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Solving drug–design problems, saving lives with yeast

There may come a time when the use of yeast to create life-saving drugs will be as common as, well, yeast itself. When that time comes, UNB Saint John can claim to be one of the places where it all started _ right in a lab on the third floor of Ganong Hall.

 With luck, the name Margaret Kayser will also go down in history as one of the scientists who developed what could just be the miracle reagent of the 21st century.

 It all started about 10 years ago when Dr. Kayser was trying to develop a synthetic form of TaxolŽ, a highly successful drug for the treatment of ovarian and breast cancer. Since TaxolŽ could be found only in the bark of the Pacific yew, a tree that is almost extinct, the need for a synthetic version was pressing.

 The problem was that TaxolŽ is a very complex molecule. It is quite unlikely that even total synthesis, which requires expensive reagents and many steps, could meet demand.

 The answer was to aim for partial synthesis. A compound from another type of yew found right in New Brunswick would make up the core of the TaxolŽ molecule, while the important side chains would be synthesized using yeast-catalysed reactions.

 While working on this research, Dr. Kayser realized she could elicit some amazing and valuable chemical reactions if she made slight modifications to regular yeast.

 The new designer yeast, as she and co-researcher Jon Stewart of the University of Florida dubbed it, had the ability to produce results that usually required toxic or explosive chemicals. And when the designer yeast was used to produce new molecules, the resulting products were amazingly pure.

 "This is very important, especially in the world of drug synthesis," says Dr. Kayser.

 Many chemical compounds are chiral, she explains, which means they have two sides that are mirror images of each other, like left and right hands. In the case of drugs, one form might produce the reaction you want while its mirror image "antipode" may result in a less desirable effect. That's what happened with thalidomide, where the antipode produced birth defects.

 Usual chemical reactions produce both sides of a compound, but Dr. Kayser's new yeast makes only one side, resulting in a purity that is very rare.

 This discovery – that a humble yeast molecule can produce so-called optically pure compounds – is an exciting step forward for the pharmaceutical industry, where such pure compounds are a must.

 The fact that these yeasts are easily produced and environmentally friendly, requiring no toxic agents and leaving no toxic bi–products, is equally important. No wonder, then, that a number of forward-thinking companies are now funding some of Dr. Kayser's research and are seeking partnerships with her lab.

 And what of the TaxolŽ project that got the ball rolling? Dr. Kayser has successfully produced a partially synthetic molecule using the New Brunswick yew tree and her designer yeast. The next step is to modify the molecule's all-important side chains to develop a form of TaxolŽ that may be useful against other cancers.

TURNING UP THE HEAT— Kinesiology professor Gordon Sleivert monitors the muscle response of Shawnda Morrison, a master of science in exercise and sport science student, who is wearing a temperature–controlled hood and pants. The garments allow Dr. Sleivert to control the temperature of various sections of the body.

Keeping a cool head...and torso

Research helps athletes, workers maintain safe body temperatures

HHow do you keep athletes from overheating when competing in high temperatures?

 Finding a solution to that problem has sparked a series of research projects for Gordon Sleivert, a kinesiology professor at UNB Fredericton.

 "A lot of my research has focused on active cooling strategies to control body temperature during exercise in the heat," says Dr. Sleivert. He has worked with many elite athletes on this project, including those at the summer Olympics in Atlanta and at the Commonwealth Games in Malaysia.

 "I've developed a cooling vest, in collaboration with clothing and textile scientists, that can be used by athletes before a competition to cool body temperature," he explains. "Cooling the body's core temperature before exercise slows the rise in body temperature during competition and gives the athlete a larger margin of safety for maintaining a safe body temperature."

 Initially based on sport, Dr. Sleivert's research has transferred over to military and industrial applications — anywhere people are working in hot conditions.

 "I've focused on developing practical applications to use in the field not only to increase workers' performance but also for their health and well-being," he says. "Firefighters, for example, could use the vest or other cooling strategies to drop body temperature on the way to an emergency or intermittently during work to maintain a body temperature as close to normal as possible."

 Dr. Sleivert has also worked with the Australian military on strategies to help soldiers reduce heat stress when wearing CNB (chemical, nuclear, biological) protective clothing.

 "My research has not just focused on the torso," says Dr. Sleivert. "Different areas of the body have different impacts on our perception of temperature and on the body's response. It can be quite dangerous to feel cool when you're not."

 His work in the area of behavioural thermal regulation demonstrated that when the head is cooled, people choose to exercise or work at a higher intensity. "By cooling the head, you are taking some heat out of the body," he explains. "But is it enough? You have to balance thermal regulation with thermal perception."

 While much of his research has centred on the prevention of hyperthermia — the body's becoming too hot — Dr. Sleivert is also conducting research on how the body responds to cooling and hypothermia. One of his five graduate students is examining hand function in the cold and cold adaptation for her doctoral thesis.

 "The ultimate goal of this project is to develop interventions to maintain neuromuscular function in the cold," explains Dr. Sleivert. "The result of this research can be transferred directly to people who work outside in the winter, such as hydro line workers and those in the fishing, logging and mining industries."

 He's also studying how temperature affects the body's ability to produce and use force.

 "This has implications not just for work performance but for injury prevention," Dr. Sleivert says. "The manipulation of temperature has a lot of therapeutic and rehabilitative applications too. I'd like to examine how manipulating body temperature might reduce muscle atrophy for astronauts."