© 2011 Fort Worth, Texas magazine Reprinted by Permission

A two-issue feature on UNT Health Science Center research in the October and November 2011 issues of Fort Worth, Texas magazine

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Bench to BedsideCollaboration. Consortium. Commercialization: Words you hear

often at the University of North Texas Health Science Center.by Gail Bennison

The knowledge or technology needed to save your life may already exist in laboratories and research projects but is too far down in the pipeline to help you when you need it now.

“It takes an average of 13 years to introduce a new proven meth-odology to the practice of medicine,” said University of North Texas Health Science Center President Dr. Scott Ransom.

Under Ransom’s leadership, UNTHSC is encouraging and supporting research from basic lab work through clinical trials to commercial applications. That involves cooperation among uni-versities and medical centers in North Texas and elsewhere and with commercial and other collaborative ventures that will take the research product to market.

Research funding at the center reached an all-time high of nearly $40 million in 2010 — up nearly 300 percent in just 10 years. Federal funding is around 75 to 80 percent, says Vice President for Research Dr. Glenn Dillon. Overall funding has been relatively flat on average

for the past several years, but the federal stimulus bill put money into the National Institutes of Health research budget for 2009 and 2010.

“Private industry is up about 8 percent. That’s an area where we continue to grow. Everybody has heard about the tightening, and one of our strategies is to diversify our funding through partnerships,” Dillon said.

“We’ve been on a tear the past decade,” said Dillon. “We’ve gotten great people who like to think collaboratively, so we can build teams to get those big grants. Once we get people to visit, we can usually seal the deal.”

In this issue of the magazine and next month’s edition, we’ll intro-duce you to the men and women and the institutions and businesses involved in this far-reaching effort.

To introduce this two-part series, we look at both efforts to develop new and quicker ways to identify cancer and also at research projects that have implications for detection and treatment of Alzheimer’s disease and autism.

One treatment for autistic children is to encourage inter-action with others, something often difficult for them. But the work of UTA Professor Dr. Dan Popa and UNTHSC' Professor Dr. Nicoleta Bug-nariu indicates that those with Autism Spectrum Disorder (ASD) may communicate more easily with robots.

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Step by StepWhen we walk, we use three sensory inputs to let us know where our body is in space — what we see, the sensation from our feet and our inner ears. Aging or neurological loss can create balance problems.

“As long as you’re looking where you’re walking, you’re fine, but as soon as you look up, problems arise,” says Dr. Nicoleta Bugnariu, associate professor of physical therapy at UNTHSC. “The moment you have a second task, like turning your head to speak with someone, you still have to walk and keep your balance, but a lot of people expe-rience falls when they have to do more than just walk.”

Bugnariu is conducting clinical research with Janice Knebl, DO, Endowed Reynolds Chair of Geriatrics and professor of internal medicine, and Rita Patterson, Ph.D., professor of manipulative medi-

cine, to analyze and treat gait and balance problems using virtual reality equipment called the V-Gait Computer Assisted Rehabilitation Environments (CAREN) system.

The technology is used by the military to deal with wounded sol-diers, but the research has implications for balance and other mobility problems for civilians and offers the possibility of early detection of autism. The CAREN system combines an instrumented self-paced, dual-belt treadmill with real-time motion capture and a three-dimensional interactive virtual environment.

The Health Science Center is one of only five locations — the only academic institution — to house this system. The U.S. Department of Defense owns the other four, which are used mostly for therapy on lower extremities.

Bugnariu said this research will help with understanding sensory-motor integration, leading to new and better rehabilitation therapies.

Bugnariu collaborates with Advanced Arm Dynamics and the Osteopathic Manipulative Medicine and Osteopathic Surgery departments to learn the best training methods for upper-extremity amputees. The team also collaborates with Texas Medical Research Collaborative, which includes Texas Health Resources, Texas Instru-ments, the University of Texas at Dallas and the University of Texas at Arlington.

Autism DetectionAn exciting implication of the research is that it may provide a way to identify autism in children earlier than has previously been possible.

