Steve Mirsky:  Welcome to Scientific American's Science Talk posted on September 16, 2015. I'm Steve Mirsky. On this episode…

Richard Johnson:        There was a loss of tropical rainforests, and the apes basically had to knuckle-walk and they had to go on what we call fallback foods where they were eating tubers, and it was a very tough time because fruits which contain fructose weren't available that much, and so the mutation would have provided a survival advantage.

Mirsky:  That's Richard Johnson. He's a professor of medicine at the University of Colorado Anschutz Medical Campus in Aurora, Colorado, specializing in the study of the underlying causes of diabetes, obesity, hypertension, and kidney disease. He and University College London anthropologist Peter Andrews are the co-authors of an article hot off the presses in the October Scientific American titled "The Fat Gene" and the subtitle really spells it out, "A Genetic Mutation in Prehistoric Apes May Underlie Today's Pandemic of Obesity and Diabetes." I spoke to Richard Johnson by phone. So I remember I think I started reading about thrifty genes, fat genes maybe going back to the '70s in the popular literature talking about specifically the obesity and diabetes epidemic among Native Americans in the U.S. southwest, and it appears that the idea of the fat gene, the thrifty gene has gone in and out of fashion, and now you think you've really hit on something that could explain this whole phenomenon.

Johnson:             Well, thank you very much. Yes, indeed. The thrifty gene hypothesis was actually generated by Jim Neel in the early 1960s to try to explain why there were so many people becoming diabetic at that time.

Mirsky:  He was a geneticist?

Johnson:             Correct. Little did he know how much worse it was going to get over the next 50 years, but at that time they were still concerned that there was a rise in obesity and diabetes that was occurring even back in the late '50s. In fact, if you look back, diabetes was present in only one to three people per 100,000 population in 1900, and it just has been increasing significantly ever since, and then has rapidly increased in the last 30, 40 years. Likewise, obesity in 1900 was present in only about three percent of 50-year-olds, and of course it has been increasing dramatically over the last century. Now 70 percent of people are overweight or obese. So it's not just because we're living longer, because actually even children are becoming obese – one in six children is obese today in the U.S. – so this is really quite a rise in obesity and diabetes. Now, it's been leveling off the last few years, but it's definitely been a major concern, so the question is why?

Mirsky:  Right. Those figures that you were quoting were all for the United States, right?

Johnson:             Yes, the United States and Europe, especially England, right.

Mirsky:  Okay.

Johnson:             Yes, and also there's been a dramatic rise in high blood pressure. In 1900, there were only about five percent of the population was hypertensive defined as a systolic blood pressure greater than 140, at least in 50-year-olds, and today it's over 30 percent.

Mirsky:  There was this idea that Neel came up with that there's got to be an evolutionary basis for the ability to really pile on the fat during lean times.

Johnson:             That's right, so what he did was he did a lot of studies in indigenous tribes, and he did some work with the _____ Indians and other tribes. People on native diets, there was very, very little obesity, but he was seeing that there was a significant increase in obesity and diabetes with Western diet, and he wondered if there might be some genetic predisposition that might be uncovered in the Western diet that would lead to obesity. Basically, he came up with the idea that maybe in our past there was a period of time when food was not so available and in which intermittent food shortages, or famine, might occur; that perhaps under those settings that if you acquired a mutation or a genetic change that would provide a survival advantage under a situation where there was not so much food availability that you might be able to learn how to be more efficient at storing fat, or the mutation might provide a means for storing fat and making you insulin-resistant that might help survival in those times of food deprivation. But then, if you carried this mutation _____ _____ in a world where food was plentiful, that suddenly this ability to store fat would become a disadvantage and suddenly you would be at higher risk for developing obesity and diabetes. So this was the basic idea that he generated in the early 1960s.

Mirsky:  It seems like a very reasonable hypothesis, but the problem was that it was difficult to identify exactly what the mutation or mutations might be.

Johnson:             Exactly, and there was this assumption for a while that some people would carry the gene and others wouldn't, become some people are getting overweight and others aren't, so it was thought that this wasn't necessarily a genetic change that affected the entire population but it might be a genetic change that might predispose some people to obesity and others not. One of our insights was that perhaps the mutation affects everybody but it's the exposure to certain foods that unveil its full effect.

Mirsky:  You did an interesting thing. I mean most geneticists work with other geneticists or with molecular biologists, but you teamed up with a physical anthropologist.

Johnson:             Yes, so the way that happened was kind of interesting. I was studying a substance called uric acid, and uric acid is well known to be the cause of gout. It's basically a breakdown product of DNA and RNA, and it circulates in our blood, and most people thought of it as just kind of a waste that we excrete in the urine or in the gut, and that if it gets too high in the blood it can crystallize in joints and cause inflammation and the disease we know as gout. For years, it was just thought to be the cause of gout, but it had been discovered back in the '50s, and actually, if you go way back into the late 1800s, that people with gout not uncommonly developed diabetes and high blood pressure, or kidney disease and obesity and heart disease.

