Date: Dec 27, 2016 Author: QUENTIN HARDY Source: New York Times (
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A crystallized version of malonic acid, made by yeast, at Lygos, a clean tech start-up in Berkeley, Calif. The acid is traditionally derived from cyanide for use in cosmetics. Credit Jason Henry for The New York Times
BERKELEY, Calif. -- A decade ago, a group of biologists, venture capitalists and computer whizzes gathered under the name "clean tech." They hoped to overturn polluting industries with microorganisms cheerily excreting industrial chemicals through the miracle of reprogramming nature's genetic code.
The idea lost billions of dollars. Genes may indeed be programmable code, akin to computer software, but it turned out nature was more complex than first believed.
Now, with less fanfare, a few clean tech companies are aiming for a comeback. And the big idea has not changed much: Create cheap, safe and natural materials for fuel, cosmetics and other goods, much the way yeast ferments sugars into alcohol.
This time around, they believe they have better tools for editing genetic codes, measuring results and automating how chemicals are produced at a large scale. They have also set their sights lower, for now targeting just a few chemicals, not remaking how the world powers cars.
Most strikingly, the way they propose to create their bio-based "software" parallels recent changes in the way computer software is written. Instead of grand, complex projects, they are targeting little changes at a fast rate, and adjusting as clever analysis yields more information -- a concept high-tech firms call agile programming.
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"This is like agile programming, but for biology," said Eric Steen, a co-founder of Lygos, a start-up here creating yeasts that make malonic acid, an ingredient in fragrances commonly derived from cyanide. "Evolution is the most powerful algorithm ever, but you have to figure out how to stack it in your favor."
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Eric J. Steen, left, and Jeffrey Dietrich are co-founders of Lygos. "Evolution is the most powerful algorithm ever, but you have to figure out how to stack it in your favor," Dr. Steen said. Credit Jason Henry for The New York Times
In computer-based agile programming, small teams reinforce positive signals about the way their code is working online. The Lygos version of this is to rapidly measure the performance of a novel yeast strain, and quickly build on those results with gene-editing tools that are 100 times faster than when Dr. Steen was in graduate school 15 years ago.
"It's a big data problem," he said, echoing one of the trendiest terms in computing. "There's 2,000 genes in this yeast, and each gene may use 300 amino acids. There's well over a million variants. Our first successful strain had just a tiny poop of malonic acid as a byproduct, but we seized on that, and kept building on it."
The company, which Dr. Steen and others spun out of the University of California, Berkeley, in 2011 with a $150,000 grant from the federal Energy Department, recently secured $13 million, on top of $8 million it got from the government and a few private investors over the years.
Lygos plans to use the money to make its acid at an industrial scale, sometimes in partnerships with larger producers working in this new system. It is enough, Dr. Steen said, to make "tons" of the chemical next year, and "rail-car sizes" within two years.
It is natural to look at genetic engineering and think of H. G. Wells's Dr. Moreau, creating an island of miserable and dangerous freaks. At the same time, altering genes is what mankind has done for millenniums, breeding wolves into Chihuahuas and cobs of loose-podded maize into big, uniform ears of corn.
What is different, and troubling to some, are the tools and the time scale. By directly altering the genetic makeup of plants and animals, the creations happen a thousand or more times as fast.
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The Lygos lab has lots of sensors and programs measuring and predicting which yeast strains will be productive and robust. Credit Jason Henry for The New York Times
Lygos and other contemporary bio-based manufacturers benefit in particular from a tool called Crispr, which can snip into a sequence of DNA and insert desired features, like a propensity to create malonic acid. The process underlying Crispr was first observed in bacterial behavior and then experimentally demonstrated in 2007, too late for the first bio-based chemical companies.
This capability, commonly spoken of as the genetic version of cutting and pasting in a word-processing program, bypasses the slow adjustments to a complex ecosystem that happen when nature brings forth a new species.
Nature's complexity is one reason clean tech fell short. Amyris, a clean-tech pioneer in Emeryville, Calif., first worked on anti-malarial drugs with backing from Bill Gates, then set out to make biofuels. It found that organisms created in a California lab behaved differently in a Brazilian factory. The company spent $250 million trying to figure out the problem, while regular oil prices fell.
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"It turned out we had to track every part of the process, and automate as many things as possible," Peter Denardo, a company spokesman, said. "We've hired a lot more software and analytics people."
It has also moved from competing with big oil companies to making things like patchouli, used as a base chemical in fragrances. Even so, its stock, now worth pennies, trades 98 percent below its 2011 high.
Early on, Amyris had scientists transfer yeast with toothpicks from one dish to another, creating all sorts of unseen variations and errors. Now, the company has enzymes that act as sensors where material is produced, and takes measurements of every part of the lab and production building, so it can trace any problems.
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A tray of raw malonic acid at Lygos. The start-up plans to use the funding it has secured to make its acid at an industrial scale. Credit Jason Henry for The New York Times
Lygos and others appear to have learned something from the clean tech crash. Dr. Steen's modest lab, a few blocks from a brewery and a mile or so from the university where he studied, has lots of sensors and programs measuring and predicting which yeast strains will be productive and robust.
Elsewhere, scientists toil with petri dishes and automated pipettes to test new strains. Small piles of malonic acid, a white crystal in refined form, mark the way to a wall of deep freezers, where the champion strains await industrial vats.
Though Dr. Steen never worked for Amyris, his college adviser, Jay D. Keasling, helped found the company.
"I was involved with them as a grad student," Dr. Steen said. "Trying to tackle gasoline was too much; it doesn't make sense to compete at first with someone's core product for over 100 years." He figures that his product, malonic acid, has a market worth $250 million -- small enough that there has not been too many thoughts about efficiency.
At least some big producers agree that these new tools and styles of genetic coding are reviving the clean tech field.
"We have better tools, better computational biology," said Markus Pompejus, who runs a biotechnology program for BASF, the German chemical giant. "The whole thing is very real. It's already getting big."
His company uses fungi to make vitamin B2, and has a license agreement with Genomatica, a company that spent most of the $200 million it had raised on industrial chemicals in the first wave, and now fashions E. coli bacteria to spit out the basics of biodegradable shopping bags.
Still, Dr. Pompejus said, "petrochemicals won't go away."
"We make 3,000 metric tons of B2 a year; that's a specialty amount of production," he added. "When you talk about things like citric acid, or lysine for animal feeds, you're talking about 200,000 metric tons a year."
Correction: December 30, 2016
An article on Wednesday about clean tech companies referred incorrectly to spending by Genomatica. It has devoted most of the $200 million it has raised to industrial chemicals; it has not spend $300 million on biofuels.
