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C&EN’s 2021 10 Start-Ups to Watch

Chemistry entrepreneurs see a path to both profits and a better planet

by Michael McCoy
November 21, 2021 | A version of this story appeared in Volume 99, Issue 42
An illustration showing representations of different technologies featured in this year's 10 Start-Ups to Watch stories.

Credit: Laurent Hrybyk


Just 10 days ago in Glasgow, Scotland, political leaders from around the world wrapped up a United Nations climate conference intended to chart a course toward a low-carbon future. The goal: saving Earth from carbon dioxide–driven destruction.

Critics say the big nations in attendance didn’t commit enough to meeting the goal—that they are willing to trade the long-term health of the planet for short-term economic growth. But what if technologies that are good for the planet, and its citizens, can also bring economic growth?

Such world-improving innovation, powered by chemistry, is at the core of each of the young companies profiled in C&EN’s 10 Start-Ups to Watch for 2021. C-Zero, for example, can create hydrogen and capture the carbon by-product as a solid rather than as a gas that heats the atmosphere. Factorial Energy is developing batteries that will send electric cars long distances without catching fire. Sudoc is rolling out cleaning products certified to not cause endocrine disruption.

Venture capitalists—not people inclined to throw money at do-gooders—seem to agree that these companies show business promise. Over the past year, investors have put millions of dollars into most of them.

And if C&EN’s record of picking winners continues, more money will follow. Since September, Solugen, one of our 2018 Start-Ups to Watch, raised $357 million from investors to advance its method of turning sugars into chemicals using enzyme and chemical catalysts; Via Separations, a 2019 pick, brought in $38 million for its graphene oxide–based separation membranes; and Culture Biosciences, a 2020 winner, raised $80 million for its synthetic biology outsourcing concept.

Where do we find these companies? Readers from around the world submit nominations via our website. We also log the new firms we hear about in our day-to-day reporting. After much discussion and debate each year about more than 200 companies, we select 10 for their science and the importance of the problems they are working to solve.

We can’t guarantee that any of this year’s picks will fix a problem that confronts our planet. But we are confident that, in the hands of entrepreneurs, chemistry can be a power for good. If you know about a chemistry start-up doing good, nominate it for our 2022 feature at



Growing insect pheromones in yeast cells for sustainable pest control

by Vanessa Zainzinger, special to C&EN


Credit: BioPhero
From left: BioPhero CEO Kristian Ebbensgaard, business development director David Llobet Calaf, chief financial and marketing officer Mikael Bechsgaard, chief scientific officer and founder Irina Borodina, and chief technology officer Jesper Dohrup

At a glance

Publicly launched: 2016

Headquarters: Copen­hagen, Denmark

Focus: Affordable biological pest control

Technology: Production of insect sex pheromones in large-scale fermenters

Founder: Irina Borodina

Funding or notable partners: $20.5 million from DCVC Bio, FMC Ventures, Novo Holdings, Novo Seeds, Syngenta Group Ventures and Syddansk Innovation and an undisclosed amount of European Union grants through the Olefine and Phera projects.

In some of the larger silkworm moth families, males travel nearly 50 km to a female, following a pheromone trail in the air.

Most insects rely on pheromones to communicate and, importantly, to find a mate. This includes crop-eating pests that every year cost growers millions of dollars and force them to douse their fields with chemical pesticides.

Environmentalists have long been interested in leveraging this insect behavior for pest control. Spraying insect sex pheromones into the field can stop males from locating a female. As a result, fewer insects find a mating partner, and not as many females get fertilized, so they don’t lay eggs that develop into hungry larvae.

The Danish start-up BioPhero says disrupting insect mating patterns is the future of pest control. “We have this vision of sustainable agriculture,” says CEO Kristian Ebbensgaard. “But in order to make that happen, we need a real value proposition.”

Although pheromone-based mating disruption is used in specialty crops like apples and grapes, it hasn’t taken off in row crops like corn, soybeans, and rice because producing insect sex pheromones—with their diverse chemical nature and often unusual cyclic structures—by chemical synthesis is too difficult and expensive. One company offering a more economical method of production is Provivi, one of C&EN’s 10 Start-Ups to Watch in 2015, which incorporates biocatalysis in the synthesis.

BioPhero reckons it can take affordable pheromone production a step further with its fermentation technology, which grows insect pheromones in a manner not dissimilar to brewing beer. The process makes use of the knowledge that the cells of insects contain all the biological tools required to naturally produce specific pheromones, Ebbensgaard says. “We take a look at how the female insect makes exactly the right combination of double bonds in the pheromone gland, then we copy those out and put them into yeast cells,” he explains.

Unlike insect cells, the yeast cells—which come from a family widely used in food production—are able to grow in industrial-scale fermenters, making the process efficient, scalable, and cost effective for use on row crops. While current pheromone-based pest control treatment can cost $200 per hectare, BioPhero says it can bring that down to $20 per hectare.

Cheaper pheromones
Pheromones are effective at stopping insects from mating, but they are expensive to synthesize. BioPhero says its yeast-based fermentation process is cheaper than chemical synthesis and yields pheromones at a price that enables them to be used on row crops.
Credit: Yang H. Ku/C&EN/Shutterstock

The idea for BioPhero emerged when Irina Borodina, a professor in yeast metabolic engineering at the Technical University of Denmark (DTU), found herself in a quandary about the cost of organic vegetables. “She thought, Surely we must be able to produce them so everyone can have access to healthy food,” Camilla Hebo Buus, BioPhero’s communication manager, says. Borodina wondered whether her research in yeast cells could be applied to producing pheromones, and so she founded BioPhero as a spin-off from DTU.

The firm was backed by the European Union–funded Olefine project, which gives grants to researchers specifically looking to make cheap pheromones as alternatives to chemical insecticides.

Starting with a modest 1 L fermenter in 2018, BioPhero raised $3.5 million from a consortium including agrochemical giant Syngenta. By 2020, the money had helped the team scale up to a 180,000 L fermenter. “That’s very fast,” says Ebbensgaard, who spent 10 years at the Danish enzyme giant Novozymes before joining the start-up.

