and why the sick ones succumbed. He hoped to discover some answers in graduate school at the California Institute of Technology.

“I decided to work on the plant cell wall because there was nothing known about it. It turned out to be 90 percent carbohydrate, which I didn’t know when I started,” Albersheim said. “So it was a challenge. I guess I liked a challenge.”

“Today, national meetings on plant cell walls attract 500 presentations; 1,000 if they pick a good location,” Albersheim said.

He was a graduate student at Cal Tech and assistant professor at Harvard in the late ’50s to early ’60s. Those were tremendously exciting times in science.

Several Nobel laureates in-the-making were in his Cal Tech class and the late George Beadle, who shared the 1958 Nobel Prize in Physiology or Medicine, headed the department. Beadle earned the prize for the hypothesis that one gene encodes for a single specific enzyme. Albersheim had been Beadle’s teaching assistant the year before and helped roast a pig for the celebratory Nobel Prize luau.

Albersheim was at Harvard when James Watson received the 1962 Nobel Prize for his landmark paper with Francis Crick that described DNA’s molecular structure and attended that Nobel celebration as well.

Unraveling DNA’s structure and all the discoveries that followed in its wake not only had a profound influence on the young scientist but also delivered two subtle messages. First, uncovering a molecule’s structure often points to answers about how it worked. Second, solving the puzzle of DNA’s structure required ideas and approaches from several disciplines: In the case of DNA, physics and chemistry were essential to understanding biology.

Those themes — deciphering molecular structure and involving scientists from diverse backgrounds — became ideas central to the carbohydrate research center Albersheim and Darvill would establish at the University of Georgia.

The team’s beginnings

By that tea time at the Goring Hotel, the pair had been working together for some seven years.

Eighteen years Albersheim’s junior, Darvill had earned a doctorate at University College of Wales, Aberystwyth — one of Britain’s leading research universities in plant science. There he studied how carbohydrates and plant cell walls were involved in controlling plant growth, an abiding interest his lab continues to investigate.

“Peter’s group in Boulder, Colo., at that time, was publishing heavily in that field, so it was an obvious place to try and go to after I finished my Ph.D.,” Darvill said. Plus he and his wife, Janet, figured they needed to see the world for a year. They arrived in Colorado with two suitcases and two carry-ons, not suspecting that they would never return to live in England.

That first year stateside had its ups and downs.

For several months, Darvill worked on a cell wall project, making little progress. Just months away from the end of Darvill’s funding, Albersheim called him into a meeting: The research would have to be abandoned if something didn’t happen soon. In the nick of time, Darvill had a major breakthrough. He and coworkers discovered two previously unknown cell wall carbohydrates. Twenty-seven years later, Darvill and Albersheim’s lab continues to study these specific molecules called RGI and RGII; just two years ago they uncovered the function of RGII (See Research Magazine Summer 2002).

Albersheim recognized Darvill’s talent as a scientist.

“We’ve been together since 1976. Smartest move I ever made in my life was to get this guy to stay and become part of the team,” Albersheim said.

They shared a strong drive for success, compatible scientific interests and similar goals, although each had different personal styles.

“Al is a good leader and people like him,” Albersheim said. “I liked him and could trust him. He could take criticism and build on it.”

They also became friends. Their families enjoyed backpacking trips and skiing together in the Rockies. They traveled to Australia and Bora Bora together.

“We quickly formed a good, interactive group between us and it just progressed from there,” Darvill said.

The pitch

Fresh from their consulting trip to England, Albersheim and Darvill had a new mission: Establish a carbohydrate research center based on the principle of interdisciplinary collaboration and find a supportive institution. That meant they had to get the word out that they were willing to leave Colorado. They drew up a list of 12 universities and research institutes and crisscrossed the country, pitching their ideas.

On a cold January day in 1984, Albersheim invited an old friend to brunch at the Hotel Boulderado, a Victorian-era hotel in Boulder, Colo. As it turned out, that friend — Joe Key — headed the University of Georgia’s division of biological sciences and was on a sabbatical with a fledgling biotechnology start-up company based in Boulder.

