Scholarship & Creativity
U-M experiments take the express route to evolution
A U-M molecular biologist and his colleagues have bypassed half a billion years of evolution by coaxing proteins to subtly alter their shape and perform new tasks in laboratory Petri dishes.
Using a technique called directed evolution, James Bardwell’s team modified a protein called DsbG so that it more closely resembled a distant relative, DsbC, that has the natural ability to protect cells from the toxic effects of exposure to the element copper.
The laboratory-altered version of DsbG gained the capacity to protect against copper toxicity, a function that DsbC acquired through several hundred million years of evolution. The power to reshape protein structure in this manner could help researchers make better pharmaceuticals, said Bardwell, a professor of molecular, cellular and developmental biology and a Howard Hughes Medical Institute investigator.
“If you can understand something, you can build it,” Bardwell says. “We took one protein that was related to another and tried to see if we could convert the first protein into one having the function of the second protein.”
The team’s findings were published online July 3 by the Proceedings of the National Academy of Sciences.
Bardwell’s research focuses on the molecular machinery that helps proteins fold into their proper shapes. The work could eventually lead to a better understanding of disorders such as cystic fibrosis and Alzheimer’s disease, which are thought to involve protein-folding errors.
His team particularly is interested in disulfide bonds, which act like bolts or stiffening struts to keep proteins correctly configured.
“The correct arrangement of disulfide bonds is often so important to a protein that without the right arrangement, the protein does not fold correctly and is destroyed,” says Annie Hiniker, a medical degree and doctoral student and first author of the new paper.
DsbC counteracts the toxic effects of copper inside cells by ensuring that the sulfur bonds are properly positioned in proteins. The goal of the latest study was to see if directed evolution could reproduce those protective effects by reconfiguring a related protein.
“You could change one protein into one having the function of another just by single mutational changes,” Bardwell says.
School-based programs that encourage safe behavior among teens are especially important in Latin America where total HIV/AIDS cases increased to nearly 2 million people last year, a new study says.
A U-M researcher who conducted an initial study as part of his dissertation at the University of South Florida shows how HIV/AIDS prevention programs that are in English and created in the United States can be translated into Spanish to advance research and program evaluation efforts to target Hispanic populations.
“The most important finding is that this questionnaire can be used to assess HIV/AIDS knowledge and attitudes in youths from Latin America and with Latinos in the United States,” says Carlos Zometa, the study’s lead author and an assistant research scientist in the School of Social Work.
The findings appear in the June issue of AIDS Education and Prevention.
HIV/AIDS continues to be a serious international and domestic problem. In 2006 UNAIDS reported 1.7 million people live with HIV/AIDS in Latin America and 1.4 million in the United States. Since young persons are vulnerable to HIV infection, there is a great need to increase the number of school and community-based programs to prevent transmission, Zometa says.
He documented the process to translate to Spanish from English a questionnaire initially developed by the Centers for Disease Control and Prevention that assessed knowledge about HIV transmission and attitudes towards peer pressure, abstinence, drug use and the threat of HIV infection. Specifically, programs have highlighted the importance of attitudes toward condom use and abstinence in reducing transmission, he said.
The process involved translating and cross culturally adapting the questionnaires from English to Spanish by using a procedure requiring less time and resources than traditional methods. Among the questions answered correctly by more than 90 percent of the students (All answers are true):
• HIV can be found in semen, vaginal fluids and blood;
Millions of Americans take medications for hypertension but do not achieve control of their blood pressure. Now, a new international study involving more than 10,700 people with high blood pressure finds that single-tablet combinations of drugs may be what it takes to get blood pressure under control, even in people with moderate hypertension.
“These data suggest strongly that single tablets containing two drugs will control the vast majority of patients who are taking medication but have not achieved ideal blood pressure. These data may affect the blood pressure control of over 38 million Americans,” says study leader and lead author Dr. Ken Jamerson, a professor of cardiovascular medicine at the Medical School and member of the Cardiovascular Center.
Jamerson presented the 18-month data recently at the American Society of Hypertension meeting in Chicago. The six-month data are published simultaneously in the journal Blood Pressure.
As many as 60 million Americans have high blood pressure. But because high BP doesn’t cause symptoms, most people who have it don’t know it. Over time, uncontrolled blood pressure affects the blood vessel walls, encouraging the growth of weak spots called aneurysms and the formation of narrowed and inflamed areas that can lead to clots that can break off and cause heart attacks and strokes.
The trial randomly assigned patients to one of two drug combinations. Both combinations contained a drug called benazepril, which belongs to a class of medicines known as ACE inhibitors. The other drug in one of the combinations is a diuretic called hydrochlorothiazide; in the other combination pill, the drug is called amlodipine, one of a class of medicines called calcium channel blockers.
Only 30 percent of Americans who have high blood pressure, and only 60 percent of those taking medicines for hypertension, currently have their blood pressure under control. Data suggests that combination tablets have the potential to improve control rates to over 80 percent.
In addition to Jamerson, study authors from U-M include Bertram Pitt and Sverre Kjeldsen of the Cardiovascular Center.
A synthetic derivative of a pungent desert shrub is now a front-runner in ongoing experiments to find out if certain chemicals, known to inhibit inflammation, cancer and other destructive processes, can boost the odds of living longer.
That’s according to the early results of a federal study, which suggests male mice fed a normal diet plus an anti-inflammatory substance may live longer than control mice.
U-M scientist Richard A. Miller reported the early results last month at the annual meeting of the American Aging Association, based on a mouse study his lab and two others are conducting for the National Institute on Aging. The study, now in its fourth year, will test as many as two dozen possible anti-aging agents in animals in the next five years.
The scientists were surprised to find so quickly that one agent showed promise: NDGA, a compound derived from creosote bushes. These common North American desert shrubs have been traditionally used by Native Americans as healing remedies.
The preliminary results, to be published in August in the journal Aging Cell, show that male mice fed a normal diet and NDGA so far have survived in significantly greater numbers than mice on a normal diet. No significant difference occurred in female mice. “It may be that the female mice because of their hormonal status have other pathways to death and disability, or need higher or lower levels of NDGA to see an effect,” says Miller, professor of pathology at the Medical School and associate director of the U-M Geriatrics Center. Miller is also a research scientist at the Ann Arbor VA Medical Center.
The large controlled study at three sites, called the NIA Interventions Testing Program, is intended to provide some of the first reliable data on potential drugs to slow aging and its accompanying ills.
“If NDGA turns out to extend maximal lifespan by 20 or 30 percent, people would accept that as an important finding,” Miller says. The research is funded by the National Institute on Aging, part of the National Institutes of Health.