Anyone lucky enough to receive a new Lego set gets instructions on how to build the model on the cover of the box. But there is no step-by-step manual to guide entrepreneurs creating new businesses.
This year’s selection of 10 start-ups to watch were chosen by C&EN’s writers and editors because they have both innovative chemistry and the vision to use discoveries to solve important problems, targeting unmet needs in agriculture, chemical identification, drug discovery, materials design, and renewable products.
Not all the chemistry they use is brand-new. For example, lyotropic liquid crystals have been known for years, but the start-up Light Polymers has found a niche for the materials in improving digital displays. In agriculture, Boragen is exploiting boron chemistry first used in pharmaceuticals to craft highly targeted crop protection chemicals.
Other companies to keep an eye on are harnessing advances in artificial intelligence, analytics, and visualization. These developers of futuristic tools will make it possible to watch proteins change shape, identify molecules in the field, and develop new drugs and materials through experiments designed by machine-learning algorithms.
All start-ups face difficult odds. Statistics show that only 1.1% of start-ups grow to employ at least 50 people in their first 10 years. According to the National Venture Capital Association, venture capital investors are now backing fewer firms at later stages of growth.
The trick is to put the right bricks together at the right time. We think these 10 start-ups have the blueprints for success.
And if you know an exceptional new company based on chemistry, nominate it for next year’s feature at cenm.ag/startupnom.
Funding or notable partners: $38 million from investors including Canaan Partners, Advent Life Sciences, Pfizer, and Celgene
If you’ve only ever seen RNA pictured in an introductory biology textbook, you could be forgiven for thinking it would make a pretty bad target for small-molecule drugs. In contrast to structurally complex proteins, which feature nooks and crannies for drugs to bind, RNA is a floppy, noodlelike strand of genetic code that at first glance doesn’t offer any stable structures for drug docking.
Yet if small molecules could target specific RNA strands, a vast new continent ripe for drug discovery would be opened. Of the over 20,000 human proteins, only about 15% are believed to be accessible by small molecules. Since messenger RNA (mRNA) is the chemical courier between a cell’s DNA script and its protein actors, an mRNA-binding drug should be able to halt production of proteins, including the ones out of reach via traditional chemistries.
When Michael Gilman first heard about a biotech start-up pursuing this idea, he was dumbstruck. After shaking off his initial disbelief, he thought, “Wow, if you could figure out how to do that, it would be really great.”
Credit: Yang H. Ku/C&EN/Shutterstock
Most small-molecule drugs target proteins, but Arrakis is designing compounds that bind RNA molecules. Those that bind mRNA—the genetic precursor to proteins—could prevent cells from producing disease-causing proteins that are difficult to drug themselves.
Gilman is now CEO of that start-up, Waltham, Mass.-based Arrakis Therapeutics, which was founded in September 2015 by Russell Petter, former vice president of chemistry at Celgene and now chief scientific officer for Arrakis.
“It’s a bit like getting the band back together again,” says Gilman, who previously worked at Biogen along with Petter and Arrakis Chief Business Officer Daniel Koerwer in the late ’90s through mid-2000s.
Many companies have tried targeting RNA in the past decade using techniques based on RNA interference, or RNAi, in which a strand of RNA binds to and helps eliminate a complementary strand in the body. It’s been difficult to get the technique to work well in humans, however, except for one recent success in treating liver disease.
Arrakis is attempting to block RNA with the same chemistries used in protein-binding drugs. Gilman thinks that’s possible because contrary to oversimplified illustrations, RNA is more intricate than a simple strand; it twists and folds around itself into structures that present promising binding spots for drugs. Gilman doesn’t expect all RNA molecules to selectively bind a drug, but he says that Arrakis wants to “find small molecules that stabilize one of these transient, dynamic structures of RNA and essentially lock it down.” The small molecule would thus prevent an mRNA from forming a protein or inhibit a noncoding RNA that controls gene expression.
“People will always ask, ‘Why haven’t we found selective RNA-binding compounds in the past?’ ” Petter says. “Well, you actually have to look.”
Koerwer says Arrakis hopes to make a name for itself by doing that searching. Arrakis has one disclosed program: targeting mRNA for huntingtin, which is the protein associated with Huntington’s disease. After that, Arrakis isn’t committing to any particular diseases. Instead, the company will “screen as many libraries as we can against hundreds and hundreds of targets, and then choose from that data set,” Koerwer says.
