National Geographic

A Resurrected Cretaceous Answer to the ‘Disease of Kings’

Gout—a disease of red, painful, swollen joints—has an unfair reputation as a disease  that only affects the wealthy after a lifetime of overindulgence. In reality, it’s the legacy of evolutionary changes that took place more than 20 million years ago, which we’re still paying for now. Gout was once called the “king of diseases and the disease of kings”. It could equally be the “disease of apes”.

The substance responsible for the condition is uric acid, which is normally expelled by our kidneys, via urine. But if there’s too much uric acid in our blood, it doesn’t dissolve properly and forms large insoluble crystals that build up in our joints. That explains the painful swellings. High levels of uric acid have also been linked to obesity, diabetes, and diseases of the heart, liver and kidneys.

Most other mammals don’t have this problem. In their bodies, an enzyme called uricase converts uric acid into other substances that can be more easily excreted.

Uricase is an ancient invention, one that’s shared by bacteria and animals alike. But for some reason, apes have abandoned it. Our uricase gene has mutations that stop us from making the enzyme at all. It’s a “pseudogene”—the biological version of a corrupted computer file. And it’s the reason that our blood contains 3 to 10 times more uric acid than that of other mammals, predisposing us to gout.

How did it come to this? Why did we do away with such an important enzyme? And when?

To find out, a group of scientists led by Eric Gaucher at the Georgia Institute of Technology resurrected long-gone editions of uricase that haven’t been seen for millions of years.

Team members James Kratzer, Miguel Lanaspac and Michael Murphy compared the uricases in modern mammals to infer the sequences of ancestral varieties. “It’s like what a historical linguist does, when they study modern languages and try to understand how an ancient ones were pronounced,” says Gaucher. Then, the team actually built these ancient enzymes in their labs, and compared their ability at processing uric acid.

The oldest version, which was wielded by the last common ancestor of all mammals 90 million years ago, was the most active one. It outperformed all its modern descendants. Since that ancient heyday, things have gradually gone downhill.

Throughout mammalian evolution, and especially during primate evolution, uricase has picked up mutations that have made for progressively less efficient enzymes. In the last common ancestor of all apes, uricase had already been hobbled to the point of near-uselessness. The ape-specific mutations that turned our uricases into broken pseudogenes merely disabled something that was already FUBARed to begin with.

Why this slow, creeping decline? Gaucher suspects that the answer involves fruit.

The biggest drops in uricase’s efficiency coincided with a time when the Earth’s climate was cooling. The ancient fruit-eating primates of Europe and Asia faced a glut of food in the summer, but risked starving in winter when fruit was unavailable.

Here’s where uric acid comes in. Our cells produce the stuff when they break down fructose, the main sugar in fruit. In turn, uric acid stimulates the build-up of fat—a process that uricase counters. Indeed, when Gaucher’s team dosed human cells with the ancient, efficient uricases, they became less good at making fat when exposed to fructose. But with later inactive uricases, they produced a substantial amount of fat.

So, disable uricase and you risk building up high levels of uric acid, but you also become a champion at turning fruit into fat. For ancient primates facing an increasingly seasonal food supply, that trade-off may have been worth it.

It’s a nice story, although it only explains the final act of uricase’s downfall. Other factors almost certainly played a role in the enzyme’s gradual decline. For example, Michael Hershfield from Duke University notes that early primates lived in rainforests, had easy access to water, and could make a lot of urine—all the better for getting rid of surplus uric acid. He speculates that these conditions might have reduced the need for uricase enough to allow the enzyme to accumulate disabling mutations.

Still, Gaucher’s results provide some support for an old but unproven idea called the thrifty gene hypothesis. Proposed in 1962, it says that humans have genes that suited our ancestors during times of scarce food, but predispose us to diabetes and obesity in the modern age of free-flowing calories. Uricase is the first good example. Our broken version may have helped our primate ancestors to thrive but it leaves us prone to gout and other illnesses linked to uric acid, whose rates have soared in recent years.

The team’s resurrected enzymes may be able to help with that too.

