Can you translate that, please?
How do discoveries made at the lab bench ever reach the bedside of patients who need them?
Moving research discoveries from "bench to bedside" to treat patients is the goal of translational research. Translational research takes discoveries made in a field or in one context and figures out how to apply them to a different field.
"Using that definition, there are a lot of things that we do at The University of Texas Health Science Center at Houston (UTHealth) that constitute the translation of new discoveries into their implementation," says Peter Davies, MD, PhD, provost and executive vice president for research.
Discovery may begin at a laboratory bench, using model systems, like cultured cells, purified proteins and animal models. At this stage, a researcher studies the basic mechanisms of a disease or illness to unlock its mysteries at the cellular and molecular levels. The next step is for the basic laboratory discovery to move forward into evaluations conducted with human subjects or sometimes human tissues that are designed to see if the same processes discovered in the laboratory actually occur in humans suffering from specific diseases.
"One of the most commonly cited examples of translational research is studies where we move discoveries made in the basic research laboratory and work out how to apply them in a clinically relevant setting, such as by designing or developing clinical trials," Davies says.
Bench to bedside and back again
"We also may move in the other direction and take observations made in the clinic on patients and disease processes and move them back in the laboratory to study in more controlled circumstances how those observations might be explained in terms of the mechanisms that caused them," Davies says.
Like all scientific study, translational research is often complex and expensive to conduct. In addition, it often requires access to specialized research facilities such as those to conduct clinical studies in humans or specialized diagnostic and analytical laboratories. UTHealth helps its researchers strengthen the translational aspect of their work by providing the necessary resources and research infrastructure that enable them to apply for and then to obtain the support from federal agencies, such as the National Institutes of Health (NIH) that actually fund the research studies.
For example, in 2006, funding from the NIH allowed UTHealth to create the Center for Clinical and Translational Sciences (CCTS), one of the original 12 such centers funded by NIH. This grant enabled UTHealth and its two partners, The University of Texas MD Anderson Cancer Center and Memorial Hermann Healthcare System, to put in place specialized research infrastructure and training programs that will both prepare new investigators to conduct translational research and provide them with the facilities to conduct such research.
Faster, better treatment is the goal
The goal of the CCTS is to shorten the time it takes to develop new treatments and to apply them to patients. The CCTS includes very active and productive components including integrated clinical research units; biomarker-driven research trials; core laboratories in genetics, genomics, proteomics, immunology and imaging methodologies; bioinformatics; and career development training for junior investigators.
Ultimately, Davies says, the success of UTHealth as a leader in clinical and translational research will be based not on the outstanding infrastructure that it can provide, but on the talent, innovation and dedication of its researchers, faculty, staff and trainees.
"It is incredibly difficult to develop new approaches to the diagnosis and treatment of human disease, to acquire new levels of understanding of disease processes and new strategies for preventing disease. We are fortunate at UTHealth to have the corps of outstanding researchers, superb clinical and research infrastructure and an institutional tradition of working together and with others collaboratively that are key to success in this field. The CCTS and its many programs is helping to forge new research teams and new research initiatives that draw on the talents of researchers at all UTHealth schools."
Back to the future: the best treatment for hypertension may be an old standby
Is newer always better? New generations of drugs are produced all the time. The operating theory is that the new version is an improved version. But researchers at The University of Texas Health Science Center at Houston (UTHealth) School of Public Health took a step back to look at the big picture and reconsider that assumption. Specifically, they wondered whether newer drugs actually produced better outcomes for all patients in the treatment of one of the most common but dangerous conditions: hypertension.
It’s a translational way of thinking
By the early 1990s, there were several new types of blood pressure medications on the market, including calcium channel blockers, ACE inhibitors and alpha blockers in addition to the standard treatments of diuretics and beta-blockers, explains Barry Davis, M.D., Ph.D., director of the Coordinating Center for Clinical Trials at the UTHealth School of Public Health. "Each of these had been approved on the basis of their ability to lower blood pressure, and they worked in different ways. The question arose as to whether any of the newer medications would be better at preventing the clinical outcomes of hypertension – like heart attacks, strokes, heart failure and kidney failure – than the standard, diuretics, if everyone achieved similar blood pressure control," says Davis, who is also the Guy S. Parcel Chair in Public Health.
A landmark study
Between February 1994 and January 1998, investigators at the School of Public Health coordinated the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, or ALLHAT, sponsored by The National Heart, Lung and Blood Institute (NHLBI) and directed by Davis, to see whether any of the new treatments on the market for hypertension were actually better than the standard treatment. With 42,418 participants enrolled, the landmark study was the largest hypertension treatment trial ever conducted. The results, which had implications for roughly 70 million Americans, were astounding.
