bioengineering
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Pivot Bio rakes in $430M round D as modified microbes prove their worth in agriculture
Pivot Bio makes fertilizer — but not directly. Its modified microorganisms are added to soil and they produce nitrogen that would otherwise have to be trucked in and dumped there. This biotech-powered approach can save farmers money and time and ultimately may be easier on the environment — a huge opportunity that investors have plowed $430 million into in the company’s latest funding round.
Nitrogen is among the nutrients crops need to survive and thrive, and it’s only by dumping fertilizer on the soil and mixing it in that farmers can keep growing at today’s rates. But in some ways we’re still doing what our forebears did generations ago.
“Fertilizer changed agriculture — it’s what made so much of the last century possible. But it’s not a perfect way to get nutrients to crops,” said Karsten Temme, CEO and co-founder of Pivot Bio. He pointed out the simple fact that distributing fertilizer over a thousand — let alone ten thousand or more — acres of farmland is an immense mechanical and logistical challenge, involving many people, heavy machinery and valuable time.
Not to mention the risk that a heavy rain might carry off a lot of the fertilizer before it’s absorbed and used, and the huge contributions of greenhouse gases the fertilizing process produces. (The microbe approach seems to be considerably better for the environment.)
Yet the reason we do this in the first place is essentially to imitate the work of microbes that live in the soil and produce nitrogen naturally. Plants and these microbes have a relationship going back millions of years, but the tiny organisms simply don’t produce enough. Pivot Bio’s insight when it started more than a decade ago was that a few tweaks could supercharge this natural nitrogen cycle.
“We’ve all known microbes were the way to go,” he said. “They’re naturally part of the root system — they were already there. They have this feedback loop, where if they detect fertilizer they don’t make nitrogen, to save energy. The only thing that we’ve done is, the portion of their genome responsible for producing nitrogen is offline, and we’re waking it up.”
Other agriculture-focused biotech companies like Indigo and AgBiome are also looking at modifying and managing the plant’s “microbiome,” which is to say the life that lives in the immediate vicinity of a given plant. A modified microbiome may be resistant to pests, reduce disease or offer other benefits.
Image Credits: Pivot Bio
It’s not so different from yeast, which as many know from experience works as a living rising agent. That microbe has been cultivated to consume sugar and produce a gas, which leads to the air pockets in baked goods. This microbe has been modified a bit more directly to continually consume the sugars put out by plants and put out nitrogen. And they can do it at rates that massively reduce the need for adding solid fertilizer to the soil.
“We’ve taken what is traditionally tons and tons of physical materials, and shrunk that into a powder, like baker’s yeast, that you can fit in your hand,” Temme said (though, to be precise, the product is applied as a liquid). “All of a sudden managing that farm gets a little easier. You free up the time you would have spent sitting in the tractor applying fertilizer to the field; you’ll add our product at the same time you’d be planting your seeds. And you have the confidence that if a rainstorm comes through in the spring, it’s not washing it all away. Globally about half of all fertilizer is washed away… but microbes don’t mind.”
Instead, the microbes just quietly sit in the soil pumping out nitrogen at a rate of up to 40 pounds per acre — a remarkably old-fashioned way to measure it (why not grams per square centimeter?), but perhaps in keeping with agriculture’s occasional anachronistic tendencies. Depending on the crop and environment, that may be enough to do without added fertilizers at all, or it might be about half or less.
Whatever the proportion provided by the microbes, it must be tempting to employ them, because Pivot Bio tripled its revenue in 2021. You might wonder why they can be so sure only halfway through the year, but as they are currently only selling to farmers in the northern hemisphere and the product is applied at planting time early in the year, they’re done with sales for the year and can be sure it’s three times what they sold in 2020.
The microbes die off once the crop is harvested, so it’s not a permanent change to the ecosystem. And next year, when farmers come back for more, the organisms may well have been modified further. It’s not quite as simple as turning the nitrogen production on or off in the genome; the enzymatic pathway from sugar to nitrogen can be improved, and the threshold for when the microbes decide to undertake the process rather than rest can be changed as well. The latest iteration, Proven 40, has the yield mentioned above, but further improvements are planned, attracting potential customers on the fence about whether it’s worth the trouble to change tactics.
