Centerline Fall/Winter 2007

Primate Center scientist manages research, service core, news media and more

Ricki Colman ignored a high school teacher who warned her that she wouldn't be able to hack advanced courses in math and science.

That teacher wasn't there when Colman learned as a young child how to stay focused and work hard while training eight hours a day as a competitive figure skater.

The teacher wasn't there when Colman's parents insisted she go to school, study hard and get good grades, even when, by her early teens, she was traveling the country and skating at the national level.

Nor was the teacher there when a 15-year-old Colman, both knees shot from a congenital defect aggravated by skating, wound up in the pediatrics ward at New York University, needing multiple surgeries, spending six months in physical therapy, and hanging up her skates forever.

It was during that time in rehab that Colman was sparked with an interest in science and medicine. By the time she started high school in Rockland County, New York, she had already had first-hand experience with sports medicine, orthopedics and physical therapy. "I became close friends with my surgeon and orthopedist. They took me on their rounds, I watched other surgeries. I learned a great deal and appreciated the science behind the medicine even more." Used to training all day, Colman needed to keep busy and do something, so she channeled her pent-up energy into volunteering as an assistant for the same physical therapists who had treated her for half a year.

"My parents taught me early on that, in competitive skating, you turn 16 and its over," Colman said. "Better practices and training today have extended this age limit somewhat; however, I learned early on how to budget time, concentrate and get where I wanted to go, making sure not to focus on one sport at the expense of everything else."

After high school (and acing those advanced courses), Colman began undergraduate studies in biological sciences at Washington University in St. Louis. She met her advisor, noted physical anthropologist Robert Sussman, through his behavioral anthropology class, which involved 80 hours of primate observation at the city zoo, followed by a required research paper on the experience. Sussman subsequently asked Colman, when she became his graduate student, to teach the class while he was out of the country. "I had only 20 students, but it was very intense," she said. "I learned how to advise and work with students, and I enjoyed it."

In particular, Colman took to zooarchaeology, which guided her further to specialize her interests in skeletal anatomy. "I found it fascinating: all the things that go into identifying a bone, what its markings mean, what might have caused the markings, what preyed upon it, how old it was." Colman ended up serving as a teaching assistant for that class as well.

She decided to study nonhuman primates in captivity as a career. "The skeletal work I wanted to do was not something you could do in the field. As a research focus, looking to conduct research at a Primate Center seemed more viable."

In 1994, her graduate studies took her to the Department of Anthropology at the University of Wisconsin-Madison. She began conducting research at the Primate Center as a student hourly for Joe Kemnitz, then a senior scientist at the Primate Center and now its director. Kemnitz took her onto his dietary restriction and aging project, which focused primarily on glucose regulation and insulin sensitivity in rhesus monkeys eating 30 percent fewer calories without malnutrition. A year later, she also began assisting Neil Binkley, physician and associate professor in the Department of Medicine, with an osteoporosis drug trial he was running through the Primate Center.

"The techniques that Ricki helped us develop for this study made it the 'gold standard' non-human primate study and a model against which other osteoporosis animal studies are compared," said Binkley. "In fact, the medication used for that study was recently approved for treatment of Paget's disease and osteoporosis in humans.

Along with Mark Lane at National Institute on Aging, Colman helped develop several of the research techniques Binkley used, including specialized assays and measurement of bone density using dual energy X-ray absorptiometry techniques.

Richard Weindruch joined the UW-Madison research faculty in 1990. He garnered major funding for caloric restriction and aging research in 1994 and today remains the principal investigator on the Primate Center's Caloric Restriction and Aging Program Project grant (P01). The grant continues to expand and attract international attention from scientists, students and the public. Weindruch, a UW-Madison professor of medicine, geriatrics, and gerontology, is also a scientist at the Geriatric Research, Education and Clinical Center at Madison's Veterans Administration Hospital.

"The calorie restriction and aging studies blossomed in 1994 when Rick got the program project grant," Colman said. "Joe and Neil were heavily involved, and we added 46 more animals to the study."