BioPhero is now preparing to launch its first products commercially, backed by a $17 million funding round announced in February.

We have this vision of sustainable agriculture.
Kristian Ebbensgaard, CEO, BioPhero

Initially the firm will target key pests in row crops—“Moths, basically,” Ebbensgaard says—and focus on a pipeline of 5–10 compounds. BioPhero provides the active pheromone ingredients to formulators, which turn them into specialized slow-release products that can be applied in the field using conventional farm equipment.

To Ebbensgaard, the most exciting part of BioPhero’s journey is watching a biological solution come into play in an area that is dominated by chemical ones. Driven by growing consumer demand for responsibly produced food, biological pest control is bound to capture a greater share of the agricultural market over time, Ebbensgaard says. Indeed, he sees proof in the sense of urgency shown by large agrochemical companies, including BioPhero’s backers.

“They are all saying the same thing: we need to increase the role of biologicals in our portfolio,” he says. “It’s a mandate that society is giving them.”


Bota Biosciences

Engineering enzymes with an eye on production

by Rick Mullin


Credit: Bota Biosciences
Bota Biosciences' Cheryl Cui, CEO, and Chia-Hong Tsai, chief technology officer, in lab space at the company's center of operations in Hangzhou, China. The lab does not require safety eyewear.

At a glance

Publicly launched: 2019

Headquarters: Lafayette, California; Hangzhou, China

Focus: Green manufacturing

Technology: Enzyme engineering and information technology

Founders: Cheryl Cui, Timothy Lu, and Chia-Hong Tsai

Funding or notable partners: $145 million from BASF, Matrix Partners China, Meituan, Sequoia Capital China, Source Code Capital, and other investors

Bota Biosciences, a start-up with a scheme to engineer enzymes as catalysts for making small molecules, closed a series B financing round totaling $100 million in July. It is one of several firms aiming to engineer enzymes and microorganisms for green manufacturing that received significant funding this year, but Bota can be distinguished from the pack.

The company has its eyes on more than enzyme design and fermentation. It has an information technology–enabled process of developing microbial strains and enzymes that can be scaled up to aid the production of food, nutrition products, drugs, and other products. And while many players in the field specialize in early design steps, Bota seeks to follow through to production. Bota’s eyes, CEO Cheryl Cui says, are on the end product.

“Instead of just focusing on what’s in the lab, we also try to move as quickly as we can into downstream process development and also large-scale fermentation,” Cui says. “We built an IT system to support this whole cycle.”

In fact, Bota’s digital platform, called the Bota Freeway, is cyclical in construct, mirroring the marriage of digital technology and robotics in cutting-edge autonomous labs. Data generated in the design and building of engineered organisms run back to the design stage and reenter the loop to further refine the process.

The difference between Bota’s platform and the autonomous lab is that Bota is not fully deploying artificial intelligence. At least not yet.

“We are at a stage where we are collecting sufficient data across the entire workflow,” Cui says. “We are not at the stage where the learning can be fed back entirely by the machine itself.” A biological system is often very “noisy,” she says.

Knowledge cycle
Computationally designed enzymes and microbial strains are cycled through production and fermentation on Bota Biosciences' information technology platform. Data are then passed to the lab for researcher analysis before reentering the loop.
Credit: Adapted from Bota Biosciences/Yang H. Ku/C&EN/Shutterstock

At 31, Cui has a formidable research background, including stints at Brigham and Women’s Hospital and Harvard Medical School in 2010 and 2011. She graduated from the Harvard­MIT Program in Health Sciences and Technology in 2017 with a PhD in medical engineering and medical physics. There, she had focused on synthetic biology, which turned out to be the hook for companies eager to convert to greener manufacturing processes.

Cui says she saw the need to foster new biotech companies while working on her doctorate. In 2017, she was a founding partner of the incubator and investor Nest.Bio Labs. In 2019 she pursued her ambition of starting her own company, Bota, with cofounder Timothy Lu, who was her academic adviser at the Massachusetts Institute of Technology.

In 2020, Cui connected with Chia-Hong Tsai in her search for a technical cofounder. Tsai was formerly a metabolic engineer at Amyris and had experience scaling up synthetic biology–based manufacturing processes. “From the moment we met, it was clear he was the perfect person to help start Bota because of his approach,” she says. That approach is now Bota’s, adds Tsai, who describes it as the principle of delivering a “minimal viable process.”

Instead of just focusing on what’s in the lab, we also try to move as quickly as we can into downstream process development and also large-scale fermentation.
Cheryl Cui, CEO and cofounder, Bota Biosciences

Bota is building a digitized and automated pilot plant in Hangzhou, China, to expedite the delivery of efficient processes to customers, Tsai says. And the company is looking ahead to larger-scale manufacturing of products for customers and itself. With the boost from the recent financing round, Bota is considering whether to purchase or build a plant in Asia, Cui says.

At present, Bota has two commercial contracts, one for producing a fine chemical for the nutrition market and one for a pharmaceutical chemical. And the company counts BASF as an early investor. The German chemical major announced an unspecified investment earlier this year, promoting its commitment to “white” biotechnology, the practice of making products from living organisms or systems, and noting possible applications in sweeteners, vitamins, personal care, and crop protection.

“But it might be of interest that one of our investors is Meituan,” Cui says, referring to a huge online shopping platform in China. “They were interested in Bota because of our focus on sustainable manufacturing and ingredients.”

This story was updated on Nov. 24, 2021, to correct the year that Bota Biosciences CEO Cheryl Cui connected with Chia-Hong Tsai, now the firm's chief technology officer. It was 2020, not 2019.