For over 20 years, pharmaceutical companies have tried to develop treatments for gout by using working versions of uricase from other mammals. But you can’t simply inject a pig uricase into a human patient—our immune reaction would go nuts in the presence of such a foreign enzyme.

Hershfield’s group developed a workaround by fusing the pig uricase with the baboon version. The pig bit does the heavy metabolic lifting, and the baboon bit cloaks it from our immune system. In 2010, the US Food and Drug Administration approved this chimeric enzyme, known as Krystexxa, for treating severe chronic gout.

Gaucher thinks that we can find better solutions by looking to the past. His team found that the oldest of their resurrected enzymes is both more efficient than the raw pig-baboon chimera, and lasts longer in rats. And despite its ancient nature, it’s a closer match for human uricase than even the baboon version, so it might be even less provocative to the immune system. The team have now filed a patent for the ancient uricases and formed a start-up company to turn them into an actual drug.

Hershfield anticipates bumps along the way. “It took about 17 years from the time I conceived of developing a recombinant uricase for treating refractory gout to the time it received FDA approval,” he says. “I wish [them] success, but I suspect I may not be around to witness approval of their drug.” Gaucher counters that the existing drug has already paved the way for FDA approval: “We’ll either jump through fewer hoops or we won’t have to jump as high.”

He undoubtedly has a long way to go but it’s an enticing notion that an enzyme hasn’t been around since the dinosaurs ruled the world might help gout sufferers in the future. As Belinda Chang from the University of Toronto says in a related commentary, “We are all prisoners of our history, but perhaps we can find better solutions for the future by learning from the past.”

Reference: Kratzer, Lanaspa, Murphy, Cicerchi, Graves, Tipton, Ortlund, Johnson & Gaucher. 2014. Evolutionary history and metabolic insights of ancient mammalian uricases. PNAS http://dx.doi.org/10.1073/pnas.1320393111

There are 9 Comments. Add Yours.

  1. Stephan Zielinski
    February 17, 2014

    If they tell a large pharmaceutical company that they might have a line on a drug that should interfere with the conversion of a common sugar to fat, they may well get funded before they get a chance to so much as mention gout.

  2. vince
    February 17, 2014

    wonder if it will have any interesting side effects like preventing weight loss from drinking too many sodas

  3. vince
    February 17, 2014

    err i meant weight gain. yeah, this could be a weight loss drug

  4. Ross Marks (@ross_marks)
    February 18, 2014

    Have any attempts been made to look at the genetics groups who are particularly susceptible to gout and also to diabetes, such as Polynesians.

  5. Brent
    February 19, 2014

    The genetic history is very interesting, to be sure. But I wonder why scientists insist on inventing crazy expensive drugs to “fix” basic nutritional deficiencies. Gout is often a result of too much fructose and/or alcohol combined with vitamin A deficiency. So, stop drinking. Stop eating so much high fructose corn syrup, and get good sources of vitamins A, D3, and K2. This is a much cheaper solution that is likely to resolve all sorts of other health issues. Reductionism has its limits!

  6. mikaelah
    February 19, 2014

    With fruit being genetically altered and with humans having all the mutations and free radicals throughout the body, is there not some other component to be put into food to lessen the chances of gout in a human? Is there not anything else to counteract/increase the low levels of uricase?

  7. Steve O’Brien
    February 21, 2014

    Agreed with Vince. Gene therapy is pretty awesome.

  8. turtlegirl784
    February 24, 2014

    Interesting fact, the dalmatian breed is the only one that has the genetic defect that causes uric acid buildup that can lead to gout. In case you were wondering (though I’m sure you weren’t. ;) )

  9. cancerclasses
    February 28, 2014

    No gene “therapy” required, the answer for humans is MUCH simpler.
    Since gout is caused by what you eat, principally fructose from carbohydrates, the answer is
    1. fructose avoidance via a low carb diet,
    2. A high fat ketogenic diet, or
    3. Complete food avoidance via periodic & limited duration fasting, since:
    “#Fasting & high #fat #diet increases uric acid excretion.” http://goo.gl/qWO1qn

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