Binkley succeeded Kemnitz in leading the animal core in 2000, but at the same time told Weindruch that running the core was going to be a short-term arrangement: What he had in mind was preparing Colman to manage the core. In 2001, Colman became an assistant scientist and accepted leadership of the core. She has since expanded her lab's staff from two to four technicians. She has published more than 33 peer-reviewed research papers and book chapters, nearly a third as first author. She has presented abstracts and invited talks at more than 50 scientific conferences.

"The dietary restriction study, in my opinion, is landmark work that is unlikely to ever be replicated," Binkley said. "It would not be the successful study that it is without Ricki's oversight and leadership."

Dr. Colman has had to juggle not only managing all the on-site nonhuman primate studies for the $9 million P01 grant, including studies related to energy expenditure, body composition, glucose tolerance and insulin sensitivity, bone mineral content, C-reactive protein and leptin: As head of the WNPRC Aging Resource Core, she also has to coordinate many other varied studies through the core. These have included research projects related to obesity, diabetes, AIDS, chronic wasting disease, vitamins and nutrients, polycystic ovary syndrome, endometriosis, menopause, sarcopenia, osteoarthritis, and cognition. She works with more than a dozen principal investigators in the field of aging at any given time. She has also squeezed in assisting PI's with a few rat, mouse and rabbit studies where time and resources have allowed.

Dr. Colman has also spent a great deal of time engaged in another important activity, but one most scientists never have to worry about. Along with Weindruch, she has patiently and graciously granted e-mail, phone and mostly on-site interviews to the local, national and international news and science documentary media on the caloric restriction and aging work.

"You can tell Ricki was trained early on as a national-level skater to give TV interviews," said Jordana Lenon, public information officer for the Primate Center. "No matter what questions come up, and we've had some crazy ones, she is always patient and helpful, and speaks clearly and concisely. This is just not a skill everyone has. Both Rick Weindruch and Ricki Colman have been amazing with the media, with everyone from Alan Alda of Scientific American Frontiers, who spent a whole day at the Center and asked very pointed, scientifically savvy questions, to the major TV networks, for their 3-minute newscasts, where they're in and out in an hour or two and you just hope they get the basics."

Colman is quick to acknowledge that her entire lab, including the media interviews, runs smoothly day-to-day largely because of the hard work and expertise of her staff. She is grateful to P01 program project assistant Jenny Christensen for keeping the whole grant running smoothly. She recalls the valuable assistance of Lori Mason, one of her first technicians.

"When we started the program project and then added the females and the second group of males in the 1990s, Lori helped me do my dissertation work on dietary restriction in rhesus monkeys. We spent many late nights studying and scanning monkeys. One roomful of females wouldn't go down easily on anesthesia. We think they would have preferred to stay up all night. Then, once they were all down, we had to wait for them to arise.

Colman, now an associate scientist, acknowledges Scott Baum, Julie Adriansjach, Callie Armstrong, Josh Smith who recently left and Shelly Prudom who recently joined the lab, for keeping the lab running smoothly. In addition to supervising her staff, Colman puts much needed time and effort into writing grants and papers, helping coordinate incoming protocols and new projects with Rick Weindruch and CPI staff, preparing for and giving invited talks, and being active on research policy boards. She is on the publications committee for the Gerontological Society of America, is a reviewer for eight journals, and has served on two study sections and four professional organizations in the field of aging.

Colman adds a few more words about Scott Baum: "He is the mainstay of the project," she begins. "His institutional knowledge of the project is amazing, he's the only tech who has been here since the start of the project. He knows what the monkeys were like when they were young, and he has noticed how they've changed or not changed as the study progresses, sometimes in subtle ways no one else would note."

Baum is one of the most photographed laboratory technicians in the history of the Primate Center. He has appeared on national and international news casts rolling carts of special monkey diet down the aisles, pouring cups of chow into metal feeders, and moving animals into special plexiglass viewing cages to give news and documentary crews a closer look at whole-body differences as the monkeys age.

When asked what the most challenging part of her job is, Colman responds without hesitation, "Watching the animals get older and die; this is the hardest part for me. Scott, too-it's tough for him to watch this happen."

"But the best part is anticipating the actual results of the study, as we get closer to the end, and believing that this will give us some insights into the aging process. Also rewarding have been all the connections I've made to people in the field, just being involved in such exciting research."