Pretty soon, by the 1960s and 1970s, there were many, many studies showing that if you had gout, or even if you only had a high uric acid in your blood but didn't even have gout, that you were at really significant increased risk for developing obesity and diabetes and high blood pressure and heart disease, so then became a controversy: could uric acid actually have a role in these conditions, or is it just that people who are overweight or diabetic, could they just have higher uric acids, and that's why you get gout, and that is why there's that association? In the late 1990s, the Framingham, which is the Framingham Heart Study group −

Mirsky: This is one of the biggest and most long-term health studies in the history of epidemiology.

Johnson:             Right. This is probably the number one epidemiology group in the world, and they were the ones that linked smoking with lung cancer, and they're extremely well respected. But they came out with a paper in the late 1990s saying that they were convinced that the elevation in uric acid in people with heart disease was a secondary process. It wasn't that the uric acid caused heart disease, it was that people with heart disease have a high uric acid, and they said that uric acid is not a true risk factor for heart disease or any cardiovascular problem, and it shouldn't even be measured. Yours truly realized that they were making two assumptions, and one was that a risk factor had to be "independent of other risk factors to be a real risk factor." What they had done, what I'm trying to explain, is that they had found that uric acid was strongly associated with high blood pressure and strongly associated with diabetes and kidney disease, and so they said, "Well, if we actually use statistics, it's not independent of hypertension as a cause of heart disease, and, therefore, it's not causal." But the assumption is that uric acid may not, you know, has to cause heart disease as an independent risk factor, I mean independently in a direct fashion, that uric acid would cause heart disease directly and it wasn't independent of high blood pressure.

But what if the uric acid caused the high blood pressure and that was why it caused heart disease? That is an assumption they were making, and I raised that in a letter to the editor, and I also said that the other problem is that the way a lot of science is done is not to just look at associations but to actually take an animal, a laboratory animal, and directly determine what happens when you raise uric acid in its blood, and actually no one had done that. In 1999, my group raised uric acid in rats and we expected to see nothing. But, in fact, the animals developed high blood pressure, and, subsequently, numerous studies, including the Framingham Heart Study group themselves, showed that uric acid could predict the development of hypertension. In other words, it occurred before the hypertension, and if you had a high uric acid, you were at dramatic increased risk for developing high blood pressure.

Mirsky: It's a little mindboggling that nobody did an animal study.

Johnson:             I know, it's totally amazing. So one of the problems, one of the reasons that no one had done it in the rat was because the rats have an enzyme called uricase, and this is an enzyme in their liver that degrades uric acid, so rats have very low uric acid levels compared to man, because they have this enzyme, uricase. So, in order to raise uric acid in the rat, I had to give an inhibitor for uricase, and this prevented the animals from degrading the uric acid, and then the uric acid went up in their blood and that's when they developed high blood pressure. So we then went on and identified the biologic pathway by which that occurred, and then, when we started showing that people with high uric acid developed high blood pressure, this was then shown in over 18 to 20 studies all found uric acid to be a major predictor for high blood pressure. Then, in a series of clinical studies, we actually lowered uric acid in young adolescents, actually, with high uric acid and high blood pressure, and we normalized the blood pressure in about 80 percent of them just by lowering the uric acid, and this was work done with Daniel Feig, who is a professor of pediatrics at the University of Alabama in Birmingham.

But, at the time, we were working together in Texas, and we had this remarkable finding, and subsequently other groups have also found that lowering uric acid has blood pressure-lowering benefits, and now there are big clinical trials because all these studies have been kind of small studies of 30 or 50 people. So it's not proven that lowering uric acid improves blood pressure, but in all these studies they were positive, and now big studies are ongoing. So then, this led me to realize that uric acid might have a role in high blood pressure, and I became interested in why humans didn't have uricase, whereas most mammals did. So it took me into the literature, and I discovered by my reading that – I didn't discover this, actually, but I read this, that all the great apes and humans lost uricase due to a mutation in uricase that occurred about 15 million years ago, and there are ways to actually identify when a mutation occurs by looking at similarities across species. You can actually use computer modeling to generate a date of when the mutation occurred, and that led me to realize that it occurred in a period called the Miocene, which was about 25 or 27 million years ago, and it was a period of time when the apes first basically evolved.

