The Song Remains the Same

By Eric Sauter

It's been a busy year so far for Chi-Huey Wong. Last fall, the renowned Scripps Research Institute professor of chemistry and carbohydrate research legend was elected president of Academia Sinica, Taiwan's prestigious national academy of the sciences. A few months later, the American Chemical Society announced that Wong was to be awarded the 2008 F.A. Cotton Medal for Excellence in Chemical Research. And just recently, the laboratory he directs at Scripps Research published a series of new and important research papers.

More Trans-Pacific Flights

Since his appointment last October, Wong has been commuting on a semi-regular basis between Taiwan and Scripps Research in La Jolla, California. Not that this peripatetic existence is something new for him; he was the director of the Genomic Research Center at Academia Sinica before he accepted the job as president, and regularly made the same trans-Pacific flight. But the presidency is, admittedly, something else.

As president of Academia Sinica (which means Chinese Academy in Latin), Wong oversees research, funding, and the whole delicate balancing of managing a prestigious, internationally known scientific organization covering three major scientific divisions—mathematics and physical sciences, life sciences, and humanities and social sciences—with a membership of more than 200 academicians and 6 Nobel laureates. Wong reports directly to the President of Taiwan.

While these responsibilities frequently take Wong away from his lab at Scripps Research, his group also reaps the benefits of his perspective honed by constantly looking at big scientific questions. Wong himself notes, "Although I am busy, I am also able to better see major problems in science through my interaction with various people." He points out his new position has led to a collaboration between his Scripps Research lab and Academia Sinica to develop new tools for glycoproteomics.

Wong is also frequently interacting with other top scientists as he travels around the world for a seemingly endless stream of recognition for a lifetime's work in the laboratory. There was the just announced F.A. Cotton Medal from Texas A&M, which recognizes excellence in chemistry research. In March of this year, Wong was named Doctor Scientiarum Honoris Causa by Technion-Israel Institute of Technology in recognition of Wong "as one of the world's most original and prolific researchers in bio-organic chemistry." In January, he was elected as chairman of the executive board of editors of Tetrahedron Publications, the chemistry and chemical biology section of the world's largest publisher Elsevier. And, if that wasn't enough, the Chemical Research Society of India has elected him to an Honorary Fellowship, bestowed every year onto eminent chemists from around the world for outstanding contributions to chemical science.

"Independent and Productive"

Despite his hectic schedule, Wong has every confidence that his laboratory at Scripps Research will continue to thrive, and not just because he travels back to Scripps Research and communicates with the group frequently through emails and phone calls. "The group at Scripps is really incredible, very independent and productive," Wong said. "I feel very proud and lucky to work with them."

Over the years, the group at Scripps Research has evolved into the perfect counterpart to Wong's strengths, embracing the opportunity for independence while remaining eager to build on Wong's unique insights and perspective.

William Greenberg, an assistant professor of chemistry who picks up additional administrative duties when Wong is out of town, said, "Chi-Huey warned that he'd be back at Scripps less than usual, but it's not all that different than it was before—he was always traveling. What makes the laboratory work as well as it does is that he's always selected self-motivated postdocs and graduate students. It was always about people working and discovering things for themselves."

And the Wong lab's graduate students and postdocs, indeed, echo this sentiment from their own perspective. Research Associate Richard Payne said, "You get an objective view from Chi-Huey and he encourages you to try things you might not always think of trying. As a result, we have the freedom to explore our own research path, but at the same time have the additional advantage of Chi-Huey's knowledge and insight." Sarah Hanson, a graduate student and lead author on one of the new studies, added: "Ultimately, Chi-Huey is a very wise advisor. He's there to provide the big picture and allows you to  be creative in finding solutions."

Breakthrough Methods

This management style is clearly working if measured by the quality and quantity of scientific publications, which have recently provided what Wong believes are two "breakthrough developments."

First, a pair of papers, taken together, describes a new method of assembling glycoproteins (proteins with one or more chains of sugars attached). "Sugar-Assisted Ligation in Glycoprotein Synthesis," was published in May by the Journal of the American Chemical Society, and followed shortly afterward by "Second Generation Sugar-Assisted Ligation: An Effective New Method for the Synthesis of Cysteine-Containing Glycopeptides" in Angewandte Chemie.