Developing a liquid catalyst that could usher in an era of turquoise hydrogen

by Michael McCoy


Credit: C-Zero
C-Zero founders Zach Jones (left) and Eric McFarland in front of a hydrogen-powered Toyota Mirai

At a glance

Publicly launched: 2018

Headquarters: Goleta, California

Focus: Turquoise hydrogen

Technology: High-temperature liquid that catalyzes the pyrolysis of methane into hydrogen and elemental carbon

Founders: Zach Jones and Eric McFarland

Funding or notable partners: $11.5 million in series A funding from Breakthrough Energy Ventures, Eni Next, Mitsubishi Heavy Industries, and AP Ventures

Hydrogen may be the fuel of the future, but which hydrogen?

There’s the old-fashioned gray variety, made by reforming methane and venting the resulting carbon dioxide into the atmosphere. Blue hydrogen is made by capturing that CO2 and sequestering it underground. And the gold standard, green hydrogen, is generated by turning water into hydrogen and oxygen with electricity generated from renewable resources.

California’s C-Zero is betting that turquoise hydrogen is going to be part of the mix.

This relatively new variety of hydrogen, somewhere between blue and green, is made from methane. But rather than reform methane, which generates CO2, companies use pyrolysis to decompose it without oxygen, creating elemental carbon that can be sold or buried underground. C-Zero and other backers of turquoise hydrogen argue that methane is a cheap and abundant fuel and that their technology offers the best way to keep using it for as long as necessary.

C-Zero is an outgrowth of what Eric McFarland, a chemical engineering professor at the University of California, Santa Barbara, calls his long interest in low-cost hydrogen production. In 2016, with the help of a US Department of Energy grant, McFarland’s UCSB lab started exploring high-temperature liquids that could catalyze methane pyrolysis. Traditional solid catalysts can also do it, but liquids are good at getting heat into a reactor and getting carbon out.

In late 2018, with seed funding from Shell, McFarland licensed the technology from UCSB and formed C-Zero. Soon thereafter he met Zach Jones, whose firm was considering investing in C-Zero. McFarland didn’t need the money at the time, but he did need someone to run the new company, and Jones was game. C-Zero entered the public eye in February of this year when it announced raising $11.5 million in series A funding from investors including Breakthrough Energy Ventures, a clean energy investment fund started by Bill Gates.

Hydrogen without CO₂
Burning methane for energy yields carbon dioxide and water. Heating methane in an oxygen-free pyrolysis reactor, in contrast, yields hydrogen and carbon. C-Zero has developed a liquid catalyst that expedites this process, generating relatively low-cost hydrogen and solid carbon that can be disposed of in places like old coal mines.
Credit: Yang H. Ku/C&EN/Shutterstock

Today, C-Zero employs about 16 people—several of them former undergraduate students of McFarland’s who went on to earn PhDs—and runs a lab in Goleta, California. The firm’s goal is to get a pilot plant up and running in 2022 so that it can develop a technology package for a commercial facility that will be built a few years later.

McFarland calls the catalyst C-Zero’s “secret sauce.” He describes it only as a “multiphase, multicomponent high-temperature liquid,” but he’s more open about what it can do: it gets heat efficiently into the reactor and catalyzes methane pyrolysis with few unwanted by-products, like polycyclic aromatics. And carbon is immiscible in the liquid, easing separation. “You can basically float it out of the reactor,” he says.

Our goal has always been to make hydrogen on purpose and dispose of the carbon as cheaply as possible.
Eric McFarland, chief technology officer and cofounder, C-Zero

C-Zero isn’t the only company pursuing turquoise hydrogen. Australia’s Hazer Group uses an iron ore catalyst to produce hydrogen and synthetic graphite, potentially for lithium-ion battery anodes. And the US start-up Monolith has a plasma pyrolysis process that yields carbon black, which is added to tires to strengthen the rubber. McFarland has good things to say about both processes, but he emphasizes that C-Zero focuses solely on hydrogen. “Our goal has always been to make hydrogen on purpose and dispose of the carbon as cheaply as possible,” he says.

The firm’s target price is $1.50 per kilogram, which isn’t as cheap as the gray hydrogen that comes from steam methane reforming but will be very competitive in any locale that puts a price on carbon, McFarland says. If C-Zero is successful, its technology could usher in a future in which the grandchild of a coal miner has a job sequestering carbon in the mine that their grandparent dug, he says. “Reversing that carbon flow is what we’re all about.”


Eikon Therapeutics

Superresolution fluorescence microscopy shines a light on protein movement in living cells to aid drug discovery

by Ryan Cross


Credit: Eikon Therapeutics
From left: Eric Betzig and Robert Tjian, two of Eikon Therapeutics’ cofounders, and CEO Roger Perlmutter

At a glance

Publicly launched: 2021

Headquarters: Hayward, California

Focus: Small-molecule drug discovery

Technology: High-throughput drug screening with superresolution fluorescence microscopy

Founders: Eric Betzig, Xavier Darzacq, Luke Lavis, and Robert Tjian

Funding or notable partners: $148 million in series A financing from investors including the Column Group, Foresite Capital, Innovation Endeavors, and Lux Capital

When Roger Perlmutter announced his plans to retire at the end of 2020, it didn’t take long for the phone to start ringing. As president of Merck Research Laboratories for the previous 7 years, Perlmutter had overseen clinical trial design and execution for 15 new drugs and vaccines, including the cancer immunotherapy Keytruda, which earns Merck billions of dollars every year. He was inundated with offers to serve as an adviser to companies seeking his drug development expertise.

One offer in particular stood out. Robert Tjian, a biochemist at the University of California, Berkeley, asked Perlmutter if he wanted to join the board of advisers for Tjian’s new company, Eikon Therapeutics. Tjian cofounded the start-up in 2019 with three colleagues, including UC Berkeley scientist Eric Betzig, who shared the Nobel Prize in Chemistry in 2014 for his invention of superresolution fluorescence microscopy. Eikon’s goal is to become the first company to industrialize the imaging technique and use it as a tool for drug discovery.

Superresolution microscopy has revolutionized biology, allowing scientists to see nanoscale structures that would be impossible to resolve with traditional microscopes. Betzig, Tjian, and their colleagues had already used the technique to watch how proteins called transcription factors bind to DNA and turn genes on or off in living cells. Tjian hoped to take the concept a step further at Eikon and use Betzig’s powerful new microscopes to study how small molecules subtly affect the gyrations and trajectories of proteins in cells.

