COLLEGE STATION, Texas – Faculty and researchers at the Texas A&M; College of Veterinary Medicine & Biomedical Sciences (CVM) have turned the recent increase in Chagas disease cases in Texas into a learning opportunity by developing an online case study learning module. The case study was one of only 15 selected for web
publication by the American Association of Veterinary Medical Colleges’ (AAVMC) and the Association for Prevention Teaching and Research’s (APTR) joint One Health Interprofessional Education Initiative.
Chagas disease, an infectious disease caused by the parasite Trypanosoma cruzi and transmitted by the kissing bug, has many Texans concerned. Recent spread of Chagas disease, which affects humans and animals in the southern United States and Latin America, has made media headlines. This increase in cases and growing concern over the disease led researchers to develop the Chagas case study as an educational tool for health professionals.
The module was created through a collaboration between faculty and researchers at the CVM, Baylor College of Medicine, and Texas A&M; Health Science Center–McAllen. The module was supported through funding from the Texas A&M; One Health Initiative.
The module’s content was developed by faculty and students at the CVM: Associate Professor Dr. Ashley Saunders, expert in clinical cardiology in dogs, as well as Assistant Professor Dr. Sarah Hamer, Ph.D. student Rachel Curtis-Robles, and veterinary student Trevor Tenney, experts in the ecology and epidemiology of the kissing bug and T. cruzi. Additional content addressing public health was contributed by Dr. Ann Millard, associate professor at the Texas A&M; Health Science Center–McAllen, and Dr. Melissa Garcia, research associate at Baylor College of Medicine.
The case was developed in collaboration with The Center for Educational Technologies (CET) at the CVM, including Dr. Jodi Korich and Dr. Jordan Tayce. The web-based case study allows students to make a series of clinical decisions as they follow a real case from diagnosis through treatment and is supplemented with instructional video lectures, diagnostic charts, and other reference materials in an interactive and media-rich format.
“The case study turned out really cool, and it’s interactive. That is the beauty of working with the CET,” said Saunders, who was designated as an AAVMC One Health Scholar as the principal investigator. “The whole point is that faculty at another university in other health professions could teach their students with a case study that was developed by experts from Texas A&M.;”
“It’s all digitally interactive,” said Tayce, an instructional assistant professor at the CET. “A user can be in any location at any time and still go through this case. That’s what makes our case study unique.”
The case study features a dog diagnosed with Chagas disease in Texas, but it is not limited to veterinary applications. According to the researchers, the Chagas case highlights the One Health Initiative by focusing on important connections between humans, animals, and the environment. Therefore, it can be used by students in a variety of disciplines, including human and veterinary medicine.
“It’s not just veterinary,” Tayce said. “It’s geared toward medical students, public health students, environmental science students, and others.”
According to Saunders, the collaborations that built the case study are what make it so versatile. “The AAVMC and APTR wanted the case study to not just be veterinary focused, but they also wanted to include people from all disciplines,” she said. “I knew we had enough people, and it was going to be a successful collaborative effort. I knew we could do it, so I started pulling people in from all different places to help us.”
The Chagas case study uses technology to enhance students’ knowledge and understanding of the disease, including the clinical presentation and cardiac manifestations in dogs, when to test for infectious diseases, kissing bug ecology and epidemiology, and client education on animal and human health aspects and kissing bug management.
“At the CET, we work to make sure we’re using proven educational practices in all of the material we build,” Tayce said. “We work with the faculty to make sure that from the beginning and all the way through to the end we’re using these established educational practices when we create content.”
Saunders said this module is not only suited for veterinary students, but also for students in other health-related disciplines. She noted that, as a veterinarian, she could imagine the benefits of increased education. “One of the difficult things about Chagas disease is the questions I receive from owners about how to save their dog,” she said. “We can definitely help the dogs, but even more important is what goes on at home, like where did they get exposed and who else can get infected. So, we brought in all these experts to build a case that was comprehensive and a really great collaborative effort.”
COLLEGE STATION, Texas – The USDA recently announced 35 Food Safety Grants, one of which was awarded to a team led by Dr. H. Morgan Scott, professor in the Department of Veterinary Pathobiology at Texas A&M; College of Veterinary Medicine & Biomedical Sciences (CVM), based on their research on antimicrobial resistance. The grant funding awarded to the team totaled $1 million.
The Food Safety Grants are administered by the USDA’s National Institute of Food and Agriculture (NIFA) and are designed to enable research that promotes safe and nutritious food as well as agricultural competitiveness.
Antimicrobials, including antibiotics, have been used for decades to successfully treat both humans and animals. However, strains of bacteria have evolved resistance to antibiotics, leading to growing concern about aspects of food safety related to animal agriculture. Through this research, Scott and his team hope to address these concerns.
Scott will lead a team of researchers and extension faculty: Mayukh Dass and Guy H. Loneragan of Texas Tech University, Yrjö T. Gröhn of Cornell University, Ellen R. Jordan and Jason Sawyer of Texas A&M; AgriLife Extension, Alex W. McIntosh of Texas A&M; University, and Gerald R. Midgley of the University of Hull in the United Kingdom. The team will focus on designing and implementing science-based and stakeholder-informed stewardship programs for beef and dairy cattle systems.
The overall goal of the project is to identify, evaluate, and implement practical and effective strategies for mitigating and preventing antimicrobial resistance. To do this, Scott and his team seek to recruit and engage stakeholders in designing and implementing voluntary antimicrobial stewardship programs. Additionally, the researchers will conduct field studies and develop models to better understand various aspects of this complex issue, including economics, microbiology, and the social sciences.
The research team aims to enhance environmental quality and food safety by reducing the burden of antibiotic resistance among enteric bacteria. Scott’s research will lay the foundation by which decisions can be made by stakeholders to prevent and combat antimicrobial resistance. This includes qualitative and quantitative modeling to test tools that support stakeholder’s decisions, both in the short and long term.
This project differs from previous attempts to mitigate antimicrobial resistance in animal agriculture because it focuses on voluntary stewardship programs rather than relying strictly on legislation or regulation.
“Dr. Scott’s research on antimicrobial resistance is truly exceptional,” said Dr. Eleanor M. Green the Carl B. King dean of veterinary medicine. “Receiving this grant is a testament to Dr. Scott’s commitment to excellence in research, and we are proud of him and the team he is leading.”