Recent References:

*Raman A, Baum ST, Colman RJ, Kemnitz JW, Weindruch R, Schoeller DA. Metabolizable energy intake during long-term calorie restriction in rhesus monkeys. Exp Gerontol. 2007 Jul 5; [Epub ahead of print]

*Raman A, Ramsey JJ, Kemnitz JW, Baum ST, Newton W, Colman RJ, Weindruch R,Beasley MT, Schoeller DA. Influences of calorie restriction and age on energy expenditure in the rhesus monkey. Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E101-6.

*Raman A, Colman RJ, Cheng Y, Kemnitz JW, Baum ST, Weindruch R, Schoeller DA. Reference body composition in adult rhesus monkeys: glucoregulatory and anthropometric indices. J Gerontol A Biol Sci Med Sci. 2005 Dec;60(12):1518-24.

*Colman RJ, McKiernan SH, Aiken JM, Weindruch R. Muscle mass loss in Rhesus monkeys: age of onset. Exp Gerontol. 2005 Jul;40(7):573-81.

*Blanc S, Colman R, Kemnitz J, Weindruch R, Baum S, Ramsey J, Schoeller D. Assessment of nutritional status in rhesus monkeys: comparison of dual-energy X-ray absorptiometry and stable isotope dilution. J Med Primatol. 2005 June; 34(3):130-8.

*Bruns CM, Baum ST, Colman RJ, Eisner JR, Kemnitz JW, Weindruch R, Abbott DH. Insulin resistance and impaired insulin secretion in prenatally androgenized male rhesus monkeys. J Clin Endocrinol Metab. 2004 Dec;89(12):6218-23.

*Zondervan KT, Weeks DE, Colman RC, Cardon LR, Hadfield R, Scheffler J, Goudy Trainor A, Coe CL, Kemnitz JW, Kennedy SH. Familial aggregation of endometriosis in a large pedigree of rhesus macaques. Human Reproduction. 19:2. Feb 2004.

UW scientists guide human skin cells to embryonic state

By Terry Devitt
UW-Madison press release
Nov. 27, 2007

In a paper published Nov. 22 in the online edition of the journal Science, a team of University of Wisconsin-Madison researchers reports the genetic reprogramming of human skin cells to create cells indistinguishable from embryonic stem cells.

The finding is not only a critical scientific accomplishment, but potentially remakes the tumultuous political and ethical landscape of stem cell biology as human embryos may no longer be needed to obtain the blank slate stem cells capable of becoming any of the 220 types of cells in the human body. Perfected, the new technique would bring stem cells within easy reach of many more scientists as they could be easily made in labs of moderate sophistication, and without the ethical and legal constraints that now hamper their use by scientists.

The new study was conducted in the laboratory of UW-Madison biologist James Thomson, the scientist who first coaxed stem cells from human embryos in 1998. It was led by Junying Yu of the Genome Center of Wisconsin and the Wisconsin National Primate Research Center.

"The induced cells do all the things embryonic stem cells do," explains Thomson, a professor of anatomy in the University of Wisconsin School of Medicine and Public Health. "It's going to completely change the field."

In addition to exorcising the ethical and political dimensions of the stem cell debate, the advantage of using reprogrammed skin cells is that any cells developed for therapeutic purposes can be customized to the patient.

"They are probably more clinically relevant than embryonic stem cells," Thomson explains. "Immune rejection should not be a problem using these cells."

An important caveat, Thomson notes, is that more study of the newly-made cells is required to ensure that the "cells do not differ from embryonic stem cells in a clinically significant or unexpected way, so it is hardly time to discontinue embryonic stem cell research."

The successful isolation and culturing of human embryonic stem cells in 1998 sparked a huge amount of scientific and public interest, as stem cells are capable of becoming any of the cells or tissues that make up the human body.

The potential for transplant medicine was immediately recognized, as was their promise as a window to the earliest stages of human development, and for novel drug discovery schemes. The capacity to generate cells that could be used to treat diseases such as Parkinson's, diabetes and spinal cord injuries, among others, garnered much interest by patients and patient advocacy groups.

