Author: sansom

Women scientists lead efforts to fight cancer

Vivienne Rebel, M.D., Ph.D., assistant professor of cellular and structural biology, and Gail Tomlinson, M.D., Ph.D., professor of pediatrics, are two women in science who play crucial roles at the Greehey Children’s Cancer Research Institute. Dr. Rebel dedicates her time to research that could one day translate to new therapies, while Dr. Tomlinson cares for seriously ill children and seeks to translate research discoveries.

Dr. Tomlinson, who holds the Greehey Distinguished Chair in the Genetics of Cancer, is division chief of hematology-oncology. She also holds the Greehey Distinguished Chair for the Children’s Cancer Research Institute Director at the Greehey Institute where she serves as interim director. She sees hospitalized children and has a grant from the Cancer Prevention and Research Institute of Texas (CPRIT) to study pediatric liver cancer. This work is developing into a national and international clinical research trial.

Dr. Rebel investigates the properties of stem cells in a bone marrow disease called myelodysplastic syndrome (MDS). "Stem cells are the only cells in the body that have a seemingly unlimited capacity to proliferate, just like cancer cells," she said. "I thought that by studying stem cells, we may learn about cancer." Dr. Rebel’s laboratory is using a mouse model to try to understand what is going wrong in the production of blood-forming stem cells that may eventually lead to MDS and, in some cases, to leukemia. "It is thought that the culprit cell of MDS is the blood-forming stem cell," she said.

Dr. Tomlinson became intrigued by the molecular basis of cancer while a biochemistry student at Duke University. "I was interested in how some of the biochemical findings could influence the cure of pediatric diseases such as leukemia," she said. "After I became more established, I focused my efforts on understanding genetic causes of pediatric tumors, all with a translational goal in mind to help guide therapies or understand causes so that, whenever possible, diseases could be prevented or detected early. Most pediatric cancers have historically not been thought to be preventable. It is a goal, albeit a long way out."

Dr. Tomlinson is principal investigator on a $2.7 million CPRIT grant to empower health-care providers to map out cancer risks of their patients and to share information about family history as an important factor. The grant, awarded in 2012, also supports screening services for people at high risk for cancer who may not have adequate access to screening.

Dr. Rebel admires women scientists such as Bettie Sue Masters, Ph.D., the Robert A. Welch Foundation Distinguished Chair in Chemistry at the Health Science Center. "Dr. Masters is amazing," Dr. Rebel said. "She has faced the real difficulty of being from a generation when being a woman scientist wasn’t easy. Over time, there has been improvement." Dr. Rebel also greatly respects Dr. Tomlinson for juggling both a clinic schedule and the institute. "I decided to stay with research and not go into the clinic," she said.

As these two women apply their intellect, compassion and resources to understanding pediatric cancers, the children of Texas and the world are the beneficiaries.

by sansom

Outsmarting osteoporosis

Virginia Bowden, Ph.D., loves the slopes of Telluride, Colo., where she and her husband, Charles Bowden, M.D., own a condominium. "We’ve been skiing since the 1970s, currently about 30 days a year," she said. "For me the appeal is the mountain views." In 1997 she fractured her hip while skiing at Winter Park. The bone did not heal after the Colorado surgeon inserted a pin, so the following year she underwent a hip replacement at University Hospital in San Antonio. The surgeon sent a bone specimen for clinical testing, which revealed osteoporosis.

Nearly 40 million Americans suffer from osteoporosis or are at high risk for it, according to the National Institutes of Health. This bone-thinning disease is expected to cause fractures that, by 2025, will have cost patients $25 billion to repair. Osteoporosis is most common in post-menopausal Caucasian women, some of whom live their days with the knowledge that a fracture can result from stumping a toe, getting into bed or sneezing. There is great need for translational research to speed scientific discoveries to patients. Two exciting findings in the Long School of Medicine at the UT Health Science Center San Antonio hold new promise to reduce the suffering caused by bone loss.

Dr. Bowden, director emeritus of the Health Science Center libraries, is a patient of Jan Bruder, M.D., endocrinologist with UT Health Physicians, the clinical practice of the Long School of Medicine. Dr. Bruder sees patients during a weekly osteoporosis consult clinic at the Medical Arts & Research Center. "I’ve been going to Dr. Bruder annually since that time," Dr. Bowden said. "I know what my treatment is, and I think in some ways it was good to find out I had this tendency, so I know to take my calcium, exercise and do the things I should do anyway."