If Arrakis can find selective small molecules that bind RNA and demonstrate a biological effect, Petter anticipates the firm will run drug development and clinical trials just like any other pharma company. “Our ambition is for the drugs to be painfully boring” compounds that can be packaged in pills and easily reach their targets in the body, Petter says.
Still, Arrakis must first demonstrate that it can be done. “This is going to be hard,” Gilman says. “But hard doesn’t scare me; that was actually part of the attraction.”
Protecting plants with shape-shifting boron molecules
Founders: Stephen J. Benkovic, Gerald Fink, C. Tony Liu, Paul Schimmel, and Lucy Shapiro
Funding or notable partners: $10 million from Bill & Melinda Gates Foundation, Arch Venture Partners, Flagship Pioneering, Bayer, and Syngenta Ventures
Every year, plant diseases and pests wipe out 20–40% of the world’s crops, according to the United Nations. And while trade has given farmers access to more markets, it has also helped spread serious diseases, like the strain of fusarium wilt fungus now threatening global banana production.
Even though big agriculture firms introduce new pesticides every year, there is not an available solution for every pest problem. Indeed, two of today’s four top-selling fungicides were commercialized in the early 1960s; eventually organisms develop resistance to the old standbys. None are on hand to save bananas or the many crops vulnerable to pesticide-resistant diseases.
“Agriculture needs a new chemical platform to help with issues like resistance,” says C. Tony Liu, cofounder and chief scientific officer of Boragen.
Liu and his colleagues at Boragen have built a library of plant-pest-killing chemicals that all have one thing in common: a structure based on boron.
Today’s pesticides come from traditional carbon-, nitrogen-, sulfur-, or metal-based chemistry. Boron is overlooked, Liu says, because the activity of complex boron molecules can be hard to predict.
Credit: Yang H. Ku/C&EN/Shutterstock
Boragen is developing benzoxaborole fungicides that can be mixed with traditional fungicides. The two modes of action prevent disease organisms from developing resistance to the chemicals. Further, the boron-containing molecules' effectiveness has been fine-tuned using one of two shapes to better fit the disease target.
Liu was introduced to the idea of bioactive boron molecules—and his future Boragen cofounders—at the start of his postdoctoral research at Pennsylvania State University. He met scientists who successfully deployed boron in treatments for skin infections and other diseases, proving that boron can be used to make safe, biologically active molecules.
It turns out that agriculture has plenty of biological targets to pursue with the help of boron. That opportunity gave Boragen a spot at the new Research Triangle Park, N.C.-based AgTech Accelerator. Earlier this year, the company emerged from AgTech with $10 million in funding from accelerator investors including the Bill & Melinda Gates Foundation, Bayer, and Syngenta. Boragen’s compounds can control a range of fungal diseases in plants with a mode of action entirely different from that of traditional fungicides.
What’s more, boron compounds have low toxicity to non-target species and work synergistically with traditional fungicides, the firm says. By using both modes of action, farmers can prevent the fungal organism from rallying its means of chemical resistance.
Boragen’s lead compound is a benzoxaborole, which works by throwing a wrench in a cell’s protein-making machinery. It inhibits aminoacyl transfer RNA synthetases, enzymes responsible for attaching specific amino acids to tRNA. The resulting malformed protein doesn’t work the way it should, killing the pest.
To fine-tune the activity of boron pesticides, scientists take advantage of boron’s unusual shape-shifting ability, Liu says. Boron compounds can easily be made into a trigonal planar shape or a three-dimensional tetrahedron to better fit a target site. The two shapes allow researchers to select a negative or neutral charge.
Boragen now occupies greenhouse and laboratory space in Research Triangle Park, a hotbed of commercial agriculture research, and is testing its lead fungicide in field trials.
Liu and his growing team of boron chemists and plant scientists are still exploring the many biological pathways that boron compounds can interrupt. In addition to beating fungal disease, boron chemistry could be used to combat nematodes and livestock parasites.
“We are so excited and passionate about the boron atom,” Liu says. “It gives you flexibility that you can’t get with carbon.”
Taking artificial intelligence to the materials research lab
Founders: Bryce Meredig, Kyle Michel, and Greg Mulholland
Funding or notable partners: $7.6 million from investors including Innovation Endeavors, Prelude Ventures, and Data Collective
When Greg Mulholland and Bryce Meredig met as graduate students at Stanford Graduate School of Business in 2012, they discovered a shared interest in materials research, one which they came at from different angles. Mulholland, an electrical engineer, had previously managed R&D at a transistor materials firm. Meredig, a materials scientist, had just completed his Ph.D. at Northwestern University with a focus on using artificial intelligence (AI) in R&D. Both were interested in developing software to accelerate research in materials.
