VOLUME 1, NUMBER 1 • FALL 2016
FOR 100 YEARS,
WE’VE FOCUSED ON:
DISCOVERY. EDUCATION. RESEARCH.
FEARLESS ON EVERY FRONT
CVM IMPACT | 2
DEAN’S PERSPECTIVE
As we enter the start of a new century at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM), the global challenges that face us call for a new understanding of research with impact and excellence in discovery. As we are confronted with continuous growth in the world’s population we will continue to experience increased demands for universities to step up, to tread fearlessly, to take risks, and to make a difference. We are all responsible for the future of those who follow in our footsteps. We must work together to bring about the change we need to build a better world. In that vein, our research teams are working innovatively to not just scratch the surface, but to create foundations to stand on; not to simply identify genes, but to understand the evolution of genomes; not to simply identify common diseases in foals and humans, but to develop strategies to stimulate the immune system to protect from infection; and, not to simply uncover the basic mechanisms required to regenerate tissue, but to see how the mechanisms are modified where regeneration does not occur. We are forging ahead. We are Collaborative. Innovative. Transformative. At the CVM—today’s crisis is tomorrow’s discovery. We are bold. We are united. We are one. Discover us.
Eleanor M. Green, DVM, DACVIM, DABVP Carl B. King Dean of Veterinary Medicine
CONTENTS
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IN-GENE-IOUS
SIBLING INSPIRED, GENETICALLY WIRED
INNOVATIONS IN IMMUNITY
IMPACT BEGINS AT DISCOVERY
Genetics & Genomics: A man with a plan—Dr. James Womack, distinguished professor, blazes trail in genetics research
Genetics & Genomics: Two families, one path to autism research—Dr. Scott Dindot mentors aspiring researchers
Immunology & Infectious Diseases: Dr. Noah Cohen—Strengthening foal immune systems and preventing pneumonia
Oncology & Cell Biology: Dr. Stephen Safe— Researching the AH receptor to cure cancer and improve overall health
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CONSERVATION TAKES FLIGHT
Reproductive Biology: Dr. Katrin Hinrichs—Setting the standard in equine assisted reproduction
Toxicology & Environmental Health: A treasure trove of research—Dr. Donald Brightsmith leads the Tambopata Macaw Project
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GROWING RESEARCH
A CLONE ABOVE THE REST
HEALING RESEARCH
THE TINY WORLD INSIDE YOUR PET
Oncology & Cell Biology: Dr. Ken Muneoka—Pioneering regeneration research and making myth a reality
Reproductive Biology: The Reproductive Sciences Lab— An illustrious past and a promising future with Drs. Golding, Kraemer, Long, and Westhusin
Orthopedics & Clinical Trials: Dr. Brian Saunders— Regenerative medicine and tissue engineering in dogs
Microbiome Research: Dr. Jan Suchodolski— The microscopic microcosm within the guts of our pets
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PICTURE THIS
HEALTHIER PEOPLE
HEALTHIER ENVIRONMENT,
CREATING HEALTHIER ENVIRONMENTS
Diagnostic Imaging: Dr. Michael Deveau— Multi-modality imaging and One Health
Toxicology & Environmental Health: A man on a mission— Dr. Ivan Rusyn is building a life we can only imagine
Toxicology & Environmental Health: Drs. Rusyn, Threadgill, and Chiu—Toxicology, Genetics, & Risk Assessment
2 DEAN’S PERSPECTIVE 4 CVM INFORMATION 5 ASSOCIATE DEAN’S PERSPECTIVE 6 CVM RESEARCH 8 CVM GRADUATE STUDIES
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HORSING AROUND
CVM INFORMATION
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COLLEGE ADMINISTRATION Carl B. King Dean of Veterinary Medicine Dr. Eleanor M. Green Executive Associate Dean Dr. Kenita S. Rogers ’86 Associate Dean, Professional Programs Dr. Karen Cornell Associate Dean, Research & Graduate Studies Dr. Robert C. Burghardt Assitant Dean, Graduate Studies Dr. C. Jane Welsh Associate Dean, Undergraduate Education & Dept. Head, Veterinary Integrative Biosciences Dr. Evelyn Tiffany-Castiglioni Assistant Dean, Undergraduate Education Dr. Elizabeth Crouch ’91 Interim Assistant Dean, One Health Dr. Rosina “Tammi” Krecek Assistant Dean, Finance Ms. Belinda Hale ’92 Assistant Dean, Hospital Operations Veterinary Medical Teaching Hospital Mr. Mark “Bo” Connell
Dept. Head, Veterinary Pathobiology Dr. Ramesh Vemulapalli Dept. Head, Veterinary Physiology & Pharmacology Dr. Larry Suva Dept. Head, Large Animal Clinical Sciences Dr. Allen Roussel Dept. Head, Small Animal Clinical Sciences Dr. Jonathan Levine Assistant Vice President of Development & Alumni Relations (Texas A&M Foundation) Dr. O. J. “Bubba” Woytek ’65 Director, Texas Institute for Preclinical Studies Dr. Joe Kornegay ’72 Chief of Staff Ms. Misty Skaggs ’93 Executive Director, Communications, Media, & Public Relations Dr. Megan Palsa ’08
CVM IMPACT STAFF Editor-in-Chief: Dr. Megan Palsa ’08 Managing Editor: Sara Carney ’13 Contributing Writers: Laura Gerik Roberto Molar Callie Rainosek ’17 Jessica Scarfuto ’14 Art Director: Jennie L. Lamb Graphic Designers: VeLisa Ward Bayer Audrey Bratton ’15 Photographers: Tim Stephenson Larry Wadsworth CVM Impact is published by the Texas A&M College of Veterinary Medicine & Biomedical Sciences. Contact us via email at mpalsa@cvm.tamu.edu. Permission is granted to use all or part of any article, provided no endorsement of a commercial product is stated or implied. Appropriate credit and a tear sheet are requested.
CONTACT INFORMATION Dean’s Office/Administration 979.845.5051
CVM Graduate Studies 979.845.5092
DVM Admissions 979.845.5051
Biomedical Sciences Undergraduate Advising 979.845.4941
CVM Communications 979.845.1780 Public Relations 979.862.4216 Development & Alumni Relations 979.845.9043 Continuing Education 979.845.9102
Department of Veterinary Integrative Biosciences 979.845.2828 Department of Veterinary Pathobiology 979.845.5941 Department of Veterinary Physiology & Pharmacology 979.845.7261
Department of Small Animal Clinical Sciences 979.845.9053 Department of Large Animal Clinical Sciences 979.845.9127 Veterinary Medical Teaching Hospital Administration 979.845.9026 Small Animal Hospital 979.845.2351 Large Animal Hospital 979.845.3541
COLLEGE OF VETERINARY MEDICINE & BIOMEDICAL SCIENCES • TEXAS A&M UNIVERSITY 4461 TAMU • COLLEGE STATION, TX 77843-4461 • vetmed.tamu.edu
ASSOCIATE DEAN’S PERSPECTIVE Dr. Robert C. Burghardt and Dr. Roula Mouneimne are the director and associate director of the Image Analysis Laboratory at the CVM.
Annual research expenditures at the CVM have grown steadily, reaching $30.5 million in 2015. This is due to collaborative discovery and innovation in basic, applied, and translational research as well as highly successful recruiting of both young and established investigators. These researchers have competed successfully for new individual and interdisciplinary grants totaling over $29.8 million in extramural funding this past year. Our graduate students and postdoctoral fellows are valued colleagues as we prepare them for diverse career paths available in biomedical sciences. In the past eight months, our Biomedical Sciences Graduate Programs Task Force has facilitated the development of improvements to ensure excellence in the student training experience. With an enrollment for the Fall 2016 semester of over 390 graduate students—more than double that of just five years ago—the CVM has the largest graduate program of any College of Veterinary Medicine in the nation. We are fortunate to have colleagues who share our commitment to building the vision and capacity for transformational interdisciplinary research and graduate education.
Robert C. Burghardt, MS, Ph.D. Associate Dean, Research & Graduate Studies
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The faculty of the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM) is dedicated to excellence in research to improve the health and well being of animals, humans, and the environment. As part of the One Health Initiative, our faculty members are passionate about solving complex societal problems, many of which lie at the intersection of multiple disciplines.
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CVM RESEARCH
Excellence in research at the CVM is partly evident from the millions of dollars obtained annually in extramural funding by our faculty members. For example, our faculty members are lead investigators on the National Institute of Environmental Health Sciences (NIEHS) Center for Translational Environmental Health Research grant that is a collaboration among Texas A&M University, Baylor College of Medicine, and the University of Houston, as well as the ongoing United States Department of Agriculture–Agriculture and Food Research Initiative (USDA–AFRI) animal health grant. Similarly, CVM investigators have obtained significant National Institutes of Health (NIH), USDA, National Science Foundation (NSF), defense agency, and Texas funding during recent years. Another important measure of research excellence is reflected in publication of our research in internationally reputed journals in veterinary medicine and biomedical sciences and their citations, some of which have received the covers of Nature, Science, Genomics, and Genome Research. Our research focus is on improving disease resistance in animals, increasing their productivity, enhancing their reproductive ability, and developing cures for human and animal diseases including cancer, heart disease, neurological diseases, and reproductive diseases through basic, translational, and pre-clinical trial based research. Some recent examples of our success include developing new strategies for the treatment
of endometriosis; deciphering of complete genetic material from multiple species to study diseases and traits important to industry; developing new approaches to reducing the global impact of low-profile, but very costly human diseases in developing countries; and creating a food and feed additive to protect humans and animals from deadly mycotoxins produced by molds on grain. CVM RESEARCH INSTITUTES The Texas A&M Institute for Preclinical Studies (TIPS) is home to many collaborative research efforts, which incorporate the use of spontaneous animal models into clinical trials of new drugs and devices. The Michael E. DeBakey Institute for Cardiovascular Sciences is a national leader in cardiac device research. And, in collaboration with the Texas Heart Institute (THI), the Center for Cell and Organ Biotechnology (CCOB) includes scientists, physicians, veterinarians, engineers, and business managers from both organizations and other colleges located at Texas A&M University. VETERINARY INTEGRATIVE BIOSCIENCES (VIBS) DR. EVELYN TIFFANYCASTIGLIONI, HEAD VIBS carries out teaching, research, and service across a wide spectrum of biosciences. Biomedical science represents a vital component of the foundation of medical knowledge and
includes investigation at molecular, cellular, organismal, and population levels. Faculty and students are engaged in biomedical genetics, neuroscience, reproductive biology, toxicology, epidemiology, and public health. VIBS is home to one of the only programs in science and technology journalism in the country.
VETERINARY PHYSIOLOGY & PHARMACOLOGY (VTPP) DR. LARRY SUVA, HEAD VTPP includes toxicology, cardiovascular sciences, reproductive sciences, and pharmacology. VTPP offers master’s and Ph.D. programs that are focused on both veterinary and human physiology and pharmacology. The programs utilize the unique aspects of different species to enhance insights and understanding into basic processes in all other species. The department is also the home of the Michael E. DeBakey Institute for Comparative Cardiovascular Science and Biomedical Devices and the Interdisciplinary Faculty of Toxicology (IFT).
VETERINARY SMALL ANIMAL CLINICAL SCIENCES (VSCS) DR. JONATHAN LEVINE, HEAD VSCS has three major missions: education, patient care, and scholarship. Each of these activities is intended to improve the quality of life for companion animals and their owners. The department provides clinical education in canines, felines, and exotics. Faculty researchers study health issues common to both humans and animals such as cardiology, gastroenterology, neurology, orthopedics, and oncology. CVM SIGNATURE RESEARCH PROGRAMS Biomedical Genomics; Cardiovascular Sciences; Infectious Diseases & Biodefense; Neuroscience; Reproductive Biology; Toxicology, Oncology, & Environmental Health Sciences; and Veterinary Clinical Research INTERDISCIPLINARY GRADUATE DEGREE PROGRAMS Ecology & Evolutionary Biology; Genetics; Neuroscience; and Toxicology
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VETERINARY PATHOBIOLOGY (VTPB) DR. RAMESH VEMULAPALLI, HEAD VTPB focuses on mechanisms of disease including host/pathogen interactions, ecology of antimicrobial resistance, genetics of disease susceptibility and resistance, wildlife diseases, and conservation genetics. The department’s basic disciplines include microbiology, pathology, parasitology, genetics, and laboratory animal medicine, and faculty members teach courses in these subject areas to undergraduate, graduate, and DVM students. The Ph.D. program in veterinary pathobiology produces the next generation of scientist, qualified to undertake a career in scientific research at the highest level.
VETERINARY LARGE ANIMAL CLINICAL SCIENCES (VLCS) DR. ALLEN ROUSSEL, HEAD VLCS develops excellent large animal veterinarians through outstanding teaching; delivers outstanding veterinary care to our clients’ large animals through our expertly-staffed hospital services; and creates, disseminates, and clinically applies impactful knowledge through research and continuing education in large animals. Faculty researchers are recognized leaders in the fields of stallion reproduction, equine infectious diseases, and equine regenerative medicine, and their results have translated from the laboratory to clinical application in patients.
CVM GRADUATE STUDIES by Dr. Megan Palsa & Callie Rainosek
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CVM Graduate Students take their oath at a special ceremony on Thu., Aug. 25, at Pebble Creek Country Club.
TRANSFORMING GRADUATE STUDIES Lately, there’s been much talk about the new curriculum for veterinary students at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM). But, that’s not the only program being elevated. Improvements to the graduate program in Biomedical Sciences are also underway.
the integral role that graduate students play in the university’s research enterprise. The goal is to adapt graduate education to take advantage of the many diverse biomedical science career paths in today’s world and to contribute to innovations in science that offer real benefits to a global society.
The CVM is uniquely poised to provide an unparalleled graduate research and educational experience in an environment where research expenditures exceeded $30 million dollars in 2015—the third highest among veterinary schools in the nation. The college recognizes
Over the past eight months a group of faculty formed a task force and worked with the Associate Dean for Research & Graduate Studies office to think about how to improve the training experience of CVM graduate students. The task force included faculty
CVM Graduate Studies Mission: Provide a premier degree program for preparing innovative, globallycompetitive and career-ready biomedical scientists who are committed to the improvement of the health and welfare of animals, humans, and the environment, and who have skill sets necessary to pursue diverse career paths in academic, public, and private sectors.
This process has been driven by the mission of our graduate program, which is to “Provide a premier degree program for preparing innovative, globally-competitive and career-ready biomedical scientists who CVM Graduate Students
are committed to the improvement of the health and welfare of animals, humans, and the environment, and who have skill sets necessary to pursue diverse career paths in academic, public, and private sectors.� Periodic strategic evaluation of the graduate program is undertaken to enable adaptability to emerging opportunities in an evolving research environment.
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members who could provide unique insight into graduate education from perspectives derived from experiences at different universities and interdisciplinary programs.
