High-stakes clinical trials may receive most of the publicity, but how does a treatment start advancing toward that stage in the first place? The lengthy process probably began with a researcher like Devendra Agrawal, PhD.
Agrawal is a professor of clinical and translational science, a distinctive field in which, he says, his work “goes from the bedside to the bench to the bedside.” This means that Agrawal starts with a problem that a health care clinician is trying to isolate or solve. Why do some patients develop symptoms with a disease, while others don’t? Why do some patients respond well to one course of treatment, while their peers reap no benefit from the same treatment? He works closely with clinicians to understand a problem, reads about that area and then gets to work in the lab, to seek findings that a clinician can take back to the patient’s bedside – either to aid in the diagnosis, prognosis or treatment of the disease, or eliminate it completely.
These endeavors require a vast level of knowledge and a relentless curiosity. Agrawal possesses both, with one PhD in biochemistry and one in medical sciences. Since coming to Creighton, he has added an MBA and a master’s degree in information technology management from the University – and plans to take a class in sculpture.
He came to Creighton University in 1985 to lead research in allergy and asthma even though, he says, at the time he was no expert – his work was mainly in cardiovascular sciences. Nonetheless, he successfully developed a research program in that area. Though he remains involved with asthma research, his focus has returned to cardiovascular diseases.
Matters of the Heart
As of December 2016, Agrawal is principal investigator (PI) on seven active research grants from the National Institutes of Health, to the tune of $15 million. He works with about 10 clinicians at any time – surgeons, radiologists, cardiologists, immunologists – and a small army of students and post-doctoral research fellows, to whom he serves as a valued mentor.
One problem Agrawal has been tackling for some time involves the buildup of plaque in carotid arteries. Studying plaque buildup removed from patients, Agrawal found that different groups of plaque behaved differently depending whether or not the patient had exhibited specific symptoms – such as a stroke and a transient ischemic attack (TIA), sometimes called a mini-stroke. He then set out to explore how to predict whether a patient is going to develop symptoms and ways to prevent those symptoms. His research could have major implications, considering stroke is the fifth leading cause of death in the United States and a leading cause of disability, according to the Centers for Disease Control and Prevention.
Agrawal has received about $4 million to date aimed at this line of research. He has identified two potential targets that could block molecules that seem to cause plaque buildup to break off and travel to the brain. He has submitted another grant application to continue the investigation. If successful, perhaps thousands of strokes could be prevented.
In a Similar Vein
Agrawal has several other multi-million dollar NIH awards to further his efforts in studying coronary artery disease. Traditional methods of addressing plaque buildup or atherosclerosis include balloon angioplasty to expand the artery and compress the plaque, or placement of a stent or small tube to support the artery. However, notes Agrawal, with balloon angioplasty, arteries may get blocked again within a short time, and stents may not keep the artery fully open. To make them more effective, stents now have a special drug coating. Still, those drugs have side effects and risks, and not everyone can tolerate them.
Naturally, Agrawal wanted to find a better way. He identified a molecule that is defective in subjects whose arteries are blocked. Gene therapy, Agrawal believes, could help suppress this molecule, eliminating the need for stents. In testing, Agrawal and his team have experienced promising results.
Another novel method of addressing coronary artery disease under investigation by Agrawal involves stem cells. During angioplasty, the innermost layer of the artery – the endothelial layer – becomes destroyed. When that layer is destroyed, immune cells bind and cause thrombosis. Agrawal had the idea to collect patients’ own bone marrow and isolate mesenchymal stem cells, which can replicate. He found that these can be treated in vitro in such a way that they will become endothelial cells, and can replace the damaged layer. This helps limit the risk for thrombosis.
As he examined these cells and tissues, Agrawal observed that patients whose arteries get blocked again after these procedures are vitamin D deficient. Does it make a difference if they take vitamin D supplements in advance? To find out, he is working on a $3.1 million NIH grant to examine whether vitamin D can help produce a positive immune response in patients with coronary heart disease.
Through examining countless tissues, Agrawal noticed yet another phenomenon he wanted to explore. When examining fat (adipose) tissue, he noticed that this tissue around the heart (epicardial adipose tissue) was inflamed. His lab then fed pigs a high-fat diet to examine this issue, and noticed that not only did the pigs become obese, as expected, but the fat also appeared differently as a result of this diet. With this data, Agrawal submitted a proposal for another grant and received $3.5 million to explore obesity and inflammation of epicardial adipose tissue.
Agrawal never seems content to explore just one angle of a problem. For example, in a patient for whom angioplasty, balloon angioplasty or stents have failed or are not feasible, the next remedy is bypass grafts. A vein from a patient’s leg can be used to bypass a blocked vein elsewhere in the body, Agrawal explains. However, the leg vein also gets blocked in about 30 percent of patients within only a few years.
By working closely with surgeons and looking at tissue from surgery patients, Agrawal observed two molecules that could be defective in patients who experience this failure of the leg vein. Gene and stem cell therapy, he believes, could help suppress those defective molecules. He is currently testing this method with the help of a $2.9 million NIH award.
Mentoring the Next Generation
Agrawal is working on several other projects as well and constantly submitting and resubmitting proposals for new grants. For its relative size and scale, the volume and output of his lab are remarkable.
What, then, drives him to work so hard? Grants and projects amounting to half of this workload would still indicate a successful career and robust lab. “My goal is not to develop myself – it is to mentor and support others,” Agrawal says. “I want them to be successful.” Agrawal recently developed a PhD program in clinical and translational science – the only one in the region – to provide opportunities for the next generation of researchers in the field. Mentoring and working with clinicians is central to the structure of the program.
He keeps his students’ bound theses and dissertations handy in his office, and brings them out as he recalls each of his “superstars”: one MD/PhD student received the “best researcher” award during his residency at UC San Diego and is now a spine surgeon. Ryan Trowbridge, a medical student who also completed a master’s in clinical and translational science at Creighton, published seven papers within two years as a student.
Going from the bedside to the bench to the bedside requires collaboration and patience. “It is not easy, but I have been very lucky, and I have no problem working with clinicians,” he says. And they want to work with him, as well. He constantly receives requests from medical practitioners who have encountered vexing problems and want to partner with him. And with his gift for mentoring, he doesn’t often say no. (“I’lI have to start cutting it down,” he admits with a shrug.)
But it’s all worth it. Working with clinicians and bringing the scientific method to the problems that afflict their patients, Agrawal says, “is the only way we can move science forward.”
For more details, see Agrawal’s complete expert profile.