“We present them with virtual environment like a game,” Bug-nariu said. “They explore the game, which allows us to monitor and record the performance of motor and postural tasks. A motion analy-sis system and force plates embedded in the system collect movement data as children sit, stand, walk or reach for objects in the virtual environments.”

In addition, Bugnariu is working with Dr. Dan Popa, associate professor with the electrical engineering department and the Auto-mation & Robotics Research Institute at UTA. Popa created a unique robot that potentially could help children with Autism Spectrum Disorder (ASD) more easily interact with other people.

Autism spectrum disorders are the most common pediatric diag-noses in the U.S. at one in 110 children with 36,500 new cases detected annually. It is a costly disability — up to $3.2 million over a lifetime for an individual with ASD. Bugnariu believes early and intensive behaviorally based multidisciplinary treatment is effective.

Diagnosis is now made mostly based on how children can socialize or verbalize.

“Reliable and valid diagnosis for an ASD child is currently not possible before 18 to 24 months because early social communicative behaviors look intact before the first birthday in most infants later diagnosed with ASD,” Bugnariu said. “Because the treatments are delayed, the outcomes are worse.”

But there may be another way — by analyzing how their bodies work.

“Prior to actually being able to interact with others or talk, they learn to roll, crawl or walk. The motor development is the first lan-

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Dr. Nicoleta Bugnariu is optimistic that the V-Gait Computer Assisted Rehabilitation Environments (CAREN) system may provide a way for early detection of autism in children. Pictured right and this page, the equipment assesses gait and motion issues through a range of motions. The military has made extensive use of the system.

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guage of any child,” Bugnariu said. There are differences in control and balance when scientists com-

pare how autistic children walk or run or use other motor skills.“Looking at that, we thought maybe we could identify what is

different in their first year of life and use that as a marker. If we see a specific delay, a pediatrician could use that as an earlier diagnosis, and it could be treated earlier,” she said.

A Robot FriendChildren with autism often have difficulty interacting with other people. But Popa’s research may provide a way past that issue.

The robot looks very much like a small boy about 2 feet tall. The robot’s face is expressive and has cameras for eyes so it can monitor what the child does. It can interact with children from a distance or up close.

And it can initiate behaviors — look at me, follow me, imitate my facial gestures, imitate my head-eye motion, hand extension and grasping, hand waving, verbal dialog, emotion recognition and head, face and hand coordination.

“We had this robot taken to the Dallas treatment center, and chil-dren that previously had no interest in toys interacted with the robot,” Bugnariu said. “They had a very good reaction to it. We think that this can serve as a transition from non-human to human interaction.”

Shining LightMajor technological advances have been made in the life sciences over the past two decades, and one of the fastest growing areas is fluores-cence-based detection and fluorescence imaging.

In lay terms, fluorescence can be used to light up specific cells or parts of cells — the markers — and allows scientists to track cell growth, abnormalities and the like — critical to finding new treatments and cures for many diseases, including cancer and heart disease.

In September 2005, two brothers from Poland, both with Ph.D.s and an interest in fluorescence spectroscopy, came to UNT Health Science Center. Two years later, with the support of a $2.27 mil-lion Emerging Technology Fund grant, UNTHSC established a new Center for Commercialization of Fluorescence Technology (CCFT). Today, the brothers spearhead the CCFT.

Ignacy Gryczynski, a professor of cell biology and genetics, and Zygmunt “Karol” Gryczynski, a professor of molecular biology and immunology, are taking this technology out of the research arena and developing new applications for the world of medicine.

The technology has a vast array of potential life-saving and life-enhancing applications, from monitoring minute changes in human cells, which can lead to earlier diagnosis of disease to the detection of biohazardous materials.

The mission of CCFT is to merge modern fluorescence with nanotechnology to create research and biomedical diagnostics for the 21st century, Karol Gryczynski said. Nanotechnology explores micro-scopic particles, whose size is measured in increments of one-billionth of a meter.

“For the last few years, we have been focused on development of new molecular probes and markers for fluorescence-based detection and imaging,” Karol said. “Over the last three years, we have been involved in over 50 collaborative projects that included Texas, the U.S. and international institutions.”