Perlmutter was intrigued by Eikon’s approach. “We haven’t really had any way of watching what goes on in real time inside of cells” until the development of superresolution microscopy, he says. It was clear to Perlmutter that using the imaging technique to watch proteins in living cells could be a new way for drug hunters to discover compounds that target traditionally tough-to-drug proteins, including transcription factors.

Microscopic movies
Eikon Therapeutics uses superresolution fluorescence microscopy to make short movies of how proteins move in living cells. The firm's machine-learning software analyzes the movies to detect when small-molecule compounds subtly change the protein's movement. Those compounds are then used as starting points for discovering drugs that target the protein.
Credit: Yang H. Ku/C&EN/Shutterstock

Also, after years of overseeing clinical trial strategies at Merck, Perlmutter, who started his career as a biochemist, was eager for a job that would get him closer to the nuts and bolts of drug discovery. So Perlmutter responded to Tjian’s offer with his own: What if, instead of advising the company, he ran it? In May, Eikon emerged from stealth with Perlmutter as its CEO and $148 million in series A financing.

Eikon has recruited a small army of engineers, physicists, and programmers to design the hardware and software needed to run its high-throughput screens and interpret the results. Before the screening begins, Eikon tags a protein with a fluorescent dye. It then uses its powerful microscopes to record short movies of the cells at 100 frames per second. The firm’s machine-learning software analyzes whether the movement of the tagged proteins changes when a small molecule is added to the cells.

We haven’t really had any way of watching what goes on in real time inside of cells.
Roger Perlmutter, CEO, Eikon Therapeutics

“We don’t really have to know anything about the protein or its structure,” Perlmutter says, meaning the approach could help chemists find molecules that target proteins whose structures are either unknown or difficult to study. Eikon has tested the idea on the estrogen receptor, but Perlmutter won’t say what targets the company is working on for its first drug candidates.

Currently, Eikon can study the effects of about 10,000 compounds on protein movement every day. Those experiments produce 15 terabytes of data, and Perlmutter says that figure could rise to 500 TB a day within a year. “No human being can look at this information and make any sense of it,” he says.

“There is no real secret sauce,” Betzig adds, although most labs don’t have the money, motivation, or time to do what Eikon is doing. “There is a huge amount of engineering to get it to work viably.”


Factorial Energy

Bringing batteries with polymer-based solid electrolytes to market

by Alex Scott


Credit: Factorial Energy
Factorial Energy CEO and cofounder Siyu Huang shows off the company's 40 A h battery cell, one of the largest solid-electrolyte cells in the industry.

At a glance

Publicly launched: 2021

Headquarters: Woburn, Massachusetts

Focus: Highly energy-dense batteries for electric vehicles

Technology: Battery featuring a polymer-based solid electrolyte and a lithium-metal anode

Founders: Héctor Abruña, Siyu Huang, and Alex Yu

Funding or notable partners: Over $65 million from investors including Gatemore Capital Management and Wave Equity Partners

Siyu Huang, the CEO and cofounder of Factorial Energy, is embracing the rapid transition taking place as the start-up—a developer of solid-state, highly energy-dense lithium-ion batteries—transitions from the lab to the marketplace. Top among her priorities is securing deals to supply Factorial’s battery to automotive companies to power their electric vehicles.

The firm’s battery features a polymer-based solid electrolyte and a lithium-metal anode. Such a battery is safer than one with a conventional liquid electrolyte, which can catch fire at temperatures of between 60 and 75 °C, the company says. Factorial’s battery also benefits from the use of a lithium-metal anode, which for safety reasons can’t be used with a liquid electrolyte.

“Lithium is the lightest metal on earth and has the highest specific [energy] capacity,” Huang says. Despite its new approach to battery design, the firm never had a eureka moment. “It’s an evolution. There have been many different iterations and a lot of different efforts,” she says.

Huang has experience as a versatile chemist. After earning a PhD in chemistry from Cornell University, Huang started working on the solid-state battery start-up in her spare time while holding down a day job with Johnson & Johnson.

Then, in association with Alex Yu, a postdoc research chemist, and Héctor Abruña, a chemistry professor and former department chair at Cornell who specializes in electrochemistry, she went full-time on the battery front and in 2016 pulled together the technology team that became Factorial. Although Factorial has strong links to Cornell, intellectual property associated with the company was developed in-house, she says.

The company came out of stealth in April when it announced that it had raised $40 million in committed capital. In all, Factorial has raised upward of $65 million from investors, enough to take it through a significant part of commercial validation, Huang says.

Liquid- versus solid-electrolyte batteries
Factorial Energy develops solid-state batteries (right), which use a solid electrolyte to separate the anode and cathode. This arrangement eliminates the need for a separator, which liquid-electrolyte batteries (left) use. Solid electrolytes are typically based on one of three materials—a polymer, ceramic, or sulfide—while liquid electrolytes typically consist of an organic solvent combined with lithium salts such as LiPF6, LiBF4, and LiClO4. Factorial has chosen not to disclose its specific battery architecture.
Credit: Yang H. Ku/C&EN/Shutterstock

The figure is small for a field that has attracted much hype, and it isn’t as much as that secured by solid-state battery start-ups such as QuantumScape and Solid Power. And yet in April, Factorial unveiled a 40 A h battery cell—the highest-capacity solid-state battery cell that works at room temperature, according to the company. This capacity “is a relevant size for automotive applications,” Huang says. The company can make prototypes of battery cells of up to 95 A h.

Late last month, Factorial signed an agreement to partner with the sister companies Hyundai Motor and Kia. The automotive firms, which have made an undisclosed investment in Factorial, will test the suitability of the start-up’s batteries in their vehicles. “We’ve been doing very well winning credibility in the battery industry,” Huang says. That credibility comes from data generated by the firm showing not only that its battery is highly energy dense but also that its performance remains steady under a range of test conditions.