When Albersheim mentioned the decision to form a carbohydrate research center and leave Colorado, Key asked if his group had considered Georgia. The University of Georgia soon appeared on the list.

That afternoon Key called an assistant to UGA’s president and told him that Albersheim and Darvill’s group was doing just the kind of research in biotechnology that UGA was looking to recruit. UGA had a one-time, $3 million allocation from the Georgia Legislature to advance some area of biotechnology research. After several meetings, UGA administrators decided to invest those funds in forming a Complex Carbohydrate Research Center (CCRC). By March, UGA held a reception for the group and soon afterwards details of the move were hammered out.

Albersheim and Darvill didn’t ask for a budget. If UGA would pay for faculty salaries, the pair would support the rest of their program with outside funding. UGA agreed to fund 10 faculty positions at the new center. If CCRC raised $200,000 per year per faculty member, the university would provide five additional faculty positions. By 2003, external funding exceeded the target by nearly three-fold, averaging $500,000 to $600,000 per faculty member.

“The catalyst for us, the real driving force for why we chose Georgia, was the availability of faculty slots,” Darvill said. “Because that’s how we saw you could create a real center. If you bring in new faculty who create their own research groups and you’ve got this nucleus, you can build on the nucleus.”

Cross-country caravan

In September 1985, 16 members of their Colorado research group loaded up half a dozen huge moving vans, cramming them with the contents of labs and homes. The caravan snaked across the plains and deep South, heading for Athens, Ga.

But it wasn’t all smooth sailing in the beginning. Many UGA scientists had expected a piece of the biotechnology pie from the Georgia legislature and they were clearly upset that the entire sum had been earmarked for outsiders.

Plus the university — with no available laboratory space for the new center — had negotiated for space in a federal laboratory, a decision that sparked tension. It became evident early on that the CCRC needed its own facility.

Despite the early setbacks, researchers got busy and the grants started rolling in from such sources as the U.S. Department of Energy, which had launched a nationwide request for research proposals on complex carbohydrates.

“Only two proposals were worth going after: One from Harvard and one from the University of Georgia,” said Robert Rabson, who directed the DOE’s Division of Energy Biosciences at that time. “The Harvard proposal was strictly medical and we wanted to support a more broad approach so we decided to fund the CCRC.”

By 1987, the CCRC had earned designation as a national resource center for studying complex carbohydrates in plants and microbes. That brought with it steady DOE funding.

In 1989, the CCRC finally moved into its own home: a 45,000-square-foot facility. The center had grown from 16 people to 80. And that year they also captured funding from the National Institutes of Health to establish a second national resource center — this time for biomedical research.

From that moment on, the center continued to support research on plant carbohydrates but also began to emphasize biomedical research. Two additions to the building reflected growth in the biomedical area — one enlargement added a larger nuclear magnetic resonance (NMR) facility and a second one in 1998 doubled the facility’s size because the CCRC again had outgrown its home.

The gathering

Over the past 18 years, the CCRC has assembled an international cast of faculty, visiting scientists, researchers and students. They have arrived from top universities worldwide: Johns Hopkins, Emory, Oxford, Cambridge, MIT, Berkeley, Cal Tech, Harvard, Yale, Cornell and the Weizmann Institute. And they have haled from nearly every continent.

For example, one recruit, Geert-Jan Boons, was a professor at the University of Birmingham in England when Albersheim invited him to give a talk at the CCRC. Albersheim casually mentioned that a CCRC faculty position was open.

“Well, Peter is a big name in his field so I thought, ‘Let’s be polite. He’s paying my expenses.’ I never contemplated actually moving to the United States,” Boons said. “But I was impressed by the facility and I also was impressed by the way they did things. Most places try to hire someone and then see whether they have space. Peter does it the other way around. They built the space, confident that they would go out and find someone good.”