Those partners include CCFT, Texas Christian University, the University of Maryland and the University of Copenhagen. The proj-ect was funded by the National Institutes of Health (NIH).

“In the initial stage, we are focusing on breast cancer markers for early cancer detection through a simple blood test,” Karol said.

A project in collaboration with the University of Florida, funded by NIH, is focused on Familial Hypertrophic Cardiomyopathy (FHC), which he described as “a tragic disease occurring in young athletes.” A project involving Omm Scientific in Dallas and CCFT, funded by a NIH Small Business and Innovative Research grant, will advance sensitive detection of micro-RNA, Karol said.

Brothers Ignacy Gryczynski and Zyg-munt “Karol” Gryczynski believe tomor-row’s medical diagnostic technologies will resemble what’s now seen in science fiction movies. In this photograph, Julian Boredo who works with the brothers is in the foreground with Karol Gryczynski behind him.

Courtesy UNTHSC/Jeremy Enlow/Steel Shutter

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“In the last year working with the cancer center at UNTHSC and the physics department at TCU, we are developing new nanoparticles for cancer recognition and detection, cancer diagnostics, therapy and treatment, along with post-treatment evaluation and imaging,” Karol said. “Combining all these properties in single nanoparticles leads us to new theranostic nanoparticles that have chance to quickly move to clinical applications and revolutionize the future of cancer treatment.”

The Gryczynskis believe the future is to allow physicists, chemists and medical doctors to work together comfortably.

“As you may realize, this is not an easy task,” Karol said. “Typically, all branches of medicine speak a different language. TCU has excellent students in physics and chemistry that can work with biomedical sci-ences students at the Health Science Center.”

With Karol’s primary affiliation with the physics department at TCU and with his brother at the Health Science Center, Karol believes what they are building cooperatively will result in one of the largest fluorescence-based resources in the world.

“New detection technologies and devices for disease diagnostics and tissue imaging will dominate the medicine of tomorrow,” Ignacy said.

“Diagnostic devices that will emerge from research such as ours are likely to resemble those seen in today’s futuristic movies such as Star Trek,” brother Karol added.

Hormones and Alzheimer’sBecause hormones such as estrogen and progesterone decline after menopause, a woman’s risk for diseases, including osteoporosis, heart disease and Alzheimer’s, increases significantly. Post-menopausal women are two to three times more likely than men to develop Alzheimer’s.

Hormone therapy was a common treatment protocol, but in 2002, data from the Women’s Health Initiative (WHI) concluded that it was not effective and might have adverse effects. Many physicians began recommending that patients not take hormones.

“At the time, I had a couple of colleagues who said, ‘The only way you are going to take my estrogen is if you strip it out of my cold dead hands,’ ” Dr. Meharvan “Sonny” Singh, associate professor of pharma-cology and neuroscience at UNTHSC, said with a laugh.

Patients also rebelled“A week or two went by, and I heard the knocking on the door. The women who were on it said, ‘I’m really not feeling terribly good right now; can you put me on it again?’ So a lot of women considered the therapy in spite of what the media was presenting.” Singh said.

In reality, the data did not warrant such broad generalizations, and the WHI report literally robbed women of options, said Singh. The question became which women should or should not have hormone replacement, and Singh and a group of scientists at the center are searching for a simple solution to provide the answer.

“Since we’ve reanalyzed the data and looked at some new stud-ies, the answer is that hormone therapy and estrogen therapy is a viable option, but for a [specific] population of women,” Singh said. “The women who should not be on hormone therapy are those who are more than 10 years out after menopause or have a family history of estrogen or hormone-induced cancers. An important part of our ongoing research is to better understand the critical window.

The current guideline suggests that up to five years of treatment is safe on a statistical average, Singh said.

Singh’s team is looking for a biomarker — a particular protein — that indicates through a simple test how a person would respond to a particular drug or hormone.

“Wouldn’t it be great for a physician to have in front of them a simple blood test result that tells them that this woman is a good can-didate for estrogen therapy or this woman is not a good candidate?” Singh said.

