A report by Wayne State researchers found new evidence of rapid protein evolution, signaling biochemical adaptation and positive selection in the anthropoid primate lineage. The report, (article #09714) published in the April 25-29 issue of the Proceedings of the National Academy of Sciences (PNAS), further elucidates the biochemical mechanisms involved in aerobic energy metabolism, a complex process that coincides with the expansion of the energy-dependent neocortex of the brain during the emergence of higher primates like monkeys, apes, and humans.

The study's corresponding author, Lawrence I. Grossman, Ph.D., professor and director of the Center for Molecular Medicine and Genetics, said the WSU team, which also included Timothy R. Schmidt, Derek E. Wildman, Monica Uddin, Juan C. Opazo, and Morris Goodman, found rapid evolution at the cytochrome c (CYC) binding site on cytochrome c oxidase (COX) in anthropoid primates. CYC is known to interact directly with COX during electron transport by binding to specific sites. Previous research has shown that in vertebrates CYC and COX are largely conserved and have few amino acid replacements. In contrast, the WSU researchers have identified 57 amino acids of COX that may bind CYC during electron transfer. Furthermore, the replacement rate for these residues was significantly accelerated in anthropoids compared to tarsiers, the most closely related non-anthropoid primate.

“With thorough DNA sequencing, we are identifying those positively selected mutations that shaped the genetic basis of being human,” Dr. Grossman said.

COX is the enzyme that catalyzes the final step of electron transfer through the respiratory chain, thus playing a vital role in providing energy for aerobic tissue s . Phlyogenetic analyses of gene sequences in different families indicate positively selected evolution of COX in terminal lineages of leading to gorilla, human and chimpanzee.

By parsimony from an interspecies alignment of binding site residues, the scientists discovered 27 changes from the earlier eutherians (placental mammalian ancestors) to humans, of which 59 percent were at electrostatically significant (ES) residue positions. The changes to the ES residues reduced the overall number of charged residues at the CYC binding site. The ES changes occurred only in stem-anthropoids and stem-catarrhines, and few changes occurred in the ape and Old World monkey lineages. 

“This reduction in rate of amino acid replacement is consistent with the
hypothesis that the changes in ancestral lineages were advantageous and positively selected and, in descendent lineages, have been maintained by purifying selection,” Dr. Grossman said.

Dr. Grossman and his colleagues have developed evidence that cytochrome c and subunits of complex III and COX that interact with it have undergone a period of accelerated evolution suggestive of positive selection at similar times in an ancestor of modern primates. “We believe that this remodeling of the electron transport chain supported the expansion of the energy-consuming enlarged neocortex that was taking place in these primate lineages. We are now seeking to characterize biochemically any modifications in electron transport that resulted. Finally, we are interested in the relation between rapidly evolving genes and human disease,” he said.

The full article, “Rapid Electrostatic Evolution at the Binding Site
for Cytochrome c on Cytochrome c Oxidase in Anthropoid Primates," (#09714) is featured in the April 25, 2005 issue of the Proceedings of the National Academy of Sciences. It can be viewed online at This Week in PNAS: http://www.pnas.org/papbyrecent.shtml. (Note: online publication date is April 25-29).

This paper was contributed by Morris Goodman, Ph.D., who was elected into the National Academy of Sciences in 2002. Co-authors are: Timothy R. Schmidt, Derek E. Wildman, Monica Uddin, Juan C. Opazo, Morris Goodman and Lawrence I. Grossman.

You use one every day, but how often do you get to see a real, human brain? You use your eyes all the time, too, but how often do you think about how they actually work – or get to see inside them? A few hundred Detroit-area children will have a chance to learn all about the brain, eyes and lots of other body parts as they participate in the Wayne State University School of Medicine's Future Docs event on Saturday, April 30.

Children, aged 6 to 12, will participate in fun, hands-on experiences related to medicine and the human body. In addition to studying human brains and eyes, children will have a chance to use a portable ultrasound and learn about how such an instrument is used on the international space station; see their hearts beat; build a “lung”; tour an ambulance; and find out the genes behind why some earlobes are attached while others aren't.

More than 300 people attended the event last year; as many as 500 could participate this year. Future Docs will be from 10 a.m. to 1 p.m., Saturday, April 30, in Scott Hall. For more information, please contact (313) 577-1474 or lherma@med.wayne.edu.

Register now to join the WSU: Get Pink! team for the 14th annual Komen Detroit Race for the Cure, an annual event to raise money for local breast-cancer screening, education and research. Sign up in the Scott Hall Cafeteria between 11:30 a.m. and 1:30 p.m., Wednesday, April 27, or Friday, May 6, or go online at http://www.karmanos.org/raceforthecuredetroit.

This year's event will be Saturday, June 11, at Comerica Park. Participants may chose to run 5K, walk 5K or walk one mile. Cost, which includes a T-shirt, is $25 for adults 18 and older, $10 for children ages 6 to 17 and seniors who are 65 or older. Cash and checks will be accepted in the Scott Hall Cafeteria. Donations also will be accepted.

To learn more, please visit http://www.karmanos.org/raceforthecuredetroit. To register online, please visit the same link and select the team "WSU - Get PINK" and enter the password "HOPE." The registration deadline is Wednesday, May 11.

Prostate cancer patients live longer when given goserelin immediately following radiotherapy, according to a new long-term study by the Radiation Therapy Oncology Group, a clinical research component of the American College of Radiology. David Grignon, M.D., WSU chair of pathology, served as one of the study's authors.

The publication in the April issue of the International Journal of Radiation Oncology Biology Physics, details the 10-year results of a national multicenter clinical trial that enrolled nearly 1,000 patients with locally advanced prostate cancer. The RTOG study, one of the longest and largest studies of its type, concluded that administering goserelin following radiotherapy reduces the progression of prostate cancer and significantly improves survival.