Another recruit was long-time CCRC advisory committee member James Prestegard from Yale University. Prestegard, now one of 12 Eminent Scholars at UGA, helped pioneer the use of NMR to study how cell surface carbohydrates interact with biologically important proteins. Prestegard called his move “a really good opportunity” especially given recent changes in science that favor “collaborative groups [in order] to make progress on big problems.”

By 2003, 15 faculty members had joined the CCRC. Each leads a group of senior scientists, technicians, post-doctoral associates, and graduate and undergraduate students. The CCRC includes experts in computer science, plant science, physics, microbiology, biochemistry, electron microscopy, molecular biology and chemistry, among other fields.

“Today it’s nearly impossible to do important research easily unless you have a team. It’s just too much to do, too much to know, too many techniques to master,” Albersheim said.

Collaborations

The University of Georgia should be very proud of the CCRC. There are not many times UGA can say, ‘We’re the best in the world’ at something. This is one of them,” said Gerald Hart, department director and biological chemistry professor at Johns Hopkins University School of Medicine.

Today, UGA is one of only three places in the world with the equipment and expertise under one roof poised to make major advances in understanding complex carbohydrates. These molecules are important in plant growth, cancer, arthritis, vaccine development and a myriad of other areas important to health as well as basic science.

“The CCRC’s strengths are in analytical methods, molecular modeling and NMR structural approaches. The CCRC is at the forefront worldwide,” said Hart, who chairs the center’s advisory committee on biomedical research.

In October 2003, CCRC personnel assembled under their new roof. Nearly 200 researchers and support staff moved into a new, approximately 140,000-square-foot building. The equipment inside is worth nearly as much as the $39 million building.

The new building — whose exterior could pass for a Colorado ski resort — is designed to pull people together and encourage informal interaction. Sound familiar? That’s where the good ideas come from, Darvill said.

Nine interactive areas are outfitted with comfy chairs and sofas, coffee machines and marker boards. Glass-walled staircases are intended to foster interactions among levels of the three-story building. From the outside the facility looks huge but interior spaces are ingeniously intimate.

So far, the CCRC has dominated two areas of research: unraveling the structure of plant cell walls and developing methods to study complex carbohydrate structures. Both areas are contributing to the advances being made on the biomedical front.

The Albersheim-Darvill mantra of collaboration is reflected not only in the new building’s architecture but also in the research that takes place inside.

At any one time, more than 100 collaborations are under way: among CCRC research groups, with other UGA faculty and with scientists at private, university and government labs worldwide.

Many of these collaborations promise to benefit us all. For example, CCRC discoveries with UGA textile scientists may lead to major changes in the textile industry — altering the way dyes or antibiotics or permanent press compounds are attached to cellulose fibers and resulting in less pollution. Joint research with scientists at the UGA vet school may lead to better vaccines for humans and animals that are based on microbial carbohydrates. In a combined effort with Houston’s M.D. Anderson Cancer Institute, CCRC researchers discovered and patented a component of aloe and other plants that protects skin from UV light damage, even after sun exposure. The compound has huge potential as a sunscreen additive.

“Collaborative research — sharing equipment, students, ideas and grants. It’s the hallmark of this place,” Darvill said. “It’s one reason why we’re so successful. It’s not just one person, it’s everyone.”

Darvill runs the CCRC’s day-to-day operations these days. He not only directs his own research program but also provides a sounding board for others.

Albersheim plans to finish a book and establish a $100 million endowment for the center. He may even get back in the lab to pursue his notion that complex carbohydrates may have a role in memory.

For Albersheim and Darvill this new beginning surpasses their early ideas and imaginings. “You can’t dream this,” Albersheim said. “It’s too much.”

For more information, check out the CCRC Web site at www.ccrc.uga.edu or contact Alan Darvill at adarvill@ccrc.uga.edu and Peter Albersheim at palbersh@ccrc.uga.edu.

Kathleen Cason is associate director of Research Communications at the University of Georgia.