The results open up the possibility of wide-scale chemical synthesis of homogeneous glycoproteins—a leap of significant proportion since nearly all glycoproteins exist as mixtures of various glycoforms and, as such, are difficult to evaluate when it comes to biological studies and therapeutic applications. The ability to create homogeneous glycoproteins in quantity would be a boon to both researchers and, if everything pans out, to drug manufacturing as well.

Simon Ficht, who has been a research associate in the Wong laboratory for about two years, worked on both papers. "The target itself is interesting," Ficht said. "Pharmaceutical companies are very interested in therapeutic glycoproteins, but they are difficult to study because they are produced as mixtures of glycoforms in cell culture. And the structures of the glycoforms depend on what type of cells are used to express them. The problem is that the glycoprotein products aren't homogeneous, and some of them are not even human—if you use insect cells, you will get glycoproteins with glycans typical for insects, not humans." 

Consequently, a number of researchers are working to develop both real human glycoproteins and single uniform glycoforms. The U.S. Food and Drug Administration (FDA) requires a high level of purity and homogeneity, which ensures that each batch of a drug has the same efficacy and safety profile. When it comes to glycoprotein drugs, the FDA grudgingly allows mixtures of glycoforms, since there is currently no technology that can avoid mixtures, but a method for producing single glycoforms would be highly desirable. 

"We developed a sugar-assisted ligation (SAL) to join two synthetic peptide fragments through a unique process," Ficht said. "The first step was to prove this technology could, in fact, synthesize glycoproteins. For our next step, we plan to synthesize two well-known glycoproteins to show that our method can be applied to interesting and practical targets."

Payne, who worked on development of the second generation sugar-assisted ligation process, notes its potential as a powerful new tool. "What we developed is a great method for synthesizing almost any glycopeptide, containing native chemical bonds," he said. "The real question is: Can we now step up the game and use our method to synthesize a homogeneous glycoprotein of therapeutic significance? We're working on the problem right now."

Chemical Reporting Probes

Hanson was the lead author on the third study, also published by the Journal of the American Chemical Society. The paper, "Tailored Glycoproteomics and Glycan Site Mapping Using Saccharide-Selective Bioorthogonal Probes," is a new way of tagging and identifying glycoproteins, a process that has challenged scientists in the past because of the remarkable complexity of glycans.  Scripps Research Professor Ben Cravatt was a collaborator on the project.

"We have a hard time defining the precise roles of glycans in biology," Hanson said. "Our new technology allows us to step into glycans with chemical reporting probes so that we can isolate specific types."

One benefit of this, Hanson noted, is that some carbohydrates have a more prominent role in cancer—fucose and sialic acid, specifically. Being able to isolate and define them could be critical for the development of potential cancer therapeutics, not to mention spurring more basic research into their functions.

"This is an important investigative tool," she said. "For instance, if we find a specific sialylated protein involved in tumorogenesis, it could lead to novel therapeutic targets. Because glycoproteins are so complex, we don't know as yet which forms of a glycoprotein are responsible for a particular function. This method allows us to pull out the information that's there and to identify new glycoproteins and the sites where they are glycosylated—where the sugar is added."

For Greenberg, this is the kind of research that has made the Wong laboratory a success, and for him, that song remains pretty much the same, even with the founder spending a lot of time with his new responsibilities in Taiwan.

"I think the underlying theme of our laboratory is using the tools of chemistry to understand and manipulate carbohydrates, the process of glycosylation, and the ultimate role of carbohydrates in cellular interactions," he said. "Chi-Huey's reputation is based on that and that's exactly what we continue to work on."

Send comments to: mikaono[at]scripps.edu

Professor Chi-Huey Wong is a busy man, directing Taiwan's Academia Sinica as well as overseeing his lab on the Scripps Research California campus.

Lab members in California, including Sarah Hanson, William Greenberg, and Richard Payne (left to right), work independently, while taking full advantage of Wong's unique insights.