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From Yeast, Yumanity Looks to Give Rise to Critical Neuro Drugs

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IPO hopes. Instead, Pfizer bought it in 2010 for its lead drug, which is now approved in Europe and Japan to treat FAP.

Lindquist said she “took back” her discovery work, which at that point wasn’t ready for prime time: “It was not right to be folded into a very large pharmaceutical company.” Chiefly, Lindquist wasn’t able to do with it then what she believes Yumanity can do now: identify drug targets.

Lindquist praised FoldRx’s VC backers, but after that experience she vowed she would do things differently the next time around. She wanted to hand-pick her next team, rather than have investors do it for her. She wanted to be more at the forefront of her company and to have more of a finished product to build it around.

“I learned that doing the investment right and getting the team were inextricably linked,” she said. “I wanted to get the people that I wanted to work with together first, because I want to stay very much involved with this. I really, really care deeply about this.”

She found Coles and Rhodes along the way through FoldRx. Coles came aboard as an independent director, and the two became fast friends. Rhodes did due diligence on FoldRx for Biogen before Pfizer swooped in. When her technology had come far enough, she called both of them. The first conversations took place in May; Yumanity officially emerged from stealth in December.

That type of story, in itself, is unusual in biotech. But so is what Yumanity is trying to do scientifically. The company is trying to discover drugs for difficult to treat diseases by moving up and down the evolutionary ladder.

First it tests drugs for an effect in a simple organism (yeast), then a complex cell (a human neuron). If both models produce a promising biological effect, Yumanity will go back to the yeast to figure out what’s happening. The idea is that disease-causing cellular machinery is preserved in evolution; signs that a drug might quell a disease in yeast might indicate that it could work in humans too.

Yumanity scientific founder Susan Lindquist

Yumanity scientific founder Susan Lindquist

The idea of using yeast to help discover drugs isn’t new. Yumanity is different because of its mix of what’s known as phenotypic screening—putting chemicals into living cells or organisms and seeing what happens without necessarily knowing why it’s happening—and “rational” drug design, or building drug molecules to fit the structure of specific biological targets, like a lock and key.

Phenotypic inquiry was at the foundation of the drug industry before massive computing power and understanding of molecular biology exploded. Phenotypic screens are still used, but they have largely given way to rational approaches because, as Rhodes said, “it’s very hard to find a target [with a phenotypic screen],” and researchers have a hard time figuring out “how [their] molecules work.”

Seeing an effect and figuring out why is particularly important in diseases like Parkinson’s, Alzheimer’s, and ALS, because there is so much underlying biology that isn’t understood.

For instance, many researchers believe clearance of amyloid-beta plaques from the brain of Alzheimer’s patients is the key to solving the disease. But drugs developed to do just that haven’t made patients any better.

Different biological targets, and new ways to unearth them, are sorely needed. Yumanity has already announced that it has found a novel target for Parkinson’s.

So why all the fuss about yeast? Yumanity inserts genetic instructions into the organism to produce proteins known to misfold and cause devastating diseases in humans. The yeast cell reacts similarly to a human cell when the bad proteins are produced. Yumanity is using them as models for disease—“living test tubes,” Lindquist said.

Once it has its Parkinson’s or Alzheimer’s yeast model, Yumanity tests hundreds of thousands of compounds in those altered yeast cells and hopes to get “hits”—at least a few compounds that, in Lindquist’s words “solve the problem”: they stop the cascade of events that occur after the folding error, the mistakes that trigger disease.

Yumanity then tests the successful compounds in human nerve cells evolved from stem cells of patients who have a specific disease-causing mutation. If a compound works there, too, Yumanity then goes back to the yeast to figure out why: which target does it hit? What’s the mechanism of action? Which genes are involved?

The potential advantage of building an evolutionary bridge, of sorts, between yeast and humans, is that Yumanity could have a pretty good idea of a drug’s effect before it’s more extensively tested in mice or primates.

But isn’t this back-and-forth approach time consuming and hard to scale? Yumanity executives said no, although Coles declined to explain the “secret sauce.”  He did say, though, that most of the work takes place in-house.

Another advantage is cost.

“Yeast strains are dirt cheap,” said Ethan Perlstein, a scientist in San Francisco who is bootstrapping a phenotypic effort to use yeast, zebrafish, fruit flies, and worms to find drugs for rare lysosomal storage disorders.

Outsiders we spoke with were skeptical that Yumanity’s system would carry over into real humans. They don’t know all the details behind Yumanity’s screens, but they’re also scientists who have done drug discovery for decades.

One, who declined to be identified, said that while he thinks the biology is “terrific,” Lindquist is “brilliant,” and Yumanity just might uncover some new insights, that there’ll be a translational problem. “While biology is generally well preserved across evolution, disease is not,” he said.

Former Bristol exec Sigal agreed. “I’m not sure of the connection to the human for all the approaches they have,” he said. “There may not be translation from yeast to mammalian cells, from cells to in vivo models, and from in vivo models to humans.”

Which brings us back to that slide deck, the hotel room overlooking Market Street, and the one slide Yumanity wanted to burn into investors’ brains: Some of the world’s best-selling drugs came from experiments with yeast.

“This isn’t to imply that all of these classes of molecules were first discovered in yeast and then moved into the clinic,” Rhodes said, holding up the slide. “But we use it typically to illustrate the fact that there’s tremendous conservation of the pharmacology from yeast into human cells. It helps people get more comfortable with the idea that the molecules we find in yeast will actually hit human targets with roughly the same potency and specificity.”

Will they be comfortable enough to spread around a lot of dough? The answer should arise soon enough.

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