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The staff of the CVM Associate Dean of Research & Graduate Studies office
In a desire to build a strong sense of community among our trainees—especially our incoming graduate students—the task force developed an intensive orientation week “boot camp” that provides training in biosafety and compliance, diversity and inclusion, intellectual property and patents, and Texas A&M regulations and requirements for graduation education. Additionally, the students attend an introduction to the science and scholarship of effective teaching. The experience results in increasing connections and building camaraderie among trainees while
providing foundational information that will guide them through their graduate programs. As a culmination and welcome into our community of scholars, an Inaugural Graduate Student Oath Ceremony was held on Thu., Aug. 25, at Pebble Creek Country Club. The CVM Graduate Student Association developed the oath by integrating elements of Texas A&M University’s core values, the Aggie Code of Honor, and recommendations from a Science article, “An Ethical Affirmation for Scientists” by Craig, Cather, and Culberson, which contains
“The Graduate Student Oath Ceremony was a wonderful opportunity to celebrate all of the work we’ve done as graduate students and look forward to all we’ll accomplish in the coming year and beyond. I was able to reconnect with faculty and fellow students in other departments I don’t see often, as well as meet new people. My graduate committee chair could not be more wonderful and supportive, but it’s always nice to be reminded that there is an entire college—and university—full of administrators and potential mentors holding us to the highest standards but ready to help and teach us wherever they can.” ~ Christina B. Sumners, Ph.D. student
CVM Graduate Student Oath Ceremony
an “Oath for Scientists�. This oath highlights expectations of graduate students to uphold the highest standards with respect to ethical behavior, integrity, and professionalism.
CVM Graduate Students with family and friends
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Each graduate student received a CVM embroidered laboratory coat that is symbolic of their official entry into training as a laboratory scientist, as well as an engraved nametag that will foster recognition of their unique identity and contributions to the CVM research enterprise. The students recited the oath as a group at the evening banquet.
A noteworthy and recognized feature of the CVM Graduate Studies program is its extensive menu of professional development opportunities. These include workshops on grantsmanship, scientific writing, public speaking, effective writing strategies, effective multimedia communication, and careerreadiness. The workshops complement existing college programs such as an internal student research grant program, competitive campus core facility utilization program, and highimpact research specialty training programs.
Dr. Eleanor M. Green, the Carl B. King Dean of Veterinary Medicine
CVM Graduate Student and family
CVM Graduate Students and family
Dr. Eleanor M. Green with a CVM Graduate Student
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Dr. Glen A. Laine, Texas A&M University Vice President for Research
Dr. Robert C. Burghardt, CVM Associate Dean for Research & Graduate Studies
“As a member of the 2016–17 CVM Graduate Student Association Executive Committee that initiated this tradition, it was rewarding to see both the incoming and current graduate students receive their white coat. Reciting the oath together bonded us collectively in the pursuit of sound science that will benefit humanity. The support that we continue to receive from our mentors as well as the entire college is invaluable as we pursue a common goal change the world through our scientific discoveries. ~ Alexandra Lacey, Ph.D. student
Dr. Eleanor M. Green with CVM Graduate Students
All opportunities align with the Texas A&M graduate student learning outcomes.
CVM Graduate Student Oath Ceremony
The CVM prides itself on setting its graduates apart from those of other institutions. With positive changes underway, those who complete graduate degrees from the CVM will continue to make global impacts in biomedical sciences.
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The diversity in biomedical science career paths requires more comprehensive and intensive advising to link students to available career opportunities and training that will help better prepare them for diverse careers. To this end, graduate academic advising has been centralized under the Associate Dean for Research & Graduate Studies office. Students have access to five graduate advisors with diverse experiences and backgrounds,
including doctoral studies in higher education programs and leadership, doctoral studies in biomedical sciences, and professional expertise in the policies and procedures of the Texas A&M Office of Graduate and Professional Studies and Study Abroad programs.
GENETICS & GENOMICS by Dr. Megan Palsa
IN-GENE-IOUS
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Dr. James Womack
A MAN WITH A PLAN Dr. James Womack, distinguished professor in the Department of Veterinary Pathobiology, researches inherited resistance to disease in certain animals—both individual animals and breeds. For example, certain cattle have evolved a stronger defense against bacterial and viral pathogens. Womack wants to understand the genetics behind this because it could allow breeders to develop a healthier herd. This is the topic of his most recent USDA-funded research project.
Bovine respiratory disease is the most common and costly disease affecting the North American cattle industry. “Not all cattle respond to bovine respiratory pathogens the same, and we’re trying to develop a DNA chip where a little bit of DNA can determine the relative susceptibility or resistance of a particular animal to respiratory disease,” Womack said. Womack and his team of researchers have identified some genes and clusters of genes
that convey resistance, and although they are still being validated with additional studies, they have begun to publish the data. Their goal is to give dairy and beef cattle breeders a tool, the DNA chip, to help determine if an animal is resistant to bovine respiratory pathogens. “We want to be able to look at the DNA chip and say we want to breed this individual, and this one will have offspring that are more resistant,” he said. Womack’s research isn’t restricted to cattle; he has worked extensively with mice as well as chickens. He has spent time in Korea studying
what the differences are between them. When I got here, I expanded my research into the cattle genome. My work is kind of comparative genomics, I guess, and how these little subtle differences seemed make a difference and why cattle have more genes related to immune function than other mammals,” he said. IMPACTING STUDENTS Womack noted that his students have been a large part of the success he’s enjoyed in research. His 50th doctoral student recently defended her dissertation, and he has had a myriad of master’s students as well.
WOMACK HAS BEEN PART OF THE TEXAS A&M FAMILY FOR 39 YEARS.
chickens with the same goal—finding genes that confer disease resistance. Recently, he studied a gene in rats that allows the rats to be resistant to Rift Valley fever, a disease that has taken a toll in Africa and affects cattle, sheep, and goats. “We found a rat model for it and identified that gene,” Womack said. “We occasionally work with dogs, cats, pigs, and horses, too.” Most of Womack’s research has taken place right here in College Station. He said he “got a good start” in research at the Jackson Laboratory, but he was able to continue his work in his current position. “I was very interested in the evolution of animal genomes, how the mouse genome compared to the human genome, and
“We have a genetics graduate program here, and we have 10 or 12 students every year admitted to that program,” he said. “They apply from all over the country. We also have international students here who know about our program, maybe from professors in China or Korea, who also contact us.” In fact, it was one of his former students, now a professor at Washington State University, who contacted him regarding the USDA Bovine Respiratory program. “Then, another fellow, whom I had worked with before at The University of Missouri, and a group at the University of California, Davis—we all just got together and said, ‘Let’s put
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The distinguished professor, a designation he has held since 2001, has a joint appointment in the Department of Molecular and Cellular Medicine at Texas A&M’s College of Medicine and the Department of Veterinary Pathobiology. He was promoted to professor in 1983, and two years later received the W.P. Luse Endowed Professorship. From 1989 to 1996, he was director of the Center for Animal Genetics at the Institute of Biosciences and Technology, and he was named interim associate department head for the Department of Veterinary Pathobiology from 1990 to 1993.
GENETICS & GENOMICS
HONORED BY HIS PEERS Although his list of honors is lengthy, there is one award of which Womack is most proud.
Womack with his Wolf Prize
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It’s the Wolf Prize in Agriculture, which he received in 2001 for his “use of recombinant DNA technology to revolutionize plant and animal sciences, paving the way for applications to neighboring fields,” according to the Wolf Foundation, which awards the prize. The Wolf Prize in Agriculture is awarded annually in Israel. One of six such prizes established by the Wolf Foundation, the Wolf Prize in Agriculture is considered by many to be the Nobel Prize within the field of agriculture. Prior to that honor, in 1999, he was named to the National Academy of Sciences (NAS). This organization recognizes and promotes outstanding science through election to its membership, publication in its prestigious journal, and its awards, programs, and activities. Election to the NAS is considered one of the highest honors a scientist can receive. Today, there are approximately 2,250 members and nearly 440 foreign associates, of whom approximately 200 have received Nobel prizes.
University, 2006; Distinguished Service Award, Texas Genetics Society, 2006; Fellow, American Association for the Advancement of Science, 1999; Outstanding Texas Geneticist, Texas Genetics Society, 1996; CIBA Prize for Research in Animal Health, 1993; McMaster Fellow, CSIRO, Australia, 1990; Carrington Award for Research in Cell Biology, 1990; Faculty Distinguished Achievement Award for Research, Texas A&M University, 1987; and the Alumni Citation Award, Abilene Christian University, 1983.
Womack’s other honors include the Bush Excellence Award for Faculty in International Research, Texas A&M University, 2008; Dean’s Impact Award, College of Veterinary Medicine, Texas A&M, 2007; Outstanding Alumnus of the Year, Abilene Christian
He serves or has served on editorial boards for these publications: Genomics, Journal of Heredity, Biochemical Genetics, Animal Genetics, Mammalian Genome, Genome Research, and Animal Biotechnology.
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Womack works cattle on his ranch.
one of these big grants together.’” They nominated Womack as their project leader. Womack continues to love and be inspired by teaching undergraduate students. “These are juniors and seniors, and they’re usually applying to medical schools, veterinary colleges, and graduate schools. I write a lot of letters, and then they stay in touch with me. I enjoy that. My students kind of become like my children.” COLLABORATION Being next to the break room, Womack said many “coffee pot discussions” take place outside his office. “I usually leave my door open, and the coffee pot’s right out there. I have a lot of people
coming by.” A lot of those people coming by are fellow researchers. He said it’s valuable and interesting to learn about the research of others, and that some things that would seem to be unrelated actually can shed light on other topics. Spending time with other faculty members and researchers is important to Womack and his research. He often sits down to learn from and brainstorm with his colleagues across the college. “We’ve come to realize that this fastpaced world requires strong partnerships to leverage creativity, experience, and resources. With unique thinkers, we can help one another generate ideas—and possibly arrive at viable solutions in less time,” said Womack.
GENETICS & GENOMICS by Dr. Megan Palsa
SIBLING INSPIRED,
GENETICALLY WIRED
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Dr. Scott Dindot with students Dylan Ritter and Kathleen Nelson
For most students, summer means vacation, a chance to leave the stress of school behind to relax with family and friends.
BUT FOR TWO YOUNG STUDENTS WORKING
IN DR. SCOTT DINDOT’S GENOMICS LAB in the Department of Veterinary Pathobiology at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM), summer means an opportunity to make a difference and to give back to others.
BROTHERLY LOVE: DYLAN’S INSPIRATION Dylan Ritter, an undergraduate student at the University of Mississippi who has spent the last two summers working in Dindot’s lab, was only three years old when his parents brought home Travis, his youngest brother— the third of three boys. It wasn’t long after Travis’ arrival that Dylan’s parents noticed Travis was not developing like his older brothers. After visits to several specialists, Travis was diagnosed with isodicentric 15, also called Dup15q syndrome, and with autism.
“Growing up with Travis, it never occurred to me that he was that much more different,” said Dylan. “I began to notice that most of my friends his age would be talking or walking, and he wasn’t. Something was a little off, but I was okay with it because he’s my brother. I was interested in being able to communicate with him because he’s non-verbal. He makes sounds, but he is not able to formulate words or anything like that. We used basic sign language to communicate with him. I remember babysitting and teaching him to sign and making sure he new what he was doing. That was a cool connection with him.” For Travis, Dylan has always been like a caretaker, helping his mother with Travis’ care and helping Travis when he needed something. Dylan said his desire to help people originated from his grandfather, who was a surgeon. “That was my first step. I knew that I wasn’t
Dylan discovered Dindot through a newsletter sent to those who have family members with Dup15q. “It keeps track of what the families are doing and some of the scientists and their work,” Dylan said. “This organization that focuses on Dup15q families published something, or shared an article about Dr. Dindot and the work he was doing. I started reading it and he talked about the mouse model that he was working on.” Soon after, Dylan sent Dindot an email asking if he could come to College Station and see what was going on in the lab. “When he offered me the opportunity to spend time with his team,” Dylan added, “I thought I would just be sitting back and watching what these guys do, but his lab is very handson and we all have our own little projects.” COMMITMENT TO RESEARCH For the past two summers, Dylan has worked to understand the circadian rhythms, the sleep/ wake cycle, of flies that have had the Dup15q abnormality inserted into their genetic chain. He noted that while working with flies isn’t quite the same as working with humans, studying the fly models is important because these flies exhibit some of the same symptoms as Dup15q patients. “Even just observing the flies, you could see there was an abnormality,” said Dylan. “This resonated with me because of my younger brother. His sleep-wake behavior is scheduled, but it’s irregular from the normal, twenty-four hour regular cycle.” Last summer, Dylan worked with Dindot and a mouse model of Dup15q that has been made in such a way that the gene causing Dup15q can be turned off or on using a common antibiotic. Since having too many copies of certain genes in the small region on chromosome 15, known as 15q, causes high levels of proteins to be produced, which leads to Dup15q, many
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Dup15q syndrome is one of the most frequent genetic mutations causing autism spectrum disorders. Committed to learning more about his brother’s condition, Dylan soon discovered Travis would suffer from delayed development of motor and verbal skills, and potentially even violent seizures throughout his life. Growing up with Travis put Dylan on a life-changing course that brought him to the CVM to work with Dindot, whose lab created mouse models of genomic disorders, such as Dup15q and a similar condition called Angelman syndrome.
interested in going out and doing surgery on someone,” added Dylan. “I wanted to help my brother. I found research that interests me. Originally, I thought I’d find something, and then that something came along.”
GENETICS & GENOMICS Ritter
Dylan did just that. In the application, he discussed his experience with Travis and noted that although Travis was a little different from his friends, he just needed a bit more help. “I talked about how I worked here last summer, and I was unsure about coming here,” Dylan said. “I came here, and I loved it. I did all these great projects with Dr. Dindot’s team. I wrote from the heart. It’s the best way to say it. They came back and said that I had gotten it.”
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There were only five people awarded the grant this year, two of whom are from Yale, as well as students from Stanford and the University of California, Santa Barbara. The $2,500 award covers Dylan’s stipend and laboratory supplies.
scientists want to know if the condition can be treated by lowering the levels of proteins made by these genes in the brain. The mouse models were engineered in a particular way to see if this strategy works. If it does, scientists will start looking for drugs or other therapies that can reduce the protein levels in patients. SUPPORT THROUGH PRESTIGIOUS GRANTS Dylan’s work in Dindot’s lab was supported by a prestigious competitive grant through the Autism Science Foundation. “When I talked to Dr. Dindot two summers ago, he mentioned the grant to me off-handedly,” Dylan said. “He said the chances of getting it were not that high, but he encouraged me to go ahead and apply. I didn’t wind up getting it. Again this year, I was looking at maybe shadowing a doctor, or maybe going back into research, and I decided to come back here and work with Dr. Dindot. He suggested I apply again because now I had a year of experience working in autism research, which is what they’re looking for, and writing about what I did and about my brother so I could make that connection and tell them my story.”
“Dylan could be doing anything, but he’s here,” Dindot said. “He was awarded a grant from the Autism Science Foundation that supports undergraduate research in autism research. This is an extremely prestigious grant, which is awarded after a review process, and students from all around the country compete for these funds. It’s a credit to Dylan’s drive that he received the grant. Awardees in the past have come from Harvard, Yale, other Ivy League schools, or other medical schools with strong neuroscience programs.” At the end of his summer research experience, Dylan provided a status report back to the foundation talking about his work. As a student in the Honors College at the University of Mississippi, Dylan will have to write and defend a thesis, much like a Ph.D., except on a smaller scale. He intends to write about his work and how winning this grant helped him and ensured he would return to Dindot’s lab this summer. Dylan looks at his thesis as a way to let others know about the grant and what it helped him achieve. SIBLING SUPPORT: KATHLEEN’S JOURNEY TO RESEARCH While Dylan’s journey led him to the University of Mississippi and eventually Dindot’s lab, a similar journey was beginning
Nelson
in Chicago for high school student Kathleen Nelson. Kathleen, like Dylan, has a sibling with Angelman syndrome, a chromosomal disorder. As she researched more about this disorder, Kathleen also discovered Dindot’s work and immediately contacted him to see if she could come to the CVM to work in his lab during her summer break.