“Whatever treatment we consider, we always want to weigh risks against benefit. So if the biomarker shows higher risk, the physician can suggest you move on to some other alternative,” Singh said.

Coming Next Month: DNA research leading to better criminal investigations and tests that will cut the time of identification for infec-tious disease.

Dr. Meharvan “Sonny” Singh and his team are looking for a biomarker that can help physi-cians predict how a patient will respond to a particular drug or hormone therapy through use of a simple blood test.

Courtesy UNTHSC/Jeremy Enlow/Steel Shutter

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Developing new technology and techniques is only the first step in moving medical innovations from the

laboratory to the patient.

by Gail Bennison

Bench to Bedside

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Developing new technology and techniques is only the first step in moving medical innovations from the

laboratory to the patient.

by Gail Bennison

Bench to Bedside

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The traditional image of medical research is of a passionate scientist working alone in a laboratory in search of a discovery that vanquishes an age-old foe of humanity.

That doesn’t happen very often. Medical research nowadays is a complex process of collaborative effort linking many disciplines and many institutions.

Dr. Scott Ransom, president of the University of North Texas Health Science Center at Fort Worth, directs a rapidly growing academic center with schools in medicine, public health, biomedical sciences and the health professions. He’s given credit for a burst of medical research taking place at the Fort Worth campus.

Last month in the first of this two-part series, we reported on research aimed at making diagnoses easier and quicker and on research that uses existing technology meant for one thing, to search for a better and earlier way to diagnose autism in very young children.

This month we’ll tell you how software developed in Fort Worth is making it easier to track and identify criminals and about efforts to expand that technology to fight the global problem of human trafficking. And we’ll tell you about efforts to move new ideas and concepts to market.

“Creating highly effective inter-professional teams is critical to solve today's health care challenges,” Ransom said. “By utilizing the diverse expertise of the entire team, we make greater contributions to optimize health.”

It is a continuum from basic research to clinical trials to commer-cialization to creating health policy to support the use of the product across the population.

“Determining the most effective and efficient process to create the best ideas and then implement safe and effective discoveries is a major challenge,” Ransom said.

Enter Robert D. McClain, Ph.D., associate vice president for Tech-nology Transfer & Commercialization. That includes a partnership with a local business incubator, TECH Fort Worth, which UNTHSC provides with lab space and services to emerging startup companies. McClain holds nine patented industrial technologies himself.

“We have some exciting developments and partnerships here,” McClain said.

Fighting DiseaseThe name is deoxyribonucleic acid, but most of us know it as DNA, first discovered in 1869. But how that discovery is applied is an evolving science, and Arthur Eisenberg, Ph.D., is deeply involved. Eisenberg is professor and chairman of the Department of Investiga-tive Genetics at UNTHSC and co-director of the Center for Human Identification. He’s also director of the DNA “PRO Kids” Program for the United States.

“DNA is in every organism whether you’re using it to identify a child that’s been trafficked, a person who’s been murdered, a bacteria or virus or a genetic disease,” said Eisenberg.

The laboratory is the largest in the U.S. using DNA technology to identify human remains and missing persons. It is funded by the State of Texas as well as the federal government to work throughout the U.S.

“What our Institute is looking toward is trying to get a handle on genetic diseases that you may be born with,” Eisenberg said. “The earlier they can be detected, the earlier treatment can be done.”

The Institute also is focusing on infectious disease, seeking ways to more quickly identify bacteria and determine whether that particular strain is resistant to drugs in six to eight hours — or maybe less.

Planned are parallel studies in collaboration with John Peter Smith Hospital in Fort Worth. The technology is based upon mass spectroscopy, allowing scientists to look at certain genes within bacte-ria to identify it.

Although not yet FDA approved, Eisenberg’s group hopes to develop data that, in the near future, will lead to a rapid test that can save a life.

Fighting CrimeThe Institute works with the FBI, medical examiners and law enforcement agencies in the U.S. and internationally for criminal investigations. A growing application is to human trafficking, espe-cially of children.

