Nikhil Dhurandhar’s unique work could help prevent metabolic diseases.
What if there was a vaccine for obesity?
It may sound like a crazy idea. But, if you ask obesity expert Nikhil Dhurandhar, it's not really that far-fetched.
In fact, developing such a vaccine is one of Dhurandhar's life goals. Thanks to his unique line of research at the crossroads of obesity and virology, the Texas Tech University professor is uniquely positioned to accomplish it. The rest of the world is benefiting from his research along the way.
Infectobesity
The Obesity and Metabolic Health Laboratory in Texas Tech's Department of Nutritional Sciences has a rare specialty. Led by Dhurandhar and assistant professor Vijay Hegde, it focuses on the intersection of research on obesity and research on viruses.
“That's a rare combination,” notes Dhurandhar, chair of the Department of Nutritional Sciences. “Typically, there are either virologists who know little about nutrition or nutritionists who don't think a lot about viruses, but it's a very rare combination to have people to be in nutrition and study virology.”
The main reason Texas Tech finds itself at such a juncture is Dhurandhar himself. When he came to Texas Tech in late 201 he already was an internationally renowned obesity expert.
In the 1980s, while working toward his doctorate in India, Dhurandhar had a chance conversation with a well-known veterinary pathologist. The topic of conversation was an avian virus that was killing thousands of chickens daily, but the birds were fat, not emaciated as one might have expected. Dhurandhar asked what probably sounded like a ridiculous question: Was the virus making the chickens fat?
“I don't know,” the scientist told Dhurandhar. “You're doing a Ph.D. Why don't you find out?”
So he did. Dhurandhar discovered that chickens injected with the virus gained weight in just a few weeks. Then, he obtained blood samples from the human patients in his obesity clinic and found that one-fifth of them had antibodies for the same virus, meaning they'd contracted it at some point in their lives.
But there was a puzzling addition to the finding. Although the infected chickens and humans were all obese, they did not show some of the hallmarks of obesity, such as high blood sugar, high cholesterol and high triglycerides. In fact, the cholesterol and triglyceride levels were lower in these individuals with obesity than in the general population. To Dhurandhar, this suggested an association between the virus and the metabolic health of those who contracted it.
After multiple subsequent studies confirmed the results, Dhurandhar was convinced the virus caused obesity. He coined the term “infectobesity” – meaning, obesity of infectious origin – and began to publicize his findings. But at a time when “obesity” simply meant eating too much and exercising too little, his research was panned. Some called it “preposterous.”
After Dhurandhar came to the U.S. to continue his research, he learned he could not import the avian virus from India. Going with his gut instinct, he selected another virus to test – Adenovirus 36 (Ad36), a human virus – and replicated his experiments, this time with rats, mice and monkeys. The results were the same.
It was the scientific equivalent of a mic drop.
“I latched onto this research because I understand obesity is multifactorial,” Dhurandhar said. “I like to call it ‘obesities' just to explain that, because it shows the different factors at play.”
He compares it to cancer.
“If you say to someone, ‘What are the causes of cancer?' the person will not be able to answer that question unless they ask you, ‘Which cancer are we talking about?'” Dhurandhar explained. “Every cancer is going to have a different cause. If it is lung cancer, maybe it is smoking. If it's skin cancer, maybe it is the excessive exposure to ultraviolet light. If it's uterine cancer, maybe it is a virus. So, the one word ‘cancer' doesn't do justice. In the same way, obesity actually should be ‘obesities' because there are different types of obesity and different causes of obesity.”
Dhurandhar is proud to have proven his concept and exponentially expanded the world of obesity research. To date, 12 viruses have been proven as causes of obesity, and he's sure more await discovery. To him, there's even more important work ahead.
“If a virus causes obesity, then it is preventable,” he explains. “If you have a vaccine, you can prevent that type of obesity. Not all obesity, not obesity due to other causes, but you can prevent the type of obesity caused by that particular virus or microbe. And so, that is very tantalizing for me, and that's why I've been pursuing this.”
Insparin
Over the years, Dhurandhar and his team began to focus on that secondary finding, why the cholesterol and triglyceride levels were lower following infection. Eventually, they discovered that Ad36 also lowers high glucose levels in these animal models. They successfully narrowed the effect to a single protein in Ad36: E4orf1.