So the first ape evolved around 20 million years, ago, 22 million years ago, and it was during this period of time that the apes increased in the number of species, and it was a fairly interesting time. So I decided I needed to learn about this, and I contacted David Pilbeam, who is a world expert on apes, and he and I had several conversations. But it was a very interesting time because in the early Miocene, around 20 million years ago, the world was very warm and the apes were living in tropical rainforests, and then there started to be global cooling, and by 8 or 9 million years ago, many of the apes had become extinct, especially the ones that had moved into Europe. So we published a paper way back then, or I published a paper with our group saying, "Maybe this mutation occurred at a time when basically the apes were leaving their trees and learning how to knuckle-walk, and maybe this was important in helping maintain blood pressure under settings where salt intake might have been very low."

We actually showed that this mutation, if we inhibited uricase in the rat, it really particularly raised blood pressure under low-salt conditions, and so this was the beginning. After that, I moved to the University of Florida, where we continued to study uric acid and we began to realize that this uric acid story was much bigger, because we found that uric acid also seemed to have a role in other conditions, and we found one way you can raise uric acid is to feed an animal sugar. Normally, we think of gout as being caused by drinking beer and eating shrimp, and it's true that the foods that have what you call high purines can raise uric acid, but there's another food that can raise uric acid, as well, and that's sugar, and particularly it's a type of sugar called fructose, and fructose is the main sugar of fruit, but it's also a principal component of table sugar and of high-fructose corn syrup.

To make a long story short, we started studying this. When we fed animals fructose, they developed obesity and fatty liver and elevated blood pressure, and inflammation and insulin-resistance, and all the features of metabolic syndrome. In fact, you can create metabolic syndrome in animals by giving them fructose, and, as we studied it, we discovered that you didn't even have to feed them excessive calories. If they had a diet high in sugar, they got certain features of metabolic syndrome, even under caloric restriction, like fatty liver, diabetes, and so forth. We realized that fructose was having effects that could not be explained by its calorie content, and so this was kind of a big discovery for us because, at the time, there was a lot of discussion in the literature about calories, but we could create a diabetic animal by calorically restricting them if we gave them a high-sugar diet.

Mirsky: That's really amazing.

Johnson:             Yeah, that's scary. It was scary. We knew that it raised uric acid, so Taka Nakagawa, working with me, we said, "You know what? Let's lower uric acid and see if we can block the hypertension that occurs in our model," and it did, but the amazing thing was it also blocked the insulin-resistance and some of the fat in the liver, and it had all these other effects.

Mirsky: That's with this high-fructose diet?

Johnson:             Right, and so then we started studying it, and we had this terrible discovery that uric acid actually encourages fat formation and actually particularly in response to fructose. It was about that time that I started thinking again about the Miocene and the fact that these apes were eating fruit and that there was this known period of starvation that occurred over millions of years for these apes. Then, the idea came to me that perhaps there was this mutation in uricase that would allow the animals to have higher uric acids that would make them store fat more easily in response to fruit at a time when there was global cooling and the loss of fruits. So that took me back to the literature and I realized that the world expert, the world expert on the Miocene, and not just on the primates but also on the flora and fauna and the foods was a gentleman named Peter Andrews at the Museum of Natural History in London. I had been invited to Dublin to give a talk, and I made sure that I would stop in London so that I could meet this famous anthropologist and could tell him about this idea.

So I went to the Museum of Natural History and he came down. He's a wonderful man. He took me into his office and we had an afternoon that was extremely insightful. I told him my idea, and then he told me an incredible story about how around 17 million years ago this global cooling was occurring, and the water levels fell and the land ridge formed between Africa and Eurasia, or Europe. Up until then, all the primates, all the apes lived in Africa, but, as the global cooling occurred, this land ridge formed and these apes were able to escape into Europe and Asia, and not only apes but anteaters and giraffes and all kinds of animals made it across. But in Europe it was still warm, and so they continued to live the normal life, which was to live in these tropical rainforests and to live on fruit, but as it became cooler and cooler, there was a loss of a lot of the fruit trees and a change to some deciduous trees and some savannahs, and the availability of fruit began to decrease, particularly during the cooler months. There was a loss of fig trees, which was a particularly important food staple for these apes.

Here was the fantastic insight: Peter had discovered, along with a guy named David Begun, that our ancestors probably came from a _____, and based on the fossil record, they were able to show that what happened was in our past, some apes went to Europe and it was the European apes' skeleton that correlated best with the features of modern apes and humans today. So he had previously reported that what must have happened is that some of these apes went into Europe and then went back to Africa, and some also went to Southeast Asia to become the Orangutan, but it was these apes that came back that then replaced the African apes and went on to become the great apes and also the humans, so that we all have some kind of relative that came from Europe. He had actually identified a species called Kenyapithecus as a very likely candidate, and he had been studying this Kenyapithecus in Turkey and had found that they showed evidence of intermittent starvation.