“I have three older brothers,” Kathleen said. “One of them is Ryan. He’s 26 right now, about to be 27, and he’s the one with Angelman syndrome, which brought me here to Texas A&M to work in Dr. Dindot’s lab. It’s because of Ryan I want to learn more about Angelman syndrome and what causes it. I wanted to know what work is being done for the cure, since they’re really close to finding one, although therapy is probably a better word for it.” Similar to Dup15q, people with Angelman syndrome demonstrate developmental delays. In Ryan’s case, he was diagnosed with Angelman syndrome only five years ago. The late diagnosis is due in part to the difficulty in recognizing this specific disorder versus others, such as cerebral palsy. “Ryan has Angelman syndrome, which I think is a huge blessing,” Kathleen said. “He’s always happy. He’s one of the sweetest people I’ve ever met. He’s just a really special man. He’s a great brother. Everyone who meets him loves him. He has the ability to make an impact on everyone’s lives.”
It is unusual that a high school student would give up some of the summer break to work in a university research lab, but Kathleen admits to loving sciences and credits her school for encouraging her to seek out opportunities. “At my school, they really try and push people to go and do things during their summer,” Kathleen said, “not to just sit around and go to the beach every day or just relax. There’s a student who would go and work in a lab every summer on cerebral palsy research. Through that, I figured out high school students can do research in the summer.” Kathleen and her mother talked to Paula Evans, the president of the Foundation for Angelman syndrome Therapeutics (FAST), about options for Kathleen to engage in research during the summer. Evans contacted various scientists working on Angelman Syndrome and made the connection with Dindot. “I looked at his lab and his work,” Kathleen said. “I liked how a lot of the people he was working
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Kathleen, similar to Dylan, found Dindot through researching Angelman syndrome. She wants to be a physician and was looking for things to do. Because of the impact her brother had on her and her family, she told her mother she wanted to work in Dindot’s lab and learn about what they’re doing. Dindot had a grant to develop new drugs for Angelman syndrome, so Kathleen was interested in that work. Dindot worked with Kathleen’s mother to make arrangements for Kathleen to spend some time at Texas A&M to pursue her interests with Angelman syndrome.
GENETICS & GENOMICS with all have their own projects. They’re not just doing one thing. They’re looking at a variety of things, and that sounded interesting to me.” LEARNING AND GROWING Kathleen’s goal while in Dindot’s lab this past summer was to learn as much as possible about Angelman syndrome. “I’ve been reading a lot of papers about it,” Kathleen said. “I’ve looked at what all the other people in the lab have been doing, watched over their shoulders. I’ve also had the opportunity to
stands for ubiquitin protein E3A ligase, and is the gene causing Angelman syndrome, is imprinted in the brain. Genomic imprinting is a rare phenomenon in the genome. Essentially, it is a form of gene regulation in which one allele, or “switch,” of a gene is on and the other is off. The Angelman gene is active on the chromosome that is inherited from the mother and inactive on the chromosome inherited from the father. Because of this, all individuals with Angelman syndrome have mutations on the allele they inherited from their mother.
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ACCORDING TO THE CENTERS FOR DISEASE CONTROL AND PREVENTION (CDC),
1 IN 68 INDIVIDUALS HAVE A DIAGNOSIS OF AUTISM SPECTRUM DISORDER. Most children are diagnosed when they see a physician. Typically they miss their developmental milestones, but often their parents and other caregivers notice social deficits. Since autism is a spectrum disorder, it varies considerably from individual to individual, but primary signals include social communication deficits, learning disability, and repetitive behaviors.
get my hands wet, as well, by running some PCR reactions and isolating some DNA.” The PCR reactions Kathleen has worked with involved comparing normal flies with fly models of Angelman syndrome to see if the studies were successful at developing flies that express the same symptoms as humans with Angelman syndrome. Kathleen said one of the most fascinating things she has learned was that UBE3A, which
“There are only about 100 or so imprinted genes in the human genome, out of tens of thousands according to Dr. Dindot,” Kathleen said. “The area we are investigating is pretty limited. What the lab team is looking at, is trying to re-wire the regulation of the UBE3A gene so that the paternal allele is turned on. This would then replace the faulty maternal allele.” Through their own initiative, both Dylan and Kathleen discovered Dindot’s work, and while
ADVANCING RESEARCH, HELPING PEOPLE The Centers for Disease Control say that 1 in 68 individuals have a diagnosis of autism spectrum disorder. Dup15q syndrome is the second most frequent mutation that causes autism. Most children are diagnosed when they see a physician. Typically, these children miss their developmental milestones, but one of the things also noted are the social deficits. Autism is a spectrum disorder, so it varies considerably from individual to individual. Primary signals include poor eye contact, little to no communication, and repetitive behaviors. When children present with all three of the core symptoms of autism, the anxiety they have and the expression of autism may be increased. For individuals diagnosed with Dup15q syndrome, the 15q region is duplicated. In some instances, the duplicated region becomes its own chromosome. The result is too much expression of genes in 15q. In Angelman syndrome, the 15q region is deleted on the chromosome inherited from the mother. For Angelman syndrome, the UBE3A gene is clearly the culprit
and entirely responsible for the condition. Since almost all individuals with Dup15 have a duplication of their mother’s chromosome, it is believed that UBE3A is also the gene causing the condition. Thus, having no UBE3A causes Angelman syndrome, whereas too much UBE3A causes Dup15q. They are clinically distinct syndromes, but there’s a lot of overlap in terms of the cognitive and motor deficits. Dindot recognizes that Dylan and Kathleen are exceptional students and possess a drive for understanding the disorders that have affected their families. “These students are similar in terms of the emotional connection to this work,” said Dindot. “ It’s a personal, emotional topic. They’ve chosen to pursue this with that in mind. I can’t think of anything more commendable or inspirational.” Two families. Two genetic disorders. Two students determined to find new ways to help families who also are experiencing the impact of disorders such as Dup15q and Angelman syndrome. Two separate journeys, but one path and one mentor. As Dylan and Kathleen work under Dindot’s guidance, they are not only learning research skills that will benefit their future endeavors. They are also helping to determine future pathways for genomic research for these autism-related disorders.
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some of their friends took off for vacation and summer fun, they chose to come to Texas A&M to help advance the knowledge of these disorders so that others may benefit in the future.
IMMUNOLGY & INFECTIOUS DISEASES
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by Callie Rainosek
Dr. Noah Cohen
DR. NOAH COHEN, PROFESSOR AND ASSOCIATE DEPARTMENT HEAD FOR RESEARCH AND GRADUATE STUDIES IN THE DEPARTMENT OF LARGE ANIMAL CLINICAL SCIENCES AT THE TEXAS A&M COLLEGE OF VETERINARY MEDICINE & BIOMEDICAL SCIENCES (CVM), IS LEADING THE SEARCH FOR AN EFFECTIVE STRATEGY TO PREVENT DISEASES CAUSED BY RHODOCOCCUS EQUI (R. EQUI), A BACTERIUM THAT COMMONLY CAUSES DISEASES IN FOALS AND IN HUMANS AND ANIMALS WITH SUPPRESSED IMMUNE SYSTEMS.
INNOVATIONS IN IMMUNITY R. equi may not always cause disease in an infected animal, but when it does, pneumonia is most often the disease that develops. R. equi frequently infects the lungs of foals, causing severe symptoms, such as fever and coughing, which can potentially lead to death. In addition to disease in the lungs, R. equi can affect bones, kidneys, the intestinal tract, and other parts of the body.
COMING TO THE CVM In 1988, Cohen came to the CVM as an assistant professor in veterinary public health. However, his interest in applying epidemiology to large animal medicine soon led him to a residency in large animal internal medicine at the CVM. “I was honored and excited about my residency,” he said. “There were outstanding equine internists at Texas A&M, including Drs. Kent Carter, Joe Joyce, Tom Kasari, Bill McMullen, Dub Ruoff, and Allen Roussel. I knew that the excellent clinical training would enable me to identify critical questions for research. The opportunities and clinical questions seemed endless.” Before he started his residency, Cohen had the opportunity to meet Dr. Ronald J. Martens, the department head of what is now the Department of Large Animal Clinical Sciences. Several years before Cohen came to the CVM, Martens founded the Texas A&M Equine Infectious Disease Laboratory (EIDL) to combat infectious diseases such as those caused by R. equi. Martens’ work in infectious diseases as a
“Dr. Martens had the vision to recognize that a clinician-scientist with an interest in epidemiology would be of benefit to the department,” Cohen explained. “He encouraged me to complete my residency training in internal medicine, and then he recruited me to become a member of the large animal medicine faculty.” After he completed his residency, Cohen began researching R. equi in the EIDL under the direction of Martens. The main goal of Martens’ research was to find an effective preventative measure against infections caused by R. equi in foals because none previously existed. Treating pneumonia caused by R. equi can be difficult because treatment is lengthy, expensive, must be administered multiple times daily, can cause serious side-effects, and isn’t always effective. This is why Martens began working on ways to decrease foals’ susceptibility to developing disease from the bacteria. On breeding farms, pneumonia caused by R. equi is the most common and severe form of pneumonia in foals that are between the ages of one and six months. Pneumonia is a leading cause of disease and death for foals, which has motivated researchers like Martens and Cohen to seek an effective preventative strategy against pneumonia caused by R. equi. A vaccine to directly prevent the disease would be a major breakthrough for the health of foals on breeding farms, according to Cohen. Martens recognized the prevalence of R. equi in foals and knew the importance of preventing R. equi–related diseases, especially
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To combat this potentially deadly pathogen, clinician-scientists like Cohen are working to develop strategies other than antibiotics that stimulate the patient’s immune system to help protect them from infection.
clinician-scientist inspired Cohen to complete his residency and join the faculty of the CVM.
IMMUNOLGY & INFECTIOUS DISEASES
pneumonia. Martens’ biggest contribution to the prevention of R. equi disease was the use of hyperimmune plasma, which is harvested from the blood of horses that were vaccinated to produce high concentrations of antibodies against R. equi. The plasma is then transfused to foals. These transfusions partially protect foals against infection with R. equi.
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“The collection and transfusion of plasma that is hyperimmune against R. equi remains the only acceptable and commercially available approach for preventing R. equi pneumonia,” Cohen said. “Unfortunately, it is not completely effective and has some other limitations, such as being expensive, labor-intensive to administer, and carrying some health risks for foals. Although the concept of preventing the
having the patient’s immune system protect them from infection rather than antibiotics,” Cohen said. “First, we are working on developing a vaccine, which is a traditional and effective approach for preventing infections. Second, in collaboration with investigators from the Texas A&M University System’s Institute for Biosciences and Technology in Houston, we are investigating if a mist inhaled into the lungs can stimulate a foal’s immune system to protect it against R. equi infection.” COLLABORATION The CVM’s collaboration with numerous researchers worldwide is a critical component of Cohen’s goal to prevent R. equi pneumonia in foals. Cohen has collaborators in Brazil, Canada, Germany, Japan, and other countries,
TREATING PNEUMONIA CAUSED BY R. EQUI CAN BE DIFFICULT BECAUSE TREATMENT IS LENGTHY, EXPENSIVE, must be administered multiple times daily, can cause serious side-effects, and isn’t always effective.
disease by administering antibiotics has been demonstrated to be effective, this approach isn’t acceptable because it isn’t uniformly effective and, most importantly, can contribute to antibiotic resistance from overuse.”
all of whom have contributed to the growing research in R. equi pneumonia prevention.
Martens was also interested in identifying alternatives to traditional antibiotics to control R. equi pneumonia because of emerging resistance to drugs commonly used to treat the disease. When Martens retired, he passed on the directorship of the EIDL to Cohen.
In addition, Cohen said his research project benefits significantly from many researchers in the United States and the CVM. “We collaborate with numerous investigators from many countries,” he explained. “We work especially close with Dr. Steeve Giguère from the University of Georgia, one of the world’s authorities on this disease. We are also fortunate to benefit from many scientists at the CVM.”
Exploring alternative treatments of R. equi pneumonia as opposed to traditional antimicrobial drugs remains an area of interest for the EIDL. “We are working on two strategies for preventing R. equi pneumonia based on
RESULTS To reduce the risk of antibiotic resistance, Cohen and his team are investigating new drugs and potential methods of administering
Photomicrographs of R. equi bacteria in an infected foal (Images courtesy of Dr. Noah Cohen)
preventative and therapeutic agents. After over five years of trying, Cohen and his team at the CVM have produced encouraging results with a vaccine for R. equi pneumonia.
because bacterial diseases remain important causes of disease for all species, and the emergence of antimicrobial resistance is a global health crisis in veterinary and human medicine.”
“We are exploring new approaches that we hope will be effective and not promote antibiotic resistance in R. equi,” Cohen said. “Examples include using inhaled substances that facilitate the foal’s own immune system by stimulating receptors of the immune system that eliminate R. equi, and drugs such as metal-based compounds and antibiotics that will reduce the risk of resistance.”
RESEARCH SUPPORT As Cohen continues his research on R. equi, he links his accomplishments and new findings to the support that Martens provided him when he began his journey at the CVM. Martens was more than an administrator or a clinician-scientist for Cohen to look up to; he was a mentor.
“Our vaccine research on R. equi might be an appropriate strategy for preventing TB, which would be of global importance for human health,” Cohen explained. “Additionally, the strategy developed by Dr. Gerald Pier and his colleagues at the Harvard Medical School, with whom we collaborate, is innovative and could lead to a ‘broad-spectrum’ vaccine that is effective against many infectious agents.” The One Health Initiative, which stresses the connection between animal health, human health, and the environment, is an integral part of Cohen’s research. “Although our hearts and minds are committed to improving equine health, we are very much engaged in the One Health Initiative with our activities,” he said. “Developing new types of antibiotics and vaccines that can reduce the need for antibiotics is important for equine and human health
Before retirement from the CVM, Cohen hopes to develop a vaccine to control R. equi pneumonia because “it is of global importance.” He would like to help shift the emphasis of treating infectious bacterial disease with antibiotics to methods that help the patient’s immune response protect them against infection. This is of utmost importance because bacteria are rapidly developing resistance to antibiotic treatment. Cohen also recognizes the significance of students, believing they are the leaders of tomorrow. He aspires to make a positive impact on students by encouraging their research efforts. “During my time at the CVM, I would like to have trained scientists, including veterinary clinician-scientists, whose future contributions will far surpass mine,” he said.
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ONE HEALTH The strategies Cohen and his team are exploring may have positive implications for other animals, including humans. Since there are striking similarities between R. equi and Mycobacterium tuberculosis, the bacteria that causes tuberculosis (TB), their research on R. equi may give rise to potential therapies or preventives against TB in humans.
“I learned so much from him, and we worked synergistically,” Cohen said. “One of the most important things I learned from Dr. Martens was that research is always better when done as a team. Martens was a role model for leadership, and he helped create a work environment in which we could work passionately, assiduously, and enjoyably. He offered advice and humor that made it fun to come to work each day.” In addition, Cohen expressed his gratitude for the cooperation and support from everyone at the CVM because it has positively impacted the success of his research.