The potential for recurring revenue and growth (by their current estimate they are currently able to address about a quarter of a $200 billion total market) led to the current monster D round, which was led by DCVC and Temasek. There are about a dozen other investors, for which I refer readers to the press release, which lists them in no doubt a very carefully negotiated order.
Temme says the money will go toward deepening and broadening the platform and growing the relationship with farmers, who seem to be hooked after giving it a shot. Right now the microbes are specific to corn, wheat and rice, which of course covers a great deal of agriculture, but there are many other corners of the industry that would benefit from a streamlined, enhanced nitrogen cycle. And it’s certainly a powerful validation of the vision Temme and his co-founder Alvin Tamsir had 15 years ago in grad school, he said. Here’s hoping that’s food for thought for those in that position now, wondering if it’s all worth it.
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Cutting out carbon emitters with bioengineering at XTC Global Finals on July 22
Bioengineering may soon provide compelling, low-carbon alternatives in industries where even the best methods produce significant emissions. Utilizing natural and engineered biological process has led to low-carbon textiles from AlgiKnit, cell-cultured premium meats from Orbillion and fuels captured from waste emissions via LanzaTech — and leaders from those companies will be joining us onstage for the Extreme Tech Challenge Global Finals on July 22.
We’re co-hosting the event, with panels like this one all day and a pitch-off that will feature a number of innovative startups with a sustainability angle.
I’ll be moderating a panel on using bioengineering to create change directly in industries with large carbon footprints: textiles, meat production and manufacturing.
AlgiKnit is a startup that is sourcing raw material for fabric from kelp, which is an eco-friendly alternative to textile crop monocultures and artificial materials like acrylic. CEO Aaron Nesser will speak to the challenge of breaking into this established industry and overcoming preconceived notions of what an algae-derived fabric might be like (spoiler: it’s like any other fabric).
Orbillion Bio is one of the new crop of alternative protein companies offering cell-cultured meats (just don’t call them “lab” or “vat” grown) to offset the incredibly wasteful livestock industry. But it’s more than just growing a steak — there are regulatory and market barriers aplenty that CEO Patricia Bubner can speak to, as well as the technical challenge.
LanzaTech works with factories to capture emissions as they’re emitted, collecting the useful particles that would otherwise clutter the atmosphere and repurposing them in the form of premium fuels. This is a delicate and complex process that needs to be a partnership, not just a retrofitting operation, so CEO Jennifer Holmgren will speak to their approach convincing the industry to work with them at the ground floor.
It should be a very interesting conversation, so tune in on July 22 to hear these and other industry leaders focused on sustainability discuss how innovation at the startup level can contribute to the fight against climate change. Plus it’s free!
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Allozymes looks to upend chemical manufacturing with rapid enzyme engineering and $5M seed
Part of the complex process that turns raw materials into finished products like detergents, cosmetics and flavors relies on enzymes, which facilitate chemical transformations. But finding the right enzyme for a new or proposed drug or additive is a drawn out and almost random process — which Allozymes aims to change with a remarkable new system that could set a new standard in the industry, and has raised a $5 million seed round to commercialize.
Enzymes are chains of amino acids, the “building blocks of life” among the many things encoded in DNA. These large, complex molecules bind to other substances in a way that facilitates a chemical reaction, say turning sugars in a cell into a more usable form of energy.
One also finds enzymes in the world of manufacturing, where major companies have identified and isolated enzymes that perform valuable work like taking some cheap base ingredients and making them combine into a more useful form. Any company that sells or needs lots of any particular chemical that doesn’t appear abundantly in nature probably has enzymatic processes to aid in creating more of it.
But it’s not like there’s just an enzyme for everything. When you’re inventing new molecules from scratch, like a novel drug or flavoring, there’s no reason why there should be a naturally occurring enzyme that reacts with or creates it. No animal synthesizes allergy medicine in its cells, so companies must find or create new enzymes that do what’s needed. The problem is that enzymes are generally at least 100 units long, and there are 20 amino acids to choose from, meaning for even the simplest novel enzyme you’re looking at uncountably numerous variations.
By starting with known enzymes and systematically working through variations that seem intuitively like they might work, researchers have been able to find new and useful enzymes, but the process is complex and slow even when fully automated: at most a couple hundred a day, and that’s if you happen to have a top-of-the-line robotic lab.