If it’s not broken ...
ALLHAT revealed that none of the newer blood pressure medications – calcium channel blockers, ACE inhibitors or alpha blockers – were superior to diuretics in preventing heart attacks, strokes, heart or kidney failure. In some cases they were actually not as good.
"It was a study that examined several types of treatment for the same condition and found that the standard method was the best," Davis explains. "In fact, diuretics were better than calcium channel blockers and ACE inhibitors in preventing heart failure, and they were better than ACE inhibitors in preventing strokes, especially among African-Americans," he points out.
ALLHAT did even more than provide valuable information about cardiovascular health and the treatment of high blood pressure. It provided a model for comparative effectiveness research. In Davis’ words, "It . . . served as a model for conducting large clinical trials in the community outside of the usual academic setting by involving community-based health practices."
The final "translational" step was to apply the findings to the community at large. It was another landmark achievement. "ALLHAT was the first study of its kind to have a formal dissemination process whereby the study researchers presented and communicated their findings to the professional and patient communities in ways beyond the traditional means of scientific publication and presentation," Davis says. This type of dissemination is now required of all major NHLBI studies.
For the millions of Americans being treated for hypertension, ALLHAT yielded yet another benefit. Going back to an older generation of medicine may save them thousands of dollars.
From the Petri dish to Cameron County
The adaptability of the human body enables us to survive as we go from hot to cold, relaxed to stressed, hungry to full. Without the ability to change with the circumstances we couldn’t live for more than a matter of minutes. We don’t want that to change. Fat cells are masters of versatility; they are our allies in the survival game. We don’t want that to change either.
But there is a connection between the ability of fat to land – and stay – where it is not needed and the incidence of serious diseases. Perry Bickel, M.D., is an expert in the biology of fat cells. He is making strides in understanding the behavior of fat and how it is involved in diabetes and cancer.
The human body needs a certain amount of stored fat to function normally and to supply it with energy. This adipose (fat) tissue is specialized to store energy in the form of triglycerides, which can be mobilized when the energy demands of other tissues exceed their readily available supply.
However, in obesity, the body stores too much fat, which then overflows into tissues not well adapted to storing it, like the heart, skeletal muscle and liver. This leads to potentially severe medical complications for overweight individuals, including heart disease, fatty liver disease and type 2 diabetes.
Bickel studies how cells in the human body store fat and how the stored fat is directed to certain cell functions, such as use as a fuel or as a cellular building block.
Using cells that can change into fat cells in a Petri dish has allowed Bickel to zero in on proteins that help regulate the storage of fat within cells. "With this cellbased system, we can precisely control levels of hormones, nutrients, drugs or gene expression and then ask whether the cells store or burn more fat and how the fat is packaged into storage organelles, known as lipid droplets," says Bickel, associate professor of medicine and associate director, endocrinology, diabetes and metabolism at UTHealth Medical School, and director of the Center for Diabetes and Obesity Research at The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, part of The University of Texas Health Science Center at Houston (UTHealth).
Focusing on lipid droplets, or fat droplets, inside cells led Bickel to a discovery of "two related proteins, S3- 12 and OXPAT, that coat lipid droplets and help control levels of stored fat in fat cells and muscle cells," he says. "We were the first to discover that lipid droplets in fat cells progress through stages of maturation that are marked by changes in the coat of proteins that surround the droplets."
His lab’s discoveries have increased the awareness of how changeable and varied lipid droplets are within cells. "Such insights may provide new strategies to control the storage of fat within cells or to protect cells from the adverse effects of fat overload," says Bickel.
Bickel’s contributions to fat cell and lipid droplet biology will move beyond the laboratory. He and his collaborator Karen Lu, M.D., a gynecologic surgeon from The University of Texas MD Anderson Cancer Center, are leading an effort to develop the Collaborative Program in Cancer, Obesity and Metabolism (CoPCOM), which will address the question of why obesity increases the risk of developing certain cancers.
This group has focused its efforts on endometrial cancer, due to its strong association with obesity. "Forty percent of endometrial (uterine) cancers are attributable to obesity in affluent societies," Bickel explains.
Bickel is collaborating on translational research studies with the UTHealth School of Public Health, Brownsville regional campus, led by Joseph McCormick, M.D., and Susan Fisher-Hoch, M.D. They are following a cohort of Hispanic residents of Cameron County, which has a high prevalence of diabetes and obesity.