“Human trafficking has become the largest crime in the world, and more money is being generated than in drug trafficking world-wide,” Eisenberg said. “This affects millions of young women and children every year.”

The Institute has partnered with Life Technologies and the Uni-versity of Spain/Granada on DNA-PROKids to work with countries most affected by human trafficking. The project targets Latin Amer-ica and Southeast Asia in partnership with Thailand, the Philippines, Indonesia, Chile, Japan and China.

“With our technology, we can help establish databases in countries where parents have had their children kidnapped, forced into prosti-tution rings or as child soldiers or any number of heinous crimes that are done to these children,” Eisenberg said.

That can help reunite families and provide leads for law enforce-ment agencies. The Institute has recently developed an international training program to help other countries develop DNA databases.

“The science is only as good as what we can do in sharing it and spreading it, and that’s the unique aspect here,” Eisenberg said. “Being an institution of higher learning, we get to share our technology throughout the world.”

All in the FamilyIf you watch any of the crime shows on television — NCIS, the CSI series, the Law and Order family of shows and others — you know that DNA is a central tool in the fight against crime.

But it is only as good as the databases of DNA samples available for crosschecking. The U.S. forensic DNA database, CODIS, which stores offender and crime scene DNA evidence, contains about 10 million profiles. That covers only about 3 percent of the U.S. population.

Perfect matches can be difficult, but it is possible to find partial ones. And in some cases, that may be good enough.

People related to each other have similar DNA profiles. Finding relatives of an unknown suspect can give investigators new leads in the search for a criminal.

Research into the human DNA molecule (pictured at left) offers the possibility of significant breakthroughs in medicine and has become a critical tool in criminal investigations, including the global fight against human trafficking.

by Gail Bennison

Bench to Bedside

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Last year, the UNT Health Science Center Institute of Investigative Genetics developed new software that allows “familial searching.”

“Criminal activity generally runs in families,” said Dr. Ranajit Chakraborty, professor of Forensic & Investigative Genetics and lead for the new Center for Computational Genetics.

“This is because of bad environment or economic situations, among other factors, and not because of genetics per se,” Chakraborty said. “The statistics are staggering in the sense that in some states when inmates are asked the question of how many family members have been convicted of a crime, the answer is 20 to 25 percent.”

And that can be significant.“Partial matches are very common between biological relatives,”

said Dr. Jianye Ge, assistant professor of Forensic & Investigative Genetics. Ge wrote the software called MPKin FS edition™ while he

was a Ph.D. candidate under Chakraborty’s professorship. The new software searches the database and ranks partial matches by kinship.

The software has been tested with the help of the Texas Depart-ment of Public Safety and has been used in several crime laboratories.

“We wanted to eliminate false leads and make the system more efficient,” said Chakraborty. “Now we have a useful tool for investiga-tion.”

Testing for Alzheimer’s DiseaseAlzheimer’s is the sixth leading cause of death in the nation. Perhaps 15,000 people have the disease in Tarrant County alone. Since 2005, the Texas Alzheimer’s Researching Consortium (TARC) has been seeking ways to improve prevention, early detection and treatment of the most common form of dementia.

UNT Health Science Center’s Dr. Robert Barber, associate profes-sor of Pharmacology and Neuroscience, serves as TARC’s Scientific Coordinator. TARC involves five of the state’s leading medical research institutions: the UNT Health Science Center, Baylor College of Medicine, the University of Texas Southwestern Medical Center, Texas Health Science Center and Texas Health Science Center San Antonio.

The consortium has developed and is testing the first blood test for Alzheimer’s disease.

“It’s remarkable that several other folks have attempted this,” Barber said. “In most of those efforts, people were looking for a single protein, and that has never worked.”

Barber said the test predicts with 95 percent accuracy someone who has the disease versus someone who does not. If validated by the Food and Drug Administration, the test will let doctors routinely screen patients, referring those who test positive for more advanced analysis.

Barber stresses the importance of early detection because by the time people show clinical symptoms, cells in the brain have died, less-ening the chance that any treatment can successfully restore cognitive function.