Key evidence of its performance is that the battery retains 97.3% of its energy capacity after 675 charging cycles at ambient temperature. Until now, batteries based on polymer electrolytes have had poor cycle life.

We’ve been doing very well winning credibility in the battery industry.
Siyu Huang, CEO and cofounder, Factorial Energy

Factorial is at an advanced stage in scaling up its production processes. One reason, Huang says, is that compared with batteries containing other solid-electrolyte materials—such as ceramic—polymer-electrolyte batteries are relatively easy to manufacture at large scale.

Another advantage Factorial may have over some of its competitors is that its battery can be produced using 90% of the infrastructure already in place to make standard lithium-ion batteries with liquid electrolytes. Huang anticipates that after testing and qualifying by prospective partners, the firm could begin commercial production in the next 3–5 years.

Huang says her aim is not to create a business that generates huge personal wealth but to introduce a product that contributes to sustainable development. “Making money is not the goal,” she says. “I want to make valuable products that last for a long time.”


Kojin Therapeutics

Developing small-molecule drugs that exploit a new type of cell death, ferroptosis

by Lisa M. Jarvis


Credit: John C. Eaton
Stuart Schreiber (left) and Vasanthi Viswanathan, two of Kojin Therapeutics' cofounders

At a glance

Publicly launched: 2021

Headquarters: Cambridge, Massachusetts

Focus: Small-molecule drug discovery

Technology: Drugging ferroptosis-sensitive cell states

Founders: Benjamin Cravatt, Stephanie Dougan, Stuart Schreiber, and Vasanthi Viswanathan

Funding or notable partners: $60 million in series A funding led by Polaris Partners, Newpath Partners, and Cathay Health

As Vasanthi Viswanathan was wrapping up her postdoc in chemical biologist Stuart Schreiber’s lab at Broad Institute of MIT and Harvard, she found herself at a crossroads. Viswanathan had devoted her training to understanding the mechanics of an iron-dependent cell death called ferroptosis. First described in 2012 by her graduate adviser, Columbia University chemical biologist Brent Stockwell, ferroptosis occurs when iron in a cell reacts with lipid peroxides, generating free radicals that push the cell to a fiery death.

Studies by Viswanathan and others suggested that molecules inducing ferroptosis might work against cancer cells that resist conventional therapies triggering apoptosis, a more common kind of cell death. In particular, she found that an enzyme called GPX4 could rescue cells from iron-induced cell death by reducing lipid peroxides to lipid alcohols. GPX4 inhibitors, on the other hand, could drive cells in that iron-dependent state over the edge.

Viswanathan had several offers to start her own academic lab but was struggling to pick a direction. Then came what she describes as a mind meld with Schreiber. He asked her, “What do you think is the most important thing that needs to be done in the field?” She didn’t need more than a beat before replying, “Probably make a drug.”

Thus began a 2-year process of discussions with investors to sketch what a drug company might look like, culminating in June in the formal launch of Kojin Therapeutics. The biotech firm, where Viswanathan is a cofounder and head of discovery biology, has $60 million from investors to design drugs targeting cells that are vulnerable to ferroptosis.

CEO Luba Greenwood, who formally took the reins in September after serving as a Kojin investor and board member, says the new class of treatments may overcome the long-standing problem of drug resistance.

Fiery death
In a type of cell death known as ferroptosis, cancer cells oxidize polyunsaturated lipids to form lipid peroxides, which in turn react with iron to form lipid radicals that cause the cells to die. As a graduate student, Vasanthi Viswanathan, a Kojin Therapeutics cofounder, showed that cancer cells saved themselves by using the enzyme GPX4 to reduce those lipid peroxides. She also found that small-molecule inhibitors of GPX4 could push cells to their death.
Credit: Adapted from Nature

Industry has largely focused on inducing apoptosis—either by finding better drug targets or by better identifying the patients who will respond to the drugs. The catch, Viswanathan points out, is that “cells are able to put on these two outfits.”A drug might initially reduce the size of a tumor while its cells are wearing the outfit that makes them vulnerable to apoptosis. But the tumor can recur because any remaining cells are able to change into the outfit that makes them vulnerable to ferroptosis. Kojin executives think this cellular plasticity could explain why approved cancer drugs work only about 30% of the time.

It took years for academic scientists to understand the mechanism of action of ferroptosis and how small molecules might induce it to work. That’s because the drug targets are found not by, for example, sequencing the genome of a tumor but rather by perturbing a cell to understand which outfit it’s wearing.

Viswanathan says the tools are now in place to assemble an atlas of ferroptosis-inducing drug targets for specific types of cancer. Kojin scientists can systematically test hundreds of compounds in, for example, a thousand cell lines to assess whether cells are sensitive to ferroptosis or apoptosis.

Cells are able to put on these two outfits.
Vasanthi Viswanathan, head of discovery biology and cofounder, Kojin Therapeutics

The company initially wants to identify cancers in which nearly all the cells are in the ferroptotic state, because a small molecule would stand a good chance of being effective as a stand-alone therapy. So far that list of potentially vulnerable tumors includes sarcoma, liver, ovarian, and kidney cancers.

Greenwood says Kojin is 2 to 3 years away from clinical candidates for cancer. At the same time, the company is exploring the role of ferroptosis and cellular plasticity in immunology and an undisclosed disease area.


MOBILion Systems

Improving biotherapeutic characterization and biomarker discovery with better separations

by Celia Henry Arnaud


At a glance

Publicly launched: 2017

Headquarters: Suburban Philadelphia

Focus: Improved characterization of biotherapeutics and biomarker discovery for clinical diagnostics

Technology: High-resolution ion mobility separations

Founders: Melissa Sherman, founding CEO

Funding or notable partners: $115 million from D1 Capital Partners, aMoon, Agilent Technologies, IP Group, Hostplus, Cultivation Capital, and other undisclosed investors

When Melissa Sherman worked for IP Group, an investment company that funds early-stage technology, her job was to scout disruptive technologies at multiple US national labs. At the Pacific Northwest National Laboratory (PNNL), she found a technology that excited her enough to take the leap from portfolio manager to CEO at a start-up.