Hexavalent chromium (CrVI), a toxic form of the heavy metal chromium, is widely used in more than 50 industries such as welding and painting. Due to increased usage and improper disposal, CrVI contaminates the environment, including drinking water. New research from the Texas A&M; College of Veterinary Medicine & Biomedical Sciences (CVM) indicates that, despite its widespread use, CrVI can cause detrimental health effects, particularly when it comes to fetal ovarian development.
The study, which appears on the cover of Toxicology and Applied Pharmacology, examined developing rat whole fetal ovaries in cell cultures to explain how early exposure to CrVI causes cell death, known as apoptosis, in the female offspring’s developing ovaries. Ultimately, increased apoptosis during ovarian development can lead to premature ovarian failure and early menopause in the adult life.
“My main goal is to see what happens to the children if pregnant women are exposed to hexavalent chromium, since it readily crosses the placenta and directly targets the fetal organs, mainly the ovary,” said Dr. Sakhila Banu, assistant professor in the Department of Veterinary Integrative Biosciences and the lead author of the study.
Banu and other Texas A&M; researchers studied the effect of CrVI on rat ovaries grown in a cell culture in the earliest stages of development-as soon as cells began to develop into ovaries. They looked at several genes and proteins that regulate the ovary’s development and the onset of apoptosis in ovarian cells.
Although it is normal for cell death to occur in some cells during the development of the ovary, accelerating apoptosis during early ovarian development can have consequences later in a woman’s life.
“Many chemicals can cause cell death,” Banu said. “If liver cells or intestinal cells are targeted they rejuvenate to a certain extent. But, every woman is born with a specific number of immature eggs, called oocytes, in the ovary. If during early development the oocytes are exposed to chromium, which particularly targets those cells, and if chromium accelerates those molecular pathways that program cell death, then you could end up with premature ovarian failure.”
Additionally, the researchers noted that this study creates a model in which the whole fetal ovaries can be grown in a organ culture for direct examination to determine harmful effects of chemicals on ovarian development. Thus, future research can be done to better understand the effects of other chemicals, such as drugs or environmental contaminants, on ovarian development.
Currently, the U.S. Environmental Protection Agency recommends 0.1 parts per million (ppm) as the safe limit for chromium in drinking water. However, Banu and her team determined that this level was still high enough to cause ovarian damage, suggesting that the regulatory limit of chromium be revisited.
“Dr. Banu is a highly productive young scientist and a leader in the area of chromium toxicity mechanisms and remediation strategies through funding support from the National Institute of Environmental Health Sciences,” said Dr. Robert Burghardt, associate dean for research and graduate studies at the CVM. “This is another outstanding example of One Health research being conducted at the College of Veterinary Medicine & Biomedical Sciences that benefits animals, humans, and the environment.”
COLLEGE STATION, Texas – Research scientists at Texas A&M; University and Pontifícia Universidade Católica do Rio Grande do Sul in Brazil have moved a step closer to understanding the rich evolutionary history of the cat family. In a paper, featured on the cover of Genome Research, the researchers constructed extensive family trees of the 38 cat species, which illustrated maternal, paternal, and biparental lineages within the cat family. However, they found that lineages are not completely linear. Instead, this study revealed that feline ancestry has been shaped throughout its evolutionary history by hybridization.
For this study, researchers used genome-wide Single Nucleotide Polymorphism (SNP) data-which identifies differences in individual base pairs-with genes from both the X and Y chromosomes and autosomal, or non-sex chromosomes, in addition to sequencing complete mitochondrial genomes, which indicate maternal lineage. This data was complemented by new whole genome sequencing data from the closest species to the domestic cat, as well analysis of the tiger, snow leopard, and lion genomes.
“Our results finally resolve much of the discrepancies in the literature over the past two decades as to how cats are related and the cause for many of the conflicts between different scientific publications, ” said Dr. William Murphy, professor in the Department of Veterinary Integrative Biosciences (VIBS) at the Texas A&M; College of Veterinary Medicine & Biomedical Sciences and an author of the study.
“The results also highlight an emerging trend in the literature that hybridization between different species is common and may actually be adaptive. One novelty of our study is the illustration as to how common this process is across a broader phylogenetic scale-within an entire family of mammals-than previously has been shown in isolated pairs of species.”
“Dr. Murphy is an extremely meticulous investigator whose prior work helped create the field of phylogenomics, which uses genome analysis to establish evolutionary relationships of species,” said Dr. Evelyn Tiffany-Castiglioni, department head of VIBS. “This new work will contribute greatly to our understanding of hybridization as a force that has shaped and is shaping speciation in cats.”
The researchers found that there were nine differences between the maternal and biparental trees. For example, the maternal tree indicated that the puma lineage was more closely related to the lynx/bay cat group, whereas the biparental tree showed the puma lineage as more closely related to the Asian leopard cat/domestic cat group. Researchers concluded that the most likely cause of this, and other discrepancies between family trees based on different modes of inheritance, is due to ancient hybridizations. Hybrids may have then mated with non-hybrids, introducing variations back into the species.
Additional factors influencing feline evolution include the fact than male hybrids are more often sterile than female hybrids and the males are often more geographically dispersed than females.
“We identified traces of hybridization within the genomes of more than half of the eight cat lineages, where stretches of DNA sequences are far more closely related between pairs of non-sister species than would be expected by random processes,” Murphy said. “In several of these cases, the evidence for hybridization in the nuclear genome, which is inherited from both parents, is matched by similar patterns in the mitochondrial DNA, which is only inherited from the mother.”
Ancient hybridization may have led to the discrepancies between the biparental and maternal lineages of the snow leopard. Specifically, genes on the X chromosomes of lions and snow leopards were shown to have diverged at a more recent date than did genes on autosomal chromosomes. Additionally, snow leopards retained a mitochondrial genome that is more similar to the lions’ mitochondrial DNA, when compared to other parts of its genome. The study suggested that these results are likely due to early hybridization between the ancestors of the two species.