ONCOLOGY & CELL BIOLOGY
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by Sara Carney
Dr. Stephen Safe
IT’S SAFE TO SAY, IMPACT
BEGINS AT DISCOVERY Discovery and the unexpected—these are recurring themes in the research career of Dr. Stephen Safe, a distinguished professor at the College of Veterinary Medicine & Biomedical Sciences (CVM). Trained as a chemist, Safe eventually found himself studying toxicology and examining the biochemical mechanisms of cancer with the hopes of developing effective drug treatments. Safe looks at receptors, a molecular lock to which chemical signals are the keys. When these chemical signals bind to the receptor, or turn the metaphorical key, it leads to a Rube Goldberg-like process, where one action affects another and then another, ultimately powering various biological processes.
“Receptors are needed for life,” Safe said. “They are sensing molecules. They sense light. For example, you need sunlight to produce Vitamin D. What does Vitamin D do? It would do nothing if there wasn’t a Vitamin D receptor.” And, it all started with a single receptor—the aryl hydrocarbon, or AH, receptor. Known to play a role in a chemical’s toxicity in the body, the AH receptor was not known for its health benefits. However, research trends led Safe and his colleagues to suspect that this receptor’s function was far from black and white. There were, in fact, health benefits yet to be uncovered. “I started off working on toxic compounds that bound to the AH receptor. It was always thought to be a receptor that was important for
“We’ve been looking at ligands—or compounds that bind this receptor—that aren’t toxic.
WE’RE USING THEM FOR TREATING
CANCERS, AND INVESTIGATING
THE HEATH BENEFITS OF THE
RECEPTORS IN GUT MICROBIOTA.”
Excited by the possible health benefits associated with the AH receptor, Safe began looking for practical solutions to ailments such as pancreatic cancer. Through partnerships with pharmaceutical companies, Safe is working toward developing effective drug treatments that would specifically focus on receptors like the AH and NR4A1 receptors to promote pathways that prevent cancer growth. “We’ve got a new group of drugs that look like they’re really going to knock your socks off,” Safe said. Safe’s interest in the AH receptor has stimulated an interest in other receptors, such as NR4A1, which Safe and his colleagues are investigating for the treatment of multiple cancers including rhabdomyosarcoma—a devastating children’s cancer. “We think the AH and NR4A1 receptors are really important in cancer, and we’ve been developing drugs that target them through different pathways,” he said.
Developing these drugs can be a balancing act, looking for the appropriate dose to ensure effectiveness. “We’re trying to develop drugs that we can give at a much lower concentration to hopefully be below the toxic threshold. We think that they have relatively low toxicity and expect that the side effects will be minimal. In addition, they’re also useful for combination therapies.” Safe’s fascination with the AH receptor has caused his research to take an unexpected turn. In collaboration with other researchers at Texas A&M, he is focusing on the effects of microbial and food-derived AH-receptor compounds on gut health. For example, eating cruciferous vegetables, such as cabbage, could provide similar effects as the compounds acting on the AH receptor. “Maybe plants that produce a lot of AH receptor compounds, like cruciferous vegetables, which are known to be health-protective, could be combined with what the microbiota produces. The two in combination could be dynamite,” he said. The twists and turns of Safe’s research has lead to continuous learning and a deep curiosity. “The good thing for me is I started off as a chemist and all we do in my lab is oncology and molecular biology. So, I’m learning all the time,” he said. Beyond the AH receptor discovery, Safe continues to search for much needed practical, life-saving therapies.
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driving toxicity of various chemicals that bound to it,” Safe said. “Many people have discovered in the last 20 years that this receptor plays a huge role in all sorts of things, including the health of your gut, the health of your skin, and autoimmune diseases. We’ve been looking at ligands—or compounds that bind this receptor—that aren’t toxic. We’re using them for treating cancers, and investigating the heath benefits of the receptors in gut microbiota.”
ONCOLOGY & CELL BIOLOGY by Dr. Megan Palsa
(Photomicrograph courtesy of Dr. Ken Muneoka)
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GROWING RESEARCH For nearly all of human history, regenerating body parts has been the stuff of mythology. Greek legends warned of the Hydra, a vicious monster that regrew two heads for every one struck off. The Aztecs marveled at the axolotl, a salamander that can regrow its limbs, lower jaw, and parts of its organs. Because of these regenerative properties, the axolotl may have been associated with the Aztec god Xolotl, who supposedly helped regenerate life to create the present world and changed himself into an axolotl after a falling out with the other deities. As with most legends, these tales have some elements of reality. The axolotl, in particular, is a prime example of the real potential of limb regeneration, which made it the perfect subject for Dr. Ken Muneoka’s Ph.D. dissertation. “I got completely stuck on the idea of being able to regenerate things,” Muneoka said. Born in Honolulu, Hawaii, Muneoka grew up in Los Angeles and completed his bachelor of arts in biology and zoology in 1976 at Humboldt State University. While taking a course on embryology, at the Marine Biological Laboratory in 1978 in Woods Hole, Massachusetts,
taught by his future adviser and friend, Dr. Susan Bryant, Muneoka found a new way of looking at biology. Intrigued by Bryant’s research on limb regeneration in salamanders, he joined her laboratory at the University of California, Irvine. He completed his Ph.D. in developmental and cell biology with the help of the axolotl in 1983, and he began doing postdoctoral research to take his interest to the next level: limb regeneration in mammals. EARLY WORK Muneoka’s postdoctoral work attracted the attention of Howard Schneiderman, the former dean of biological sciences at UC Irvine hired by the Monsanto Company to be the company’s Senior Vice President for Research. Schneiderman, who had helped bring genetic research to the company and was interested in regeneration’s potential, as well, supported Muneoka’s research on the relationship between embryonic development and regeneration, which fascinated Muneoka since taking Bryant’s course. “The approach that I have always taken has been more of a development approach,”
“THE GOALS OF OUR
RESEARCH HAVE BEEN TO TRY TO UNCOVER THE
BASIC MECHANISMS THAT ARE REQUIRED FOR REGENERATION, he said. “If an organ can develop in the embryo, why can’t it be regenerated?” As an organism develops from an embryo and moves toward adulthood, it slowly loses it regeneration abilities. Muneoka’s early work thus focused on examining embryos to try to find what stimulates or inhibits regeneration. After completing his postdoctoral research, Muneoka accepted an assistant professorship from Tulane University to open his own lab in 1986. Although his work at Tulane coincided with a period of lessened interest in regeneration, Muneoka managed to continue his research. “This was a time when the regeneration field was in a slump,” he recalled. “I was fortunate enough to have survived that slump. It wasn’t until after around 2000 that the scientific community became slowly convinced that it might be possible to regenerate structures.”
Major scientific breakthroughs involving embryonic cells in the early and mid-2000s, such as the successful creation of the first cloned sheep, Dolly, rekindled interest in the prospect of limb regeneration and related research. The U.S. Department of Defense (DoD), faced with finding ways of helping soldiers who had lost limbs during military campaigns in the Middle East, was one prominent organization keen on supporting regenerative medical research. The Defense Advanced Research Projects Agency (DARPA), the research arm of the DoD, began funding Muneoka’s work at Tulane. His DARPA program manager, John Mogford, would later become the Vice Chancellor for Research for the Texas A&M University System. Muneoka started studying MSX1, a transcriptional regulator gene, in mice. Although the gene’s precise function is still unknown, it has been shown to repress differentiation and maturation of cells.
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and then to see how those mechanisms are modified in situations where regeneration doesn’t occur.”
ONCOLOGY & CELL BIOLOGY
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Mutations in this gene resulted in the loss of the ability to regenerate the tips of fingers and toes, which is a trait all mammals have (and the only regenerative ability humans naturally possess). Mice that lacked MSX1 also had low levels of the growth factor BMP4. When these mice were given BMP4, their regenerative ability was restored. The revelation that BMP4 was one potential factor in finding a way to regenerate limbs opened up a new avenue of inquiry for Muneoka and his lab. “The goals of our research have been to try to uncover the basic mechanisms that are required for regeneration, and then to see how those mechanisms are modified in situations where regeneration doesn’t occur,” he said.
Dr. Ken Muneoka
Muneoka began studying BMP2, another growth factor from the same family as BMP4, as a possible way to stimulate skeletal growth from an amputation wound. Yet a third BMP family member can direct cells to make joints in the limb. Understanding the roles of these growth factors and how they interact with cells, thus became a crucial aspect of his research into potential ways of initiating regeneration. MOVING TO TEXAS A&M Nearly three decades after beginning his lab at Tulane, Muneoka was approached by the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM) about moving his work to Aggieland. After gaining the support of his lab colleagues, he accepted. The
Imagery showing distal phalanx (P3) wound closure and blastema cellular formation from one through nine days post amputation (DPA) (Images courtesy of Dr. Ken Muneoka)
opportunity to continue his work with larger animal models was especially appealing. “One of the attractions of coming to the vet school at Texas A&M is that we hope to have the opportunity to try to work on larger animals to see if we can take our mouse studies and bring it to a different level,” he said.
Combining these findings with those from his earlier work, Muneoka has found that allowing an amputation wound to heal and then
“It turns out that the cells in your body know a lot about your body,” Muneoka explained. “If you can tap into how to get them to get involved in the regenerative response, they know to make the appropriate bone structure that is lost.” Like the regenerative processes he studies, Muneoka’s work has slowly laid a solid foundation for future growth. No longer the stuff of myth and legend, regenerative medicine is increasingly becoming an amazing scientific possibility. “What we’ve done is to provide a proof of concept,” he said of the research he and his colleagues have done. “Prior to our work, I think most people thought, ‘This isn’t possible. This can’t happen.’ I think that we’ve made some inroads into the field, so that people are starting to think, ‘Maybe it can happen.’”
Bone island formation (Image courtesy of Dr. Ken Muneoka)
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Muneoka’s most recent work has focused on reaching that level. Using oxygen to initiate the release of cells from tissues in a way that favors regeneration, has revealed the role of osteoclasts and osteoblasts in the regenerative process. Osteoclasts degrade bone, thus freeing up cells from the degraded tissue. Once the osteoclasts complete their work at a wound site, osteoblasts begin rebuilding bone structures. Both cell types are constantly maintaining the skeleton, but in the cases of wounds and regeneration, they work on a larger scale that often creates more bone than necessary. Macrophages, the cells from which osteoclasts are formed, also appear to play a role in regeneration by clearing bacteria from the wound site.
introducing BMPs and other factors produces the best regenerative response. This approach underscores the idea that limb regeneration in larger animals and humans is possible because the cells are already capable of doing much of the work necessary to regrow a limb and just need to be encouraged to further the process.
REPRODUCTIVE BIOLOGY by Dr. Megan Palsa & Callie Rainosek
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HORSING AROUND
ICSI-in vitro produced blastocyst stained for three different cell types (Image courtesy of Dr. Katrin Hinrichs)
SETTING THE STANDARD FOR EQUINE ASSISTED REPRODUCTION
Dr. Katrin Hinrichs, professor and Patsy Link Chair of Mare Reproductive Studies in the Department of Veterinary Physiology & Pharmacology and the Department of Large Animal Clinical Sciences, grew up riding horses as a hobby. As an adult, she is internationally recognized for her research in equine reproductive physiology and for overseeing one of the few labs in the world capable of performing intracytoplasmic sperm injection (ICSI), a process that has now become the standard in assisted reproduction in horses.
cloned foals to aid in her research on the application of cloning in equids. Although she faced a number of challenges throughout her journey, Hinrichs’ work paved the way for the clinical and research application of many forms of assisted reproduction in horses.
A more complex and precise form of in vitro fertilization (IVF), ICSI is the only process that can efficiently produce a fertilized equine embryo outside of a mare’s body. Hinrichs’ research ultimately led to success and improved efficiency in ICSI, a goal that once seemed unreachable for equine reproduction researchers.
TESTING THE POSSIBILITIES When Hinrichs accepted the offer to teach physiology at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM) she began researching cloning and in vitro fertilization. Two years later, she brought in Dr. Young-Ho Choi as a collaborator, who began as a post-doctoral trainee and is currently a Research Associate Professor.. The two began exploring the possibility of producing a fertilized equine embryo in vitro, a basic tool for research and clinical use in other species that was not yet feasible in the horse.
In the last year, Hinrichs was named a Texas A&M Regents Professor and was awarded the third Simmet Prize in Assisted Reproduction by the International Congress on Animal Reproduction. Her other achievements include producing the first cloned horse in North America, named Paris Texas, as well as other
In conventional IVF, sperm are placed in a dish with a mature oocyte, and one sperm penetrates the oocyte to fertilize it. Given ideal laboratory conditions, the egg will develop into an early embryo, which can be transferred to a recipient female for further development. However, traditional IVF had yet to be achieved
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Dr. Katrin Hinrichs (seated) with staff and students in her lab
REPRODUCTIVE BIOLOGY
CVM IMPACT | 36
in horses. Unlike those of other livestock species, such as cattle, horse eggs and sperm do not seem to respond to traditional IVF methods. Therefore, Hinrichs and Choi took a different approach by looking into a more complex assisted reproduction method: ICSI. In ICSI, a single sperm is manually injected into the cytoplasm—the fluid inside the cell—of the mature oocyte. The fertilized oocyte is then placed in an incubator in hopes that an early embryo can develop. The embryo can then be transferred into a recipient mare’s uterus for gestation. Because so few sperm are needed, in theory, a single straw of frozen semen from a valuable stallion can produce thousands of offspring. This means that deceased stallions can continue to reproduce reproduce using semen that was frozen from them previously. Mares who are no longer able to reproduce naturally but still produce healthy oocytes can also continue to produce offspring through ICSI. OVERCOMING CHALLENGES AND MOVING FORWARD To see if the ICSI process could even be performed in their lab, Choi began working with
a micromanipulator and a powerful microscope that allowed for manipulation of horse oocytes. Using the micromanipulator, Choi was able to hold the oocytes in place and inject a single sperm into each egg using a very fine pipette. This marked the beginning of a journey toward successful assisted reproduction for horses; but the rest of the journey would not be easy. After Hinrichs and Choi discovered that the ICSI process could be successfully performed to fertilize a horse oocyte in the lab, the next challenge was to provide the ideal conditions for an early embryo to develop—a goal that would take over three years to reach. “We could put the sperm into the oocyte, but we did not have the right environment for it to develop in vitro,” Hinrichs explained. “IVF had never worked in horses, so nobody had produced early equine embryos in the laboratory, so no one had done studies on how you culture an equine embryo to get it to develop.” Promising results led to research support in the form of grants, which were instrumental in the success of Hinrichs’ ICSI program. More funding led to more research, and
Dr. Young-Ho Choi performing ICSI using a micromanupulator and a powerful microscope
CLONING WAS ONE OF
CHOI AND HINRICHS’ GOALS,
AND THE FINDINGS FROM
PERFORMING ICSI HELPED TO ADVANCE THEIR WORK IN THAT AREA.