“Our backgrounds clicked naturally,” Meredig recalls. “It was a nice kind of handshake,” leading to a partnership that included Kyle Michel, a scientific computing expert Meredig met at Northwestern. The three launched Citrine Informatics, which has taken a unique tack among the armada of new companies developing AI for research.
AI has made significant inroads in laboratories in recent years, allowing researchers to glean meaning from overwhelming stores of data that traditional digital technology can’t handle. While most AI software developers initially crafted products that can be used in any research or business setting, Redwood City, Calif.-based Citrine caters strictly to the problems of one industry.
Credit: Yang H. Ku/C&EN/Shutterstock
Citrine has combined the principles of artificial intelligence and machine learning in cloud-based software that expedites and advances materials research through modeling based on in-house and publicly available data.
Launched in 2013, the company developed algorithms that allow computers to zero in on the chemical and physical laws underpinning materials research, Mulholland says. Its software was also designed to access a huge store of untapped data—information about failed experiments that is traditionally trashed. “These companies are driven by confirmation bias,” says Mulholland. “They celebrate a successful materials win, but when a material doesn’t work, they just throw that away as a failure.”
Materials science was ripe for AI, says Mulholland, looking back on his experience in commercial R&D. “We were very good at generating data about our processes and our materials, but we weren’t good at using it for anything. We didn’t do much with it other than look for pretty straightforward trends.” As a result, R&D was slower and more challenging than Mulholland felt it should have been.
He and his partners also sensed urgency, viewing the sector as on the cusp of changes that would require a leap forward in the lab. “Materials are about to take center stage in the next generation of products. The companies that will succeed will be the ones that can innovate most rapidly,” Mulholland says.
While developing ideas, the company began working with a research group at the University of California, Santa Barbara, which had put together a database on thermoelectric materials. The firm worked with other academic research groups and began marketing to industry in 2014.
Citrine isn’t naming customers, but in September, it reported that scientists from UCSB and a joint venture of General Motors and Boeing used its software to solve a long-standing challenge hindering the use of aluminum alloys in three-dimensional printing.
Citrine, which has eight Ph.D. materials chemists on its staff of 26, has completed two rounds of investment, most recently a $7.6 million series A led by Innovation Endeavors, Prelude Ventures, and Data Collective. The World Economic Forum selected the company as one of the 30 most promising technology pioneers for 2017, and Citrine won the World Materials Forum Start Up Challenge Award this year.
Mulholland says Citrine, which opened an office in Pittsburgh over the summer, has no plans to move beyond materials science, despite inquiries from other sectors, notably pharmaceuticals. “We respectfully decline,” he says, “because we are focused on advancing the next generation of advanced product development software in materials rather than for general chemistry.”
Funding or notable partners: U.S. government agency grants totaling more than $1 million, angel investor, and undisclosed AkzoNobel project funding
Undertaking multiple biotransformation steps to get to a final product could soon be old technology.
A more efficient alternative, being cooked up by Ecovia Renewables, involves deploying families of engineered microbes that can carry out multiple biotransformations seamlessly in one pot. Ecovia achieves this by engineering bacteria so that one strain consumes—and then transforms—the metabolite of another.
The firm describes its approach, named EcoSynth, as creating synthetic microbial ecosystems. “We knew we were one of few groups looking to do it this way,” says Jeremy Minty, cofounder and CEO, whose Ph.D. thesis from the University of Michigan—along with research from cofounder and chemical engineering professor Nina Lin—provides the basis for the fledgling company’s approach.
Founded in 2014, Ecovia selects target processes by identifying known chemical pathways in microbes and addressing inefficiencies at each production stage.
Credit: Yang H. Ku/C&EN/Shutterstock
Many pots go into one
By engineering families of bacteria to carry out multiple biotransformations in a single pot, Ecovia’s EcoSynth system could cut chemical production costs by almost two orders of magnitude compared to conventional processes, the firm claims.
Once a family of bugs has been engineered, the fermentation process is simple and can be fed with inexpensive raw materials, Minty says. He predicts that the commercial cost of running some of the firm’s fermentation-based processes could be almost two orders of magnitude cheaper than existing routes.
Ecovia is currently focusing on producing high-value industrial chemicals, including molecules for the personal care sector. It is working with a range of raw materials, including glycerin, an abundant by-product of biodiesel manufacturing.