“We know that ancient hybridization in the wild is consistent with extensive evidence for hybridization that has occurred between many distantly related cat species in captivity, such as the liger-a male lion crossed with a female tiger,” Murphy said. “One of the world’s most popular cat breeds, the Bengal, is a hybrid between the domestic cat and the Asian leopard cat, and several other increasingly common cat breeds are of hybrid origin.”
The researchers also note that, while hybridization is a natural part of evolution, factors such as poaching, loss of habitat, and climate change have the capacity to affect future feline evolution, particularly in endangered species. They also emphasize the importance of understanding natural versus human-caused hybridization.
COLLEGE STATION, Texas – Today, horses come in a variety of coat colors, but most lack the camouflaging coat of their ancestors. However, a trace of that legacy remains in horses with the dun pattern, which characterized by pale hair covering most of the body, a dark stripe along the back, and zebra-like stripes on the legs. A recent study, published in Nature Genetics, reveals a new mechanism that explains the genetic roots of the dun pattern and uncovers why the pattern does not appear in most domesticated horses.
The study is the work of an international team of scientists, led by Texas A&M; University Institute for Advanced Study (TIAS) scholar Dr. Leif Andersson and is the result of a collaboration between groups at Texas A&M; University, Uppsala University in Uppsala, Sweden, and the HudsonAlpha Institute of Biotechnology in Huntsville, Alabama.
The dun pattern camouflaged ancient wild horses, protecting them from predators. However, domestic horses, like other domestic animals, have been selected over many generations to appear different from their wild counterparts. As a result of selective breeding, most domestic horses today are not dun and have coat colors that are more intensely pigmentation and uniformly distributed across the body.
“Dun is clearly one of the most interesting coat color variants in domestic animals because it does not just change the color but the color pattern,” Andersson stated. “We were really curious to understand the underlying molecular mechanism of why the dun pigment dilution does not affect all parts of the body.”
“Unlike the hair of most well-studied mammals, the dilute-colored hairs from dun horses are not evenly pigmented,” explained Freyja Imsland, a Ph.D. student in Andersson’s group. “They have a section of intense pigmentation along the length of the hair, on the side that faces out from the body of the horse, whilst the rest of the hair has more or less no pigment. The hairs from the dark areas of dun horses are in contrast intensely pigmented all around each individual hair. In spite of scientists having studied hair pigmentation in detail for a very long time, this kind of pigmentation is novel to science and quite unlike that seen in rodents, primates, and carnivores.”
Genetic analysis and DNA sequencing revealed that the dun color is determined by a single gene, which codes for the T-box 3 (TBX3) transcription factor. “Previous studies in humans and laboratory mice show that TBX3 controls several critical processes in development that affect bones, breast tissue, and cardiac conduction,” explained Dr. Greg Barsh, whose group at HudsonAlpha led the tissue analysis. “We were surprised to find that TBX3 also plays a critical role in skin and hair development.”
Researchers measured TBX3 distribution in individual hairs relative to other molecules known to regulate pigmentation. The researchers suggest that the signals governing where TBX3 is expressed could help to explain zebra stripes. In horses that have lost their dun color, TBX3 mutations do not inactivate TBX3 protein function and instead only affect where, both on the individual hair and on the horse’s body, the gene is expressed.
“In growing hairs, TBX3 mirrors the distribution of melanocytes, the cells that produce pigment,” explained Kelly McGowan, a senior scientist in Barsh’s lab. “Our results suggest that TBX3 affects differentiation of specific cells in the hair, creating a microenvironment that inhibits melanocytes from living in the ‘inner’ half of the hair.”
The team also discovered that there are two forms of dark, non-dun color: non-dun1 and non-dun2, which are caused by different mutations. Non-dun1 horses differ from dun horses in that they have a darker coat and less contrast between the stripes and the rest of the body. On the other hand, non-dun2 horses show no stripes at all.
“Non-dun horses have much more vibrant color than dun horses. Non-dun1 horses tend to show primitive markings similar to dun horses, whereas non-dun2 horses generally don’t show primitive markings,” Imsland stated. “These primitive markings in non-dun1 horses can sometimes lead horse owners to think that their intensely pigmented non-dun1 horses are dun.”
The study indicates that the non-dun2 variant occurred recently-most likely after domestication. In contrast, the dun and non-dun1 variants predate domestication. Evidence of this conclusion can be found in the DNA of a horse that lived about 43,000 years ago, long before horses were domesticated, which carried both dun and non-dun1 variants.
“This demonstrates that horse domestication involved two different color morphs-dun and non-dun1-and future studies of ancient DNA will be able to reveal the geographic distribution and the abundance of the two morphs,” Andersson said.
COLLEGE STATION, Texas – The ruff is a Eurasian shorebird that has a spectacular “lekking” behavior where highly ornamented males gather in a single location and compete for females. Now two groups, one led by researchers at the Texas A&M; University College of Veterinary Medicine & Biomedical Sciences (CVM) and Uppsala University, report that males with alternative reproductive strategies carry a chromosomal rearrangement that has been maintained as a balanced genetic polymorphism, leading to three types of ruff males, for about 4 million years. The two studies are published today in Nature Genetics.
Three different types of ruff males occur at the leks of this species. Independent males show colorful ruffs and head tufts and fight vigorously for territories. Satellite males are slightly smaller than Independents, do not defend territories and have white ruffs and head tufts. Faeder is the third body type, or morph; these are disguised males that mimic females by their small size and lack of ornamental feathers. The Independent and Satellite males show a remarkable interaction, where the Satellite males allow Independent males to dominate them on the leks.
“Both Independents and Satellites benefit from the interaction because it increases their mating success by attracting females that are ready to mate,” explained Dr. Fredrik Widemo, who did his Ph.D. on ruff lekking behavior. Widemo also noted that fighting over territories and females is both energetically costly and risky. This created an opportunity for the evolution of alternative male mating strategies in which males spend less energy on fighting.
Previous studies have indicated that these remarkable differences between male morphs are under strict genetic control and are determined by a single genetic region. These most recent studies represent an explanation for how such complex differences in behavior, size, and plumage have a simple genetic basis. To arrive at the answer, the research teams sequenced the entire ruff genome.