Choi and Hinrichs discovered that an equine embryo needed a complex medium to grow for the seven to 10 days until it could be placed in a recipient mare. After more successful attempts at producing early equine embryos in vitro, Hinrichs and Choi were able to move on to perform the process clinically. “It took a couple of years for us to develop a method where an embryo could develop in vitro to the point where we could transfer it to the uterus of a recipient mare to make a pregnancy,” Hinrichs said. “It turns out the developing equine embryo needs a lot to survive; it needs a complete cell culture medium. Luckily, you can buy a cell culture medium at the cell culture store. It’s got everything in it a cell would ever need.” The clinical ICSI program quickly became successful. In 2015 Hinrichs and Choi performed more than 450 procedures on oocytes from valuable client-owned mares. A large part of this demand is due to low semen supplies of stallions who are deceased or too old to
reproduce any longer. In comparison to other forms of assisted reproduction, such as artificial insemination, ICSI is more efficient in these cases. For example, artificial insemination of a mare with frozen semen could potentially take several straws of sperm to produce a pregnancy, while for ICSI, one straw of frozen sperm can be thawed and diluted so that it yields enough doses to perform hundreds of ICSI procedures. In addition to external grants, Hinrichs credits The Patsy Link Equine Research Endowment Fund as playing a major role in their success. “The Patsy Link endowment was what funded us to keep researching ICSI so that we could get the process to work,” Hinrichs said. “This helped fund Dr. Choi’s salary and our supplies in the laboratory. Recently, income from our clinical ICSI program has started to replace the Link funding, freeing up money to support other equine research programs at Texas A&M.” Increasing the efficiency of ICSI solved many challenges associated with assisted reproduction in horses. The research and time Hinrichs and
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In reproductive cloning, researchers recover unfertilized eggs from mares and eliminate all DNA from the eggs. They then collect a tissue sample, usually skin, from the valuable donor horse and culture cells from the sample. The DNA from the donor cell is then transferred through a needle into an egg that had its own DNA removed. Given the right laboratory conditions, an early-stage embryo can develop and will be placed into a mare’s uterus for further development. The resulting foal has the same genetics as the donor horse—an “identical twin” born years later.
REPRODUCTIVE BIOLOGY
WHAT IS IN VITRO FERTILIZATION?
CVM IMPACT | 38
Commonly referred to as IVF, in vitro fertilization refers to having the process of fertilization—that is, the combining of a sperm and a mature oocyte, or unfertilized egg—occur outside of the body in the laboratory. In standard IVF, an egg is placed with sperm together in a dish, and one sperm must penetrate the egg. Under the right conditions, an early embryo can develop. If the process is successful, the embryo is then transferred into the uterus for further development. Although this process has been successful in many species, it has not had repeatable success in equine species because the sperm do not penetrate into the egg.
WHAT IS ICSI? Intracytoplasmic sperm injection (ICSI) involves manually inserting a single sperm into a mature oocyte via a pipette. This produces a fertilized egg, and if the laboratory provides the right conditions, an early embryo can develop. In theory, only one sperm is needed for each egg, so ICSI provides a method by which numerous offspring can be produced from a small store of frozen sperm. This process has proved successful for assisted reproduction in horses, and Texas A&M is home to one of the world’s few laboratories that can successfully perform this procedure.
WHAT IS CLONING? In reproductive cloning, researchers remove all the DNA from a mature oocyte. Scientists collect a single somatic cell, any cell except sperm and eggs, from the donor animal. The DNA from the somatic cell is then transferred through a needle into the egg that has had its own DNA removed. Given the right laboratory conditions, an early-stage embryo can develop and will be placed into a mare’s uterus for further development.
Choi devoted to successfully performing ICSI also aided advancements in another aspect of assisted equine reproduction: cloning. CLONING: THE NEXT STEP Cloning—a process that has been successful in many species such as cats, cattle, and deer— was one of Choi and Hinrichs’ goals, and the findings from performing ICSI helped to advance their work in that area. In reproductive cloning, researchers recover unfertilized eggs from mares and eliminate all DNA from the eggs. They then collect a tissue sample, usually skin, from the valuable donor horse and culture cells from the sample. The DNA from the donor cell is then transferred through a needle into an egg that had its own DNA removed. Given the right laboratory conditions, an early-stage embryo can develop and will be placed into a mare’s uterus for further development. The resulting foal has the same genetics as the donor horse—an “identical twin” born years later. Hinrichs funded her research in cloning through research agreements with private individuals who wanted to support advancements in this area and have cells from their horses used in the work. While reproductive cloning offered an opportunity for Hinrichs to further study the biology of the horse oocyte and early embryo, it also lead to her interests in endangered exotic equids. Hinrichs hopes that her cloning research can eventually assist in saving endangered equids, such as Grevy’s zebra, by producing fertilized cloned embryos in the laboratory and then allowing the cloned animal to develop in a recipient mare. The cloning process would aid populations with extremely low numbers and low genetic diversity by cloning deceased or old individuals that had not reproduced in that population. “A lot of people wonder why you would clone a horse,” Hinrichs said. “I’ve always been enthusiastic about cloning as a way to save endangered species or even endangered rare breeds. In fact, I have been in contact with people who work with rare breeds of horses who want to work with me on cloning and ICSI
rhinos in the United States to maximize their numbers and genetic diversity, as a fallback if every single rhino in Africa is poached.”
A NEW PROJECT: SAVING THE NORTHERN AND SOUTHERN WHITE RHINO In addition to hoping to save endangered equids, Hinrichs recently became involved with a project initiated by the San Diego Zoo that aims to replenish the populations of African northern and southern white rhinoceros. Only three northern white rhinos, which live in Kenya, remain in the world, while about 20,000 southern white rhinos remain in Africa. In the United States, there are approximately 100 southern white rhinos kept in captivity.
Because of the genetic similarities between the rhinos, Hinrichs said it is highly likely that a northern white rhino’s DNA could develop normally inside a southern white rhino’s oocyte. “If we develop a way to get oocytes from the live southern white rhinos in the United States, then we could use the eggs for two purposes: first, we could increase the genetic diversity in the United States southern white rhino population by using southern white rhino sperm in the frozen zoo to produce southern embryos through ICSI. Second, we could use the southern white rhino eggs as ‘host’ eggs, to clone northern white rhinos.” For embryos produced by both ICSI and cloning, the southern white rhino would serve as a recipient; but there is an additional challenge of finding a way to transfer the embryo without surgery to the female. The size of the rhino makes both obtaining oocytes from female rhinos and placing them into a recipient a problem, one to which the rhino conservation group is now trying to find solutions.
“I got involved with this project through my membership in the International Embryo Technology Society,” Hinrichs said. “At our annual meeting, there was a day on which the society had a course on exotic animal reproduction. One of the people that was at the course, Dr. Barbara Durrant, director of reproductive physiology and Henshaw Chair at the San Diego Zoo, asked me if I wanted to meet with her to talk about assisted reproduction in the rhinoceros.” Since the 1970s, the San Diego Zoo has been collecting and freezing cells from the zoo’s deceased animals. This “frozen zoo” includes northern white rhino sperm and skin cells. By collaborating with Hinrichs, the San Diego Zoo hopes to produce rhino embryos through ICSI and cloning. However, there are many challenges in the way of this goal. “Scientists in this project are trying to develop a way to get the eggs from rhinos that are still alive,” Hinrichs explained. “The rhino is so big that traditional methods of collecting oocytes, as used in other species including horses, can’t be performed. In addition, shipment of exotic animals and their sperm and cells is getting more difficult because of government regulations, so we cannot receive eggs from rhinos that die, say, in South Africa. This results in scientists trying to manage the population of southern white
Three embryos produced by ICSI, after four days culture in vitro. (Image courtesy of Dr. Katrin Hinrichs)
39 | CVM IMPACT
because there are only a few specimens left of certain breeds. For me, a major application of cloning is for saving endangered equids.”
REPRODUCTIVE BIOLOGY by Sara Carney & Jessica Scarfuto
A CLONE ABOVE THE REST
CVM IMPACT | 40
Dr. Charles Long, Dr. Mark Westhusin, and a student in the RSL
For the past 17 years, the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM) has served as a leader and innovator in cloning, making something that once seemed like science fiction a reality. The efforts of CVM faculty ultimately gave way to successfully cloning two bulls, a cat, and a deer among other animals. Along the way, researchers gained greater understanding of biological processes, such as how certain traits are inherited and practical applications of cloning. Today, the lab has a number of research interests, including early embryonic development, in vitro fertilization, and epigenetics. At the center of the work on cloning at Texas A&M is the Reproductive Sciences Lab
(RSL) Department of Veterinary Physiology & Pharmacology, composed of Dr. Duane Kraemer, Dr. Mark Westhusin, Dr. Charles Long, and Dr. Michael Golding. The lab was originally established in 1975, when Kraemer returned to Texas A&M University. In its early days, the lab focused on embryo transfer. But along the way, the lab was involved in the founding of several companies, including Granada Genetics, the world’s largest embryo transfer company; Genetic Savings and Clone, the first company to be devoted to pet cloning; and Viagen, which commercially cloned horses and livestock and still exists today. Establishing these companies also brought several of the researchers to the lab, such as Long, who
began as a technician at Granada, earned his Ph.D., and then went to work for the RSL. At the RSL, researchers are involved in a number of assisted reproductive and genetic technologies. “Our research has been focused on genetic engineering of livestock and also understanding the early embryo and its development,” said Long. “Our lab has refocused on genetic engineering, and I try to support that,”
could not only improve the health of some animals and make them more efficient, but could improve human health as well. “Now we could not only select the best animals through traditional means, but we could also make those animals even better,” Long said. “Now we work more on genetic modification. We’re working mainly on genes that are involved with disease resistance, and genes that have to do with muscle development. We also
“A LOT OF OUR RESEARCH
INVOLVES THE DEVELOPMENT
PRODUCTION OF ANIMALS
THAT COULD SERVE A
COMMERCIAL PURPOSE, like increased muscle development and resistance to disease,” said Westhusin. “We have a whole other area of science going on that is focused on more basic research—understanding developmental biology, and reproduction efficiency.”
Kraemer said. “I’m not a genetic engineer, but I’m the veterinarian in the group.” This research includes producing genetically engineered (GE) and transgenic animals, which are processes that create an animal with superior traits. GE involves direct manipulation of an organism’s genetics. On the other hand, a transgenic animal has genes from another organism inserted into its DNA, allowing it to have capabilities that it didn’t have before. Such genetic technologies
have some interest in producing vaccines and pharmaceuticals,” Westhusin said. One example of these efforts is a project studying a transgenic goat that produces a malaria vaccine in its milk. “Some drugs and therapeutics can be made more inexpensively and in much higher volumes when done using goats or cows,” Westhusin said. The RSL doesn’t plan on slowing down any time soon, and there are a number of new projects on the horizon, particularly biomedical models. “Large animal models
41 | CVM IMPACT
OF TECHNOLOGIES AND
REPRODUCTIVE BIOLOGY
SECOND CHANCE
In 1999, a team of Texas A&M researchers led by Dr. Mark Westhusin, professor in the Department of Veterinary Physiology and Pharmacology (VTPP), successfully cloned the first male calf from an adult Brahman steer: Second Chance. This marked the CVM’s beginning as a leader in cloning technology. Chance (the first) was a mild-tempered bull that belonged to a rodeo clown named Ralph Fisher for much of the 1980s and 1990s. Fisher wanted to clone him because of his gentle nature.
CVM IMPACT | 42
DEWEY THE DEER
In addition to pets and livestock, researchers at the CVM cloned Dewey, a white-tailed deer, in 2003. The deer was named after Dr. Duane “Dewey” Kraemer, a senior professor in VTPP instrumental in a number of clones produced at the CVM, including Dewey. “We were the first in the world to clone a white-tailed deer,” Westhusin said. “We call him Dewey after Dr. Kraemer, just to honor him.”
BULL 86
Although cloning cannot preserve personalities, there are other characteristics it can preserve, such as disease resistance. Cloned in 2001 by Westhusin and his team, a Black Angus bull named Bull 86 was naturally resistant to brucellosis, a disease that can be devastating in livestock and can transfer to humans through contact with an infected placenta. Although consumption is one way to contract brucella, that’s not the most common. Typically infections arise from drinking unpasturized milk or handling fetal tissues of infected animals. Bull 86 was studied for years as part of a breeding research program to try to determine what gene was responsible for making him resistant to brucellosis.
CC THE CAT
CC was a particularly interesting case, because CC, a tabby, did not resemble her host, a calico. As in the case of Second Chance, CC and her donor, Rainbow, also had different personalities. CC was a shy cat, whereas Rainbow was more outgoing. These differences illustrate the limitations of cloning. “This is reproduction, not resurrection,” Westhusin said. “There’s no guarantee the animal is going to look or act the same. If you clone a black cat you’re going to get a black cat. If it’s a multicolored cat, there’s no way to predict that all the colors will come out in the same spots—that’s just not how it works.”
Dr. Duane Kraemer works with students in the RSL in the 1990s.
The lab plans to continue working on understanding fundamental biological processes. “A lot of our research involves the development of technologies and production of animals that could serve a commercial purpose, like increased muscle development and resistance to disease,” said Westhusin. Long and Westhusin with students in the RSL in 2016
“We have a whole other area of science going on that is focused on more basic research—understanding developmental biology, and reproduction efficiency.” The RSL has a productive and illustrious past, but that is simply part of who these researchers are. As the lab’s research interests evolve, so do their successes. Success for them is not a thing of the past.
43 | CVM IMPACT
are, in many cases, informative in drug development,” said Westhusin.
ORTHOPEDICS & CLINICAL TRIALS by Dr. Megan Palsa
CVM IMPACT | 44
Dr. Brian Saunders and a veterinary technician examine a dog.
HEALING RESEARCH For decades, medical researchers around the world have been developing regenerative medicine and tissue engineering strategies to treat patients who are suffering from debilitating bone and joint diseases, such as arthritis. Despite extensive research efforts using stem cells and scaffolds, these new approaches have yet to solve the problem of bone and joint damage in patients with diseases like osteoporosis, non-healing
bone trauma, and joint arthritis. However, veterinary medicine may provide insight. Similar cases of weakened bone in animals and the need for an effective solution in humans have led veterinarians, such as Dr. Brian Saunders, an assistant professor at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM), to study regenerative medicine and tissue engineering in dogs. Though conditions
Before
such as osteoporosis are not as widespread in dogs as in humans, Saunders is optimistic that his team of researchers will one day develop tissue-engineering systems to heal bone and joint injuries in both humans and animals. Saunders, a small animal orthopedic surgeon and stem cell biologist in the Department of Small Animal Clinical Sciences (VSCS), is a Texas native who grew up raising large animals, particularly horses. “My family is made up of physicians and medical professionals. Because of my interest in large animals and the medical professional aspect of my family, I became interested in veterinary medicine,” he said.
After graduating veterinary school, Saunders completed a rotating internship at the University of Tennessee. He decided he wanted to specialize in small animal surgery, but this was put on hold while he pursued a Ph.D. in vascular biology. Saunders became fascinated by cell biology while working with Dr. George Davis, a renowned vascular biologist, who was at Texas A&M’s Health Science Center College of Medicine at the time. Working for four years in Davis’ lab and completing his Ph.D. prepared Saunders for his future decision to
An x-ray of a patient’s radius and ulna before and after treatment. After the infected bone was removed, implants were installed, and stem cells were used to promote healing. (Images courtesy of Dr. Brian Saunders)
pursue stem cell research for animal medicine. Saunders completed his post-DVM education by completing a small animal surgery residency at the CVM, eventually becoming a Diplomate of the American College of Veterinary Surgeons and joining the faculty in 2009. “Around the time I was working in Dr. Davis’ lab, there was interest developing in stem cell therapy in dogs with orthopedic problems, primarily arthritis.” Saunders explained. “The small animal orthopedic surgeons began getting phone calls from clients and veterinarians saying, ‘We want stem cell therapy. Tell us about stem cell therapy.’ Some of these calls were funneled to me because of my basic science experience and training. Those phone calls and interest were what stimulated me to focus my own laboratory’s research efforts on stem cells.” Despite Saunders’ training in vascular biology, he had no experience with stem cell therapy at the time and began to study the subject on his own. “I found that a lot of the perceptions people had about stem cell therapy were misplaced. The evidence-based literature on what these cells are and what they’re capable of doing in both humans and in dogs is limited,” he said. “That void in the knowledge base is what provided me the opportunity to focus our research efforts on canine mesenchymal stem cells.” After gaining his faculty position, Saunders started his lab and assembled a team of collaborators, research assistants, and
45 | CVM IMPACT
Saunders attended veterinary school at the CVM to pursue his passion for large animal medicine, specifically equine ambulatory work. In veterinary school, Saunders developed new interests and his career took a different turn. “I became interested in joint replacement about halfway through veterinary school,” he said. “At that time, my family was dealing with some major orthopedic issues and I was simultaneously attending lectures by a small animal orthopedic surgeon, Dr. Don Hulse, who mentored me through the later stages of veterinary school, portions of my residency, and even to this day. I went and visited him in his office, shared a bit about my family’s orthopedic challenges and my interest in his lectures, and he took me under his wing. I started working with him on some research projects, and that got me interested in research. With his mentorship, we published the first paper on video-assisted endoscopic surgery (arthroscopy) of the hip joint in dogs.”