This protein has been a vital part of Dhurandhar's research for nearly 20 years. During that time, he has received about 50 patents related to its use in treating Type 1 diabetes, Type 2 diabetes and non-alcoholic fatty liver disease.
Diabetes occurs when glucose builds up in the blood instead of being used by cells for energy production. In a normal circulatory system, glucose molecules in the bloodstream will enter the fat and muscle cells that line the blood vessels. Insulin, a hormone, is needed to start the molecular reaction that pulls the glucose into the cells.
In Type 1 diabetes, the person's body doesn't produce insulin. Type 2 diabetes is known as insulin resistant; the body produces insulin but is ineffective in promoting glucose intake by the body's cells. In both types of diabetes, glucose can build up in the blood at dangerous levels. Providing insulin or drugs that promote the action of insulin are some of the main approaches to decrease glucose levels in the blood, thus treating diabetes.
E4orf1 reduces blood glucose levels even in the absence of insulin and without mimicking the action of insulin. This reduces the requirement of insulin that the body has to produce to handle glucose. Because of this “insulin sparing” action, Dhurandhar dubbed it “Insparin.”
As successive, ongoing studies at Texas Tech and many other universities have repeatedly shown Insparin's ability to improve glucose reuptake and limit the accumulation of fat in the liver – a risk factor for cardiovascular diseases – independent of diet or other interventions, Dhurandhar and his team have become increasingly excited about its potential as a future treatment for metabolic diseases.
And they're not alone.
The American Heart Association granted Dhurandhar, Hegde and collaborator Ramakrishna Ranganath, an interventional cardiologist in Lubbock, $189,000 to study Insparin's role in halting – or even reversing – liver fat accumulation by using Insparin.
Separately, Dhurandhar and Hegde recently received more than $1 million to begin the commercialization process, bringing Insparin through clinical trials and, hopefully, into the marketplace.
“I'm particularly proud of this,” Dhurandhar said. “It's not every day that a technology developed at Texas Tech receives outside investment. This is an investment from outside investors who want to see it taken further.
“If we get U.S. Food and Drug Administration (FDA) approval, and we go through phase one, phase two and phase three trials, we are talking about a huge effect – in revenue and work – down the road. That would be good for Texas Tech and everybody else, but that's not the objective. The objective is to get the drug for diabetes for those who need it.”
Impacts
Of course, while Dhurandhar, Hegde and the rest of the team have been working to develop a treatment for diabetes, they were affected as much as the rest of the world by another disease: COVID-19.
In some ways, one might argue their team was affected even more. As researchers specializing in viruses, they felt compelled to help as the world was being ravaged by one. And it turned out that Dhurandhar's expertise in diabetes medications was especially relevant.
You see, it's important to realize the relationship between obesity and virology goes both ways. While Dhurandhar's work specializes in viruses that cause obesity, it must be understood that obesity and related conditions also predispose individuals to infections.
With a $160,000 grant from the National Science Foundation (NSF), Dhurandhar, Hegde and Rajesh Khare, a professor and assistant dean in the Department of Chemical Engineering, teamed up to examine why people with diabetes may be more susceptible to COVID-19 infection than those without. It is likely not diabetes itself that's responsible – it's the medication for the condition.
“When the COVID-19 virus enters a cell in our body, it uses something called a cell receptor that it binds to, which acts like a doorway to the cell,” Dhurandhar explained. “Now, if there are more cell receptors, more of the virus is going to bind, and there is going to be more infection or a worse prognosis. It turns out that some diabetes medications increase the number of those receptors in the body, and we are studying that to see if we can identify which diabetes medications increase those receptors and which don't.
“In theory, in the case of a COVID-19 patient, we would not give those diabetes medications that increase those receptors; we would focus on using only those medications that don't increase receptors.”
Dhurandhar's team also is taking part in another COVID-19 study that will have a large impact on future knowledge about the disease, including how long COVID-19 antibodies last and how infection or vaccination influences antibody status. Dhurandhar is conducting this study in collaboration with Nutritional Sciences faculty member Kristina Petersen at Texas Tech's clinical facility – the Nutrition & Metabolic Health Initiative (NMHI).
With this $1.26 million grant from the Indiana University Foundation, the NMHI is providing not only critical research during a global health crisis but also real-world, experiential learning opportunities for the students involved.
Taken together, these varied projects make Dhurandhar extremely excited about the outlook for his work. With such a large potential impact, it's something we can all get excited about, too.