So when Allozymes comes in with a claim that it can screen up to ten million per day, you can imagine the level of change that represents.
Image Credits: Allozymes
Allozymes was founded by Peyman Salehian (CEO) and Akbar Vahidi (CTO), two Iranian chemical engineers who met while pursuing their PhDs at the National University of Singapore. The three years of research leading up to the commercial product also occurred at NUS, which holds the patent and exclusively licenses it to the company.
“The state of the art hasn’t changed in 20 years,” said Salehian. “When we talk with big pharma, they have whole departments for this, they have $2 million robots, and it still takes a year to get a new enzyme.”
The Allozymes platform will speed up the process by several orders of magnitude, while decreasing the cost by an order of magnitude, Salehian said. If these estimates bear out, it effectively trivializes the enzyme search and obsoletes billions in investments and infrastructure. Why pay more to get less?
Traditionally, enzymes are isolated and selected over a multi-step process that involves introducing DNA templates into cells, which are cultured to create the target enzymes, which once a certain growth state is achieved, are analyzed robotically. If there are promising results, you go down that road with more variations, otherwise you start again from the beginning. There’s a lot of picking and placing little dishes, waiting for enough cells to produce enough of the stuff, and so on.
The process, designed by Vahidi and other researchers at NUS, is fully contained with a benchtop device, and generates almost no waste. Instead of using culture dishes, the device puts the necessary cells, substrate, and other ingredients in a tiny droplet in a microfluidic system. The reactions occur inside this little drop, which is incubated, tracked, and eventually collected and tested in a fraction of the time a larger sample would take.
Allozymes isn’t selling the device, though. It’s enzyme engineering as a service, and for now their partners and customers seem content with that. Its primary service is cut-to-size, depending on the needs of the project. For instance, maybe a company has a working enzyme already and just wants a variant that’s easier to synthesize or less dependent on certain expensive additives. With a solid starting point and flexible goal that might be a project on the smaller side. Another company may be looking to completely replace hard chemistry processes in their manufacturing, know the start and the end of the process but need an enzyme to fill in the gaps; that might be a more wide ranging and expensive project.
Peyman Salehian, left, and Akbar Vahidi.
Vahidi explained that the goal is not to “democratize” enzyme engineering. It’s still expensive and large-scale enough that it will primarily be done by large companies, but now they can get a hundred thousand times more out of their R&D dollar. The speed and value put them above the competition, said Salehian, with companies like Codexis, Arzeda, and Ginkgo Bioworks also doing enzyme bioengineering but at lower rates and with different priorities.
Occasionally the company might strike a bargain to take part ownership of an IP or product, but that’s not really the business model, Salehian said. Some early work consisted of actually making the final compound, but ultimately the core product is expected to be the service. (Still, a million-dollar order is nothing to sneeze at.)
It may have occurred to you that in the process of doing a job, Allozymes might sort through hundreds of millions of enzymes. Rest assured, they are well aware of the value these may represent. The service transitions seamlessly into the inevitable data play.
“If you have a big data set that shows ‘if you change this amino acid this will be the function,’ you don’t even need to engineer it, you can eliminate it [i.e. from consideration]. You can even design enzymes if you know enough,” Salehian said.
The company’s recent $5 million seed round was led by Xora Innovation (from Temasek, Singapore’s sovereign fund), with participation from SOSV’s HAX, Entrepreneur First and TI Platform Management. Salehian explained that they planned to incorporate in the U.S. following interest from American venture firms, but Temasek’s early-stage investor convinced them to stay.
“Biotransformation is in huge demand on this side of the world,” Salehian said. “Chemical, agriculture, and food companies need to do it, but no platform company can deliver these services. So we tried to fill that gap.”
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Zbiotics says it’s bioengineered a hangover cure
Y Combinator backed Zbiotics has spend two years developing what they’re billing as the world’s first genetically engineered probiotic. The startup’s initial product isn’t exactly world-changing but it might just save your day — given they’ve invented an elixir of ‘next day’ life: Aka a hangover cure.
Although you actually have to take it before — or, well, during — drinking rather than waiting until the moment of regretful misery when you wake up.