Bone is constantly remodeling — older bone is removed and new bone forms. Exercise places mechanical loads on bone, resulting in a healthy balance of new and old. "The need for regular exercise extends far beyond its role in reducing body fat to maintain a healthy body," said Jean Jiang, Ph.D., professor of biochemistry in the Long School of Medicine and member of the Sam and Ann Barshop Institute for Longevity and Aging Studies. "It is equally important for maintaining healthy bones to avoid osteoporosis and bone loss during aging."

Dr. Jiang’s laboratory discovered novel information about how bones, one, sense the loads being applied to them and, two, release growth factors to build new bone. The report in Proceedings of the National Academy of Sciencesspurred sufficient interest to become an Editor’s Choice article in the journalScience.

Dr. Jiang’s team discovered a lock-and-key system in load-sensing cells. A protein (integrin α5) acts as a key to open the locks, which are channels on the cells’ surface. This releases molecules that trigger bone remodeling. "Our study links the effect of mechanical forces directly to the anabolic (or growth) function of the bone," Dr. Jiang said. "This novel finding could be very useful for development of therapeutic targets to promote the opening of the channels and permit the release of bone growth factors."

Such knowledge could prevent the bone weakening and loss caused by osteoporosis, she said.

Barshop Institute member Brian Herman, Ph.D., is professor of cellular and structural biology in the Long School of Medicine, special assistant to the president of the Health Science Center and a Chancellor’s Health Fellow in Collaboration with The University of Texas System. His team published studies on age-related osteoporosis in mice. The Herman laboratory found that increasing the genetic expression of a protein called caspase 2 prevented osteoporosis development in the rodents. Their bones were 30 percent stronger than the bones of mice lacking caspase 2 expression.

"We are looking at whether caspase 2 can enhance fracture healing," Dr. Herman said. "Our plan is to license technology based on this finding or think about starting a company ourselves."

More-effective, better-tolerated treatments for bone health are needed. Bisphosphonates are the most frequently prescribed medications for osteoporosis. With continuing use, these drugs can cause nausea, abdominal pain, difficulty swallowing and risk of esophageal inflammation and ulcers. In 2010 the National Osteoporosis Foundation issued new treatment recommendations; one was for patients to take drug holidays. "There are side effects of long-term treatment of osteoporosis, and based on bone density and risk factors some people who were previously started on therapy would not be started today," Dr. Bruder, also a Barshop Institute member, said. "This is not to say that patients can go untreated, however. If you need to be on therapy, you need to be on it."

Dr. Bowden served the Health Science Center from 1970 to 2003, including as library director from 1985 to 2003. Her osteoporosis medication is re-evaluated once a year. For three years she received an annual infusion; Dr. Bruder said it was not necessary this year.

The loads from exercise on the Colorado snow continue to strengthen her bones. "I’m still skiing," Dr. Bowden said. "I stick with the intermediate-level areas and try not to fall. I was knocked down this past year on Christmas Eve by a snowboarder and broke my collarbone. The ski patrol came quickly and took me to the clinic. The bone healed within a month and I was skiing again. It (osteoporosis) hasn’t slowed me down."

by sansom

Clues from clams and hydra

Steven Austad, Ph.D., professor of cellular and structural biology, points to clams in an aquarium at the Sam and Ann Barshop Institute for Longevity and Aging Studies. The institute is part of at the UT Health Science Center at San Antonio. "The lighter ones, typically called ‘hard clams,’ are served in restaurants and live 100 years," he says. "The darker ones, called 'ocean quahogs,' live 400 to 500 years. These clams are older than any other living animal."

It’s a little-known fact that clams have beating hearts. "Its heart beats slower than the human heart but it lives much, much longer," Dr. Austad says. "In fact, it beats as many times as the human heart over its lifetime." To determine the age of a clam, its shell is cut open with a diamond saw and its internal rings are counted. From examining the width of these rings, which is much like reading a bar code, marine biologists study ancient ocean conditions.