“This is a fascinating study that exemplifies the power of modern genomics to unravel a seemingly complex behavioral and morphological phenotype. Surprisingly the alternative male morphs found in the ruff are the product of a single, yet strongly differentiated locus that was dramatically altered in just a few million years. The authors provide an additional illustration of the increasing role that structural mutations play in evolution and disease,” said Dr. William Murphy, professor in the department of Veterinary Integrative Biosciences at the CVM.
“We discovered that both Satellite and Faeder males carry a ‘supergene,’ which is not a gene with superpower but a cluster of about 90 genes kept together by a chromosomal inversion indicating that there is no genetic exchange between the three different morphs,” said Sangeet Lamichhaney, one of the PhD students involved in the study, “The simple answer is that the ‘supergene’ contains both genes like HSD17B2 affecting the metabolism of sex hormones and the MC1R gene controlling pigmentation.”
The group reports that the sequence difference between the chromosome variants is as large as 1.4 percent-higher than the average sequence difference between human and chimpanzee chromosomes. The scientists estimate that the chromosome inversion happened about 4 million years ago.
“The Satellite and Faeder male morphs are the result of an evolutionary process over million of years and involve many genetic changes among the 90 genes in this ‘supergene,'” explained Dr. Leif Andersson, who led the study at Uppsala University and also served as a Texas A&M; Institute for Advanced Study fellow. “The ‘supergene’ contains five genes that have a role in the metabolism of steroid hormones. It is particularly interesting that we see an enrichment of genetic changes in the vicinity of a gene, HSD17B2, which determines an enzyme that converts active testosterone to a more inactive form. Independents have a significantly higher level of testosterone than Satellite and Faeder males, and we think this is the reason that in turn leads to an altered behavior.”
There are many examples of associations between behavior and pigmentation in animals, but the underlying causal relationships have rarely been revealed. The present study now provides insights into why there is such a strong association between altered behavior and white color in Satellite males.
“We think that this evolutionary process started with the occurrence of the inversion about 4 million years ago and that the inversion in itself altered the regulation of one or more genes affecting the metabolism of sex hormones,” added Andersson. “This created a primitive alternative male morph, which has been further improved step by step by the accumulation of many genetic changes.”
“Nature has certainly ‘experimented’ a lot on sex determination, sexual development, and reproduction,” said Terje Raudsepp, associate professor in the Department of Veterinary Integrative Biosciences (VIBS) at the CVM, “but only excellent research and researchers can reveal its full beauty and complexity. I applaud the researchers for this fascinating discovery-and also ruff Faeder males for their effortless reproductive success.”
“Dr. Andersson has a distinguished history of elegant discoveries in the field of genetics and evolution,” said Dr. Evelyn Tiffany-Castiglioni, professor and VIBS department head. “This is an example of his creative, non-invasive way of unraveling how a species has evolved successfully by maintaining males with diverse behaviors and appearances.”
COLLEGE STATION, Texas – When billions of songbirds make their yearly trip from their winter homes in South and Central America to North America, they are not alone. Some migratory songbirds pick up hitchhikers-specifically ticks, according to a study from researchers at the Texas A&M; College of Veterinary Medicine & Biomedical Sciences (CVM) and the Smithsonian Conservation Biology Institute’s Migratory Bird Center.
Researchers screened songbirds in the springs of 2013 and 2014 at stopover sites along the Gulf of Mexico’s northern coast, where birds rest and feed during their northward migration. From this sampling, the study’s investigators estimated the number of neotropical ticks from South and Central America making their way into North America on songbirds as well as which birds were more likely to carry ticks.
The study, published in Applied and Environmental Microbiology, found 3.56 percent of the 3,844 birds sampled carried ticks, the majority of which were neotropical tick species. While this percentage may seem small, when extrapolated to all migratory birds making their way into North America annually, the researchers estimate over 19 million neotropical ticks are imported each spring.
“Even though birds carrying exotic ticks into Texas was a rare event-about 3 percent of the birds we sampled-this equates to a really large number of ticks when you consider that billions of birds move along this migratory path each spring,” said Dr. Sarah Hamer, assistant professor in Veterinary Integrative Biosciences at the CVM and an author on the study.
These ticks were not picky about which bird species they used as hosts. In fact, 36 of the 85 bird species sampled were tick carriers. “These ticks are generalists as larvae and nymphs,” said Hamer. “They can feed on a lot of different types of birds.”
Birds that were more likely to pick up ticks were those that foraged closer to the ground, according to the study. Ticks often drop onto the ground to enter their next life stage-from larva to nymph or from nymph to adult. This is when ticks seek a new host, making birds closer to the ground become more susceptible to becoming infected, said Hamer.
This tick transport could be cause for concern because of the pathogens ticks can carry. Of the ticks found of migratory birds, 29 percent carried one or more species of the bacteria Rickettsia, including some responsible for diseases such as Rocky Mountain spotted fever.
“What we found is that there are lots of diverse Rickettsia species found in ticks removed from migratory birds,” said Hamer. “Some are endosymbionts that are not known to have a negative impact on the tick or a human or an animal, but others are recognized pathogens, like spotted fever group Rickettsia species that certainly can cause disease in people and animals if they get the opportunity to infect them.”
Additionally, researchers point out that many of the tick species found in the study are not native to the United States. “Most of these species are not typically found in the U.S., except one- Ambylomma maculatum, the Gulf Coast tick,” said Lisa Auckland, a research associate at the CVM and an author on the study.
Currently, most of the tick species found in this study do not have known established populations in the United States. However, researchers caution that ticks could establish populations in the United States in the future, given an ever-shifting environment and climate change.
“It’s good to be aware of this because our environment is constantly changing,” said Hamer. “Maybe some of those changes may result in an environment that’s warmer and more receptive to the establishment of these exotic ticks. Then, we may have new medical problems on our hands.” Further research is also needed to understand what happens after neotropical ticks make their way to the United States, she said.
When a loved one is diagnosed with cancer, the first questions that often come to mind are, “why did this happen to them,” and “what can I do.” Faced with this very situation, Dr. Ivan Ivanov, clinical associate professor in bioinformatics at the Texas A&M; College of Veterinary Medicine & Biomedical Sciences (CVM), began a journey helping advance research that one day may be able to answer those questions.