How have they done this? For their first product they’ve bioengineered probiotic bacteria to produce more of the enzyme that the body naturally uses to break down a toxic chemical byproduct of alcohol which is in turn responsible for people feeling awful after too many alcoholic drinks. So you could say they’re hoping to put probiotics on steroids. (NB: No actual steroids are involved, obviously.)
While probiotics themselves aren’t at all new, having been in the human diet for thousands of years — with wide acceptance that certain strains of these live ‘friendly’ bacteria/microorganisms can be beneficial for things like human gut health — the team’s approach of using gene editing techniques (specifically fiddling with the bacteria’s DNA) to enhance what a probiotic can deliver to the person who’s ingested it is the novel thing here.
So new they haven’t yet conducted the placebo controlled, peer-reviewed clinical trials that will ultimately be necessary to back up the efficacy claims they’re making for their biotech enhanced hangover cure.
Nor are they therefore in a position to defend their forthcoming hangover elixir from accusations of supplementary ‘snake oil’ — and, well, the supplement industry as a whole often has that charge leveled at it. And yet people keep buying and popping its pills. (Therein lies the temple rub, vitamin potion and wellness capsule. And, well, also the investor appetite for carving a fresh chunk out of a very large pie.)
Zbiotics co-founders Zack Abbott and Stephen Lamb freely admit it’s going to be a challenge to stand out — and be considered credible amid all this, er, goop noise.
“This consumer space is rife with pseudo science,” agrees Abbott, who has a PhD in microbiology and immunology from the University of Michigan. “Everybody is banging the drum of real science. And so we have a huge challenge to differentiate ourselves. And really convince the consumer that we’ve built something specific.
“And it really is a first effort to invent a product to specifically address their problem, as opposed to grabbing vitamins off a shelf, putting them in a bottle and labelling it.”
“There are some companies… [that] address dehydration [for hangovers]; that’s not enough. There are other companies they just put [vitamins] into a bottle, that’s not enough. There’s so much noise out there. How do we break through that? It could take some time,” admits Lamb. “And it could take a lot of work.”
Tested in vitro — and on birthday beers
At this pre-launch stage, the founders say they’ve tested their beefed up probiotic on themselves — and will go so far as to say they’ve seen “promising results”.
“I had the fortune of having the final prototype built just a week or two before my birthday and so I ended up trying it out for my birthday and it was great,” adds Abbott.
They are also keen to say they don’t want to encourage irresponsible drinking. So don’t expect their future marketing to talk about ‘a biotech license for your next bender’. Product pricing is tbc but they say they’re aiming for widely affordable, rather than lux or overly premium.
With hangover results that could speak for themselves, their hope is that people will feel confident enough to have a pop and see whether the idea of a biotech enhanced probiotic that’s pumping out extra alcohol-metabolizing enzymes stands up to several pints of lager and a few chasers (or not).
Though — when asked — they do say they also want to carry out clinical trials to glean data on the efficacy of their hangover cure.
“We are a very science-first company and so we don’t want to be making any claims about anything that we don’t have data to back up,” says Abbott.
“At this point… we’ve done significant testing in a test tube, in vitro, and shown that the bacteria we’ve built do perform the function that they’re supposed to perform. Which is to break down acetaldehyde. But we can’t make further health claims until we do clinical trials. And we in the process of drafting up a protocol for a human clinical study with one of our scientific advisors — Dr Joris Verster — a world expert in academic hangover research. But in the meantime we can’t make those claims until we have that.”
They are also planning to launch a crowdfunding campaign later this year — in order to start making some of their own noise and trying to drum up interest and, well, willing guinea pigs.
Though they are also adamant the product is entirely safe. It’s just the efficacy vs hangover misery that’s yet to be stood up in human clinical trials.
While a hangover cure might seem a trivial problem to focus high tech bioengineering effort on, they say the unmissable fact of a hangover — or indeed the lack of one — was one of the reasons why they selected such an “everyday problem” for the first application of their technique vs going for a more fuzzy (and, well forgiving on the efficacy front) generic goal like ‘wellness’. Or indeed targeting an issue where a ‘cure’ is pretty subjective and hard to quantify (like anti-aging).
Absolutely no one is going to mistake a hangover for feeling great. Though of course the power of the placebo effect working its psychological magic cannot be ruled out — not until they’ve clinically tested their stuff against it in robust trials.
