SPECIAL REPORT
From Molecules to Manufacturing
In the highly competitive and rapidly expanding world of bioscience, how is a university’s value measured?
By the profusion of bioscience research facilities and NIH-funded centers?
By the broad scope of its research?
Or is it the depth and quality of individual fields of research that matters most?
How about all three? Last month, the UW Business News Wire highlighted the many research centers on the UW-Madison campus to acknowledge sheer numbers.
This month, we’ll consider a cross-section, ranging from one doing something very basic — identifying proteins — and ending with a story about the business realities of purifying them.
And next month, we’ll probe deeper and examine the research fields of embryonic stem cell and materials science/nanotechnology, two areas in which UW-Madison especially shines.
Case #1: The Center for Eukaryotic Structural Genomics
UNRAVELING THE STUFF OF LIFE:
UW-Madison makes progress in developing a ‘protein structure factory’
Last July, the National Institute of General Medical Sciences (NIGMS) announced that a handful of research centers around the country had won a second round of funding to continue their efforts to map the 3-D structures of proteins. The 20-year, $600 million project, called the Protein Structure Initiative (PSI), includes universities and researchers the world over.
The Center for Eukaryotic Structural Genomics (CESG) at the University of Wisconsin-Madison was one of them. The center, the employer of some 40 scientists, technicians and administrative staff, will receive $20 million over five years.
The award was a tacit pat on the back for John Markley, a UW-Madison biochemist and CESG director. At a meeting in Karachi, Pakistan, in 1999, Markley heard a novel technique based on wheat germ that showed promise in speeding the production of proteins. Later, he visited Professor Yaeta Endo’s laboratory at Ehime University in Japan, where the technology was developed, and ultimately signed on to use it here in Madison.
Mapping proteins, also known as structural genomics, is one of the next big goals in the quest to understand what makes life tick exactly as it does and why. Why do some people get Alzheimer’s disease but not others? The answer may lie in the particular fold of a protein. Eventually, that protein might be the target of a high-tech anti-Alzheimer’s remedy. It’s not out of the question.
Structural genomics piggybacks on a prior accomplishment: deciphering the genetic makeup of a raft of different organisms ranging from various plants to mice, yeast and bacteria. Many are pathogenic.
But since genes code for proteins, scientists need to know that structural code to understand what triggers a disease. “It’s a fundamental step in biology,” Markley says.
Fortunately, proteins form families that share similar characteristics, so researchers save time by making many inferences, he says.
In 2000, when the first phase of the PSI was launched, the technical hurdles to solving protein structures were huge. But Markley and others found improved ways to reduce the time required and, correspondingly, the money needed.
One of those ways, in vitro translation of messenger RNA by improved cell-free wheat germ extracts, was the technique Markley heard about while in Pakistan. “Wheat kernels have everything that a plant needs to sprout. They go through a rapid period of protein production, so they have everything built in,” he says.
In cases when cell-free methods aren’t suitable, CESG can use E. coli cells to produce proteins. CESG has made important advances in this technology as well, particularly for making large quantities of protein for X-ray crystallography.
The final step is determining the protein structure. To do this, the center can choose between two methods: X-ray crystallography or nuclear NMR spectroscopy. All new structures are filed with the free worldwide Protein Data Bank.
In 1965, when Markley began his graduate work in NMR spectroscopy, the techniques to determine the physical skeletons of protein were in their infancy. It would be two decades before a single NMR structure was determined. “Lots of work was involved, including that leading to a couple of Nobel prizes,” he says.
Today, the goal is to develop technology that will enable new structures to be determined much faster — three days, quite possibly, Markley thinks.
On the one hand, it’s an amazing accomplishment, Markley says. “On the other hand, it’s taken a long time,” he chuckles.
Case #2: The Biomedical Engineering Center
MARRYING DIVERGENT DISCIPLINES:
When the sciences partner, great technology often results.
Translational: “To change from one form, function, or state to another; convert or transform: translate ideas into reality*.”