To create new knowledge in this multidisciplinary environment requires the ability to ask questions and design
studies that are based on scientific principles, and communicating that complexity requires a common foundation-a foundation Ivanov is helping to build. However, it was more than an interest in collaboration and complex systems that led Ivanov to his research in cancer biology; it was a series of life events.
The Journey Begins
When Ivanov was a middle school student in the former communist country of Bulgaria, his teacher suggested he apply to a national high school that specialized in mathematics. After speaking with his mother, he decided to apply and was accepted after taking two required entrance exams.
“From there, I went to the university, and I was successful because the teachers I had at the high school were not ordinary teachers,” Ivanov said. “They were Sofia University professors. They ignited one’s curiosity, and that was very exciting.”
While still a mathematics student at the university, Ivanov’s former father-in-law was diagnosed with cancer and he deteriorated quickly. “I was thinking how he could be such a great man, a nonsmoker, a good father and husband, a hard worker-he does everything right, and then he’s hit by this disease,” said Ivanov. “He died after two months. I carried him around in my hands because he lost 50 percent of his weight. I wondered how this could be helped. I was just a mathematician, a mathematics student. I didn’t know anything about biology, and it was very complicated to me.”
Years passed after his former father-in-law’s death and Ivanov left Bulgaria, finished his Ph.D. in mathematics at the University of South Florida, and, after a one-year postdoctoral position at Syracuse University, arrived at Texas A&M; University for a postdoctoral fellowship in the mathematics department.
Once at Texas A&M;, Dr. Edward R. Dougherty, a distinguished professor in the Department of Electrical and Computer Engineering, asked Ivanov if he would be interested in doing some work in cancer biology. Still asking himself, “Why did this happen to my father-in-law, and what can I do about it?” Ivonov began his journey with Dougherty.
Dougherty, who also has a Ph.D. in mathematics, explained some of the problems that cancer investigators were working to solve. He asked Ivanov to write a brief paper involving the Probabilistic Boolean Network modeling of genomic regulation. As a result, Ivanov earned a postdoctoral position in the Training Program in Biostatistics, Bioinformatics, Nutrition, and Cancer led by Dr. Raymond J. Carroll-a distinguished professor in the statistics department at Texas A&M.;
For the next two and a half years, Ivanov began to learn more and more about biology and biological systems. It was during this time he was invited to work on a project with Dr. Robert Chapkin-a distinguished professor in the Department of Nutrition and Food Science. Through that collaborative effort, Ivanov was soon invited to consider a position at the CVM. After giving a talk to the faculty of the interdisciplinary program in toxicology, Ivanov spoke with Dr. Glen Laine, former head of the veterinary physiology and pharmacology department.
“Dr. Laine, who has a background in physics, understood the importance of the mathematics behind my presentation, and he offered me a position,” said Ivanov. “Totally by accident, or by fate, I ended up in the veterinary school, and then things started blossoming. I began collaborating with people from the college and other places. Now, in collaboration with the Fred Hutchinson Cancer Research Center in Seattle, Washington, we are taking part in a human trial about the potential benefit of lignan food supplementation in promoting colon health that may have direct application to cancer prevention. So, by coincidence, all of this is one big circle, supported by the foundation of mathematics.”
From Computers to Cancer
Engineers, according to Ivanov, have long examined mathematical models to help control complex systems like airplanes, cars, and computers. Following in the footsteps of other disciplines such as physics and chemistry, these advances underline the importance of the scientific approach: from experimental design, to developing a predictive mathematical model, validating the model with additional experiments, and ultimately controlling or influencing the system in question.
“It is now time when biology begins to evolve into a mathematically founded discipline,” said Ivanov. “Every time
you investigate areas like molecular biology and cancer, you begin to see complex systems. Gene (dis)regulation, for example, is a current focus in cancer research. In many aspects this process could be modeled after a computer’s architecture and logic. It [gene regulation] is a network. A computer is essentially what is known as a Turing machine, so things that are developed already by mathematicians and engineers-like logical gates and circuits-could be applied directly to biology, especially in cases where complex biological systems are faced with choices, and decisions are made by their regulatory elements.”
From Ivanov’s perspective, without having a systems approach to biology there would be less progress, because scientists would be missing a great part of the picture. Where many would see a wall between the sciences, Ivanov sees opportunity. Mathematical modeling, for him, has gone beyond just a discipline. It is becoming that common foundation, that common language that brings disciplines together. “If we don’t speak a common language, we will never do anything together,” said Ivanov. “Engineers will keep working on circuits and computers, and biologists will just do what Darwin used to do, which is categorizing all the different observed cases and trying to comprehend and explain huge degrees of variation. This is impossible for a human brain to do without a proper foundation.”
From Theory to Application
“The current understanding is that cancer is a molecular disease, which means it’s based on genes and their regulatory interactions within the cell. These genes are not alone, they communicate via different pathways with other genes and external to the cell stimuli,” explained Ivanov. “In this way, they form a communication network. Focusing on an individual gene might not lead to the desired result, because if you hit that gene with a drug, the cancer cell often has the capability to re-route its regulatory activity and still reach a proliferative state that causes the cancer to metastasize.”
“What is needed is to model the entire network or pathway of how the genes are communicating with each other,” said Ivanov. “Using these models, we can predict which genes are ‘turned on’ or highly expressed or ‘turned off’ or down regulated. You have to look beyond just the one gene and target the network if you want to control cancer.”
Ivanov explains that using mathematical models in biology has led to the concept of master-slave gene regulatory networks where one “master” gene controls the activity of a large number of “slave” genes. The thought is that if you can control the masters or some of the intermediate genes, you actually control the entire system. But this can be a tricky and difficult task. “You have to discover them [the master genes], and usually they are well-hidden because they are not usually highly up or down regulated,” said Ivanov. “What is highly up or down regulated are the slave genes, because they are controlled by the masters. You have to figure out which one of the entire section is the master gene and then develop a model-based strategy to control it.”
Ivanov is quick to admit that the potential of this approach is not going to immediately result in a cure for cancer, but it could lead to the ability to control the cancer and stop it from spreading in the body. In addition to his ongoing work in developing mathematical models for cancer biology, Ivanov also continues to collaborate with his colleagues in the food and nutrition sciences department. A recent study that used his mathematical models involved examining the microbiota that naturally live in the digestive tract and how they react with gut epithelial cells. The study found that babies fed a certain type of formula develop genetic signatures similar to babies born prematurely.