After
ORTHOPEDICS & CLINICAL TRIALS
graduate students with the goal of developing tissue-engineering devices to treat bone or cartilage defects in veterinary patients, and even potentially humans. “Say an animal or human with a massive defect in their bone from fractures isn’t healing correctly,
Saunders and other faculty co-investigators have been using stem cells and regenerative medicine in clinical patients. Honey, a toy breed dog who came to the CVM with a non-healing injury to the forearm, was one of the team’s first patients. Honey had broken her leg after
“…A LOT OF THE PERCEPTIONS PEOPLE HAD ABOUT STEM CELL
CVM IMPACT | 46
THERAPY WERE MISPLACED.
THE EVIDENCE-BASED LITERATURE ON WHAT THESE CELLS ARE AND WHAT THEY’RE CAPABLE OF DOING
IN BOTH HUMANS AND
IN DOGS IS LIMITED. That void in the knowledge base is what provided me the opportunity to focus our research efforts on canine mesenchymal stem cells.”
or they have joint infections, weak bones, or even osteoporosis,” Saunders explained. “Tissue-engineering devices may prove to be one exciting method to improve healing and a successful outcome.”
a fall, and had undergone several operations and months in cast and bandages. The result was a large bone defect of the forearm that had progressed to a non-healing condition known as non-union. They approached Honey’s challenging case by harvesting her stem cells
from a bone marrow sample, culturing her cells under conditions to enhance bone formation, and mixing these cells with a soft collagen gel for incorporation into her bone defect. This treatment, combined with a surgery to revise the implants in her broken leg, encouraged her own tissues to heal the bone. Though there are many companies offering stem cell therapy for dogs in the United States, the work done at the CVM is unique. “The difference in what we’re doing, compared to other providers of adult stem cells, is that we are isolating individual canine patients’ skeletal stem cells from bone marrow samples in our lab, characterizing those cells, enhancing the cell’s ability to transition to bone-forming cells, and combining the cells with three-dimensional scaffolding material to retain cells at the site of injury and encourage repair,” said Saunders. “It’s a targeted, customized approach for an individual patient. It’s a wonderful proof of the concept that we can use these types of tissue engineering and regenerative medicine approaches in dogs that really don’t have any other options.” Though the innovative research could potentially save the limbs of many dogs with
bone and joint disease, the cost of the research and procedures are expensive and time consuming. Another challenge is having enough patients to work on to make advancements in the field of study; more patients mean more opportunities for researchers to study the conditions in a variety of contexts. With the goal of applying his research to human medicine, where the demand is higher, Saunders has collaborated with Dr. Carl Gregory, an associate professor in the Texas A&M Health Science Center. Through this partnership, Saunders has contributed to other projects on bone and cartilage repair. According to Saunders, demonstration of success with regenerative medicine or tissue engineering approaches using animals larger than the typical lab rat, such as dogs, sheep, and goats, increases the probability that these techniques will translate to human medicine. There are also advantages to testing new regenerative medicine procedures in animals before introducing the techniques to physicians. “The nice thing about working with dog cells is we have the chance to use these types of treatment approaches in spontaneous
47 | CVM IMPACT
Saunders discusses a patient’s x-rays with staff.
ORTHOPEDICS & CLINICAL TRIALS
CVM IMPACT | 48
disease. Honey’s fracture is an example. She had a number of surgeries trying to repair the fracture, but they ultimately failed,” Saunders explained. “In these types of settings, you have a situation that closely mimics the clinical scenario in humans, as opposed to a small or large lab animal in which a simulated injury is created and immediately treated.” Though Saunders and his team are motivated to make an impact in stem cell therapy for human medicine, the current regulatory obstacles, particularly in the United States, remain a challenge. Once cells are harvested from a human patient and taken to a lab and grown under culture conditions, regulatory agencies in the United States prevent the cells from being re-administered to the patient. At that point, the cells are restricted to a more intense level of regulatory overview. “In today’s regulatory environment, approaches in which cells are harvested and manipulated in the laboratory to improve bone healing aren’t possible in humans due to concerns, many of which are valid, regarding changes that might occur within the patient’s cells in the lab,” Saunders said. “When you take the cells, whether they are bone marrow cells or cells from other tissues, and you enhance them, culture them, and expand them, those are considered manipulated biological tissues.” Despite the challenges to veterinary stem cell research, like identifying good candidates in his canine patients, locating funds and grants to run the research lab, and regulatory obstacles, Saunders and his team continue to work toward a solution for canine patients who suffer from bone and joint disease. Developing tissue-engineering systems that can heal bone and joint injuries in dogs that suffer from a pre-existing bone disease, and then potentially transferring these techniques into human medicine, is one of many goals for the team. “Regenerative medicine and tissue engineering hold a tremendous amount of promise for treating animals and humans with debilitating bone and joint disease,” Saunders said. “However, it’s important to remember that we are just at the infancy of understanding what
Stem cell growth, as seen under a microscope, after eight days (Image courtesy of Dr. Brian Saunders)
these cells from dogs do, what they’re capable of doing, and what we can use these cells to accomplish. Lastly, it’s important for me to acknowledge that in today’s competitive world of translational research, none of this work is possible without a complimentary team. I’m fortunate to have brilliant collaborators, such as Dr. Gregory and Dr. Melissa Grunlan, who have developed many of these tissueengineering approaches, a dedicated team in my lab (Shannon Huggins, Robert Bearden, Melissa MacIver, and numerous veterinary students) who share my vision and make this work possible, and small animal orthopedic faculty members and residents who support our work. I’m also grateful for our funding sources such as the Texas A&M Foundation’s Bone and Joint Fund (http://vetmed.tamu.edu/ giving/opportunities/bone-and-joint-fund), a Foundation fund developed to support the lab, and the American Kennel Club–Canine Health Foundation (AKC-CHF) who has generously supported work in the lab.”
MICROBIOME RESEARCH by Sara Carney
Dr. Jan Suchodolski
INSIDE YOUR PET The word “ecosystem” often evokes images of vast terrain and large expanses of wilderness, often at the continental or planetary scale. But, ecosystems aren’t always so massive. In fact, people, dogs, cats, and all other animals harbor tiny ecosystems within their guts and on their skin. This tiny world made up of microbes and metabolites is known as the microbiome. The microscopic microcosm within the guts of our pet cats and dogs is the subject of Dr. Jan Suchodolski’s research. As the associate director of research and head of microbiome sciences at the Texas A&M College of Veterinary Medicine & Biomedical Sciences’ (CVM) Gastrointestinal (GI) Laboratory, Suchodolski is much like a biologist trekking through unknown terrain to characterize and understand the life
present. And, he is part of one of only two labs in the nation specializing in research on the companion animal microbiome. The microbiome is a relatively new field of study, making Suchodolski’s research cutting edge. He has spent much of his research career uncovering what makes up our pet’s digestive tract. But, Suchodolski’s work is more than just identification; he is also working on understanding how the microbiome affects the overall health of the digestive system and beyond. “In the past, we focused on understanding ‘who’ makes up the microbiome, categorizing the bacterial groups present in the GI tract,” Suchodolski said. “Over the last 10 years, we
49 | CVM IMPACT
THE TINY WORLD
MICROBIOME RESEARCH have acquired newer, better tools to characterize the bacteria. The next big step is understanding their function, and that’s what we’re doing now.”
CVM IMPACT | 50
Understanding function means understanding how the microbiome influences disease processes and what a healthy—or unhealthy— microbiome looks like. This means being able to understand the root causes of and contributors to various illnesses, including inflammatory bowel syndrome (IBD), obesity, and diabetes. “We now have diagnostic tests that can help veterinarians pinpoint a disease process in the microbiome,” Suchodolski said. Instead of looking at a single group of bacteria, Suchodolski takes a holistic approach and examines the entire ecosystem, looking at the positive and negative effects of the microbes working in concert. “It’s like a football team. You have two competing teams. The players are different, yet they’re doing the same thing,” Suchodolski said. “In the microbiome, every player is unique. In function, they’re quite similar. But, like a football team, not everyone is going to become Super Bowl champions, and not every individual will have the same stable microbiome.” Suchodolski is particularly interested in bile acids including how they are metabolized and how they interact with bacteria to aid in digestion. “The reason that’s important for our research is that bacteria actually transform
the bile acids in a physiological way. Normally, so-called primary bile acids are converted into secondary bile acids by bacteria. This perfect ratio of secondary bile acids to primary bile is really crucial to maintaining health. When you have a change in the microbiome, for whatever reason—disease, drugs, or antibiotics—you don’t have this right conversion anymore. Suddenly, it becomes a real problem. Abnormal bile acid metabolism has been linked to obesity, inflammation, and diabetes.” Although the microbiome is a completely new world with much left to explore, diagnostic tests that examine the relative abundances of certain microbial groups have already been developed. “The bile acids that we’re focusing on, which are measured in fecal material, are part of the next big test that we’re going to start offering. That’s going to be really useful for diagnosis and treatment. It could also be a nice monitoring tool for the progression of disease.” It can be difficult to characterize an entire ecosystem in a single lab test, but Suchodolski and his team have helped to make it possible. What was previously a cumbersome test to interpret, which included multiple values reflecting the microbes present, Suchodolski and his colleagues have reduced to a single value for the veterinarian to interpret. “Before, veterinarians ran tests to look at all those bacteria groups separately, and they got this huge printout,” Suchodolski said. “It was very
“…WE FOCUSED ON UNDERSTANDING ‘ WHO’ MAKES UP THE MICROBIOME,
CATEGORIZING THE BACTERIAL GROUPS PRESENT IN THE GI TRACT. Over the last 10 years, we have acquired newer, better tools to characterize the bacteria.…”
The intestine harbors 100 trillion bacterial cells. Its inner lining contains many bacteria (red), which are in close proximity to the host’s cells (blue). This close interaction between bacteria and the intestine contributes to the importance of the microbiome to the host’s health. (Image courtesy of Paula Giaretta)
Suchodolski’s work is an example of One Health—the intersection of human, animal, and environmental health—and how veterinary medicine can be translated into human medicine. Recently, he and his colleagues published a study comparing the microbiome between humans and dogs with IBD, showing striking similarities. “The test showed that the patterns we see in humans with IBD are quite similar to canine IBD. That makes the dog a good model for human disease, at least at the microbiome level,” Suchodolski said. Suchodolski’s work is not just about One Health, it’s also about one being and the inseparability of animals from their microbes. “I think we really have to understand a more holistic point of view. Bacteria are a part of us. Bacteria are part of our evolution. We are really one physiological organism.” In studying a whole new microcosm, the potential for discovery seems endless. “There’s a lot of work to be done in the future,” Suchodolski said. “There are so
many other components that we never even thought about.” A few of those possibilities include leveraging the microbiome during treatment. Illnesses caused by microbial imbalance, such as those using antibiotics, could be treated by transplanting healthy microbiota into the GI tract of the patient to “jump start” the gut’s health. Additionally, “who makes up the microbiome” can vary widely between individuals as well. Just as a dog’s DNA is uniquely his, so too is his microbiome. This opens the doors for personalized medicine and precision treatments that are tailored to the individual for maximum effectiveness. There is still much to be learned before treatments can be developed and the full potential of this tiny world can be unveiled. “It’s not as straightforward,” Suchodolski said. “I think we still have a long way to go to develop optimal therapeutics. On one side, we’re highly precise. We have all of these hightech instruments, and they’re excellent. On the other side, a crucial component of our well being is based on ecological principles. It’s like gardening. If you like to garden, you know that it takes a long time for a gardener to get experience and to answer questions like, ‘How do I really do to take care of my garden and keep it weed free?’”
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difficult for you to say, by looking at twenty variables, is the patient normal or abnormal? To put the bacterial groups mathematically into one single unit, suddenly you have one number, called a dysbiosis index, and that one number can better classify if the patient’s microbiome is normal or abnormal.”
DIAGNOSTIC IMAGING by Dr. Megan Palsa
CVM IMPACT | 52
Dr. Michael Deveau
PICTURE THIS The Diagnostic Imaging & Cancer Treatment Center (DICTC) was formed in 2011 when the CVM gained a 3-Tesla MRI. This powerful tool allowed researchers and clinicians at the CVM to quickly capture detailed images of tissues and cells in small and large animals. “When the MRI was commissioned for clinical use, it was one of three in all of Texas. That includes human facilities,” said Dr. Michael Deveau, clinical assistant professor in oncology. “We have a veterinary facility with technology that most of the state of Texas didn’t have access to at the time, including human patients and clinicians.”
The center’s capabilities are not limited to MRI. Other imaging modalities include small and large animal radiology, small animal ultrasound, CT scans, and nuclear medicine. Utilizing multiple types of imaging technology improves the ability of the clinicians to provide an accurate diagnosis and create a treatment plan. “The literature supports no single modality as superior to any of the others,” Deveau said of the various imaging options available at the center. “They all have their strengths and weaknesses. When you put the information from all of them together, that’s when you see a tremendous benefit, as compared to any one by itself.”
GOALS OF THE DIAGNOSTIC
IMAGING & CANCER TREATMENT
CENTER ARE TO ADVANCE VETERINARY HEALTHCARE BY
PROVIDING OPTIONS AND SOLUTIONS FOR CONDITIONS
that animal patients face and to fulfill part of the One Health Initiative.
“The facility was built in part to answer the Initiative,” said Deveau. “It was a huge intellectual and financial investment by Texas A&M University, the CVM, and the donors. The facility helps utilize veterinary companion animals as representative translational models for human conditions.” Both goals are broad and cover a wide range of fields and research studies. “I think imaging is quite a large topic. It has its fingers in practically every aspect in medicine,” said Deveau of the breadth of the center’s abilities. One example Deveau gave of how the center’s equipment can be applied involved creating a 3-D model of a patient’s gut. The virtual model, constructed from CT scans of the patient’s digestive system, can be used to understand how a piece of food travels through and is processed by the patient’s gut. Such a model, of any system or organ or even a section of tissue, can have multiple applications for both research and clinical practice. Additional imaging technologies can also be utilized for the same patient to add greater
depth to the diagnostic picture, but at a cost. In addition to the financial expense associated with testing, animal patients also have special considerations, as many types of imaging require the animal to be under general anesthesia to ensure they remain motionless. “When you start talking about doing multimodality imaging, it adds up quickly,” explained Deveau. “Even if you combine it all under one round of anesthesia, you still have the cost that comes out of pocket for the tests and the anesthesia.” Still, being able to use multiple tests to develop a comprehensive understanding of a patient’s unique needs can be invaluable for conditions such as cancer. Precise imaging is particularly important when using targeted radiation therapy, as it is essential to know exactly where the cancer cells are before you can attack them. In addition to revealing location, imaging also allows doctors to monitor tumors during therapy. Being aware of changes in a tumor’s size or the presence of additional tumors can help doctors know if a therapy is working or if it needs to be modified. “The more modalities you use, the more information you get,” said Deveau. “Having more information will potentially set you up for a more optimal therapy.”