But embryonic stem cells also sparked significant controversy as embryos were destroyed in the process of obtaining them, and they became a potent national political issue beginning with the 2000 presidential campaign. Since 2001, a national policy has permitted only limited use of some embryonic stem cell lines by scientists receiving public funding.

In the new study, to induce the skin cells to what scientists call a pluripotent state, a condition that is essentially the same as that of embryonic stem cells, Yu, Thomson and their colleagues introduced a set of four genes into human fibroblasts, skin cells that are easy to obtain and grow in culture.

Finding a combination of genes capable of transforming differentiated skin cells to undifferentiated stem cells helps resolve a critical question posed by Dolly, the famous sheep cloned in 1996. Dolly was the result of the nucleus of an adult cell transferred to an oocyte, an unfertilized egg. An unknown combination of factors in the egg caused the adult cell nucleus to be reprogrammed and, when implanted in a surrogate mother, develop into a fully formed animal.

The new study by Yu and Thomson reveals some of those genetic factors. The ability to reprogram human cells through well-defined factors would permit the generation of patient-specific stem cell lines without use of the cloning techniques employed by the creators of Dolly.

"These are embryonic stem cell-specific genes which we identified through a combinatorial screen," Thomson says. "Getting rid of the oocyte means that any lab with standard molecular biology can do reprogramming without difficult to obtain oocytes."

Although Thomson is encouraged that the new cells will speed new cell-based therapies to treat disease, more work is required, he says, to refine the techniques through which the cells were generated to prevent the incorporation of the introduced genes into the genome of the cells. In addition, to ensure their safety for therapy, methods to remove the vectors, the viruses used to ferry the genes into the skin cells, need to be developed.

Using the new reprogramming techniques, the Wisconsin group has developed eight new stem cell lines. As of the writing of the new Science paper, which will appear in the Dec. 21, 2007 print edition of the journal Science, some of the new cell lines have been growing continuously in culture for as long as 22 weeks.

The new work was funded by grants from the Charlotte Geyer Foundation and the National Institutes of Health. In addition to Yu and Thomson, authors of the new study include Maxim A. Vodyanik, Kim Smuga-Otto, Jessica Antosiewicz-Bourget, Jennifer L. Frane and Igor I. Slukvin, all of UW-Madison; and Shulan Tian, Jeff Nie, Gudrun A. Jonsdottir, Victor Ruotti and Ron Stewart, all of the WiCell Research Institute.

Reference:

Junying Yu, Vodyanik MA. Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, Nie J, Jonsdottir GA, Ruotti V, Stewart R, Slukvin II, Thomson JA. Induced pluripotent stem cell lines derived from human somatic cells. Science. Nov. 22, 2007. Online publication.

Primate study shows excess vitamin A can be stored during fetal development

UW-Madison News Release, Oct. 8, 2007
by Jordana Lenon

A new University of Wisconsin-Madison study suggests that pregnant women who take some types of vitamin supplements or eat fortified foods may be passing excess vitamin A to their developing fetuses. Reported in the October issue of the Journal of Comparative Medicine, the finding could guide efforts to develop future formulations of vitamins.

Best known as retinol because it produces the eye's retinal pigments, vitamin A is important for fetal development and to establish and maintain healthy lactation in breast-feeding mothers. For these reasons, many U.S. women are either prescribed or begin taking over-the-counter vitamin supplements during the first trimester of pregnancy.

However, it's still unclear how much vitamin A is too much, making it important to learn the levels at which vitamin A compounds - present as retinyl acetate and palmitate in supplements - begin affecting the early fetus, says UW-Madison nutrition professor Sherry Tanumihardjo.

"The high intake of vitamin A from supplements and fortified foods worldwide has caused us to be concerned," she says.

Using Primate Center resources, first author Jordan Mills, a nutritional sciences graduate student, and Tanumihardjo found that when mother monkeys consume excess vitamin A in fortified food, this results in increased storage of the vitamin - in a form called retinyl ester - in fetal livers during early gestational stages.