TARC has an active study group of 1,500 participants that includes people with Alzheimer’s disease, people with mild cognitive impair-ment and cognitively normal individuals. The study is in its sixth year.

“Internally, the goal of the consortium is to sort out the genetic risk factors that impact risk for a progression of Alzheimer’s disease as well as identify biomarkers in the blood that can tell us more about how the disease progresses and why some people are at greater risk than others,” Barber said.

“Eventually, we would like to use all these data to implement phase II clinical trials. That’s a little bit in the distance, but it’s our ultimate goal.” Barber said.

Externally, TARC is interested in synergy and collaboration with anyone in the state doing Alzheimer’s research, whether they’re a member of TARC institution or not, Barber said. A key goal of the consortium is to act as a clearinghouse and facilitate communication.

Barber said that with the aging Baby Boomer generation, Alzheim-er’s disease could bankrupt the health care system.

Dr. Ranajit Chakraborty, professor of Forensic & Investigative Genetics and lead for the new Center for Computational Genetics at the University of North Texas Health Science Center, says the unfortunate fact that criminal activity often runs in families opens new possibilities in criminal investigations where there is not an exact match in DNA samples. Courtesy UNTHSC/Jeremy Enlow/Steel Shutter

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“TARC’s ultimate goal is to end this disease by developing and improving methods of treatment and prevention,” he said.

“The days of being able to achieve a momentous discovery work-ing in a lab alone to the wee hours are pretty much gone,” Barber said. “It still does happen, and it’s an important part of science, but more and more the big discoveries are coming out of collaborative relation-ships with multiple labs and multiple universities.”

To MarketThe final step in the sequence is moving from bench to bedside, and a major player in that process is Robert D. McClain, who oversees Technology Transfer & Commercialization for UNTHSC.

One of the companies he deals with is Omm Scientific of Dallas, whose president is Don Stewart of Fort Worth.

“Don has been a part of our business incu-bation program here at TECH Fort Worth,” McClain said.

Omm had an option for technologies developing out of Karol and Ignacy Gryczinski’s Center for Commercialization of Fluorescence Technologies (CCFT) lab at UNTHSC (See: Bench to Bedside, October 2011, page 92).

Stewart’s company received a National Insti-tutes of Health grant from the Small Business and Innovative Research (SBIR) program, used to facilitate innovative technologies in small business. The goal is to develop RNA biomarkers for cancer.

“As an example, if a man is getting a test for prostate cancer every year, this may be a more sensitive and accurate replacement for that test, depending on the biomarkers. That is the goal from Omm’s angle,” McClain said.

“Omm is very easy to work with,” said McClain. “There’s interplay between the Health Science Center and TCU, Omm, TECH Fort Worth and the scientists. The things that are happening are symbolic of the way we like to see things go.”

Ophthalmology research represents an incredible potential at the Health Science Cen-ter, McClain said.

“If I had a crystal ball and could look ahead, I think there’s going to be some tremendous opportunities to come about because of our activities in that area. We have an incredible scientific team led by Dr. Abe Clark and Dr. Thomas Yorio. Clark, Yorio and other scientists at the center focus on research to cure glaucoma and other eye diseases,” he said.

TECH Fort Worth client ZS Pharma Inc. received $2 million in an Emerging Technology Fund (ETF) investment from the State of Texas

to fund research to help patients with liver or kidney disease. At the Health Science Center, ZS Pharma will spend part of the ETF funding on advancing the commercialization of its technology.

The Emerging Technology Fund was designed to attract top scientists and entrepreneurs in life science technologies and pharma-ceutical development to Texas.

“When I take a step back and look at the scientists we have here with business expertise, I think that’s the beginning of something that can really be exciting for us, both for the Health Science Center and for the City of Fort Worth. The ground is fertile for these opportuni-ties to grow and more to come along,” McClain said.

The process is what Ransom considers central to meeting the nation’s health care challenges — collaborative consortiums that focus on getting the right solutions to the right people at the right time.

Researchers at the Institute for Applied Genetics pull DNA from samples submitted to the UNT Health Science Center from around the world. Courtesy UNTHSC/Jeremy Enlow/Steel Shutter

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