In another room, Dr. Austad encourages visitors to peer through a microscope at hydra — small polyps typically found on the underside of aquatic vegetation in freshwater pools and streams. These fascinating invertebrates don’t age and have virtually unlimited regenerative potential. He compares hydra to a villain from one of the "Terminator" movies who, whenever shot or otherwise maimed, pools himself back together. Hydra species can be disassembled into "a pile of cells that remarkably can reassemble themselves into a whole hydra again," Dr. Austad says.

Dr. Austad, interim director of the Barshop Institute, studies the comparative biology of aging.The field asks questions about species because of their exceptionally slow or rapid aging rates. The goal is to understand the unknown and unexplored mechanisms of aging. What causes us to age? What factors, both genetic and environmental, impact the process?

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In clams, he is assessing the rate of protein turnover. In hydra, he is inducing the polyps to reproduce, which ends the polyps’ immortal status and sets them on the path of aging. "This tells us which genes are important," Dr. Austad says. In one of his many scientific articles, he writes of the hydra: "Thus, we have the intriguing phenomenon that aging and its absence can potentially both be observed in the same species."

Mexican free-tail bats, selected small nonhuman primates, and birds such as budgerigars, canaries and zebra finches are also under study or are candidates for study. Because of new cellular and molecular techniques for investigating novel species, "the new comparative biology of aging is poised to dwarf earlier contributions," Dr. Austad says.

by sansom

Preserving memory

After the 40th birthday it becomes necessary to write notes — and then try to remember the location of the notepad. Learning and memory decline with age, and for some the cliff is Alzheimer’s disease. Thankfully, scientists from the Sam and Ann Barshop Institute for Longevity and Aging Studies at the UT Health Science Center at San Antonio are studying a compound that could rescue our flagging memories.

The researchers added a bacterial product — rapamycin — to the diet of healthy mice throughout their life span. Rapamycin, first isolated from soil on Easter Island, enhanced learning and memory in young mice and improved these faculties in old mice, studies showed.

"We made the young ones learn, and remember what they learned, better than what is normal," said the Barshop Institute’s Veronica Galvan, Ph.D., assistant professor of physiology in the Long School of Medicine. "Among the older mice, the ones fed with a diet including rapamycin had an improvement, negating the normal decline you see in these functions with age."

The drug also lowered anxiety and depression-like behavior in the mice; anxiety and depression are factors that impair human cognitive performance. Jonathan Halloran of the Galvan laboratory conducted scientifically reliable tests to measure these cognitive components in the rodents.

Mice are burrowers and are happy in a tunnel with walls. Halloran used an elevated maze of tunnels leading to a catwalk without walls. "All of a sudden the mice are in open space," Halloran said. "It’s pretty far from the floor for their size, sort of like if you’re hiking and all of a sudden the trail gets steep. It’s pretty far down and not so comfortable."

Mice with less anxiety are more curious to explore the catwalk. "We observed that the mice fed with a diet containing rapamycin spent significantly more time out in the open arms of the catwalk than the animals fed with a regular diet," Halloran said.

The second test measured depression-like behavior in the rodents. Mice do not like to be held by their tails, which is the way they are moved from cage to cage. Inevitably they struggle to find a way out. "How much and how often they struggle is a measure of the motivation they have to get out of an uncomfortable situation," Dr. Galvan said.

Some mice barely struggle to get free, but if an antidepressant is administered they struggle a lot more. "We found rapamycin acts like an antidepressant — it increases the time the mice are trying to get out of the situation," Dr. Galvan said. Anxiety and depression-like behavior decreased in all ages of mice fed with the rapamycin-enhanced diet.

The researchers measured levels of three "happy, feel-good" neurotransmitters: serotonin, dopamine and norepinephrine. All were significantly augmented in the midbrains of mice treated with rapamycin. "This is super-interesting, something we are going to pursue in the lab," Dr. Galvan said.

Rapamycin rescued learning and memory in mice affected by Alzheimer’s-like deficits, the team previously reported. In the new studies, the enhancements are demonstrated even in healthy mice. The elevation of the three neurotransmitters, which are chemical messengers in the brain, may explain how rapamycin accomplished this, Dr. Galvan said.