Liver storage may occur when vitamin A levels outstrip the immediate demands of the developing fetus, possibly as a way to protect against vitamin A toxicity. Tanumihardjo attributes the excess vitamin A to lab diets containing high concentrations of the vitamin. "Those diets should be reformulated," Tanumihardjo says. In addition, new vitamin A formulations for people might be developed that could still meet the needs of mother and fetus, while avoiding the problems that excess vitamin A might cause, she adds.

Previous data from human fetuses suggest that liver vitamin A concentrations increase until sometime in the third trimester. They then drop steadily until birth, after which the baby's consumption of breast milk causes them to rise again. But until now, early human data - or any primate data, for that matter - has been rare, says Tanumihardjo.

"Although data exist for late-stage fetal and neonatal liver vitamin A storage in humans and rodents, few data exist regarding early-stage fetal tissues of all species, including primates," she says. In addition to sharing approximately 95 percent genetic homology, Old World monkeys and humans exhibit comparable organ growth rates and sizes throughout fetal and postnatal development, making monkeys useful models for early human development.

In the study, the researchers obtained maternal diet information and necropsy tissue from the Primate Center for three Old World species: rhesus macaques, cynomolgus macaques, and vervets, to maximize study samples. They then used a series of chemical extraction and analysis techniques to measure relevant vitamin A compounds in tissue, including retinoic acid, retinol, and retinyl esters.

The excess vitamin A the researchers discovered in the monkeys didn't appear to cause problems, likely because the maternally derived vitamin A was stored primarily as relatively harmless retinyl esters in the liver, rather than being converted to harmful retinoids. This type of storage occurs either through fetal conversion of retinol to retinyl esters or direct transmission of retinyl esters from mother to fetus, or as a combination of these routes, Tanumihardjo says. Preferential shunting of maternally derived vitamin A to storage as retinyl esters may help protect against vitamin A toxicity in the fetus.

"Monkeys are less sensitive to the harmful effects of retinoic acid than are humans and rodents," Tanumihardjo says. "Our observations may explain why there have been no reports of vitamin A-induced birth defects in neonates from primate colonies that are fed the standardized commercial diets for monkeys, despite evidence of excess vitamin intake A by their mothers. This mechanism may be an adaptation to constant exposure to a lab diet high in vitamin A."

But have humans similarly adapted to protect their early fetuses from excess vitamin A concentrations? The new research indicates that this may be so; however, Tanumihardjo is eager to compare her monkey data to more human data, especially earlier in development.

The research was supported by the National Institutes of Health and the Wisconsin National Primate Research Center.

Reference:

Mills JP, Terasawa E, Tanumihardjo SA. Ingestion of excessive preformed vitamin A by mothers amplifies storage of retinyl esters in early fetal livers of captive Old World monkeys. Comp Med. Oct;57(5):505-11. 2007.

Horwich earns first WNPRC Jacobsen Conservation Award

Robert Horwich, director of Community Conservation, a nonprofit primate conservation organization based in Gays Mills, Wisconsin, is the first recipient of the Lawrence Jacobsen Conservation Research Award. This award from the Wisconsin National Primate Research Center supports studies in applied conservation biology that protect non-human primate species and their habitats. The award will benefit Dr. Horwich's ongoing work to conserve the golden langur (Trachypithecus geei) in India

The Golden Langur Conservation Project blends conservation, research, education, economic development and community development. "We focus on the full range of the golden langur in western Assam, India," Horwich said. "We work with more than 130 villages to create forest protection committees and self-help groups that create economic opportunities for villagers."

Horwich will use the award to step up conservation and evaluation efforts at one focal area, the 17.2 sq. Kakoijana Reserve Forest. He and project participants, including national forest members and villagers from adjacent communities, plan to measure changes in reforestation, the increase in golden langurs, and changes in economic development within 10 communities surrounding Kakoijana.

The project leaders aim to provide definitive proof of the success of the holistic community conservation approach by:

• Providing data supporting the success of the conservation efforts.
• Creating a monitoring program for one golden langur population.
• Creating a community-based research program.
• Gathering data on ecology and behavior of golden langurs in Kakoijana.
• Training villagers in simple data gathering methods.
• Encouraging villager interest in the forests, the monkeys and their conservation.
• Providing community incentives to protect the langurs and their habitat.