"From the Cameron County Hispanic Cohort, we hope to learn how differences in the genes and proteins that regulate lipid metabolism may contribute to diabetes risk in obese humans," Bickel says. "These studies will attempt to translate what we have learned in cell-based studies and in mouse models to human obesity and diabetes, problems that disproportionately undermine the health of many Texans."
Research on biomarkers may lead to saliva test for breast cancer
If one researcher at The University of Texas Health Science Center at Houston (UTHealth) Dental Branch has his way, early breast cancer detection will one day happen in the dentist’s chair, during a routine oral screening. That’s the dream of saliva researcher Charles F. Streckfus, D.D.S., who is examining ways that saliva might become a supplementary diagnostic tool for the detection of breast cancer.
Streckfus is a professor of diagnostic sciences and an expert in salivary diagnostics, a field where researchers study saliva as a biomarker for disease detection.
"We like saliva because it is easy to collect," Streckfus says, adding that saliva’s use as a diagnostic tool offers many other advantages. "It’s non-invasive and it doesn’t hurt. It can be collected repeatedly without any difficulty."
Streckfus would like to use saliva as a supplement to mammography for breast tumor detection.
"For example, if a mammogram is not clear, then a saliva test could be used to help make the decision whether it is cancer or not," he adds.
Working with William Dubinsky Jr., Ph.D., a biochemist and professor of diagnostic sciences at UTHealth Dental Branch, Streckfus studied saliva samples to search for cancer-related proteins.
"Dr. Dubinsky had the technology I needed to find the markers in sufficient numbers and quantities so I could identify the proteins I needed to investigate," Streckfus explains. "We wanted to look at, on a large scale, what exactly was in saliva and how it related to breast cancer."
Saliva specimens from 30 women were analyzed with a mass spectrometer. One pool of samples came from healthy women (control group), another pool from women with benign breast tumors and a third pool from women diagnosed with a malignant form of breast cancer.
The results of these comparisons showed some protein differences in the pools of samples of the healthy control group and the benign and cancer patient groups. Further study will be required to validate the preliminary observations and to determine whether they may be useful in developing diagnostic tests.
Streckfus and Dubinsky’s collaboration to find cancer associated proteins in saliva is a great example of "bench to bedside" research.
"Dr. Dubinsky and I worked at the bench to search for biomarkers in saliva," Streckfus explains. "His machine gave us the biochemistry that we needed. It was truly a laboratory accomplishment. Now we will prepare antibodies and study whether they can be used to screen for cancer."
Study focuses on ensuring that more efficient technology keeps patient safety in mind
Bankers’ hours. Many of us remember having to get to that building "downtown" before 4 o'clock – on a weekday. Now we slip an ATM card into a machine around the corner from the office – or near the Louvre, at the hotel in Kuala Lumpur, in the Munich airport. Access is easy. Cash is in hand and we are ready to go on with our trip to the grocery or the next port of call.
And, unless we give out our pin numbers, our money and information are secure.
Researchers in bioinformatics in The University of Texas Health Science Center at Houston (UTHealth) School of Health Information Sciences are using that model of financial accessibility coupled with security to revolutionize access to medical records.
Medicine has lagged behind fields such as banking in creating global, portable, secure access to records. But Dean Sittig, Ph.D., associate professor of health informatics, is working on changing that. Sittig is studying the design, development, implementation and evaluation of all aspects of clinical information systems (CIS), more commonly called electronic health record systems (EHRs). "I am interested in the socio-technical aspects of these systems with a particular interest on ensuring that they are used in a safe and effective manner," Sittig says.
While creating EHRs would benefit patients, doctors, hospitals and payers, Sittig is aware that there are pitfalls associated with the process as well. Through interviews and observations of health care providers, he has identified nine major unintended consequences that can occur following the implementation of state of- the-art clinical information systems.
They include more/new work for clinicians; unfavorable workflow issues; never-ending system demands; problems related to paper persistence; untoward changes in communication patterns and practices; negative emotions; generation of new kinds of errors; unexpected changes in the power structure; and overdependence on the technology.
"I have edited a book, Clinical Information Systems: Overcoming Adverse Consequences, to help organizations learn to identify and overcome the unintended consequences of implementing and using these systems." He has also identified eight "rights of safe EHR use" that can keep these problems from occurring in the first place. See below.
Sittig’s discoveries not only have helped others to better understand complex information systems, they have led to advancements in medicine and improved the quality and safety of patient care. "In a VA study, we were able to identify an error that resulted from a chain of errors or mistakes that consisted of five linked events," he says. "Briefly, this error sequence resulted in over 30 percent of patients with an abnormal colon cancer screening test not being followed up appropriately. After we identified the problem, we were able to fix it and demonstrate that the percent of inappropriate follow-up dropped to less than 7 percent."