The RTOG study showed that the chance of survival 10 years after treatment was 10 percent higher for men who received goserelin immediately following their radiation therapy for locally advanced prostate cancer rather than beginning hormonal therapy only upon tumor progression (49 percent vs. 39 percent). Likewise, local progression was reduced from 38 percent to 22 percent for men receiving adjuvant goserelin.

Prostate cancer is the most commonly diagnosed cancer in men in the United States with over 230,000 new cases expected this year; it is the second leading cause of death due to cancer.

The RTOG study evaluated the effectiveness of administering goserelin to patients with prostate cancer treated with radiotherapy. Nearly 1,000 patients with locally advanced prostate cancer received either radiotherapy followed by monthly adjuvant goserelin 3.6 mg, or radiotherapy alone followed by observation and goserelin administration at relapse.

 

The Wayne State University Academy of Scholars will present a special gene therapy program on Tuesday, April 19 featuring two high-profile medical scientists.

Jean Bennett, M.D., Ph.D., professor of ophthalmology and cell & developmental biology at the University of Pennsylvania, will discuss "Gene Therapy for Retinal Disease: The Story of Lancelot." Katherine High, M.D., William Bennett Professor of Pediatrics and an investigator at the Howard Hughes Medical Institute at the University of Pennsylvania, will lecture on "Current Status of Gene Therapy for Human Disease."

The back-to-back presentations will be from 2:30 p.m. to 5 p.m., in Green Lecture Hall, Scott Hall. For more information, please contact Dr. J. M. Lusher at (313) 745-5515.

Children's Hospital of Michigan and the Wayne State University Department of Pediatrics have been named one of only six centers in the country to be accepted for participation in the National Institutes of Health's Collaborative Pediatric Critical Care Research Network.

Kathleen Meert, M.D., WSU professor of pediatrics, serves as principal investigator for the Detroit arm of this five-year, multi-center program designed to perform multiple clinical trials and translational research for children who are critically ill.

“It is vitally important to advance pediatric critical care. Because of the urgent demands of children in this intensive care unit (ICU) setting, current treatment modalities are based on limited tested knowledge,” Dr. Meert said. “Within a pediatric intensive care unit, there are many different types of diseases--sepsis, trauma, congenital heart problems and brain tumors, for example. This makes it difficult to do sound clinical research. We need large numbers of patients with the same underlying problem to be able to expand treatment options.”

According to the National Institute of Child Health and Human Development, this collaborative clinical research network will accelerate pediatric critical care research and lead to evaluation of promising new approaches to life support and critical decision-making in complex illnesses. It might take a single institution several years to gather enough data for thorough analysis, but the six NIH-designated centers working together can bring about meaningful research more rapidly. The other five centers are: Arkansas Children's Hospital, Children's National Medical Center in Washington , D.C. , Children's Hospital of Pittsburgh , Children's Hospital Los Angeles, and Children's Hospital and Regional Medical Center in Seattle . The data coordinating center is Children's Hospital in Salt Lake City , Utah .

 

“Given that there are 120 pediatric departments in the country, all with critical care units, the competition was fierce to become one of the first six centers in the NIH network,” said Bonita Stanton, M.D., WSU chair of pediatrics. “This critical care group already has a highly productive research portfolio, and now they are participating in the establishment of a national network that is on par with the Neonatal Intensive Care Units Network, the Maternal-Fetal Medicine Unit Network, and the Pediatric Pharmacology Research Unit Network—all of which are already in operation at WSU. I am especially thrilled because the research Dr. Meert proposes deals with non-traditional topics of death and bereavement in the ICU, potentially expanding the research focus of the network beyond biomedical research to behavioral and quality of care issues. All of these areas are of great importance and overlapping in their consequences as we strive to further improve the care of critically ill children and their families.”

Each qualifying principal investigator submitted a research proposal outlining the expertise he or she planned to contribute to the comprehensive research agenda. While the other centers stuck to traditional biomedical topics, Dr. Meert's $1.7 million proposal deals with critical behavioral research dealing with death and bereavement for parents of pediatric patients.

If approved as a network project, Dr. Meert plans to expand her current line of research and study “The Effect of Physician-Parent Post-Mortem Conference in Parental Grief Outcomes.” Dr. Meert sees immense value in developing and testing a strategic communication intervention in which the physician who was with a child at the time of death has a personal consult with the child's parents approximately six weeks later to discuss the illness, go over autopsy reports, answer questions, offer guidance and provide compassionate counseling and bereavement resources. This meeting would be followed up for one year with measurements of the family's grief, psychological status and family relationships.

“Unfortunately, these personal meetings with grieving families rarely happen. When they do, however, we find that parents more than anything want reassurance. They want to know that the parents and doctors did all they could do. They want to know that solid decision-making took place. They want to understand more about the illness or complications and feel comforted that all best efforts were made. And general information about disease is not good enough. The parents need to rely on the relationship they formed with the physician who personally cared for the child. This can be very constructive,” Dr. Meert said. She is also interested in providing best practice guidelines for physicians, for example: how to say it, tone, body language, who should attend such an intervention, etc. She is developing this encounter with Terrance Albrecht, Ph.D., a WSU professor of family medicine and health communication expert at the Barbara Ann Karmanos Cancer Institute.

“Most children who die in the United States die in hospitals, and most of those are in intensive care units. This is a difficult setting and we need to do everything we can to help the children we care for and their parents,” she said.

Dr. Meert graduated from the Wayne State University School of Medicine in 1984, did her pediatric residency at the Detroit Medical Center , and since 1989 has been an attending staff at Children's Hospital and a faculty member at WSU.