Horwich explained that traditional conservation efforts are based on the assumption that poor rural villagers respond mainly to financial incentives. "We have found, however, that by treating villagers with respect and giving them responsibility, they become active conservationists," he said. "While we provide them with education on creating community institutions for empowerment, economic gain and conservation awareness, we also educate them and involve them in all aspects of the project, including mapping and data-taking methods." This engenders conservation awareness in individuals who are already knowledgeable about the flora and fauna, Horwich explained. It also encourages those with untapped interests and abilities to contribute. "We expect to involve approximately 15 to 20 individuals from the Kakoijana villages in this way, as informal educators within their community," he said.

The Kakoijana site is surrounded by villages and other cleared inhabited areas; it had been classified as mixed deciduous forest but is currently a mosaic of various states of degradation-mixed forest, degraded areas, open areas, cultivated areas, teak monoculture, mixed tree plantations, and riverine-swamp areas. Trained villagers will assess and map its habitats, mark hundreds of tree and plant species using GPS, and select trees for conservation according to which are the most important langur food trees but including other common trees as well.

Horwich and his assistants will conduct three complete yearly censuses of trees, plants and animals. Data sheets will be prepared in the Assamese language for the community assistants. They'll record troop locations with GPS units and follow the langurs daily for one to two months at census time, identifying numbers, sexes and ages. Once the familiar groups are censused and mapped, other areas will be searched for any potentially missed troops. An additional three troops will be selected for more intensive studies based on relative tree density (good forest, degraded forest and highly degraded forest). Community assistants will compile lists of plant species and parts that the troops eat.

Census data analysis will include habitat assessment and mapping, tree phenology-including seasonal graphs of fruits, leaves and flowers-troop censuses and home range estimation, and langur ecology and behavior. Studies of the three selected troops will include behavior graphs for individual days, months and seasons. Estimation of amount of intervals feeding on specific foods will be tabulated to determine the percentage of time spent feeding on certain species and food types. Horwich and his team will compare feeding behavior among sexes and ages, and compile a list of all food species and plant parts. Arnab Bose and Raju Das, the main project researchers, will also evaluate the community effort aspect.

"Overall, our conservation efforts on two forests seem to be showing success, which we hope to monitor yearly," Horwich said. "In both the Kakoijana and the Nadangiri Reserve Forests, surrounding villages are replanting and protecting forest sections and we are helping them to form federations for regional forest protection." Reserve forests do not have as much protection as wildlife sanctuaries or national parks, he explained, so raising community awareness and creating community groups and organizations to protect the Reserve Forests serves an important function.

"Thus, through this project, we will use Kakoijana as a model to determine the effectiveness of the conservation effort," Horwich said. "While these communities are already actively reforesting and protecting Kakoijana, the additional incentives from working on the project and learning more about the golden langurs and the forests will add to the villagers' involvement and ownership of the project."

The project will run from January to December 2008. Some data-taking is already occurring for two troops in the Kakoijana area. The Jacobsen grant will fund personnel, including the hiring and training of additional community research assistants, to total 15-20, plus on-site transportation, binoculars and GPS units. During that time, the participants will also complete mapping of the study sites. Continual data will then be taken for the next ten months, ending at the end of December 2008, to complete the grant cycle. Additional data will be taken in 2009 to complete a 12-month yearly cycle.

The Lawrence Jacobsen WNPRC Conservation Research Award supports studies in applied conservation biology that protect nonhuman primate species in their habitat. Preference is given to those working directly with a nonhuman primate species on the IUCN threatened or endangered list. The annual, $5,000 award is available to students and faculty who are affiliated with an academic institution or a non-governmental agency with a focus on primate conservation. Larry Jacobsen was director of the Primate Center Library from 1973-2003. His many honors have included the Distinguished Service Award from the American Society of Primatologists in 1997 and the Library of the Year Award from the Wisconsin Library Association in 1995. Anne Savage, conservation biologist at Disney's Animal Kingdom, was chair of the first award committee.

The Wisconsin National Primate Research Center at the University of Wisconsin-Madison is one of eight federally supported (NIH-NCRR) National Primate Research Centers and the only one in the Midwest. More than 250 center scientists, through competitive grants, conduct research in primate biology with relevance to human and animal health.

