Welch Award recipients explore chemistry carried out
by enzymes, lay foundation for new treatments

BOSTON, May 13, 2010 - This year's Welch Award recipients have helped explain how enzymes, proteins that act as catalysts to speed up reactions millions-fold, have evolved to carry out difficult and ingenious chemistry critical to life.  Their basic research has laid the groundwork for therapeutic advances in medicine, particularly the treatment of cancer.  Today, The Welch Foundation, one of the oldest and largest sources of private funding for basic research in chemistry, honors JoAnne Stubbe and Christopher T. Walsh with the Welch Award in Chemistry for their achievements in the field.

"These two scientists, long-time friends who share a passion for knowledge, have made hugely important contributions to our understanding of the chemistry of biological functions in the enzymes that make life possible.  Their work has led to new therapeutic treatments, including new antibiotics and new cancer treatments, among other advances that improve the quality of life," said Ernest H. Cockrell, chair of The Welch Foundation.

While both scientists share in interest in enzymes, their focuses and approaches differ.

Dr. Stubbe, Novartis Professor of Chemistry and Biology at Massachusetts Institute of Technology, has been called a "scientist's scientist."  Her laboratory is known for using multiple tools - often working with collaborators to create new research techniques - to explore a particular area in great depth.  Her most noted work, for which she was awarded the National Medal of Science last year, involves a key class of enzymes that play an essential role in DNA replication and repair.

Dr. Walsh, Hamilton Kuhn Professor at Harvard Medical School, calls himself a "prospector" for new reactions in biology that involve unusual or novel chemistry.  He works at the intersection of chemistry, biology and medicine to explore - and eventually enable others to leverage - nature's use of enzymes to undertake complex tasks, focusing much of his work on antibiotics.

"Drs. Stubbe's and Walsh's work underscores the critical importance of basic chemical research in improving life - the guiding principle behind the Welch Award," explained Dr. James L. Kinsey, chair of The Welch Foundation's Scientific Advisory Board.  "While their research is focused at the most fundamental levels of biological chemistry, we have already been able to see some direct benefits of this increased knowledge.  The light they have been able to shed on how nature accomplishes very complicated tasks is being translated into applications with therapeutic or other life-enhancing value."

JoAnne Stubbe
Dr. Stubbe has focused most of her career studying the mechanisms of enzymes involved in nucleotide metabolism, central to the biosynthesis of DNA and RNA.  Her success in unraveling the specific steps in enzymatic reactions over the past four decades has had profound impacts on fields ranging from cancer drug development to synthesis of biodegradable plastics.

While most enzymes carry out their chemical transformations without disrupting the normal tendency of electrons to pair up, those studied by Dr. Stubbe involve species with unpaired electrons.  Such molecules with unpaired electrons are called "free radicals" and they have high chemical reactivity.  Ionizing radiation from the sun, for example, produces "bad" free radicals that react indiscriminately with DNA, causing mutations that lead to disease.  However, nature has figured out how to harness the extreme reactivity of radicals in an exquisitely controlled fashion, and these "good" free radicals carry out beneficial, but very difficult, chemical reactions in the body.  Today, scientists have identified more than 3,000 proteins that use free radicals in many unique chemical transformations, and Dr. Stubbe has spent much of her career unraveling how these enzymes work.

For example, she discovered how certain enzymes, called ribonucleotide reductases, use free radical chemistry to convert the monomeric RNA building blocks (nucleotides) to the monomeric DNA building blocks (deoxynucleotides), essential to make and repair DNA.  Dr. Stubbe's detailing of this nucleotide reduction process has led to the design of mechanism-based inhibitors; one of these is the drug gemcitabine, used clinically in the treatment of advanced pancreatic cancer and non-small cell lung carcinomas.

Dr. Stubbe is renowned for her creative use and development of physical methods to study biochemistry.  For example, she explained how the antitumor antibiotic bleomycin, used clinically in many combination chemotherapies, kills cancer cells by binding to and degrading DNA.  She also has recently begun to examine how bacterial enzymes can be used to produce biodegradable plastics.