The technology that inspired her was a separation method called structures for lossless ion manipulation (SLIM), invented in the lab of PNNL chemist Richard D. Smith. “This was an incredible opportunity to be able to take forward a platform technology that has an incredible number of applications and opportunities,” Sherman says.

So with backing from IP Group, she founded MOBILion Systems, which licensed SLIM from PNNL.

Based on a type of ion mobility, SLIM separates ions in a device in which metal electrodes are patterned on printed circuit boards. Applying voltages to some of the electrodes creates conduits through which ions can float and move, even around corners, without hitting surfaces and being lost. Applying voltages to other electrodes creates a sinusoidal electric field—also called a traveling wave—that pushes ions through the device. Smaller ions move through the device faster than larger ones.

Credit: MOBILion Systems
MOBILion Systems CEO Melissa Sherman

MOBILion calls its version of SLIM “high-resolution ion mobility,” or HRIM. In ion mobility, separation resolution improves as the length of the path over which the ions travel increases. Printed circuit boards let the company create serpentine patterns that allow long path lengths—potentially on the order of kilometers—to fit in a small space, the company can thus achieve high-resolution separations in a compact device. With its first product, called Mobie, MOBILion has decided to stick with a conservative path length of 13 m. “We wanted to keep our first product the simplest iteration we could,” Sherman says.

MOBILion has set its sights on the liquid chromatography/mass spectrometry market. “The largest segment of the LC/mass spec industry is pharmaceutical customers using LC/mass spec to characterize drugs and to facilitate their drug development process,” Sherman says. “As pharma companies are going from small-molecule to large-molecule therapeutics, these more advanced therapeutics require more advanced analytical tools to adequately characterize them.”

Better separations
MOBILion Systems’ high-resolution ion mobility is based on the structures for lossless ion manipulation (SLIM) platform. The SLIM technology, which consists of metal electrodes patterned on a printed circuit board, is used to separate and identify molecules in biological samples. Applying voltages to some electrodes creates conduits through which ions can move without hitting surfaces, thus preventing loss. Applying voltages to other electrodes sets up an oscillating electric field that propels ions through the device. SLIM separates components by both size and shape. The longer the path, the more effectively components can be separated and identified. The separations can be used to improve drug characterization and biomarker validation.
Credit: Adapted from MOBILion/Yang H. Ku/C&EN/Shutterstock

What HRIM brings to separations, the firm says, is speed and sensitivity. “In some applications, we have enough separation horsepower to be able to replace LC,” Sherman says. In other applications, a chromatographic separation is still needed, but the run time is much shorter than usual. For example, peptide mapping, a method for characterizing protein therapeutics, involves a 90 min LC/mass spec workflow, according to Sherman.“We can put MOBIE in the middle of that, and so we might do a 5 min, really quick and dirty LC gradient just to spread the sample out so that we get optimized ionization,” she says. Each run ends up being 7–10 min instead of 90 min.

The first version of Mobie is designed to work with Agilent Technologies’ quadrupole time-of-flight mass spectrometer.

As pharma companies are going from small-molecule to large-molecule therapeutics, these more advanced therapeutics require more advanced analytical tools to adequately characterize them.
Melissa Sherman, CEO and founder, MOBILion Systems

MOBILion also wants to target biomarker discovery for clinical diagnostics. HRIM can switch between different classes of biomarkers, including proteins, lipids, and carbohydrates, with little or no downtime in between. “The idea that we can significantly accelerate biomarker validation and translation to the clinic is really exciting for us,” Sherman says.

She expects great things from MOBILion’s technology. “We’re only scratching the surface,” Sherman says. “This is a platform technology that if you get the right engineers and scientists to build and redesign it, the sky really is the limit.”


Natural Fiber Welding

Creating a circular economy around soft goods

by Craig Bettenhausen


Credit: Originally published in the September 2020 issue of Peoria Magazine. Reprinted with permission.
Luke Haverhals, CEO and founder of Natural Fiber Welding, shows off a shoe made with company materials.

At a glance

Publicly launched: 2015

Headquarters: Peoria, Illinois

Focus: Plant-based materials for soft goods

Technology: Fiber welding and oil polymerization

Founder: Luke Haverhals

Funding or notable partners: $40 million from investors including Ralph Lauren, Allbirds, Smart Shirts, BMW i Ventures, Ethos Capital, For Good Ventures, and Prairie Crest Capital

Natural Fiber Welding (NFW) makes materials for soft goods such as garments, shoes, bags, and car seats from natural feedstocks that might otherwise be considered waste. It does this by meeting nature halfway.

Founder Luke Haverhals started exploring the chemical interactions between ionic liquids and natural fibers such as hemp and silk while he was a researcher at the US Naval Academy working under chemistry professor Paul Trulove. It was possible to dissolve the materials down into small molecules, he noticed, but doing so meant losing the intricate natural structures that made them strong and flexible.

As a chemistry professor himself at Bradley University starting in 2013, Haverhals began to develop ways to break natural materials down as little as possible while molding and shaping them into new forms. He made some progress but decided to form a company in 2015 so he could raise the capital needed to bring his ideas to life.

Six years later, NFW has about 140 employees and two product families: the recycled thread Clarus and the leatherlike material Mirum.

The chemistry behind Clarus is the technology that Haverhals founded NFW on: fiber welding. Textiles are difficult to recycle because the individual fibers get cut and broken as plants or animals become yarn or thread, which then becomes garments or other soft goods. Taking a product apart for recycling shortens the fibers further. Cotton fiber, for example, is worth about $2.2 per kilogram if the fibers are 3.5 to 4 cm long. At 2.5 cm, it’s basically garbage.