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DICTC has two primary goals. First, it aims to advance veterinary healthcare by providing options and solutions for conditions that animal patients face. Second, it fulfills part of the One Health Initiative.
TOXICOLOGY & ENVIRONMENTAL HEALTH
CVM IMPACT | 54
by Dr. Megan Palsa
Dr. Ivan Rusyn
HEALTHIER ENVIRONMENT,
HEALTHIER PEOPLE Dr. Ivan Rusyn, a professor at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM), was born in Kiev, Ukraine, the son of two engineers. From the beginning, the importance of education played a large role in his family; his parents were each firstgeneration college graduates who impressed their appreciation for science and learning on their children. So, perhaps it came as no surprise to the elder Rusyns when their son went on to get his M.D. then Ph.D. in toxicology, and their daughter a Ph.D. in biochemistry. “We’re trying to one-up our parents,” Rusyn joked.
It was his parents’ education that brought the Rusyn family from a coal-mining community in southeastern Ukraine and a farming village in western Ukraine to the capital city Kiev. His parents were sent there in the 1960s after getting their college degrees to “repay” the free education the government provided. As a result, Rusyn grew up in Kiev during a unique period in Ukraine’s history. In May of Rusyn’s eighth-grade year, the infamous Chernobyl nuclear power plant accident occurred—only 30 miles from Kiev.
iCell® Human endothelial cells growing in culture (green is a fluorescent stain for the cytoplasm, blue are cell nuclei). (Image courtesy of Dr. Ivan Rusyn)
Despite the lack of official information in the immediate aftermath, news of the danger spread fast. “The biggest immediate threat was from radioactive iodine,” Rusyn explained. Although it wasn’t potentially hazardous for Kiev adults, children were at risk because the iodine could affect thyroid development.“ All of that wasn’t common knowledge, but it became common knowledge fast enough,” Rusyn recalled. “It took about two weeks for the [government] propaganda machine to actually admit what happened, but the rumor mill worked very fast. A lot of kids started disappearing from school.” Rusyn soon joined the flight of children from the affected area to “safer places.” His parents stayed behind, sending him to his maternal grandmother’s home in southeastern Ukraine for the summer. When school started, he went to his father’s hometown in western Ukraine for the semester. It was nearly a year before he returned to his parents’ home in Kiev.
Although Rusyn started his residency in ear, nose, and throat surgery, he couldn’t resist the research career. During a trip to a conference in Germany he met Helmut Sies, one of the leading researchers studying oxidative stress at the time. Sies made Rusyn an offer he couldn’t refuse:
After spending a year in Germany, Rusyn was thoroughly hooked on research—with a particular interest in toxicology. On the advice of colleagues, he applied to graduate school in the United States. In 1996, he began his doctoral studies in toxicology at the University of North Carolina (UNC) at Chapel Hill, followed by two years of post-doctoral work at UNC and the Massachusetts Institute of Technology (MIT). He then returned to UNC in 2002 to launch his career in academia as an assistant professor. He made full professor in just eight years—quite the feat. TEXAS A&M UNIVERSITY In 2014, Rusyn moved to College Station to join the CVM team. As with many of his career changes, it wasn’t an expected move. He was happy at UNC but was ultimately swayed by Texas A&M’s commitment to the One Health Initiative which fit his research in environmental health. “The concept of One Health was a very big attraction because I knew this wasn’t just an attempt by university administrators to bring in one person,” he explained. “It was a concerted effort with all these outstanding researchers coming together in the college, having this drive. It was very important for me to feel that the administration had a commitment to the broader [One Health] picture, rather than just a commitment to me and my lab.”
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EDUCATIONAL PATH TO SCIENCE After high school, Rusyn went on to medical school at the Bogomolets National Medical University in Kiev where he spent the next six years training to become a physician. However, as he progressed through his studies, his interests began to veer away from clinical medicine. “I was really enjoying training to be a physician,” Rusyn said, “But I dabbled into research in the last two years [of medical school] and really, really liked it.” Once again, the Chernobyl blast altered the course of Rusyn’s education, albeit a bit more subtly this time. “[In our research] we were working with [Chernobyl] first responders and their blood samples and looking into reactive oxygen species and DNA damage. This work was both important and immediately applicable to prevention of the deleterious effects of radiation.”
an invitation to work in his lab for a year on a German government fellowship (DAAD). Rusyn leapt at the opportunity. He left his residency in Kiev for Germany and never looked back.
TOXICOLOGY & ENVIRONMENTAL HEALTH Since moving to the CVM, Rusyn has devoted himself to filling in the gaps in knowledge about the chemicals in our environment that affect human health. “The biggest problem in the field of environmental health and toxicology is lack of comprehensive safety information on most chemicals in the environment and commerce. There is this paradigm: no data, no hazard; no hazard, no risk. Most of the chemicals in the environment have not been tested for safety, so we just assume that they’re safe,” Rusyn explained. Here at the CVM,
with people that are sick is A, expensive, and B, not very effective. Trying to prevent diseases has a potentially larger impact.” To that end, Rusyn works with both regulators and the industry to develop models that determine the safest levels and combinations of the chemicals in our environment. He works with industry toxicologists to identify gaps in knowledge about their products, then designs and conducts experiments to produce safety information. On the other side of the aisle,
“As a former physician in training, I would much rather prevent diseases than treat them, but you also need to make sure we are using solid science to protect human and environmental health while allowing safe use of chemicals in our lives.
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DEALING WITH PEOPLE THAT
ARE SICK IS EXPENSIVE
AND NOT VERY EFFECTIVE. TRYING TO PREVENT DISEASES HAS A POTENTIALLY LARGER IMPACT.”
Rusyn is working to develop experimental models that explore the connections between chemicals and human health and quantify inter-individual differences in chemical effects. Using his background in medicine and toxicology, Rusyn seeks to understand the root causes of environmental disease and to assist both the government and industry with making science-informed regulatory decisions. “As a former physician in training, I would much rather prevent diseases than treat them, but you also need to make sure we are using solid science to protect human and environmental health while allowing safe use of chemicals in our lives,” he said. “Dealing
Rusyn addresses the big-picture concerns of regulators at state, federal, and international levels, listening to their questions, using his research to produce answers, and understanding how best complex scientific information can be communicated. “We’re trying to serve as an impartial broker between the regulators and the regulated and listen to both sides and try to come up with solutions,” Rusyn said. “A strong institutional commitment to multidisciplinary research and applied solutions creates an incentive for our work with the industry and governmental partners to figure out what challenges they have. We can design and do experiments and connect all the dots, and that’s extremely rewarding to me.”
Much of Rusyn’s research focuses on analyzing the combined effects of multiple chemicals on human health. By focusing on complex substances, such as petroleum refining products which “may contain a myriad of individual chemicals,” he seeks to develop experimental models that will radically change the way we look at chemical toxicology, shifting the focus from testing and regulating individual chemicals to complex mixtures, a much more realistic exposure scenario. “Human exposures are not one chemical at a time, but we try to regulate and protect human health one chemical at a time,” Rusyn explained. “Petroleum substances are an excellent example of complexity of chemical exposures and we’re trying to stay on the cutting edge of the field.”
In addition, he led a team of researchers at A&M and beyond to propose a large research program to the National Institutes of Health to analyze the impact of chemical disasters and develop first-response tools to protect human health. From tropical storms and flooding events to oil and chemical spills, we live in a world of constant environmental threats. The consortium’s goal is to “develop faster, cheaper, better tools for decision-makers to decide quickly whether there is a danger or hazard” and how those dangers may affect different individuals or populations. “We’re trying to develop tools that can be used to actually get a [high-level] answer within days rather than months or years, because within months or years, it’s too late. Most decisions right now are, ‘Let’s just move people out because we really have no idea,’” he said. Rusyn is a pragmatist at heart. His ultimate goal is to provide the research tools and data
COLLABORATIVE EFFORTS Since joining the CVM, Rusyn has been impressed by the interdisciplinary cooperation that makes his research possible. “The beauty of this campus is that there are lots of very smart people and you can collaborate with many of them. The overall intellectual and physical capacity of this campus is just staggering.” He embraces the CVM’s spirit of innovation and gets just as much satisfaction from teaching the next generation of toxicologists as from his research. Just as his parents encouraged him to exceed their accomplishments, he enjoys training his students to succeed in their own rights. Rusyn measures his own success not by recognition or awards, but by the accomplishments of his mentees and colleagues. “Success of trainees is easier to measure,” he said. “I see how many of them have successful careers in academia, industry, or government, how many of them I see being successful and sought after and become stars. I think that would be a better measure of my contributions to the field.” Rusyn’s emphasis on sensible, data-driven solutions and collaborating for a better future falls in line with his pragmatic world view. “I’m just a simple person. I’m trying to communicate at the right level,” he said. Whether he’s working with industry or government, teaching students, or speaking in the international media, Rusyn’s goal is clear: Get the facts, communicate the message to the right people, and make this world a safer place for all.
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Rusyn and his lab and collaborators are developing models that look at mixtures both forward and backward. He’s not just looking at known chemical combinations, but also creating methods to analyze the effects of an unknown mixture to predict the chemical components and how they will affect human and environmental health as a whole.
that will allow for responsible decision-making on both sides, to identify acceptable exposures rather than ignore problems or raise false alarms. “The challenges are many and daunting, but they’re not completely intractable,” he said. “What makes me excited is that we’re trying to bridge between the industry and the regulators and while being protective of human health, at the same time bring facts and data for them to make decisions.”
TOXICOLOGY & ENVIRONMENTAL HEALTH
CVM IMPACT | 58
by Roberto Molar
CREATING HEALTHIER
ENVIRONMENTS From left: Dr. David W. Threadgill, Dr. Ivan Rusyn, and Dr. Weihsueh A. Chiu
No one knows for sure, but experts estimate there are between a couple of thousand and a couple of tens of thousands of commodity chemicals in the environment. These chemicals satisfy global markets. Commodity chemicals are ubiquitous in the environment, and exposures to some of them have clear effects on human health. “The vast majority of the chemicals that we encounter in our daily life have not been tested for safety,” said Dr. Ivan Rusyn, professor in the Department of Veterinary Integrative Biosciences (VIBS) in the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM).
Rusyn and Threadgill collaborate to study how genetics influence health effects related to exposures to single chemicals and other mixtures, like pesticides or petroleumbased substances. “By understanding how the genetics and the environment are interacting, we should have a much better understanding of what actually drives disease processes,” Threadgill said. Rusyn and Threadgill also work with VIBS professor Dr. Weihsueh A. Chiu, a quantitative risk scientist and former branch chief at the U.S. Environmental Protection Agency (EPA). Chiu integrates experimental data to provide quantitative risk assessments that can be then used for better regulatory decision making. LIVING IN THE CHEMICAL WORLD Rusyn, a toxicologist by training, focuses on people’s variability in their response to chemicals. He said understanding variability is a key question in regulatory decision making, especially given the lack of experimental
Rusyn explained that the EPA establishes safe exposure levels to chemicals. Typically, these are the highest exposures to which a person could be exposed during their lifetime without adverse health effects. The EPA establishes these parameters using laboratory animals that have been exposed to various doses of a particular chemical. However, this approach uses default assumptions to account for individual variability. “What [Threadgill and I] are trying to do in the lab is provide scientific information for each chemical,” Rusyn said. “Then what [Chiu] is trying to do is create new ways in which these data can be incorporated into quantitative risk assessment for regulatory decision making.” Rusyn collaborated with scientists from the National Institutes of Health and geneticists at UNC–Chapel Hill, and they conducted the first large-scale experiment to test effects of environmental exposures on cells from a wide range of human populations. In the study, they tried to capture as much genetic diversity as exists in human population. Over 1,000 individuals provided cell lines representing populations from Asia, Africa, Latin America, Europe, and the United States. Then, these cells were exposed to 180 chemicals. One of the practical applications of this study was that it showed for the first time on such a large scale the limitations of using default assumptions in assessing chemicals’ effects on human health. The study also showed that more experiments could be done to provide chemical-specific information in the nexus between chemistry, genetics, and the environment. “Right now we are regulated by ‘one size fits all,’” Rusyn said. However, some chemicals might need stricter regulations, while for other chemicals the same protection could be provided with less regulation. “We cannot
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Moreover, until recently studies generally have left out the factor of human genetic variability. But, these chemicals in the environment only function in the context of genetics, said Dr. David W. Threadgill, a professor in the Department of Veterinary Pathobiology at the CVM, a distinguished professor and the director of the Texas A&M Institute for Genome Sciences and Society.
evidence. “When you’re trying to protect humans from exposure to a chemical,” he said, “you need to be protecting not just an average person, but also some of the most vulnerable or genetically susceptible.”
TOXICOLOGY & ENVIRONMENTAL HEALTH eliminate chemicals,” he said. “This is important so we can help the chemical industry, regulators, and the public to live in the chemical world.” CONSIDERING GENETIC VARIABILITY Threadgill said the first step is to validate the models he has been developing in collaboration with Rusyn, so that the scientific community
TRANSLATING DATA Results from basic discoveries in mouse genetics and experiments in toxicology must be translated to humans before they affect regulation and public health protection. To do that, Chiu uses data generated in Rusyn and Threadgill’s labs to estimate possible adverse health effects under various scenarios.
“What Threadgill and I are trying to do in the lab is provide scientific information for each chemical,” Rusyn said.
“THEN WHAT CHIU IS TRYING TO DO
IS CREATE NEW WAYS IN WHICH CVM IMPACT | 60
THESE DATA CAN BE INCORPORATED
INTO QUANTITATIVE RISK ASSESSMENT FOR REGULATORY DECISION MAKING.” begins using them. These models will allow scientists to better understand how mammalian systems are programmed. Ultimately, this will determine how genetic networks drive or prevent disease processes, how genetic variations alter these networks, and the role of the environment in altering them. “Considering genetic variability as a new parameter, we can clearly show—and have shown—that the variability in response to toxicants or drugs is far greater than what studies with a lack of a genetics angle have shown.” His studies with Rusyn on the toxicological effects of acetaminophen, the active ingredient in Tylenol, have shown that individuals respond differently to it. Even at recommended daily dosing, Threadgill explained, some individuals develop clinical indicators of potential liver damage due to their genotype.
Chiu specializes in dose response assessment, quantitative statistical modeling, and pharmacokinetics, the science of a chemical’s fate as it enters and eventually leaves the organism. The body breaks down chemicals into different compounds. Analyzing those breakdowns is important, Chiu explained, because those breakdown products might be more toxic than the chemicals to which an individual was originally exposed. To study that, Chiu uses physiologically based pharmacokinetic modeling, a mathematical model that allows him to understand how blood carries chemicals throughout different tissues in the body. Computer-based models allow Chiu to learn what happens to chemicals inside the body. And to study what chemicals are doing to cells in the body, animal-based and cellbased experiments like those by Rusyn and
iCell® Human Cardiomyocytes (blue are nuclei, green are cytoplasm, and red are calcium [Ca2+] ions exiting the cells during beating) (Image courtesy of Dr. Ivan Rusyn)
Threadgill are helpful. These experiments together help to measure different biomedical parameters, like whether an organ is being damaged by certain chemical exposures. “I don’t actually do the experiments, but I take those data and I analyze them mathematically to see what the increase in severity of effects is as you increase exposure,” Chiu said.