"I am honored to receive the Welch Award," Dr. Stubbe said, "but I couldn't have done any of this without many creative collaborators and my outstanding and creative students and postdocs.  I have always been fascinated by how nature has evolved over millions of years to do these very tough chemical reactions.  Enzymes do a lot of pretty cool things and I love discovering exactly how they do it."

Born in Champaign, Ill., Stubbe earned her B.S. in chemistry from the University of Pennsylvania and her doctorate from the University of California, Berkeley.  She taught at Williams College before returning to research at Brandeis (working as postdoc in 1995 Welch Award recipient Robert Abeles' lab), Yale and the University of Wisconsin-Madison.  She joined the MIT faculty in 1987, recruited there by co-recipient Dr. Walsh.

Christopher T. Walsh
Dr. Walsh says his career has been driven by his overlapping interests in three areas:  chemistry, biology and medicine.  He has pursued molecular discoveries at those interfaces with interest in how they can ultimately be translated into therapeutics.  His primary focus is on understanding the mechanisms by which enzymes bring about chemical transformations in biological systems.

He began his career at MIT with studies of "suicide substrates," a class of enzyme inactivators with major implications for how drugs work.  It was as MIT where Dr. Walsh's group developed a style of prospecting for novel chemical transformations in biology to study.  One example:  his group unraveled the process by which bacteria detoxify mercury-containing molecules in the environment by cleaving carbon-mercury bonds and then reducing the mercuric salt to elemental mercury.

After 15 years at MIT, where he was a professor of both biology and chemistry and chaired the chemistry department, he moved to Harvard Medical School to learn more biology and medicine.  "I think like a chemist, but I'm interested in medicine and figuring out new therapeutics," he said.

At HMS, Dr. Walsh continued to study biocatalysts and began exploring antibiotic and antitumor agents.  One of his first major findings there explained the mechanism by which resistance develops to the antibiotic vancomycin.  This resistance was a major problem as vancomycin served at the time as the antibiotic of last resort for many life-threatening infections, particularly among cancer patients.  His work provided the foundation to create new antibiotics that circumvent the problem.  Over the years, he has published more than 100 of his 750 papers and one of three books on how antibiotics work, how resistance develops and how antibiotics are made by the organisms that produce them.

Dr. Walsh is widely recognized for spurring a renaissance in natural product biosynthesis.  His group currently is exploring the biosynthesis of natural product antibiotics and the chemical logic and enzymatic machinery of how they are made in order to identify new antibiotics, antitumor agents and immunosuppressants and to improve the efficiency of production.

"I dig up the chemical secrets of nature to better understand life and how therapeutic agents work," Dr. Walsh said.  "I look at biology from a chemical viewpoint.  Our goal is to define signposts for others who can improve these bioactive molecules to treat patients.  My thanks to The Welch Foundation for recognizing the importance of this work and I can't think of a better person than JoAnne with whom to share the honor."

A Boston native, Dr. Walsh earned his undergraduate degree in biology from Harvard and a doctorate in life sciences from The Rockefeller University.  After postdoctoral work in biochemistry (also with 1995 Welch Award co-recipient Robert Abeles), he joined the MIT faculty.  He has spent the last 22 years at Harvard Medical School and four of those in the 1990s as president and CEO of Dana Farber Cancer Institute.  He pursues his interest in translating basic science into treatments by consulting with pharmaceutical and biotechnology companies.

The Welch Foundation
The Welch Foundation supports science through research and departmental grants, funding of endowed chairs, an annual chemical conference and support for other chemistry-related programs.  In addition to the Welch Award, the Foundation annually bestows the Norman Hackerman Award in Chemical Research to recognize the accomplishments of "rising star" chemical scientists in Texas.  The 2010 Welch Award recipients will share #300,000 and each will receive a gold medallion.

For more information on the Foundation and a list of previous Welch Award recipients, please visit www.welch1.org .