Circular materials
Natural Fiber Welding wields nine patent families to create a range of natural-material composites. The two most commercially advanced are its eponymous fiber welding technology, which extends the length of natural fibers (Clarus top), and its chemical and mechanical process for turning biomaterials into leatherlike polymer sheets (Mirum, bottom). The firm can also make foams and rubberlike materials by tweaking formulations and manufacturing techniques. Products from all of NFW’s platforms can become Mirum feedstock and are also biodegradable.
Credit: Yang H. Ku/C&EN/Shutterstock

The discovery powering Clarus is that certain ionic liquids cause natural fibers to swell and unravel a bit. If they’re in close contact with other fibers, the outer layers will mix, mingle, and start to form hydrogen bonds. Remove the ionic liquid, and the mingled fibers shrink again, locking in the connections and welding them into a tight, strong thread.

The process allows NFW to produce recycled threads that are stronger and longer than typical recycled fibers—and often even than virgin fibers. That circularity attracted the iconic fashion brand Ralph Lauren, which was looking for ways to make its products more sustainable and circular. Ralph Lauren led NFW’s $13 million series A funding round in 2020 and is already buying metric tons of Clarus, Haverhals says.

To make Mirum, NFW reacts a polyfunctional carboxylic acid such as citric acid with a vegetable oil that has had epoxy groups added along its fatty acid chains. Hydrogen peroxide and acetic acid are the main epoxidation agents. The carboxylic acid creates bridges between the epoxides to form a flexible and strong polymer that can be used on its own or blended with other biobased ingredients, including Clarus and agricultural waste such as cork dust.

NFW can even recycle scraps and old products made of Mirum, grinding and blending them with the fresh material. During the pressing and shaping that occur in this process, the bonds within Mirum’s polymer structure break, shuffle, and re-form.

Both Clarus and Mirum contain nothing but natural materials in more-or-less natural states, so they are also fully biodegradable in soil. “This can be recycled in profoundly different ways than anything made of petrochemicals,” Haverhals says.

This can be recycled in profoundly different ways than anything made of petrochemicals.
Luke Haverhals, CEO and founder, Natural Fiber Welding

It’s a value proposition that’s catching on. NFW raised $2 million from the eco-shoemaker Allbirds in February and another $15 million in July from investors including BMW’s venture arm. The firm is using the money to expand capacity in Peoria, Illinois, and new locations. Haverhals says NFW will be able to make around 10,000 m2 of Mirum and multiple metric tons of Clarus per week by the middle of 2022.

Other biobased and vegan textiles are appearing on fashion runways and limited-edition products, and they are great for advancing the sustainability conversation, Haverhals says. But NFW is scaling up to be able to fill customers’ mass production orders. “The product teams of those companies are talking to NFW about doing real-scale business,” he says.

This story was updated on Nov. 22, 2021, to correct the number of employees at Natural Fiber Welding. The firm has about 140 employees, not almost 40.


Rome Therapeutics

Searching repetitive DNA for ways to tackle disease

by Megha Satyanarayana


Credit: Rome Therapeutics
From left: Benjamin Greenbaum, David Ting, and Rosana Kapeller, founders of Rome Therapeutics

At a glance

Publicly launched: 2020

Headquarters: Cambridge, Massachusetts

Focus: Modulating the repeatome

Technology: Artificial intelligence and advanced sequencing

Founders: Benjamin Greenbaum, Rosana Kapeller, and David Ting

Funding or notable partners: $132 million from GV, Arch Venture Partners, Partners Innovation Fund, Section 32, and others

One scientist’s trash is another’s treasure.

At least this is what Rome Therapeutics is hoping. Its scientists are mining the vast stretches of DNA with repetitive sequences—part of what’s long been called junk DNA—for information that can be used to create better treatments for illnesses like autoimmune diseases and cancer.

Rome started in 2019 and came out of stealth in 2020 with $50 million in series A funding. It recently raised $77 million in series B funding. And earlier this month, it revealed experiments showing that an undisclosed small molecule it is calling compound A blocks a product of junk DNA that seems to spur an overactive immune response.

The company is led by veteran entrepreneur Rosana Kapeller, who is also a cofounder. It’s relying on artificial intelligence and advanced sequencing technology to determine what aspects of repetitive DNA—the things that control it or the things that come out of it—might make good drug targets.

Rome is building its own technology that focuses on these repeats, known as the repeatome. Repeats make up 60% of junk DNA, and junk DNA makes up 98% of the human genome. To mine the repeatome, Kapeller says, “you need biology; you need chemistry; you need data sciences, genomics to be able to piece all these things together.”

The company’s story began about 10 years ago, when Rome cofounder and oncologist David Ting was staring at sequenced tumor DNA while training at the Massachusetts General Hospital Cancer Center. He was baffled. Much of the sequence—50% of it in just the first tumor he examined—seemed to match the repetitive elements of junk DNA. This DNA had long been declared unimportant, yet it made no sense for a tumor, eager to grow and spread, to waste so much energy activating DNA that had no purpose. He asked around and came up empty.

Junk hunting
Human DNA is full of repetitive sequences that yield RNA and proteins with many functions, including to prompt the earliest parts of the immune system to act. The sum of these repetitive sequences is called the repeatome, and Rome Therapeutics is looking to develop therapies that modulate the output of these repetitive elements. For example, some of these repeats, including human endogenous retroviruses (HERVs), are remnants of viruses, and inappropriate activation of the repeats can spur an interferon response that leads to autoimmunity. Rome hopes that one of the small molecules (compound A) it is developing will interfere with this unwarranted immune activation and quell autoimmunity.
Credit: Yang H. Ku/C&EN

“No one could tell me anything because no one studied junk anymore,” Ting says. He says that was when he “realized the junk is not the junk.”

Since then, Ting says, many scientists have delved back into the repeatome, finding that these repetitive sequences—transposable elements, short and long interspersed nuclear elements (SINEs and LINEs), and human endogenous retroviruses (HERVs), among others—are not lazing about. During human embryo development and in tumors, these elements are activated and transcribed into RNAs, and those RNAs are translated into proteins. A bunch of the repeatome is likely HERVs—remnants of viruses that long ago integrated into our DNA.