“This is an exciting finding and is important because people know if a baby is premature, it has a much higher risk of developing some kind of immunological problem in the future; therefore, babies who are fed that particular type of formula might have that same risk,” said Ivanov. “Babies who are breastfed showed the same kind of gene expression variations we would expect in a normal population.”
The research team determined that such gene expression signatures are strongly related to the composition of the gut microbiome, which suggests that there exists a certain epigenetic “programming” through the interactions of the nutrients, microbiota, and the epithelial cells in the digestive tract.
“These interactions represent a very complex system,” said Ivanov. “We have so many microbes naturally living in our digestive system, and many different cell types. We had to develop a way to model that interaction. That’s very exciting.” Ivanov’s expertise in abstract mathematics and mathematical modeling of complex systems enables him to serve as a bridge among diverse scientific fields. He aids leading edge research by developing theoretical approaches to controlling complex systems, finding applied methods for controlling cancer initiation and progression, and understanding how microbes in the digestive system influence human development from a very early stage of an infant’s life.
Ivanov engages investigators through his work in the Center for Translational Environmental Health Research (CTEHR). The CTEHR, a collaboration among Texas A&M; University, Baylor College of Medicine, and the University of Houston, has a mission to “improve human environmental health by integrating advances in basic, biomedical, and engineering research across translational boundaries from the laboratory to the clinic and to the community and back.” Here, Ivanov directs the CTEHR’s Quantitative Biology Core, which provides investigators with genomic, bioinformatics, and statistical and computational biological support services for their studies. This also includes helping to develop mathematical models.
Mentoring and Modeling
Even though Ivanov has played an integral role in bridging the gap between scientific disciplines, he says his greatest accomplishment is the success of the graduate students he mentors.
“One of my best students, Jason Knight, just successfully defended his doctoral dissertation, and I’m very proud of him,” said Ivanov. “His work was focused on developing modelbased frameworks for classification, finding gene signatures for any kind of condition-not just cancer. In mentoring students like Jason, I can bring in colleagues from many different fields, experts, to create a unique and meaningful graduate experience.”
In addition to his work with colleagues and mentoring graduate students, Ivanov is passionate about his work and the potential it has to impact cancer prevention and treatment, and perhaps other chronic conditions. “I am trying to find ways to reduce the complexity of these mathematical models of gene regulation,” said Ivanov. “We know that we can never model a thirty thousand gene network. It might be possible only with a supercomputer, but even then the computations that predict the dynamic behavior of the system would not be finished until after human beings are long gone. I’m trying to figure out how we can start with a large gene regulatory network model and reduce it to the most important twenty to fifty genes. Of course, we lose information, but maybe the larger regulatory system or a portion of it can still be controlled sufficiently well so that a new drug or other treatment can be developed to control cancer or some other chronic condition. In other words, the goal is to prevent or control a complex disease and keep it from progressing.”
Consequently, Ivanov views his work through the lens of complex systems. When asked the best part of his job, Ivanov replied, “It’s getting my hands on a model and finding a way to simplify it, it’s watching students develop that understanding of the complexity of the world around them, and it’s learning from my colleagues. It’s all of the above. Those things, in a way, form a network that induces my curiosity. I learn from my students and I learn from my colleagues because they have different perspectives. Then I go into my own world and I rethink all of those interactions and what I learn from them. What I take from them shows me how I should proceed. It’s great.”
A disease most people have never heard of, which has come to the Americas only in the last year, may soon become a major public health issue in the United States. Chikungunya (pronunciation: chik-en-gun-ye) virus has been recognized as the cause of periodic epidemics in Africa and Asia since the 1950s and has now spread to all but six countries in the Americas, with over 1.4 million suspected cases since first arriving in the Caribbean in late 2013. There have been 11 cases thus far reported in Florida where the patient had not reported any recent travel.
“We have local transmission in the United States,” said Dr. Rosina “Tammi” Krecek, a visiting professor and interim assistant dean of One Health at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM). “We also have imported transmission. An example of local transmission is ‘I didn’t leave home, a mosquito bit me, and I became infected.’ Imported transmission is ‘I flew to an endemic country, a mosquito bit me, and I became infected and returned with the infection.'”
The virus is spread among humans by the bite of either of two species of mosquitoes: Aedes aegypti (“yellow fever mosquito”) and, less commonly, Aedes albopictus (“tiger mosquito”). When the mosquito bites an infected person and then subsequently bites a healthy individual, the virus can be transferred to that second person. Aedes aegypti can be found in the southeastern United States from Texas to South Carolina, while Aedes albopictus can be found as far north as New York City.
“In some parts of the country, there’s really no risk of initiating transmission, but anywhere in the southeast, there is a risk, especially during the summer,” said Dr. Scott C. Weaver, director of the Institute for Human Infections and Immunity at The University of Texas Medical Branch at Galveston, who collaborates with Krecek and others at Texas A&M on this disease.
One worry the scientists have is that if the virus were to mutate to make it more easily spread by Aedes albopictus mosquitoes, a much larger percentage of the United States population could be affected.
Health officials in the Caribbean are urging businesses and individuals to eliminate standing water and take other precautionary measures against mosquitoes. Unfortunately, these kinds of mosquitoes tend to thrive in urban areas, including inside buildings, so simply fumigating the outside areas with insecticide is unlikely to have much effect. Therefore, travelers must take it upon themselves to exercise reasonable precautions, including wearing mosquito repellent and sleeping in rooms with screened windows, air conditioning, or mosquito netting. As there is no treatment or vaccine for the chikungunya virus, preventing mosquito bites remains the only defense.
Chikungunya virus comprises a clear example of One Health defined as the inextricable link between animal, human, and environmental health. Because animals and the environment are considered important factors in human disease, the best way to combat a virus like chikungunya is a One Health approach. Furthermore, humans are not the only ones who can become infected. “There is some evidence that animals-including non-human primates, small mammals, and birds-may act as reservoirs for the virus,” said Dr. Christine Budke, an associate professor at the CVM. “However, because it’s a new virus to this part of the world, there’s very little information on non-human reservoirs in the Americas.”