Another challenge, according to Threadgill, is to encourage the public and decisionmakers to appreciate the power of modern techniques in genomics to improve health. Further, regulatory decision making faces an urgent need for modernization. United States laws classify chemicals as drugs, pesticides, and commodity chemicals. The U.S. Food and Drug Administration and the EPA have strict regulations for the first two classifications. But commodity chemicals— which make up most of the chemicals in the environment—are a different story. Those chemicals are regulated under the outdated Toxic Substances Control Act (TSCA) of 1976. “Chemicals are chemicals in all of those three
Under TSCA, chemical companies weren’t required to provide detailed information sets about a chemical’s safety. That is, unless the EPA required them to do so, in which case the EPA needed to explain why chemical companies need to provide more data. Thus, the burden of proof was in full on the regulators. On the contrary, other laws, like the European Union’s Registration, Evaluation, Authorisation and Restriction of Chemicals, enacted in 2006, require manufacturers to prove their chemicals safe for humans and the environment. In other words, in the EU the burden of proof is on the chemical companies. The Frank R. Lautenberg Chemical Safety for the 21st Century Act, signed into law on June 22, 2016, is a bipartisan bill to reform TSCA that aims to deliver on the promise of better protecting the environment and public health. Thus, the pace of implementation for the discoveries in biomedical science into decision-making process is accelerating on both sides of the Atlantic. Rusyn, Threadgill, and Chiu’s research aims to contribute to a nationwide collaboration to modernize United States regulations. The EPA and the National Institutes of Health alone screen thousands of chemicals. In this massive effort, Rusyn, Threadgill, and Chiu’s research on human variability will be crucial. “We are the only ones trying to fill this very critical step in the regulatory process, which is understanding or defining how much variability there is in individuals,” Rusyn said.
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BETTER DECISION MAKING Communicating those health-related risks to the public and decision-makers isn’t always an easy task. One of the big challenges, Chiu said, is incorporating new data and modern animal- and cell-based techniques. Because it is impossible to test thousands of chemicals on all human variations, he said non-traditional techniques are the only way to understand human variation and safety of chemicals. Therefore, Chiu’s role is critical, since regulators typically struggle to digest this kind of information.
categories,” Rusyn said. “Because of how laws are written, the regulatory environments are completely different, even though it could be the same structure if it’s a drug, a pesticide, or something that will be used in a plastic.”
TOXICOLOGY & ENVIRONMENTAL HEALTH by Laura Gerik
CVM IMPACT | 62
Scarlet and blue-and-yellow macaws take flight. (Photo courtesy of Alan Lee)
CONSERVATION
TAKES FLIGHT Deep in the Peruvian rainforest, 20 kilometers from the nearest road, stands the headquarters of the Tambopata Macaw Project, a combination ecotourism lodge and scientific research station. Waking up well before sunrise, teams of dedicated parrot researchers make daily trips into the jungle, braving intense humidity, thick forests, and unpredictable rivers to observe macaws in their native habitat. They climb up 150-foot trees; spend hours counting birds at clay licks; and carefully gather, measure, and return chicks to nests—while keeping a close eye on the birds’ movements through the rainforest canopy.
students, foreign volunteers, and Peruvian employees work under the leadership of Dr. Donald Brightsmith, assistant professor in the Department of Veterinary Pathobiology at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM).
These adventures are all in a day’s work at the Tambopata Macaw Project, where an ever-changing crew of scientists, graduate
FROM LONG ISLAND TO THE AMAZON Brightsmith grew up on Long Island, New York, just outside New York City. Despite his
Since Brightsmith took over as director in 1999, the group has collected years of data on macaws. “I’ve had researchers recording data every single day since November 2000,” he said. It’s a treasure trove of research that Brightsmith hopes will fill in the knowledge gaps about macaw conservation and ecology.
THE PROJECT BEGAN IN 1989
WHEN PERUVIAN RESEARCHERS AND ENTREPRENEURS NYCANDER
AND HOLLE FOUNDED BOTH RAINFOREST EXPEDITIONS,
A FOR-PROFIT ECOTOURISM
COMPANY, AND THE
urban roots, he has been a lifelong naturalist and bird watcher, “much to the joy of my classmates, who would pick on me for it all the way through graduate school,” he observed humorously. That early love of birds propelled him through academia, from his bachelor’s degree in natural resources at Cornell University, to his master’s degree in wildlife ecology at the University of Arizona, to his doctorate in zoology at Duke University. During these years, Brightsmith’s passion for birds focused on a growing interest in parrots. A trip to Costa Rica in graduate school sparked his fascination with tropical birds, and his first wife introduced him “to the world of crazy parrot owners,” he said. But Brightsmith credits a single book—Beissinger and Snyder’s New World Parrots in Crisis (1992)—for opening his eyes to the plight of tropical parrots. “It pointed out that we don’t know much about parrots in the wild,” he said. “They’re having serious problems. They’re highly valuable both as a tourism resource and a captive resource.
Yet, especially in the early ’90s, we knew almost nothing about where parrots breed, what they eat, or what habitats they use in the wild. It was an incredible disconnect.” Around the time he was finishing up his doctoral research in zoology at Duke, Brightsmith was introduced to the Tambopata Macaw Project. Established in 1989, the project had briefly earned international recognition for its work on parrot clay licks and macaw nesting, but since the early 1990s had been languishing. Brightsmith said he saw a golden For more information on the Tambopata Macaw Project or to come and work as a volunteer, visit www.macawproject.org. If you want to visit the site as a tourist or guest, check out Rainforest Expeditions at www.perunature.com.
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TAMBOPATA MACAW PROJECT.
CVM IMPACT | 64
opportunity to revitalize the project and “make a difference by looking at this group of birds that are hard to work with.” In 1998, he flew to Peru and met with the project leaders. “I convinced them that if they gave me a small amount of money, I wouldn’t be a full-time employee, but I would start to run this research as a scientific endeavor again,” Brightsmith said. His pitch was successful, and the Tambopata Macaw Project was reborn under his enthusiastic leadership. A MARRIAGE OF ECOTOURISM AND RESEARCH The project began in 1989 when Peruvian researchers and entrepreneurs Eduardo Nycander and Kurt Holle founded both Rainforest Expeditions, a for-profit ecotourism company, and the Tambopata Macaw Project. From the beginning, Rainforest Expeditions owned and operated the remote lodge that served as both a research base and a tourist destination. “From the beginning, it was always a mixture of tourism and research,” Brightsmith explained. “They wanted the two to feed off of each other.” So far, the venture has been uniquely successful and financially sustainable. Rainforest Expeditions provides lodging, food, and utilities, charging the macaw researchers a reduced fee.
Foreign volunteers pay higher daily fees, and the difference goes toward paying wages and lodging for Peruvian workers. In exchange, every group of tourists at the ecolodge receives a scientific presentation from the researchers about current research and threats to macaws. The marriage of ecotourism and conservation research is not only a boost to the Peruvian economy but also one of the main reasons the Tambopata Macaw Project has been able to carry on so successfully for decades. Brightsmith estimated that Rainforest Expeditions provides over $30,000 in project funding every year. “It’s not a completely sustainable system right now, but all it requires is a few thousand dollars of extra financing, which is much cheaper than a full research lab,” Brightsmith said. “This is one of the reasons why the project is still going after 20 years.” THE SCHUBOT CONNECTION Of course, the data they collect still requires a laboratory and experts to analyze it. That’s where Texas A&M’s Schubot Exotic Bird Health Center comes into play. Brightsmith was recruited to Texas A&M by Schubot Center Director and Distinguished Professor Dr. Ian Tizard in 2005. After some initial research collaborations with Brightsmith, Tizard visited the Tambopata Center and offered Brightsmith a job as a lecturer at the CVM. For Brightsmith, the Schubot Center was an irresistible draw, and the relationship has paid off. “The Schubot Center provides the platform for my work,” he said. “Over the years, they have provided financial assistance and a community of scholars. Because the center exists and it’s endowed, it will always attract a group of people interested in bird research, even those who don’t know that they’re interested in bird research.” Brightsmith credits Tizard with making the Schubot Center a vibrant hub for avian research, always bringing new scientists from different disciplines into the fold. “If he needs a microbiologist, he finds a microbiologist who knows what a bird is,” Brightsmith said. “Right Dr. Donald Brightsmith and Dr. Gabriela Vigo Trauco with a blue-and-yellow macaw they collared as part of movement studies (Photo courtesy of the Tambopata Macaw Project)
now we’re working with a geneticist who works on conifer trees, but all of these people are now working on bird-related issues because the Schubot Exotic Bird Health Center exists. I am within that milieu, and it provides a community of people interested in exotic bird issues.” CURRENT RESEARCH Groundbreaking studies about macaws using clay licks to gather essential minerals put Tambopata on the map in the 1990s, and that research continues today. Brightsmith’s team has also published papers explaining their success using artificial nest boxes to increase breeding success. However, over time, the Tambopata project’s main focuses have shifted to new questions.
“At this point, we’ll be able to reflect back and see what happens when you have this odd change in plant resources and how that impacts [macaw movements and breeding],” explained Brightsmith. “Understanding what happens in an El Niño year may give us a better view into the future of what happens as larger-scale climate change alters the plants and their fruiting and flowering.” Similarly, a shift in movement from one clay lick to another has piqued Brightsmith’s curiosity about the future. “We don’t understand how climate change and clay lick use are rippling through the environment and changing things. We need to look more carefully at these climate-related issues—the annual variations and how they correlate with the environment—which will give us a better ability to predict global change ideas.”
Scarlet macaws use an artificial nest box designed by the research team. (Photo courtesy of Liz Villanueva Paipay)
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Right now, Brightsmith’s main interest is the macaws’ movements and how they change in relation to seasonal events. Researchers use lightweight collars to track the movements of individual birds. Brightsmith said he is concerned about the macaws’ most recent breeding season, which was off to a late and slow start. He speculates that the El Niño
weather patterns and the resulting low food supply might have something to do with it. To sort out the irregularities and what they might mean for the future of the species, he hopes to compare data from the past several years.
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Brightsmith’s wife, Gabriela Vigo Trauco, Peruvian ecologist, Tambopata project coordinator, and current Ph.D. student in Wildlife and Fisheries Sciences at Texas A&M, is “studying scarlet macaw breeding systems using a combination of ecology, animal behavior, and genetic analysis.” The Tambopata location is perfect for her research because that species is not yet endangered in the Peruvian Amazon. “There we can study things that you cannot study in areas in which the species is endangered,” Vigo Trauco explained. “So, that’s the way I want to lead my research.” CVM students are also using Tambopata as a site for fieldwork and graduate research. Every year, Brightsmith and Dr. Sharman Hoppes, clinical associate professor at the CVM, take two to four veterinary students on a study abroad experience at the station. Students from around Texas A&M’s campus spend time in Tambopata as both volunteers and doctoral researchers. HOPES FOR THE FUTURE These days, Brightsmith and Vigo Trauco only make it to Tambopata twice a year. It’s not as much as they’d like, but their life in College Station keeps them busy. Brightsmith is a full-time assistant professor and admits that he spends most of his time behind a computer, analyzing and writing up data collected from years of research. “Right now, if you told me I could never take another data point on a macaw, I probably could finish out my career publishing on the amount of information we have,” he joked. “We’re currently publishing some of the important relationships between breeding and clay lick use and food and movement. It’s building a jigsaw puzzle where the first thing you have to do is build each piece. We’re building the pieces and fitting them together as we go.” Vigo Trauco is immersed in reviewing video data from macaw nests. Additionally, she is restarting her genetic research; a 10year ban on exporting genetic materials out of Peru was lifted this year, allowing her to move forward with her projects.
Most of all, the couple is devoted to raising their daughter, four-year-old Amanda Lucille, or “Mandy Lu.” For the Brightsmith family, the Tambopata Macaw Project is now a family affair. Brightsmith and Vigo Trauco met on the project, and now they bring their daughter to share in their love of the rainforest and its vibrant inhabitants. Mandy Lu—“our little rainforest monster,” as Brightsmith affectionately calls her—seems to share her parents’ enthusiasm for the Amazon. “Maybe it’s because we like it, and she sees that we’re super happy in the rainforest,” Vigo Trauco speculated. “Maybe she is connecting happiness with being in the jungle.” Either way, sharing her beloved rainforest with Mandy Lu has shifted Vigo Trauco’s long-term goals for the Tambopata Macaw Project. She envisions the Tambopata project as an opportunity to get Peruvian students interested and involved in conserving their country’s unique natural resources. “I think it would be nice to involve young people— young adults, in high school or their first years of college—and try to put that seed in their brains that conservation can actually help and actually can happen and be fun,” she said. Brightsmith is also enthusiastic about the opportunities to teach conservation values to people in Peru and around the world. “We’ve had thousands of tourists who have gone through our talks and seen the site and the birds and really gotten a feel for what the real rainforest is like,” he said. He’s also seen changes in local attitudes. “The project has played into this shift in mindset,” he explained. “While some locals use the money they make from ecotourism to buy bigger chainsaws, there is the development of a mindset that has led this community to be much more deliberate in their planning as to how they’re going to use their natural resources.” Both Brightsmith and Vigo Trauco look to the younger generation of Peruvians and conservationists—hopefully some from the CVM—to build a brighter future for macaws and the rainforest.
AVIAN VETERINARIAN IN THE JUNGLE for measurements and sampling. Hoppes states that “they become more used to the handling over time, but even with the chicks, you have to be prepared and monitor how long you have them out.”
For two to three weeks, Hoppes trades in her zoo clinic at the Small Animal Hospital for a small, rustic Amazonian research facility with minimal electricity and no air conditioning. There, she runs the veterinary side of the operation, training students and making sure everybody’s projects stay on track.
When they are trapping adult birds, Hoppes trains her team to work with assembly-line efficiency. Her goal is to minimize contact with the birds, aiming for 10–11 minutes from capture to release. Her team practices their roles in advance using bundled-up towels. “The most important thing is that we’re really prepared and make sure that we have everything within hand’s reach, everything ready to go,” Hoppes said. “Everybody knows their part, and we all know that when we get to this time period, even if we’re not done, we let the bird go.”
Hoppes’ main concern is animal welfare. Working with wild birds unused to human handling adds a layer of complexity to her research. “I’m always very aware that we don’t want to over-stress a bird that we are handling, making it weak or tired and having it potentially eaten by a predator,” she explained. Most of the work they do is with the chicks, taking them out of the nest
Veterinary work in a hot, humid jungle can be challenging, but this self-professed “city girl” revels in it. “This project changed my life,” she said. “I love it there!”
Dr. Sharman Hoppes in Tambopata with a 25-year-old scarlet macaw that was hand-raised and released by the Tambopata Macaw Project (Photo courtesy of Dr. Sharman Hoppes)
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Since teaming up with Brightsmith in 2008, Dr. Sharman Hoppes, DVM, ABVP, and clinical associate professor at the CVM, has been flying south for the winter, straight to the Tambopata Macaw Project.
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