In the field of biomedical research, it’s a word with real significance. “Translational” research, the transformation of scientific discoveries into practical solutions, is a top goal of the National Institutes of Health. For it to succeed, however, creative teamwork across disciplines is essential.
UW-Madison has long been a leader, with a respectable list of med-tech breakthroughs and faculty collaborations to its credit. TomoTherapy, a new medical imaging technology invented at UW that gives oncologists and radiologists more precise information about tumor locations, is one recent entry that is quickly being adopted by hospitals nationwide.
Many medical and engineering school faculty are affiliated with the Biomedical Engineering Center, an interdepartmental research center based in the Department of Biomedical Engineering.
In November, the department learned it had been awarded a Wallace H. Coulter Foundation Translational Research Partnership Award in Biomedical Engineering. The award will provide $580,000 per year for five years.
As a way to acknowledge both the Coulter award and the heightened emphasis on translational research, the Biomedical Engineering Center will now be known as the Biomedical Engineering Center for Translational Projects and Programs, according to its director, Robert Radwin, chairman of the biomedical engineering department.
“Our strategic vision for the department is ‘we will advance healthcare by integrating education, discovery, innovation and entrepreneurship.’ Realigning the BME Center is one strategy for accomplishing this vision,” Radwin says.
In theory, translating laboratory breakthroughs into therapies and useful products has always been the implied goal of science. But barriers exist and are even increasing, due partly to institutional habit and partly to the growing complexity of science.
The NIH hopes to reverse that trend with new grants to encourage bedside doctors to collaborate more frequently with lab scientists.
At UW-Madison, “translational” research was being conducted long before anybody coined the name.
In the late 1970s, medical physics professor Charles Mistretta foreshadowed the trend when he invented digital subtraction X-ray angiography (DSA) with the help of a neuroradiologist, Pat Turski. Today, DSA is the gold standard for detecting arterial disease due to arteriosclerosis. DSA technology was patented by the Wisconsin Alumni Research Foundation (WARF) and incorporated into products by 30 companies within one year of its introduction.
Today, another biomed engineer, David Beebe, is investigating the potential advantages of microfluidics in assisted reproduction. Microfluidic systems — known informally as “laboratories on a chip” — are poised to transform the way in vitro production is practiced in both animals and humans. Vitae LLC, a company Beebe co-founded in 2000, has recently licensed technology to Minitube of America in Verona, Wis., to commercialize the first microfluidic products for assisted reproduction.
Beebe, who was recently profiled in Nature magazine, received a five-year NIH retraining grant to allow him to study biology under oncology professor Caroline Alexander.
In medical physics, Thomas “Rock” Mackie and Minesh Mehta have been known to innovate as well.
Mackie, a professor of biomedical engineering, human oncology and medical physics, and Mehta, an oncologist, spent a decade imagining a novel type of radiation therapy only to see their sponsor, GE Medical Systems, discard the idea as unworkable. But Mackie and Mehta labored on, got help from WARF and investor groups and eventually founded TomoTherapy Inc. Today, the company is setting the pace for this new type of radiation treatment.
The therapy uses a beam that rotates around the patient, allowing for less damage to surrounding tissue but more intense penetration of tumors. It is particularly useful in hard-to-reach tumors, such as those found in pancreatic and prostate cancers.
“It’s sort of like the same rationale you would have for precision bombing,” Mackie says. “There’s no point in precision bombing unless you can do precision guidance of the bombs.”
The radiation instruments, manufactured at TomoTherapy headquarters in Madison, are now found throughout the United States and around the world, including Hong Kong, Japan, Belgium and Italy.
Mackie is now developing another radiation therapy, similar to tomotherapy, which uses proton beams instead of high-energy x-ray beams. It’s being funded by the National Cancer Institute to the tune of $1.5 million a year.
Case # 3: UW-Madison Biotechnology Center
TOYS FOR PROFS:
New instruments and services allow bioscientists to work at a real clip