Catching up with physician, researcher Paul Kaufman

Paul Kaufman, Professor and Chair of the Department of Ophthalmology and Visual Sciences, School of Medicine and Public Health, has been an affiliate of the Primate Center since 1978. We last featured him in Centerline in Fall 1997. Kaufman uses WNPRC Pathology and Surgery Services to conduct monkey studies supporting the understanding of presbyopia and glaucoma and their therapies.

His glaucoma research involves studies of the physiology, pharmacology, morphology, neural control and aging of the aqueous humor formation and drainage and accommodative mechanisms in the non-human primate, seeking to understand the pathophysiology and develop new therapies for the human diseases of glaucoma and presbyopia. Glaucoma is the second most common cause of irreversible visual loss in adult Americans (and the most common among Black Americans), while presbyopia is the most common of all ocular afflictions.

The specific aims of his current studies are to (1) determine the effects of long-term in vivo therapy with viral vector transgenes that modulate the cytoskeleton; (2) determine the mechanisms of intraocular pressure (IOP) reduction of other classes of potential glaucoma pharmacotherapeutic agents and their interactions; (3) determine the effects in organ-cultured anterior segments and in vivo of agents that could potentially alter aqueous humor outflow.

His work related to the use of cytoskeletal drugs to lower IOP has resulted in several patents, one of which has resulted in the development of a novel glaucoma therapy that is now in clinical trials in humans. In 2006, he received the Ernst Bárány prize from the International Society for Eye Research for his lifelong body of work related to this area.

His collaborative research endeavors have demonstrated that central nervous system changes that occur in glaucoma may be an important target for glaucoma therapy if visual loss is to be prevented or reversed.

His second major area of research involves studies of presbyopia, the age-related loss of the ability to accommodate, which is the most common ocular affliction affecting every human over the age of 45 years. Its pathophysiology is poorly understood. In the rhesus monkey, the only known animal model for the human condition, the ciliary muscle loses its configurational response to cholinomimetic drugs or central stimulation with age. Although some evidence suggests that this loss of mobility may be due to restriction by a progressively inelastic posterior attachment, it is not clear that the muscle's contractile machinery continues to function normally, nor what roles the lens and zonule might play. The long-term goals of this research are to understand the mechanism of accommodation, to characterize the factors leading to the loss of accommodative amplitude at the organ, tissue, and supramolecular levels, and to develop strategies to retard, or even reverse, the progression of presbyopia. His presbyopia related studies (in rhesus monkeys encompassing the entire species lifespan) will determine; (1) the real-time dynamics of ciliary muscle, lenticular and zonular movement in response to midbrain stimulation in living surgically aniridic animals, by digital image analysis of Scheimpflug and goniovideographic recordings; and (2) the effect of extra-and intra-capsular lens extraction, and regional zonulolysis on these real-time dynamics.

One important finding of this research has been there is sufficient movement remaining in the aging ciliary body and lens capsule to allow functioning of an accommodating intraocular lens.

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Ultrasound biomicroscopic images of the temporal quadrants in three normal iridectomized monkey eyes ages 6 (A, D), 15 (B, E) and 23 (C, F) years in the unaccommodated and accommodated states. The degrees represent the angle between the anterior aspect of the ciliary body (CB) and the inner aspect of the cornea (CB-cornea angle). During centrally stimulated accommodation (focusing), the CB moved forward and inward, and its anterior aspect (D, white arrowhead) moved past the scleral spur at higher accommodative amplitudes in the young eye but not in the older eye. The anterior aspect of the CB did not move past the scleral spur at any stimulus current in the older presbyopic eye and did not form an acute angle with the inner aspect of the cornea. The young eye accommodated 11.25 D and the older presbyopic eye accommodated 3.25 D. From (Croft et al., 2006) (Photo courtesy of the Kaufman lab.)