They were probably starving on a seasonal basis, and he could tell that by looking at their teeth. The teeth, when they're growing, the enamel will develop a ring of what we call hypoplasia, basically thinning of the enamel, when there's famine. He could see rings on these teeth of I think numerous Kenyapithecus apes. I think he had a collection of nine of them that all showed this intermittent starving. All the apes died off in Europe, but he believes that some of these Kenyapithecus and other species made it back to Africa, and in fact there was some Kenyapithecus skeletons discovered that are dated several million years later in Africa suggesting that these apes, that many of them died off in Europe but some of them made it back to Africa.

Well, while we were talking about this, which was fascinating, he also made a very important point, so he asked me about this mutation, and I explained to him how in animals we could show, that we could potentiate the effects of fructose to store fat, that we could potentiate the effects of fructose to induce insulin-resistance, which keeps the blood glucose higher in your blood, which is important for the brain, and so I realized that this mutation would have been a survival advantage in the setting of food shortage. Then he had the brilliant insight to say, "Well, you know what happened was that in Europe, the global cooling was so severe that there was a loss of tropic rainforests and the apes basically had to knuckle-walk, and they had to go on what we call fallback foods where they were eating tubers, and it was a very tough time because fruits which contain fructose weren't available that much, and so the mutation would have provided a survival advantage in Europe."

But he said, "In Africa, even though there was global cooling, as well, temperatures were still much higher. Just because there's global cooling doesn't mean the temperature is the same everywhere, and in Africa, temperatures still stayed hot. So although they got cooler, the tropical rainforests retracted but never disappeared. So the apes were still able to eat fruit year round, and so there was no survival advantage to having this mutation in Africa, whereas there was in Europe," and BOOM, then suddenly we realized that this mutation, which timed exactly to this period in Europe when there was starvation going on, probably occurred there. What was interesting is the mutation is shared by the orangutan and the great apes and humans so that it explained that a common site where this mutation would have hit one species that then survived and spread to the rest of the world, and then evolved into the different species of ape today and into humans.

Mirsky: Right, it has to be a common ancestor for all the _____ apes and humans.

Johnson:             Exactly, so the whole thing fit. So then we started studying it more, and there's a wonderful, brilliant, two brilliant scientists, Steven Benner and Eric Gaucher, who are molecular geneticists and biologists, and Steve was one of the first ones to ever resurrect an extinct gene, and Eric was his student and went on to become a full professor himself and working with Eric. Eric actually resurrected this extinct uricase from the primate, from the Kenyapithecus, we think. Then, _____, my group, put it into cells and showed that when the uricase is present, it blunted the effects of fructose to store fat in liver cells, but when he took away and knocked it down, or removed it, suddenly the human liver cells could accumulate a lot more fat in response to the same dose of fructose.

Mirsky: That's incredible –

Johnson:             Yeah.

Mirsky: − an incredible story. Really, it's better than The da Vinci Code. It's really such a great detective story.

Johnson:             It's a true adventure story, for sure, and it's not finished, because although we've been able to show that this is a pathway in laboratory animals, the proof will be if the future shows that uric acid has all these effects in humans, and there are pilot studies out there that clearly show that lowering uric acid appears to have benefits on blood pressure, on kidney disease. There's a couple pilot studies that show that it helps prevent weight gain in adolescents and in adults. There's a study that's going to come out soon that shows that lowering uric acid can improve insulin-resistance in humans. But they're all small studies, and we need large studies, and certainly it's sort of rocking the boat because a lot of people have not viewed uric acid as a true risk factor, but there's more and more excitement about it, and so time will tell. But it definitely is a pretty interesting story.

Mirsky: The important thing in terms of future medical practice is at least now we have a good candidate to look at.

Johnson:             Right, and there is tremendous interest, and now there are clinical trials on lowering uric acid that are going on in Australia, in Europe, in the United States, in Japan, and so hopefully we'll get some answers to this really interesting possibility. It would be wonderful because it's remediable. It's something we can treat, and there are drugs out there that are generic and inexpensive that can help lower uric acid and potentially have some benefits on this. There are so many people suffering from this that if this turns out to have a lot of benefits, it certainly would be wonderful because it wouldn't cost very much to treat, only pennies.

Mirsky: Yeah, absolutely. As I said, it's a great detective story. You can read about it in the October issue of Scientific American, and in addition to the information in the text, there are some beautiful illustrations and charts that will help you follow the whole line of reasoning that you engaged in here. It's just really fascinating, and I thank you for your time.

Johnson:             Thank you, Steve. It's a real pleasure.

Mirsky: That's it for this episode. Get your science news at our Web site, www.scientificamerican.com, where you can also check out the entire October issue of the magazine, including the Richard Johnson/Peter Andrews article, "The Fat Gene," and follow us on Twitter, where you get a tweet whenever a new item hits the Web site. Our Twitter name is @sciam. For Scientific American Science Talk, I'm Steve Mirsky. Thanks for clicking on us.

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