Rapamycin is an antifungal agent administered to transplant patients to prevent organ rejection. The drug is named for Rapa Nui, the Polynesian title for Easter Island. This island, 2,000 miles from any population centers, is the famed site of nearly 900 monolithic statues (pictured above). If rapamycin proves to be a suitable therapy for human cognition, this mysterious atoll could be called the Easter Island of learning and memory.

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by sansom

The CTRC A-Team

In the ongoing battle against a deadly disease, the Cancer Therapy & Research Center has assembled the ultimate team of professionals.

In November 2007 Texas voters passed Proposition 15, the constitutional amendment that established the Cancer Prevention and Research Institute of Texas (CPRIT). The amendment authorizes the issuance of $3 billion in bonds to support the institute, which exists to enhance cancer research, prevention and control programs across Texas.

Thanks to this historic vote, biochemist Dmitri Ivanov, Ph.D., is the inaugural CPRIT Scholar in Cancer Research at the UT Health Science Center San Antonio.

Ask Dr. Ivanov and he will tell you: The excitement of scientific discovery is in his veins.

He grew up in St. Petersburg, Russia, the son of two material scientists. His father, Dr. Nikolay Ivanov, is a plastics expert and his mother, Dr. Raisa Grishmanovskaya, is an expert in stainless steel. "In general, the reason I came into science is that I came from a family of scientists," the younger Ivanov said.

His interest in cancer is personal, given that his father was diagnosed with bladder cancer in 2005 when Dr. Dmitri Ivanov was a postdoctoral research fellow at Harvard Medical School. "That stimulated an interest in using my expertise to fight cancer," he said.

His research examines how cells repair damage to their genetic instructions, called DNA. Cells respond to genetic insults wreaked by environmental factors, ultraviolet radiation in sunlight, and oxidative stress generated by the cells’ own energy consumption. Efficient DNA repair should be a good thing, but tumor cells take advantage of it for nefarious purposes, namely to grow. "What intrigues us is there are a lot of very intimate connections between DNA repair pathways and signaling pathways that are deregulated in cancer," Dr. Ivanov said.

Thanks to the CPRIT Scholar grant, which is $2 million over four years, Dr. Ivanov’s research program in San Antonio is getting a strong start. At Harvard he helped identify a potential target for inhibition of one of the key DNA repair pathways, called nucleotide excision repair. At the Health Science Center he wants to expand into different DNA repair pathways. "In particular we will study the Fanconi anemia pathway," he said. "Fanconi anemia is a rare genetic disorder. People with Fanconi anemia have this DNA repair pathway impaired, and one of the hallmarks of the disorder is high incidence of cancer. We will investigate whether this pathway could be targeted for anti-cancer therapy."

Because cancers can use DNA repair to survive, lowering the amount of repair activity can curb tumor growth while still enabling healthy cells to enact repairs.

Dr. Ivanov used a battlefield analogy: "In combat you don’t want to explode a big bomb that kills your enemy but kills your own troops, too. You want your bomb to go to a specific location or not go to a specific location. Similarly, we would like to be more discriminate in the way we block protein function. We don’t want the bomb to go where our own troops, aka the healthy cells, are."

Dr. Ivanov has an ambitious research agenda and is willing to take risks on new ideas. "The CPRIT program really gives us the luxury to be innovative and try new things," he said. "When you are a young scientist, you are more likely to take the unexpected route. CPRIT’s support is an invaluable resource for scientists at the early stages of their careers."

Bruce J. Nicholson, Ph.D., professor and chairman of biochemistry in the Graduate School of Biomedical Sciences, spoke about the team of scientists in San Antonio working on discoveries that have potential to be carried into clinical trials.

"Dr. Ivanov’s arrival is a key component of our plan to build a team of biochemists who will provide essential insights into the structure of multi-molecular complexes essential to the control of many cell processes. The knowledge of these structures is being used in the development of anti-cancer agents that can be tested in Phase I clinical trials [first-time use in humans] at the Cancer Therapy& Research Center at the UT Health Science Center.

"Coordinated with expanding efforts in medicinal chemistry and high-throughput screening in collaboration with The University of Texas at San Antonio and Southwest Research Institute, drug discovery is undergoing a rebirth in San Antonio that promises exciting prospects for the near future."

by sansom