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Kaufman is also on the faculty of Animal Health and Biomedical Sciences. He was named a Best Doctor in America ® in 2006, and maintains an active clinical, training and teaching, research and lecture schedule. He gives many lectures nationally and international each year. He also serves on several advisory boards for vision research foundations and is a consultant for several pharmaceutical companies. He has just completed several years as executive vice-president for ARVO - the largest international ophthalmology research meeting. He is about to take on a new role as editor of a major ophthalmology journal - Investigative Ophthalmology and Visual Science.

Kaufman lab web page

Researchers seek early detection for hard-to-diagnose disease

By Jordana Lenon
UW-Madison press release, April 10, 2007

Polycystic ovary syndrome (PCOS) is characterized by infertility due to anovulation, abnormal secretion of androgens and other hormones, and insulin resistance. PCOS is the most common female endocrine disorder, affecting 4-7 percent of women in their reproductive years - the syndrome accounts for 75 percent of all anovulations. PCOS has staggering adverse physiological, psychological and financial consequences for women's reproductive health.

With funding from the Wisconsin Institutes for Discovery (WID) seed grant program, UW-Madison scientists will now use their collective expertise to develop the first diagnostic test for PCOS.

The interdisciplinary nature of the work requires four equal principle investigators leading a team of 12 researchers. Leaders are Fariba Assadi-Porter, staff scientist of biochemistry; Hamid Eghbalnia, assistant scientist of biochemistry and mathematics; Michael Shortreed, associate scientist of chemistry; and Leah Whigham, associate scientist of obstetrics and gynecology. They will steer efforts to develop a novel "metabolic analysis" method to detect and statistically model changes in a subset of molecules within the body's total pool of metabolites that have proven to be reliable, early indicators of PCOS.

The method will derive from measuring biomarkers in women as well as in rhesus monkeys with PCOS at the Wisconsin National Primate Research Center. These animals have been well characterized and studied during the past two decades by David Abbott, professor of obstetrics and gynecology.

"The idea is to use a nonhuman primate model of PCOS in parallel with human samples to develop a novel diagnostic test," says Assadi-Porter. "With this, we will begin to analyze patient samples to develop the portrait of PCOS in humans. Our approach could be used to develop similar tests for a variety of other diseases."

The strength of the team's grant application was its description of a highly innovative and challenging approach that uses a combination of technologies and resources unique to UW-Madison. The researchers plan to use stable isotopes, NMR, MS and advanced mathematical computation, which are all centered around clinical and medical sciences with broad clinical applications. The investigators also established their project's relevance to the WID mission of advancing knowledge, inventions, treatments, cures and economic development through their previous patents with the Wisconsin Alumni Research Foundation for several inventions related to this proposal.

The other team members are animal sciences professor Mark Cook, obstetrics and gynecology professor Steven Lindheim, biochemistry professor John Markley, zoology professor Warren Porter, chemistry professor Lloyd Smith, and researchers Daniel Butz and Marco Tonelli.

Primates contribute to obesity research

Nikhil Dhurandhar, a long-time WNPRC affiliate in obesity research at the Pennington Biomedical Research Center, made headlines in August with research advances showing how adenovirus-36 can cause obesity in humans.

Dr. Nikhil Dhurandhar has also collaborated with several scientists at the Wisconsin National Primate Research Center to study the effects of adenovirus-36 in nonhuman primates.

*Atkinson RL, Dhurandhar NV, Allison DB, Bowen RL, Israel BA, Albu JB, Augustus AS. Human adenovirus-36 is associated with increased body weight and paradoxical reduction of serum lipids. Int J Obes Relat Metab Disord. 2005 Mar;29(3):281-6.

*Dhurandhar NV, Whigham LD, Abbott DH, Schultz-Darken NJ, Israel BA, Bradley SM, Kemnitz JW, Allison DB, Atkinson RL. Human adenovirus Ad-36 promotes weight gain in male rhesus and marmoset monkeys. J Nutr. 2002 Oct;132(10):3155-60.

*Cites the Wisconsin National Primate Research Center

See also: Contagious Obesity? Identifying The Human Adenoviruses That May Make Us Fat

Marmoset curiosity

Countless visitors have enjoyed viewing and learning about the common marmoset (Callithrix jacchus) since this live animal display originated at the Primate Center 15 years ago, moving to its present location in the Primate Center's main lobby in 2002. (J. Lenon photo)