Program aims to 'Catch' and curb childhood obesity before long-term health issues start
With the rising rate of childhood obesity, a University of Texas Health Science Center at Houston (UTHealth) School of Public Health study works to reduce the epidemic with a school-based program that teaches children that eating nutritious foods and exercising are keys to a healthier life.
CATCH, Coordinated Approach To Child Health, is a diet and exercise behavior change program for children and adolescents that was originally designed to target risk factors for heart disease. Through the years, CATCH has evolved to prevent other chronic diseases, including obesity and diabetes. The program is school based and works by using several components to give children coordinated and consistent health messages.
"CATCH uses behaviorally based strategies to build children’s confidence in making healthy choices for eating and exercise, provides role models for these behaviors, reinforces healthy behaviors, builds social support at the school for healthy behaviors and encourages children to set goals for eating and physical activity," says Deanna Hoelscher, Ph.D., R.D., director of the Michael & Susan Dell Center for Advancement of Healthy Living. She is professor of health promotion and behavioral sciences at the UTHealth School of Public Health Austin regional campus. "In addition, CATCH is fun, so both teachers and children enjoy the activities, and tasty, healthy foods are emphasized."
CATCH trains a team from each school to use its four components, including child nutrition services (the school cafeteria), classroom curricula, a physical education (PE) program and a parent program. Almost everyone at the school, and at home, becomes a participant in CATCH.
"Classroom teachers teach the lessons, cafeteria managers and food service workers use our Eat Smart program and PE teachers use the CATCH PE box," Hoelscher explains. "We also have activities for the families that include a Family Fun Night health fair, as well as lessons that children work on together with their families."
CATCH works. Hoelscher says that initial data showed that the CATCH program changed children’s behavior by decreasing their fat consumption and increasing their vigorous physical activity. Additionally, CATCH successfully changed the school environment to make school meals healthier and provide more opportunities for physical activity.
Not only has CATCH changed eating and exercise behavior in children and made school meals more nutritious, it also has helped to measurably reduce the obesity epidemic.
"A replication study conducted by researchers from The University of Texas at El Paso found that the CATCH program had an obesity prevention effect in children from 3rd to 5th grade," Hoelscher says. "Data from a statewide obesity surveillance study confirmed that obesity levels in the El Paso region, an area in which CATCH was heavily implemented, together with community-based programs, significantly decreased from 2000-02 to 2004-05 among 4th grade children. Finally, data from a recent demonstration program in the Travis County area found that underserved schools that implemented CATCH together with community involvement showed a significant decrease over a one year time period."
Originally, CATCH was designed as a randomized controlled clinical trial that was strictly regulated. Since that study, Hoelscher says, CATCH has been disseminated throughout Texas and the United States. Through this process, CATCH has learned some valuable lessons, which make the program easier to translate to all schools.
"Materials have to be developed to be in a 'kit' or a box that a person can take and use immediately," Hoelscher explains. "In addition, training of staff is essential for program implementation. We also have learned that a CATCH champion and school-level CATCH committee are effective ways to implement the program at the school level. And, community involvement seems to amplify the program’s effects."
Study explores link between impulsivity and addiction
A man is at a party and is offered cocaine. He impulsively says "sure" and months later, finds himself addicted. It is an oft-told story, but one that may be more complex than originally thought. What if his addiction stemmed not only from the addictive power of cocaine, but from some characteristic that made the man throw caution to the wind?
Acting without regard to proper forethought is known as impulsivity, which can sometimes lead to substance abuse problems.
"Impulsivity has been defined by our research group as a propensity to respond to stimuli without regard to the consequences," says F. Gerard Moeller, M.D., professor of psychiatry and behavioral sciences at The University of Texas Health Science Center at Houston (UTHealth) Medical School. "This leads to a number of psychiatric problems. In terms of substance abuse, it is associated with initiation of drug use and eventual addiction to drugs."
Moeller leads a team of UTHealth researchers, including Joy Schmitz, Ph.D., Scott Lane, Ph.D., Joel Steinberg, M.D., and Charles Green, Ph.D., who make up the university’s Center for Neurobehavioral Research on Addictions. The goal of the center is to develop new therapies to treat patients with substance abuse problems, which often result from impulsivity. Findings from their work have shown that impulsivity is a key feature of drug addiction.
"We also have shown that key measures of impulsivity are related to brain structure in drug users, and that cocaine leads to similar changes in brain structure that we are seeing in our drug users," Moeller adds. "This is evidence that at least some of the impulsive behaviors associated with cocaine use are related to changes in brain structure and function caused by chronic cocaine use."
