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Biotech Startup Aims to Make Use of Humanity’s Genetic Outliers

From 5/28/2020:

The Sherpa people living at high altitudes in Nepal and the Himalayas have a genetic trait that puzzles and fascinates scientists. They’re able to lead healthy, active lives with blood oxygen levels far below what most humans need to function properly. Where other people in high altitudes have adapted to boost their oxygen to typical levels over time, the Sherpa have gene variants that let them live in what should be a hypoxic, or oxygen-starved, state. “They don’t suffer any ill health effects,” says geneticist Stephane Castel. “It’s incredible.”

Castel is the co-founder of Variant Bio, a startup that’s spent the past couple years scouring the planet for genetic outliers. His team is betting that by sequencing such people’s DNA, Variant will be able to untangle the root causes of desirable traits—superior metabolism, eyesight, immune response—and synthesize drugs and other therapies that could pass some of these benefits on to the rest of us. If Variant’s software and scientific analysis can pinpoint the right bits of genetic code, the company will begin the painstaking, multiyear process of trying to develop drugs and therapies based on that data.

The science behind therapies inspired by genetic studies is well understood. You find the DNA that turns on a particular trait, then create a drug around it that goes into the patient’s cells and tweaks them to trigger a similar reaction. Some mainstream cholesterol-lowering drugs, for example, are based on studies of DNA from people of African descent with atypically low LDL, or “bad,” cholesterol. In the case of something like Covid-19, which attacks the respiratory system and can inflict serious damage on a patient’s lungs, Variant’s scientists say genetic alterations such as those of the Sherpas ought to prove helpful. “You can end up dying from hypoxia with Covid-19,” Castel says. “Perhaps there’s a way to keep people healthy while they’re still in that condition.”

Isolated academic researchers have spent years studying people who’ve adapted to their environments in remarkable ways, but Variant appears to have undertaken the first serious effort to sequence the DNA of many thousands of people around the world with actionable lessons in mind. In New Zealand the company is looking for people of Polynesian descent who have high rates of obesity but also seem to have some protections against diabetes. In other places, Variant has discovered people who metabolize their high-fat diets more effectively than others.

“There are also people who can hold their breath underwater for a long time or that need just an hour or two of sleep,” says Josh Wolfe, the co-founder of Lux Capital, the venture firm that has provided most of the $16 million Variant has raised. “Wouldn’t it be amazing if some secrets of human health were possessed by these small groups of people, and they could ultimately benefit the rest of the world?”

While this may sound like a wild fantasy about sort-of-superpowers, both Castel and his co-founder Kaja Wasik, a molecular geneticist, cringe at any suggestion that they’re hunting for X-Men. They say they take seriously the very real moral and ethical questions that exist around how people with special DNA are treated and compensated. “There is this really long, unfortunate history of people doing studies and research in a way that is not good,” says Castel. “It has led to a lot of distrust.”

Researchers have historically behaved in rather mercenary fashions as they’ve barged into a community, gathered up their samples, and done little to account for the effects they might have had on the area. With an eye to those issues, Variant’s first hires included anthropologists and ethicists who mediate interactions with different cultures and figure out what compensation should look like. The company’s model includes funding local health care and education projects selected by or chosen in conversation with the given community. Variant executives say the communities that agree to provide DNA samples will also profit over the long term from data-sharing and drug revenue once the company has therapies for sale.

Variant’s new chief executive officer, Andrew Farnum, has experience in negotiating communication with far-flung societies as well as with biotech research. He previously ran the $2 billion investment arm of the Bill & Melinda Gates Foundation and focused on global health and infectious diseases. “There are huge advantages here for drug discovery,” Farnum says of Variant’s research. “People will see how seriously we take this and how we conduct our projects, and other populations will want to work with us.”

The startup’s approach is the inverse of the household names in the DNA-testing business such as 23andMe or Ancestry, which rely on vast stores of DNA data from a customer base with a much more similar genetic makeup. Such companies also have little to show in terms of major health breakthroughs. Genetic marvels are a research area untapped by the current generation of DNA experts, says Jay Flatley, a Variant adviser who previously ran the sequencing company Illumina. “Nobody has gone after this in a systemic way,” he says. “I’m surprised that it has taken this long.”

Along with conducting research in Nepal and New Zealand, Variant executives confirmed that they’re studying DNA in the Faroe Islands and Pakistan, though they declined to elaborate. More broadly, the co-founders predict that hundreds of populations could provide significant insights into how human bodies work. “It’s basically every group that lived in isolation or went through a genetic bottleneck,” Wasik says. “The list is actually much longer than people expect.”

Sonam Sherpa is an orthopedist who lives in Kathmandu and has volunteered to help Variant shape its research in Nepal and to facilitate conversations with local authorities. “In the past, researchers would come to our hospital, do their tests, and then, as soon as they go back, we never hear from them again,” he says. By contrast, he says, Variant has met with village leaders and Nepal’s research council and is negotiating deals with these parties to share whatever DNA data it gathers with local researchers. The company is also funding the English translation of a book about Sherpa culture and will back another project chosen by Sherpa leaders, possibly improvements to a local school.

Variant must compensate the sources of its potentially revolutionary data, says Keolu Fox, a genome scientist and an assistant professor at the University of California at San Diego who’s consulted for the company pro bono. Fox, a native of Hawaii, compares the unique DNA sequences Variant is searching for to oil or minerals. “If the people don’t get a cut, this is colonial,” he says. “It’s extractive capitalism.” People such as the Nepali Sherpas should receive free or subsidized access to any drugs they help develop, he says, and perhaps a share of the profits derived from related intellectual property.

Fox acknowledges that Variant might prove capable of changing the world for the better. Still, he says: “My job is to make sure the communities get something out of this, and, if they don’t, I’m out.”

Variant’s co-founders say they’re excited at the prospect of proving to skeptics that they can do this type of work in a fair, equitable way, including putting in the effort to build strong ties with the communities they’re studying. “This is not a straightforward thing, forming this human network,” Castel says. “It’s something people have shied away from doing because it seems too difficult. Luckily, we were either too passionate or naive.”

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