“There is a risk that the virus could use non-human reservoirs in South and Central America, where there are plenty of wild primates, but we simply don’t know if those species are competent to serve as reservoir hosts,” Weaver said. “We also don’t know if the mosquitoes that are present in the forest habitats where those monkeys live would be competent to transmit in a monkey/mosquito cycle, like exists in Africa.”
Other factors affecting the transmission of the virus may include movement of people and animals as well as changes in climate, but how that works is also largely unknown. “We don’t fully understand the role of the mosquito or the role of climate in the disease cycle,” Krecek said. “We don’t know how the mosquito is influenced by the environment. For example, what leads to a more, or less hospitable habitat for the vector?”
As of January 1, 2015, chikungunya is a reportable disease, meaning doctors must tell the Centers for Disease Control and Prevention (CDC) of any cases. Although this move demonstrates the CDC’s concern about this virus, experts say it is unlikely to result in increased numbers of cases reported, as doctors already generally report any cases they see of this unusual virus.
An issue is that this disease mimics other, more common diseases. Symptoms typically begin, three to seven days after being bitten by an infected mosquito, with a sudden high fever and joint pain, often followed by headaches, muscle pain, coughing, joint swelling, and/or a rash. Although the disease is rarely life threatening and symptoms subside in many people within a few weeks, for some of those with the disease (estimated at up to 60 percent by some studies), the joint pain may last for months or even years and can be so debilitating they are unable to go about their normal lives.
“I’ve received emails from a lot of people here in the United States who have become infected, travelers mostly,” Weaver said. “They’re a month or two out after their infection, and they’re still experiencing severe arthralgia and asking about experimental treatments, or anything else that they can do. Unfortunately, there’s not much other than our typical non-steroidal anti-inflammatory drugs that you would take for pain and swelling for people with chikungunya.”
Dr. Heather Wilson-Robles has known since she was a young child that she wanted to work with animals. “In kindergarten,” she said, “I had the teacher help me spell ‘veterinarian.’ I’ve never wanted to do anything else.” Born and raised in Memphis, it was only natural that Wilson-Robles’ journey to fulfill her dreams would begin at the University of Tennessee, where she received her doctorate in veterinary medicine (DVM). With her DVM in hand, she accepted an internship at the University of Minnesota. Following her internship, Wilson-Robles went on to complete a residency in veterinary oncology at the University of Wisconsin-Madison (UWM). While at UWM, she met the love of her life, Dr. Juan Carlos (JC) Robles Emanuelli. In 2007, they both accepted positions at the Texas A&M College of Veterinary Medicine & Biomedical Sciences (CVM), and shortly thereafter married. “We decided that after Minnesota and Wisconsin, anything below the Mason-Dixon line would be fine with us,” joked Wilson-Robles.
Wilson-Robles has since made a name for herself as one of the major players in veterinary oncology. She currently serves as associate professor in the Department of Small Animal Clinical Sciences (VSCS) and has been named the first Dr. Fred A. and Vola N. Palmer Chair in Comparative Oncology. Her husband, JC, recently lost his battle with cancer.
Inspiration to Study Medicine
Along with her life-long desire to work with animals, Wilson- Robles was also inspired to study medicine during her early days in Catholic grade school in Memphis. “My school had a connection with Le Bonheur, the children’s cancer center in Memphis,” Wilson-Robles explained. “A lot of kids would come from all over the world and they were able to go to school there, free of tuition while they were undergoing treatment at Le Bonheur.” Having many classmates undergo cancer treatments gave Wilson-Robles early insight into cancer and terminal illness. With first-hand exposure to pediatric oncology, Wilson-Robles became interested in the various treatments her classmates underwent. “I watched what a lot of the kids in my class went through-and some of them died-and I thought there’s got to be something better we can do.” Despite her interest in improving oncology care for children, Wilson-Robles knew she was better suited to a career in veterinary medicine. “I knew I could never do pediatric oncology,” she said. “I just don’t have the stomach for it. It takes a special kind of person.”
Notwithstanding her reluctance to pursue a career in pediatric oncology, Wilson-Robles would embark on a career that would provide invaluable research and medical discoveries to those children suffering from pediatric cancers. She would go about it in an unorthodox way but would come to realize that her patients-the canine ones-were immensely useful in the treatment of children with cancer.
Two Kinds of Research
In her research at Texas A&M, Wilson-Robles draws a distinction between the two different foci of her work. Splitting her time between benchtop and clinical research she is able to work on both sides of veterinary medical research. She describes her benchtop research as “working with cell lines, working with mice, signaling pathways, and a lot of work with genetics.” Largely responsible for creating proofs-of-concept for a variety of drug therapies and genetic studies, Wilson-Robles’ benchtop research often consists of “cells growing in a flask in media so it looks like pink soup. They’re growing in there and I’ll throw some drug in there and see what happens.”
Despite her cavalier description, Wilson-Robles’ benchtop work is exacting and crucially important to the success of her clinical trials. She is ever aware that the “pink soup” she’s testing for genetic anomalies may hold the key for a new treatment for a type of cancer.
Constantly vigilant and on the lookout for potential new uses for drugs, Wilson-Robles works with drugs and drug companies to test pharmaceuticals in various clinical situations to deter- mine their effectiveness in animals. Her benchtop research informs the clinical research. Having experience in both types of investigative techniques makes Wilson-Robles a premier scientist of veterinary oncology with an exceptionally comprehensive research background.
Expounding on the differences between benchtop research and clinical research, Wilson-Robles explained that laboratory work allows the researcher to tweak experiments and try new approaches based on results. “But in a clinical protocol,” she cautioned, “you follow it to a T.” The strictness of clinical protocol leaves very little room for experimentation or improvisation, which is why scientists like Wilson- Robles who are experienced in both benchtop and clinical research are particularly valuable. “There is always a place for discovery,” Wilson-Robles said, addressing the importance of benchtop research. She went on to say, “There are tons of people doing discovery on the human side and veterinary side. But there aren’t many people-a handful of us nationally-that do the clinical trials to the level that we do here at Texas A&M.”
This combination of research skills allows for a more cohesive research study and perhaps a more successful clinical trial. It is important to Wilson-Robles that her research at either end of the spectrum informs the rest of her work. “I do the initial benchtop work to figure out if a certain drug will block a pathway to make a difference,” Wilson-Robles explained. “And if it does, the next step is a clinical patient.”