The firm has a full-time staff of four. All employees—as well as an angel investor—own equity in the company. The goal is to add one or two more researchers by year-end to bolster Ecovia’s capability in downstream processing and polymer chemistry.
The firm’s approach has already attracted funding from U.S. government agencies. In April, for example, Ecovia disclosed it had been awarded a $750,000 grant by the National Science Foundation for a two-year program to develop a suite of superabsorbent polyglutamic acid-based biogels for hygiene applications, including diapers.
The biodegradable biogels will compete against synthetic polymers such as sodium polyacrylate. Success could lead to the production of fully biodegradable diapers and potentially help reduce millions of metric tons of waste every year, Minty says.
In June, the firm took a major step forward when it was chosen as one of three winners of a full partnership at AkzoNobel’s Imagine Chemistry technology competition for its polyglutamic acid-based biogels. The firm had already started developing a route to these biogels through the NSF-funded project. The AkzoNobel prize adds to this work by providing a joint development agreement to take a product to market introduction.
“Compared to our past awards, the recognition from AkzoNobel sends a strong, validating message about our business and the markets we are addressing,” Minty says. “We envision scaling up our process and launching our first products in two to three years.”
Getting a first product to market using a novel technology can be a major challenge. Ecovia is hoping its partnership with AkzoNobel will pave the way to success for its one-pot biotransformations.
Artificial intelligence cuts costs and speeds up drug discovery and design
Technology: Artificial intelligence algorithms for finding better drug candidates
Founder: Andrew Hopkins
Funding or notable partners: Evotec, GSK, Sanofi, Sumitomo Dainippon Pharma, and Sunovion
Scottish start-up Exscientia wants to dramatically reduce the time and money it takes to turn a whiteboard concept into a clinical drug candidate. And its scientists think artificial intelligence (AI) can help them do it.
It’s not as simple as saying, “Okay, computer, design me a drug,” though. Instead, says Chief Executive Officer Andrew Hopkins, Exscientia is fostering symbiotic relationships between medicinal chemists and machines. Together, Exscientia’s scientists and algorithms already completed one project for Japan’s Sumitomo Dainippon Pharma in under 12 months.
Hopkins spent 10 years at Pfizer before returning to academia for what he says was the freedom to tinker with algorithmic approaches to drug discovery and design. After five years at the University of Dundee, his team published a computational approach to crafting drugs that simultaneously bind multiple targets of interest while avoiding targets that could cause undesirable side effects (Nature 2012, DOI: 10.1038/nature11691).
Design, make, test, repeat
Exscientia’s drug discovery begins by feeding its AI algorithms mounds of existing data, which are used to design 20 first-round compounds for synthesis and testing. Those results are fed back into the algorithms for another round of designing, synthesizing, and testing.
That program formed the basis of the now-five-year-old Exscientia, whose Latin-derived name means “from knowledge.” The company hasn’t bothered raising money from external investors, preferring to make deals directly with drug companies, including Sanofi and GlaxoSmithKline. Hopkins says the program outlined in the Nature paper “only represents a very small part of our entire platform now.”
The design-make-test-repeat strategy employed by Exscientia’s algorithms should sound familiar to medicinal chemists.
First, Exscientia feeds its algorithms a hearty helping of data obtained from many sources, including the partner pharmaceutical company, scientific literature, and in-house surface plasmon resonance screening, which identifies fragments of drugs that have potential for binding a tough target (ACS Med. Chem. Lett. 2013, DOI: 10.1021/ml400312j).
The algorithm crunches the data to suggest promising compounds. Next, a chemist selects 20 realistic-to-make ones, which Exscientia’s pharma partner synthesizes and runs through a variety of screens. The results are returned to Exscientia, which embarks on another 20 compounds based on those results.
The whole cycle takes about two weeks, explains Chief Operating Officer Mark Swindells. “The speed is quite alien to some pharmaceutical companies that are happy to take two months,” he adds.
Werner Lanthaler, CEO of the German contract research firm Evotec, was intrigued and began a collaboration with Exscientia in April 2016. The two firms set out to develop a bispecific small molecule—one drug that binds two targets—to inhibit CD73 and A2AR, proteins implicated in immunosuppression of cancer.
“We picked something difficult to test-drive what Exscientia was claiming to bring to the table,” Lanthaler says. Happy with the early results, Evotec announced 18 months later that it would take an $18 million stake in Exscientia. “It is very rare that someone is overdelivering and underpromising,” Lanthaler says. “And that is the situation we have here.”