On the other hand, even if it ends up that a placebo effect is what’s making people feel better, given that the target problem is (just) a hangover there aren’t likely to be too many consumer complaints and cries for money back.
“One of the reasons why we chose this use-case was that it would allow people to try it and feel the advocacy for themselves. That was very important,” says Abbott. “It’s something you can feel the results of. So that was really important. Having a visceral read-out of efficacy. People can experience the product working for themselves.”
The other reason for choosing a hangover cure was more practical: They needed a problem that could be solved with an enzyme and therefore which could be helped by genetically engineering bacteria to produce more of the sought for substance.
“The whole point here is that we’ve engineered a bacteria to express an enzyme specifically that can solve a problem,” he explains. “Enzymes are these really powerful complex molecules that are not easy to deliver to people. So it has to be a problem that you can solve with an enzyme.
“There has to be a nice fit with the technology. So we look for things where parts of the body where bacteria has access to you; you have a lot of bacteria in your gut, in your skin, in your mouth, in your nose… places were we can deliver bacteria and they can express these enzymes to solve problems of everyday health.”
“We start with probiotics that have an extremely good safety profile, have been used in regular food by humans for centuries. And we identify those because we know that they’re going to be safe, and we know that they’re going to be able to interact with your body in the way that we want them to. And then we engineer those bacteria as oppose to choosing something that your body may never have seen before,” adds Lamb, who brings prior experience helping food companies enter new markets to the startup.
He says they’ve been safety testing their prototype probiotic for the past year and change at this point — “making sure that this is ready for market before we actually launch anything”.
“We are not going to launch any kind of product until it’s completely safety tested according to every regulatory framework here in the U.S. — and we’re totally comfortable with that,” he adds emphatically.
They do also intend to move beyond hangover cures, with the plan being to develop additional probiotics that target other use-cases. And say they’ve been building a gene editing platform that’s flexible for that purpose. Though they’re not disclosing exactly what else they’re working on or eyeing up — wanting to keep that powder dry for now.
“I spent over a year building the first product, and the lion’s share of that time was spent making sort of a genetic platform… that was adaptable to multiple use-cases,” says Abbott. “At first I just engineered the bacteria to be able to make a lot of enzyme generally. Whatever enzyme I put into the platform. And so the first enzyme I put in was to break down acetaldehydes. That being said it could be easily switched out for an enzyme to break down… a different toxin that your body has to deal with. So the platform is very adaptable and it was designed to be that way.”
“That being said there are certain use-cases we’re really excited about that may require additional optimization techniques in order to make them work specifically for that use-case. So, generally speaking, some may require more work than others but the platform we started with gives us a good launch pad,” he adds.
As well as YC’s standard startup deal, the team has raised an additional $2.8M in seed funding this year for R&D and the initial product roadmap. They’re hoping the forthcoming crowdfunding campaign will give them the additional lift to ship the consumer product into the US market.
Investors in the seed round aren’t being disclosed at this stage. Abbott also notes that he previously got a small amount of pre-seed funding, early on, to fund building the prototype.
It’s fair to say that biotech as an investment space isn’t a bet for every investor — given product development risks, timeframes and perhaps also some of the deflated hype of past years. Which perhaps explains why Zbiotics investors aren’t ready to shout all about it just yet. Even if they’re feeling great about not having a hangover.
“We’ve found different levels of success with different investors,” agrees Lamb. “Where we’ve found the most success is in investors who see the vision for the technology and understand it as something that is and can be truly innovative relative to what’s on the market today. So probiotics themselves — traditional probiotics — are a $40BN industry, and the fact is that most of those probiotics don’t do anything or are inconsistent at best. So we found investors who have a mindset where they can see how a novel probiotic, something that actually is engineered to work and is based in a high level of biotech is something that can really disrupt that area. And that may or may not be traditional biotech investors. Oftentimes it’s investors who are really looking to push the envelope.
“We definitely had to find the right investor and the traditional biotech investor often is looking for different things than we had to offer,” adds Abbott. “And different pathways — more traditional pathways. We’re going not conventionally I think with bringing this hard biotech to market quickly. So it definitely is threading the needle and finding the right investors.”
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