The patients Wilson-Robles uses for her clinical trials are nearly all client-owned dogs with naturally occurring cancers, and the research aims to treat their disease and prolong their lives. Much of Wilson-Robles’ work focuses on tumor-initiating cells. She describes tumor-initiating cells as “the worst of the worst” by explaining that all cancer cells are not created equal.
The tumor-initiating cells are those that survive chemotherapy and radiation and continue to proliferate.
It is these cells and their uniqueness that make cancers so difficult to treat. “These cells are drug resistant, radiation resistant, and they don’t replicate as quickly as the other cells do, so they’re much less sensitive to other factors,” Wilson-Robles explained.
Her work in dogs harkens back to her early interest in pediatric oncology because, as she said, “Dogs get pediatric cancers.” Working with dogs in clinical trials has allowed Wilson-Robles to contribute to important research in the human pediatric oncology field as well.
“Heather is an amazing scientist and clinician whose work will change the way oncologic diseases are treated in domestic animals and people,” said Dr. Jonathan Levine, head of VSCS. “More importantly, she is an amazing person who understands that excellence is about character and perseverance.”
Mentors Making a Difference
Focused on a course of study in veterinary medicine, Wilson-Robles met Dr. Alfred Legendre, professor of medicine in the Department of Small Animal Clinical Sciences in the College of Veterinary Medicine at the University of Tennessee, during her senior year there. Legendre quickly became a mentor for Wilson- Robles and offered important advice when it came time for her to choose her next step. “He helped me set the path I needed to take and I helped him with some research projects,” Wilson- Robles recalled. “He introduced me to clinical research and that’s really where it started.” Still working at the University of Tennessee despite being retired, Legendre remains an important influence in Wilson-Robles’ career. “He’s one of the loveliest men you’ll ever meet,” she said. “He’s supposed to be retired now, but he can still be found wandering the halls and helping out at the University of Tennessee.”
Though most of what she has accomplished in the veterinary oncology field is due to hard work and dedication, Wilson-Robles does acknowledge the importance of serendipity in her career. “One of the best things that ever happened to me was the match at the UWM, for an oncology residency,” Wilson-Robles stated. Through that match, she met Dr. David Vail, professor of medical oncology at the University of Wisconsin School of Veterinary Medicine, one of the “father figures of modern veterinary oncology.” Through Vail, Wilson-Robles was introduced to clinical trials and gained an understanding of how the research and discovery in these trials could translate to human medicine. “He’s a mentor, but he’s also a very good friend,” said Wilson-Robles of Vail. The two still keep in touch and Wilson-Robles noted that even after she left the UWM, she continually asks Vail for advice on upcoming clinical trials. “He and my husband played basketball together,” Wilson-Robles said of Vail, underscoring their close connection and mutual respect and support. Another important influence on Wilson-Robles while at UWM was Dr. David Argyle, the William Dick Chair of Veterinary Clinical Studies and the head of the school and dean of veterinary medicine at the University of Edinburgh in Scotland. He mentored her in laboratory research and taught her how to take new targets from the benchtop to the bedside.
“He was instrumental in my decision to be an academician,” Wilson-Robles said.
“It has been a great privilege in my career to train and mentor the next generation of academicians,” Argyle said. “I knew when Heather joined my team all those years ago that she would go on to have a great career as an academic oncologist.”
Future of Veterinary and Human Medicine
Understanding the ways in which dogs contract and react to cancer cells and clinical drug trials gives Wilson-Robles a greater understanding-and hope for-future treatment across the patient spectrum. “We’re all mammals,” she said, explaining that the more species that react positively to a treatment, the more likely it is that the treatment will be a successful therapy for humans. “It’s not just a dog thing,”
Wilson-Robles explained, “If I can show that a treatment works in a mouse and a dog and a rat, then it probably also works in a human. The more species it works for, the more valuable your results.”
Because of the complexity of cancer cells and cell growth, dogs are an excellent metric for trials of possible pediatric cancer treatments. Certain breeds of dogs have extremely high likelihoods of developing cancer. Golden retrievers have an 80 percent chance of developing cancer in their lifetimes, while boxers have an 86 percent chance. In fact, cancer is the number one cause of death in dogs over three years of age, and 25 percent of all dogs will get cancer at some point. While numbers like these are staggering, they are useful to Wilson-Robles who, through her research, has been given the opportunity to perform clinical trials with a number of different breeds of dogs. Such broad research bodes well for eventual human cancer treatment. Cancer in dogs tends to be akin to the most aggressive form of pediatric disease, and so, Wilson-Robles explained, “if we can get something to work on dogs, it will probably work on kids.”
However, Wilson-Robles cautioned, there is a danger in treating cancer-regardless of the species-as a singular disease. “As far as the future is concerned, I think the biggest thing is to acknowledge that there’s never going to be a magic bullet for cancer,” she said. “There’s never going to be one thing that cures cancer. Cancer is a group of diseases, and it is a genetic disease.” Underscoring the importance of personalized medicine, Wilson- Robles has praise for institutions like Baylor College of Medicine that run genetic profiles on tumors in order to better understand and treat specific cases using personalized drug and treatment recommendations. Chemotherapy, the current “catch all” method for cancer treatment, is “fighting fire with fire.”
Wilson-Robles warned of the indiscriminate nature of some forms of treatment, but said, “In many cases, this is still the best option for treatment available.”
Ultimately, the goal for Wilson-Robles and her colleagues in veterinary oncology is to perform research on dogs with an eye toward informing treatment of human subjects.
However, Wilson-Robles finds her work with animals rewarding on its own merits. “Now,” she explained, “we’re in negotiations with T-gen, Colorado State, Ohio State, and the National Institutes of Health (NIH) to do a large national multi-institutional trial looking at drugs given to dogs with osteosarcoma, which would hopefully then lead to approval for the drug for humans.”
Ever passionate about her research and clinical work, Wilson- Robles has found a home at Texas A&M. At the top of her profession- and leading the way in research for veterinary oncology and veterinary medicine- she stands poised to make important, perhaps groundbreaking, discoveries in the years to come.