To establish itself as a designer of bispecific compounds, Exscientia also formed a pact with Sunovion to create bispecifics for psychiatric disorders. It inked a deal with Sanofi, worth up to $273 million, for discovering bispecifics that manage two aspects of metabolic disorders, such as glucose levels and weight loss. Exscientia also has a deal worth up to $43 million to deliver preclinical candidates for up to 10 targets selected by GSK.
Hopkins has a catchphrase to emphasize the computer-chemist collaboration and alleviate fear of AI-induced job loss: “This is as much about IA, or intelligence amplification, as it is about AI.”
Hopkins says the structures suggested by the algorithm are reminiscent of ones a human chemist would design. “That’s been a really important cultural breakthrough in getting human chemists and machines to work together.”
Lyotropic liquid crystals for lighting and displays
Technology: Lyotropic liquid crystals for polarizers and nanosuspensions
Founder: Marc McConnaughey
Funding or notable partners: $29.3 million in venture capital funding, including from Tokyo Electron, JSR, and Tsingda International Venture Capital
Light Polymers’ chemistry has far-reaching potential. It could make light-emitting diode (LED) lighting more practical and efficient and is also being developed for the production of organic LEDs and liquid-crystal displays (LCDs).
The South San Francisco-based firm’s products are based on lyotropic liquid crystals, molecules that have hydrophilic and hydrophobic properties. They form stable structures in water and self-assemble when coated, creating unique optical properties.
Light Polymers offers water-based lyotropic-liquid-crystal materials in two varieties. One consists of small molecules incorporating aromatic structures. The other is composed of polymeric liquid crystals based on a polyaramide backbone.
Lyotropic liquid crystals are hardly exotic. One example is the surfactants found in everyday cleaning products. “Many of the cells in our bodies, including our skin cells, contain lyotropic liquid crystals,” says Evgeny Morozov, director of product solutions for Light Polymers.
But unlike surfactants, which form spherical micelles, Light Polymers’ materials form elongated structural units. These structures can be optically anisotropic, meaning they polarize light, a useful property for LCDs and OLED displays.
Credit: Adapted from Light Polymers/C&EN
A new light
Light Polymers claims its lyotropic-liquid-crystal phosphor films convert blue light to white light more efficiently than silicone-based phosphor films do. They are also thinner and use less phosphor.
The materials are also ideal for suspending particles like the phosphors used in LEDs. The suspension is used to make a thin film that aids in the down conversion of light, in which blue light is converted into white.
In conventional LEDs, the phosphors are suspended in silicone. Marc McConnaughey, Light Polymers’ CEO, says lyotropic liquid crystals can suspend the phosphors more compactly and precisely than silicone can. The result is 25% greater conversion of light.
“You can reduce these optical and thermal losses, but more importantly, we can tune the film to emit to certain spectra,” he says.
Such tuning can make for high-quality lights like those used in museums. Or light can be tuned to the red frequencies that are becoming popular for skin treatments.
The company has plans to release a series of lighting products under the Crystallin brand. One of its first products, the GrowBlade for indoor horticulture, debuted at an agricultural technology event in New York City in September.
Another target for Light Polymers is polarizers for displays. Currently, the polarizer films in LCDs are made from polyvinyl alcohol that is dyed and stretched in a solvent-based process. Light Polymers wants to replace it with water-based chemistry. “Basically, we think we can change this $10 billion industry,” McConnaughey says.
Lyotropic liquid crystals can also be used in circular polarizers for OLEDs to prevent reflection of ambient room light. They can be coated directly onto the display without being made into a film.
Light Polymers’ technology originated in Russia. In the 1970s, the Soviet Union wanted to develop a homegrown display industry. In the late 1990s, many scientists who had worked on liquid crystals formed new companies in this field of research.
Morozov and Valery Kuzmin, now Light Polymers’ vice president of synthesis, were part of the original team working on this chemistry in Russia. After first working out of a research center’s labs in Moscow, they moved to California and then joined Light Polymers, which was founded in 2013.
The firm completed a $24.3 million series A financing round in March. In July, it raised an additional $5 million in an investment round led by Tsingda International Venture Capital and joined by the semiconductor equipment maker Tokyo Electron and the Japanese chemical firm JSR.