No one could tell me anything because no one studied junk anymore.
David Ting, cofounder, Rome Therapeutics

HERVs are important, says Dennis Zaller, Rome’s chief scientific officer, because when a cell is stressed, as in autoimmune diseases, it could be pumping out the products of these repeats, sending the immune system into overdrive and potentially spurring inflammation. The company thinks that some of these HERV-based proteins, called endogenous reverse transcriptases, could lead to an uncontrolled early immune response called the interferon response. Compound A, and others the company is pursuing, could help stop interferon-based autoimmunity.

Rome relies on some basic molecular biology tools that look at different cells to see what repeats are being used or not used when a cell is healthy or sick. But because of the nature of these repeats—multiple copies and slight variations between them—the company also uses advanced sequencing technology. Rather than reading DNA in small chunks that need to be pieced together, the sequencing technology reads DNA in larger strings that when fed into computer algorithms reveal differences more readily.

Every person’s repeatome is going to vary. What the company finds could open up an entirely new type of personalized medicine.



Sustainable commercial cleaning products with oxidative catalysts that self-destruct

by Cheryl Hogue


Credit: Sudoc
Sudoc founders include, from left, chemist Terry Collins, CEO Roger Berry, Andrea Larson, and John Peterson "Pete" Myers.

At a glance

Publicly launched: 2020

Headquarters: Charlottesville, Virginia; Boston; Pittsburgh; and San Juan, Puerto Rico

Focus: Efficient, safe products to break down toxic materials

Technology: Super-ultradilute oxidative catalysts

Founders: Roger Berry, Terry Collins, Andrea Larson, Henry Lewis, Hunter Lewis, John Peterson “Pete” Myers, and Ryan Sullivan

Funding or notable partners: $10 million from the Hunter Lewis Family Trust

Sudoc—the name is an acronym for “sustainable ultradilute oxidation catalysis”—is aiming to take a healthy slice of the cleaning and environmental-remediation market.

The year-old company says its catalysts, when combined with hydrogen peroxide, are more effective than chlorine-based cleaning products or quaternary ammonium compounds, which are suspected of disrupting hormones.

Sudoc is the sole licensee of catalysts developed and patented by Carnegie Mellon University’s Institute for Green Science, CEO and cofounder Roger Berry says. The institute is led by chemistry professor and company cofounder Terry Collins.

Initially developed in the 1990s, these iron(III) tetraamido macrocyclic ligand (TAML) catalysts are small molecules that mimic the functions of oxidative enzymes and eventually decompose.

Recent innovations paved the way for commercialization of TAML chemistry. Researchers from the Institute for Green Science boosted the activity of the catalysts and decoupled the strength of reactivity from decomposition times. Sudoc executives decided that the best way to bring the catalysts to market was in cleaning and remediation products.

“Our business model is not to sell the catalysts,” Berry says. “Our business model is to create value-added products based on our proprietary catalysts.” The CEO intends to build Sudoc into a $1 billion-plus-a-year company in the next decade.

Sudoc’s inaugural product, the first in its line of Dot-branded products, is a mold-remediation treatment. The company is piloting the product with 39 professionals who treat mold infestations. It is garnering feedback and making tweaks before commercializing it by the end of 2021, Berry says. The company plans to build out Dot, short for “dilute oxidation technology,” into a suite of commercial and consumer cleaning products.

Oxidative cleaner
Sudoc’s tetraamido macrocyclic ligand (TAML) catalysts coordinate with hydrogen peroxide and release a water molecule. Then the oxygenated form of the catalyst interacts with a toxic substance to break it down. The process continues—with another hydrogen peroxide molecule coordinating with the catalyst—until the catalyst decomposes.
Credit: Yang H. Ku/C&EN

Another line of products in the works is branded Neat, an acronym for “new environmental approach to treatment.” Neat products will break down estrogenic chemicals and micropollutants in industrial wastewater and kill Legionella, the bacterium that causes Legionnaires’ disease, in cooling-tower water, Berry says.

A third Sudoc brand is Umo—ultramineralizing oxidator. These products destroy waste opioids. Berry notes that a common method for handling such unwanted prescription drugs, which are in demand on the underground market, is to bind them to activated carbon. “A smart criminal can unwind that process,” he says. Umo will allow drug take-back programs at police stations or pharmacies to destroy opioids on-site, Berry says.

In addition to its products, Sudoc is establishing what it calls a new standard for the industry. It is sponsoring independent, third-party tests of its products for potential hormone disruption, a specter over some cleaning product ingredients. The company will publish the results, Berry says. Such testing is not required by any regulatory body in the world, he points out.

We don’t want to be the sort-of-nice, slightly-more-expensive, less-effective environmental alternative.
Roger Berry, CEO and cofounder, Sudoc

The tests will follow the Tiered Protocol for Endocrine Disruption. This methodology helps chemists detect tendencies for endocrine disruption in new substances that are candidates for commercialization (Green Chem. 2013, DOI: 10.1039/C2GC35055F). Collins and another Sudoc cofounder, John Peterson “Pete” Myers, were among the coauthors of this protocol. Myers coined the term “endocrine disruption” and is coauthor of a pivotal 1996 book on the subject, Our Stolen Future.

The idea for Sudoc sprang from discussions between Collins and Myers about making endocrine disruption testing an integral part of a business based on TAML technology. Myers brought in his friend Hunter Lewis, cofounder of Cambridge Associates, an investment and financial adviser to research universities and colleges. The Hunter Lewis Family Trust, a family investment fund, put in $10 million to get the company going.

The three added four other cofounders: Andrea Larson, professor emerita of business administration at the University of Virginia; Ryan Sullivan, an environmental chemistry professor at Carnegie Mellon; Lewis’s son, Henry Lewis, an investment adviser and investor; and Berry, who came from the private equity field.

“We don’t want to be the sort-of-nice, slightly-more-expensive, less-effective environmental alternative,” Berry says of Sudoc’s products. “We want to use this chemistry because it’s so powerful.”

This story was updated on Dec. 1, 2021, to restore three paragraphs that were eliminated because of a production error. They appear before the final paragraph.

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