Professor Eyleen O’Rourke, PhD, Professor of Genomics at the University of Virginia, talks about the discovery of genes that make people more susceptible to obesity.
Interview conducted by Ivanhoe Broadcast News in May 2022.
How big of a problem is obesity right now?
PROF O’ROURKE: Obesity is a leading cause of disease. Approximately 40 percent of the American population is considered overweight or obese. Obesity, itself, is not such a serious disease, but relevance of obesity is that it is the main risk factor for other diseases that can either reduce the quality of life dramatically or can be lethal. Those include diabetes, heart disease, neurodegeneration and even cancer. For all these very relevant and severe diseases, obesity is the main risk factor.
Are there other factors at play besides exercise and diet?
PROF O’ROURKE: Yeah. It is true that environment – and that includes diet and exercise – are major factors. However, our genes also play an important role. Throughout millions of years of evolution, we have been wild species, as so many others. In the wild, food tends to be scarce. So, our genes and genomes were optimized by natural selection to take the most advantage of food when it’s available. So, we are tuned to eat as much as we can when food is available and very effectively store that energy in the form of fat, and very stingily to use it so that we can preserve it for as long as possible with the expectation that we are going to go again sometime soon through long periods of fasting or starvation. In that wild environment, that genome is great. It allows us to survive. But in the current environment in which food is so plentiful, so accessible, then, that genome plays against us and predispose us to obesity and its associated diseases.
What have you and your colleagues been able to pinpoint?
PROF O’ROURKE: We have used a combination of human genetics and animal models to discover genes that predispose to obesity, as well as genes that prevent obesity. We have identified 14 genes that if you have the variants that we have identified, you are more likely to develop obesity, so if you eat the same that your cousin that doesn’t have that variant, you are more likely to become obese, as well as three genes that if you are lucky and have those variants, you can eat more and maintain healthy weight.
Why is this knowledge important, especially going forward?
PROF O’ROURKE: We combine human genetics in this study already. So, we know that these genes are associated with human obesity. In the animal models, we can move forward from the association to causation. Now, we know that distinct variants in these genes cause the disease, so, the next step will be to develop drugs that target these genes. For example, for the genes that prevent obesity, when we inactivate them in the lab, we could develop drugs that inhibit the function of these genes that prevent their activity. And in that way, we expect to be able to prevent or even treat obesity.
How far away are researchers from being able to take this to bench to basic science?
PROF O’ROURKE: We have move forward through several steps by the fact that we have seen these in lower invertebrates, in mice and humans already. However, the process of assembling the clinical trial, going through the clinical trial, and the different phases of a clinical trial tends to take years. Nevertheless, another approach that we are taking is to test FDA-approved drugs to see if any of those known drugs that are already approved have an effect on these genes that we have discovered. If we can identify drugs that inhibit the genes that we have discovered, that will accelerate the process dramatically because these drugs have been already approved by FDA. We just need to change the labels so that they can be applied for patients with obesity.
How important is it that clinicians and patients have additional options when it comes to fighting obesity?
PROF O’ROURKE: It is critical, especially because despite being one of the most prevalent diseases not only in the United States, but across the world, there are very few treatment options for obesity and some of them are very invasive, such as bariatric surgery, the partial or complete removal of the stomach, which implies this patient is to have a lifetime of secondary effects of this surgery. And then, as for drugs, there are only a handful of them and some of them have serious secondary effects, therefore, they are only prescribed to patients with morbid obesity, extreme obesity. So, we need to develop drugs that are safe and that can be used for the average person and in that way, reduce the likelihood of developing diabetes, cardiovascular disease and all these other serious diseases that we were mentioning.
Does this suggest that your genetics are your destiny?
PROF O’ROURKE: No. So, the genes only make you more likely to develop the disease or less likely for those ones that have the lucky combination. But your daily eating habits, your exercise levels are going to define largely whether you have this disease or not.
How did you and your colleagues go about identifying these genes?
PROF O’ROURKE: There have been multiple studies, dozens of studies so far that, in principle, what they do is take a population of healthy weight people and a population of obese people and then sequence the genomes. So, in that way, you can identify some variants of the genes that are either more represented or less represented in the obese population. But now, you have some gene variants that are more likely to be found in the obese populations. But that is only a correlation. That doesn’t tell you whether that variant that is more represented in the obese population is causing the disease. And that has been a big barrier to translate those genomics studies in humans into answers and candidates to develop drugs or treatments. So, we took all that information on human genomics, and we tested all those genes – hundreds of genes have been identified as candidates in humans – in invertebrate model systems in the lab. We developed this high-throughput, very advanced technology to inactivate any gene in the genome of these tiny animals – soil worms called C. elegans – and then, see whether the inactivation of any particular gene leads to obesity or prevents obesity when we feed these animals a lot of sugar. This combination of human genomics with C. elegans, invertebrate genomics, allowed us to try to transform these candidate genes into actual causal genes. Because despite being tiny worms, 70 percent of the genes in these tiny worms are equal in humans and worms. We can infer that the direct effects that we’re seeing by inactivating genes in the worms are going to be translated to humans and vice versa and that’s how we set the experiments to discover these genes. Then, we went to mice, and we went back to human samples and confirmed that these genes are predisposing or preventing to obesity.
When you feed those worms sugar, is it the same thing as my Snickers habit in the afternoon?
PROF O’ROURKE: Exactly. In fact, we feed them an excess of fructose, which is the main sugar in processed foods – as most of us are aware, like this high fructose syrup is the main sweetener in all processed foods. And yes, the genetics of humans has not changed in the last 30 years that we have seen this rampant increase in the incidence of obesity. But our fructose consumption has gone through the roof. And has been proposed to be the main factor for the epidemics of obesity.
What are the next steps for your research?
PROF O’ROURKE: The next step is to perform these drug screens for compounds, chemicals that directly inhibit, inactivate these genes that we have identified or activate them. Once we identify those drugs, then we can start the process of clinical trials with them to see whether they have a positive effect on weight in humans.
Is there anything else that you want to make sure that people know about this?
PROF O’ROURKE: I think that an important idea that I would like to share is this idea of basic science. These teeny worms that we work with, they grow in apple orchards. They eat bacteria from rotten fruits. However, over the last few decades, they have become the leading genetic tool. So, if you want to know what genes cause any disease, you want to go to these worms. And if you think just about studies that only use humans, we are going to be very limited because we have the technology but is not ethical to put or take out genes from humans. Animal models, such as mice, are much more costly and take years to get your results. Sometimes we need to think a little bit more broadly and see how different and sometimes unusual or unexpected model systems can give us the answer to the important questions that are going to have impact in society.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
If you would like more information, please contact:
Joshua Barney
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Jdb9a@hscmail.mcc.virginia.edu
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