In October, Light Polymers agreed to form two joint ventures with the Tsinghua Innovation Center in Dongguan, China, which is supported by the government of Songshan Lake, Dongguan, and Tsinghua University. One venture is for the production of OLED polarizers and the other is for lighting.
Funding or notable partners: $9.6 million in series B funding from firms that included BASF
In 2003, 20 people were injured, some badly, when an ozonolysis reaction at DSM’s facility in Linz, Austria, went awry and the plant blew up.
Tragic events like that are why chemical companies shy away from ozonolysis in manufacturing. Research chemists also avoid the process, in part because they know it can’t readily be scaled up for commercial use.
But reacting ozone across a double bond is a simple, atom-efficient way to produce desirable diacids, aldehydes, and other oxidation products. Being able to do ozonolysis safely would open up a whole new family of reactions for industrial chemists.
That’s what P2 Science intends to do. The Connecticut-based start-up wants to use continuous-flow technology to make ozonolysis safe for chemical manufacturing.
Credit: Adapted from P2 Science/Yang H. Ku/C&EN
In P2's continuous-flow reactor system, a thin film of reactant combines with ozone as it runs down the walls of a liquid-cooled tube. The design promises safe chemistry because, compared with a batch reactor, just one one-thousandth of the volume of reactant is present at any given time.
One of P2’s founders is Paul Anastas, a synthetic organic chemist who directs the Center for Green Chemistry & Green Engineering at Yale and is often called the father of green chemistry. The firm’s other founder, and its chief science officer, is Patrick Foley, who was in the first class of Ph.D. graduates to come out of the green chemistry center.
The two scientists formed P2—named for Paul and Patrick—in 2011 to commercialize ideas coming out of the Yale program. Later that year the pair won initial seed funding from Yale-backed Elm Street Ventures. They also brought on Neil Burns, a veteran of specialty chemical companies including Pilot Chemical and Oxiteno, as CEO.
Central to P2’s strategy, Burns says, is its continuous-flow technology, patented with the European engineering firm Desmet Ballestra.
“Ozonolysis has been around for decades,” Burns notes. Like most specialty and fine chemical reactions, traditional ozonolysis is a batch process. It involves bubbling an O3-air mixture into a large reactor over eight hours. The reaction is highly exothermic and can create unstable by-products. In P2’s continuous process, the volume of reactants is one one-thousandth of that in a batch process, and the reaction time is measured in minutes, not hours, Burns says.
P2 is initially targeting aldehyde and ketone fragrance chemicals made by reacting ozone with renewable fatty acids and terpenes. Development agreements with flavor and fragrance companies including Bedoukian Research and Symrise are yielding both new molecules and renewable versions of existing molecules now derived from petrochemicals, Burns says.
The firm has been producing pilot-scale quantities of these compounds at its Woodbridge, Conn., facility. In February, it completed a $9.6 million series B round of financing that was co-led by Xeraya Capital and the venture capital arm of the chemical giant BASF. Burns says P2 will use the money to build its first commercial plant, where its flavor and fragrance molecules will be turned out in larger quantities, and new products, such as surfactants, will be pursued.
At the new facility, P2 will also scale up a vegetable-oil-based route to azelaic acid. This versatile diacid is now made mainly by Emery Oleochemicals, which calls itself the world’s largest industrial producer and consumer of ozone, at a plant in Cincinnati.
Azelaic acid is used in acne and skin-whitening products as well as industrial goods such as polyesters and polyamides. Burns and his colleagues see potential to expand the market further with P2’s safe, continuous ozonolysis process.
Probing protein motion to tackle tough drug targets
Founders: Matthew Jacobson, Dorothee Kern, Mark Murcko, and D. E. Shaw Research
Funding or notable partners: $57 million from Third Rock Ventures
In 2008, Mark Murcko spent the better part of a year thinking about a vexing problem: how to find hidden pockets and footholds on seemingly smooth proteins that, if targeted with a drug, could be the key to controlling their activity. Murcko, then-chief technology officer at Vertex Pharmaceuticals, was convinced that if he could just see a protein’s real-world behavior—the twists, stretches, and bows as it goes about its daily routine—those so-called allosteric sites would reveal themselves.
But he couldn’t figure out a good way to watch that delicate dance. “The conclusion I came to in 2008 was that it was too soon,” Murcko recalls. “The technologies were just not available, or were too primitive.”
Fast-forward to 2017, and Murcko is now chief scientific officer at Relay Therapeutics, where he is finally scratching his decade-old itch. Launched last year with $57 million in funding from the life sciences venture capital firm Third Rock Ventures, Relay has assembled a collection of edgy technologies that allow it to capture protein motion. The company will initially use the technology platform to go after tough cancer targets.