Moeller says that a person’s addiction to drugs isn’t solely the result of a craving. Something in a drug abuser’s brain doesn’t allow them to make the right choices, leading them to exhibit self-destructive behaviors, like impulsively using drugs.
"Our research has shown that in addition to craving drugs, a substantial number of drug users have impulsive drug use, and that this behavior is associated with changes in brain structure as measured by brain imaging," Moeller says. "In short, our research supports the growing body of evidence that addiction is a complex behavioral and brain disorder."
Discoveries from Moeller’s research and that of other investigators at the center have translational research aspects. Findings from human studies are explored in animals, and research findings in animals are used to develop novel medications to treat drug abuse, Moeller says.
"Based on research findings, the team is trying novel medications with the goal of reducing impulsivity and other cognitive deficits in drug users with potential protective properties for the brain to reduce long-term changes in brain structure caused by drug abuse. We are combining these novel medications with behavioral therapies aimed at reducing the habits associated with drug use."
Research into genetic links may lead to better understanding of aortic dissection
John Ritter didn’t know he was at risk for an aortic dissection until it was too late. The actor was unaware of the progressive enlargement (aneurysm formation) of his aorta before his aorta dissected. Sadly, Ritter died after the onset of chest pain while working on the set of his TV sitcom despite being rushed to a nearby hospital for emergency surgical repair of the aorta.
Research by Dianna Milewicz, M.D., Ph.D., and her team seeks to understand the genetic basis of aneurysms leading to sudden dissections of the aorta.
"Aortic aneurysms are typically not deadly, but the enlargement of the aorta leads to instability and a strong predisposition for an aortic dissection to occur. Approximately 40-50 percent of people die of the acute dissection," says Milewicz, professor and director of the Division of Medical Genetics at The University of Texas Health Science Center at Houston (UTHealth) Medical School. "Nobody has to die prematurely from aortic dissection if we can figure out who is at risk, monitor their aorta and do timely medical and surgical repair of the aortic aneurysm before it dissects."
Milewicz and her team are interested in aortic aneurysms that occur in the first part of the aorta in the chest. The aorta is the major blood vessel or artery coming out of the heart. An aneurysm is an enlargement or ballooning of the aorta.
"The natural history of an aneurysm is that it progressively enlarges over time, and that enlargement tends to be asymptomatic," says Milewicz, holder of the President George Bush Chair in Cardiovascular Medicine. "A person doesn’t know they have an aneurysm. They don’t know it’s progressively getting bigger."
As an aortic aneurysm grows, it eventually reaches a size where it becomes unstable and is prone to either rupture or dissection. More commonly, Milewicz says, it dissects.
"The blood enters the wall of the aorta and then it begins to dissect along the wall – almost like a run in your stocking," she explains. "It can dissect all the way along the aortic wall – through the arch, through your body and to your legs, a life-threatening condition."
Thanks to a novel finding, Milewicz and her team have been able to prove through clinical studies, gene mapping and sequencing that aortic aneurysms and dissections have a significant genetic factor.
"We were one of the first groups to confirm a genetic basis to the disease," she says. "We mapped the first gene for aortic aneurysms and dissections, and we’ve gone on to identify four genes that predispose individuals to these aortic diseases." The research was done through recruiting families with many members with aortic disease, and then using DNA samples collected from these families to map and identify genes causing the disease.
Milewicz has taken her laboratory findings back to patients with a family history of thoracic aortic disease.
"We can find the gene causing the predisposition to aortic aneurysms and dissections in approximately 20 percent of patients with a family history of the disease," she says. "Some of the families who have entered our study have five generations of people who have died prematurely of aortic disease. For many of those families, we can tell them about the mutation and how we treat it to prevent further premature death in the family. We know from data we’ve generated using patients undergoing aortic surgical repair in the Texas Medical Center that if somebody is repaired before they dissect, they can go on to live a near normal life expectancy."
There was little known about the causes of thoracic aortic disease before Milewicz and her team began finding the genes that cause this predisposition.
"Based on the genes we’ve identified, we are confident that the underlying problem is that the cells in the wall of the aorta are not functioning properly," she says.
Those cells are called smooth muscle cells, and they contract regularly in the aorta every time the heart beats. Their purpose is to limit blood flow and blood pressure as the heart pushes blood out of the heart into the aorta.
"We’re finding that the gene mutations causing aortic aneurysms and dissections disrupt the ability of the smooth muscle cells to contract properly," Milewicz says. "That begins to provide insight into how to treat the disease, and we’re testing some of those treatments now.