Credit: Relay Therapeutics/C&EN/Shutterstock
Previously unavailable technologies let Relay capture protein motion, revealing new pockets and crevices for docking small molecules.
So what does it take to create a molecular movie? Relay exploits a multitude of recent advances. For example, when Murcko was mulling protein motion a decade ago, chemists commonly relied on X-ray crystallography to create three-dimensional images of a protein. But those pictures were developed at cryogenic temperatures; today, it’s possible to do crystallography at room temperature, better replicating how a protein exists in the real world.
Other advances include new screening technologies that detect the conformational changes a protein undergoes when a ligand docks to it; DNA-encoded libraries that provide a more diverse chemical palette than traditional small-molecule libraries; and computational power from partner D. E. Shaw Research that allows molecular motion simulations thousands of times as fast as previously possible.
Putting these tools together, Relay develops protein motion hypotheses that it uses to pursue targets when there is a clear line from a gene to a disease. Among the more notorious examples of impenetrable targets is the oncogene KRas, which is known to be mutated in a large swath of cancers.
“Sometimes the target is extremely well validated—like KRas. If only we could make a great drug against such a well-validated target, we’re pretty darn sure it’s going to provide a benefit for patients,” Murcko says. “Those are the kinds of targets we’re focused on.”
In the last year, Relay scientists have been able to create molecules that bind to proteins that have been “like Teflon” for the industry, Chief Executive Officer Sanjiv Patel says. The biotech firm’s two most advanced drug discovery campaigns are already in lead optimization, and the researchers have created chemical matter against one target that Patel says has never been drugged before.
The key isn’t accessing these technologies but figuring out how to use them efficiently, Patel says. “A big part of what this team has done is learn how best to deploy each technology—and the collection of technologies—to address the critical questions of each drug program.”
As it moves toward its first clinical studies, anticipated to begin in 2019, Relay is expanding its team, which should hit 50 people by the end of the year. The biotech firm is in the market for a new space that will give it room to expand into a fully integrated pharmaceutical company. “I’ve come to build a company that is sustainable and will be here for the long term,” Patel says.
Developing solid electrolytes for safer, high-energy batteries
Founders: Doug Campbell, Sehee Lee, and Conrad Stoldt
Funding or notable partners: In the process of raising $15 million
Automakers have their pedals to the metal when it comes to developing battery-powered cars, but electrochemists still have their work cut out to deliver the battery performance and safety that large-scale adoption requires.
Current lithium-ion batteries typically operate with a lithium-ion cathode, graphite anode, and liquid electrolyte. But liquid electrolytes can become dangerously hot and catch fire. A safer solution—and one that could also facilitate greater energy density—is to switch to a solid electrolyte.
Solid Power, a spin-off from the University of Colorado, Boulder, claims its lithium-sulfide solid electrolyte can be produced at about the same cost as a liquid electrolyte. And batteries containing the solid electrolyte can store more energy than traditional batteries of the same size.
In tests, Solid Power’s electrolyte operates safely at temperatures of about 150 °C—an environment in which many liquid electrolytes would catch fire.
When a lithium-ion battery charges and discharges, the ions flow through its electrolyte between its electrodes. Solid Power is trying to use sulfur-based solid electrolytes, which are safer at higher temperatures than flammable liquid electrolytes are. Unlike liquid-electrolyte batteries, which use carbon or graphite anodes, solid electrolytes can also be used with a lithium metal anode, markedly boosting energy density.
Combining the electrolyte with a lithium metal anode can bring the energy density of Solid Power’s battery cells to 400–500 Wh/kg. This is more than twice the density of conventional liquid-electrolyte cells that use standard graphite anodes, says CEO and cofounder Doug Campbell.
Its two other cofounders, Conrad Stoldt and Sehee Lee, started the company in 2012 with the aim of developing cathode materials based on their research at CU Boulder. But in 2016, the firm switched to sulfide-based solid electrolytes after securing an exclusive license to commercialize technology developed by Oak Ridge National Laboratory.
Campbell is convinced Solid Power is developing the right technology at the right time. “The automotive industry is really starting to embrace the concept of solid-state batteries,” he says.
Historically, a problem with sulfide-based electrolytes has been the material’s brittleness, which can cause structural problems in a battery, according to Frank P. McGrogan, a Ph.D. candidate at Massachusetts Institute of Technology who published research on the topic earlier this year (Adv. Energy Mater. 2017, DOI: 10.1002/aenm.201602011). “You have to design around that knowledge,” McGrogan notes.
Solid Power says low-temperature processing of its electrolyte allows it to use polymer binders that mitigate brittleness. Meanwhile, the firm’s proprietary electrode and electrolyte separator chemistry and coating process ensure efficient transfer of lithium ions between electrodes, Campbell says.
A couple of months ago, Solid Power relocated to Louisville, Colo. There, the firm is starting to install what it calls prepilot production facilities where it can make hundreds of automotive-scale battery cells per month.
The firm recently initiated a series A financing round led by the battery manufacturer A123 Systems to raise $15 million to fund research and outfit the firm’s new battery assembly center.
Solid Power already has a multi-million-dollar joint development agreement with one European car company and is looking to add similar deals. Its goal is to get solid-state batteries into commercial electric cars in the next five to 10 years.
Solid electrolyte batteries can be very strong, and someday they could actually form part of a car’s structure. In the meantime, Solid Power is working to roll out solid-state cells for niche military and aerospace applications.
Two Pore Guys
Handheld nanopore sensor rivals accuracy of lab equipment
Founders: William Dunbar, Dan Heller, and Trevor Morin
Funding or notable partners: $31.5 million from Khosla Ventures and other backers
Dan Heller and William Dunbar call their molecular detection start-up Two Pore Guys because the firm’s technology relies on silicon nitride nanopores and because they thought the name was funny.
Heller, a computer scientist with an entrepreneurial streak, and Dunbar, a former computer engineering professor at the University of California, Santa Cruz, can afford to joke around. In April, their six-year-old company raised $24.5 million from the savvy Silicon Valley investor Vinod Khosla. Heller and angel investors previously kicked in about $7 million.
With the newly raised funds, Two Pore Guys hopes to get its handheld detector and disposable nanopore-enabled test strips into the hands of assay developers next year. Those developers will use Two Pore Guys’ hardware to design rapid, low-cost tests for viruses such as HIV and Zika, food-borne pathogens, and environmental contaminants.
A vote of confidence came last month from Monsanto, which agreed to evaluate the firm’s detection system for biomolecules in crops, pests, and pathogens.
Credit: Yang H. Ku/C&EN/Shutterstock
Blood, saliva, or another analyte is dispensed on a slide that is then inserted into a detection device. Microfluidic channels conduct the sample to a silicon nitride-nanopore chip. A charge from the detector pulls molecules across the chip, detects signals produced by the molecules, and sends them to a computing device for interpretation. Results can be displayed on the detector's screen.
Heller describes the battery-operated detector as a fast, “single-molecule-sensing platform with the accuracy, precision, and sensitivity of reference lab equipment” such as high-performance liquid chromatography/mass spectrometry instruments and fluorescence detection systems.
“We can cut out a lot of equipment, time, and cost with our device,” Heller says.
The basic technology for using nanopores as measuring tools has been around for 20 years, Heller acknowledges. Oxford Nanopore Technologies and Illumina, for instance, both use biological nanopores for DNA sequencing. Some of the technology to do that originated at UCSC, where Dunbar worked with nanopore pioneers David Deamer and Mark Akeson.
But Two Pore Guys’ technology, in part developed by a third founder—UCSC researcher Trevor Morin, who joined the firm in 2013—isn’t intended to sequence DNA, at least for now. Instead it is designed to screen for electronic signals from molecules such as disease-causing agents or environmental contaminants.
At the heart of Two Pore Guys’ detection system is a test strip etched with a microchannel leading to a silicon nitride chip with a 25- to 125-nm hole. The slide-plus-chip combo costs about 50 cents when made in low volumes; it could be much cheaper if made in high volumes in an electronics factory, Heller says.
The analysis gets under way when a user inserts the test strip into the handheld detector. A sample, placed on the reagent-containing strip, passes through the channels to the chip, where an electric current from the reader pulls molecules across the nanopore.
Apps loaded into the detector and specifically designed for each assay allow the reader to recognize and count the electronic signals from targets of interest as they pass through the nanopore. The detector transmits the raw data for interpretation to a smartphone or tablet. Results can be displayed on the detector’s screen.
The company—which has 70 employees, up from 50 earlier this year—is now ramping up device and test strip manufacturing, Heller says. “If you want to rapidly detect a molecule,” he says, “you’ll want our device.”