Form Bio team at their office in Austin, TX.
If you were tasked with resurrecting an extinct animal, where would you even begin?
Colossal Biosciences, a synthetic biology company founded in 2021 by a Harvard geneticist George Church and entrepreneur Ben Lamm, thought a good place to start was sequencing the remains of woolly mammoths that they dug up from the Arctic permafrost. The frozen bodies of these prehistoric creatures were nearly perfectly preserved and unveiled 3.1 billion letters of the extinct animal’s genetic code. Sequencing the entire woolly mammoth genome was, no doubt, a significant step. But with it, came the arduous task of figuring out which parts of that code made the woolly mammoth so well adapted to cold climates and how to bring cold-loving elephants back to life.
Teasing out meaning from billions of letters of DNA is a colossal computational task. The mammoth genome has enough letters to write 6888 novels – roughly ten times the number of books an average person will read in their lifetime. But the team’s goal was not just to read it, but to find the differences between the woolly mammoth and its closest living relative, the Asian elephant. Turns out, the two share 99.96% of their genome, but the remaining 0.04% make all the difference. Colossal wants to edit those genes into an elephant embryo using CRISPR to bring back the megafauna that once roamed the Earth. But first, they need to identify which of those genes to target.
To tackle this problem, they created a custom computational pipeline capable of analyzing vast amounts of bioinformatics data. They developed special tools to search, understand, and compare genomes, design CRISPR edits, and more. The founders of the company quickly realized the value of what they had built and how these tools could benefit the broader scientific community. As a result, a new company, called Form Bio, was spun out of Colossal Biosciences with a mission to help scientists analyze data and reach breakthroughs easier and faster.
Form Bio was launched last September with an oversubscribed $30 million Series A financing round. The company’s product is a comprehensive software platform that replaces cumbersome, code-heavy bioinformatics processes with user-friendly, visual software. And there are plenty of scientists who cannot wait to get their hands on it. A big pain point for many biologists is having to learn to code in order to do their job. It catches many by surprise: someone who is interested in understanding the intricate workings of living organisms, may not expect to also have to learn programming languages.
But as biology moves from bench science to data science, the ability to handle vast amounts of sequence data and run bioinformatics workflows has become an integral part of the job. To make biologists’ jobs easier, Form Bio has assembled a team of world-class software developers, life scientists, and data science experts at their Texas headquarters to create a solution that would make the computational side of synthetic biology more user-friendly. Experts from the team, including Form Bio’s Chief Strategy Officer Claire Aldridge and Product Manager Ami Elliott, will be speaking at the SynBioBeta Global Synthetic Biology Conference this May.
“Biologists are asked to also be bioinformaticists,” says Olivia Stearn, MarCom Director at Form Bio. “And so, we're trying to automate out some of the steps that might lead to bottlenecks and longer timelines in both construct design for manufacturing and data analysis.”
Form Bio’s platform integrates core components of data management, analysis, results visualization, and collaboration that allows researchers to access validated workflows and wrangle the terabytes of data hidden in DNA. For example, they have created workflows for analyzing RNA sequencing data to help make meaning of the gene expression patterns inside cells. This type of analysis usually involves learning multiple software packages and potentially some coding, making it largely inaccessible to anyone who has not been specifically trained in this type of data processing. But Form Bio makes it easy for anyone with an understanding of biology to run these workflows:
“The way that we like to think about Form Bio is that it's a platform to enable synthetic biology,” explains Stearn. “Typical synbio organizations have heavy R&D investment on the science side of things, but the data science side might be under-resourced. Our platform is a one-stop shop for all things data management, visualization, analysis, workflows, and collaboration.”
As such, the platform facilitates preparing data for publications, grant proposals, patent applications, and conversations with stakeholders. And the benefit from it may spread well beyond the customer base: the stakeholders, in this case, encompass almost every citizen of our planet.
Big stakes
Form Bio’s first customer, not surprisingly, is their parent company Colossal. Keeping up with its original purpose, Form Bio is still the computational power behind resurrecting the woolly mammoth. And that effort is gaining speed: Colossal has just closed a $150 million Series B funding round to add to the $60 million they had raised in Series A. The investor support is a testimony to the significance of their work: the team at Colossal is re-creating extinct animals not just to show off their gene editing skills or to bring Jurassic Park to life. They are doing it to save the planet.
The woolly mammoth was once a keystone species – an essential animal that shaped and supported an entire ecosystem. Its native habitat stretched across the arctic plains of Eurasia and North America. This was once a vast steppe of grasses and low shrubs that flourished every summer, capturing carbon from the air and storing it for centuries in the thick layer of permafrost. But now, with the temperature of our planet rapidly rising, the 1,600 billion metric tons of carbon that is stored in the topsoil of the Arctic tundra – most of it in the form of potent greenhouse gas methane – threatens to be released.
The woolly mammoths, along with other large herbivores like reindeer, bison, and wild horses, used to roam these plains. Large herds of animals contributed to the preservation of the northern grasslands by stomping out young trees, which allowed the soil to stay colder and keep the organic carbon stored securely in its depths. Packing down the topsoil could lower the temperature of the permafrost by as much as 4 degrees Celsius
Ice Age Playground
The hypothesis that the reintroduction of ancient megafauna could play a major role in protecting our current climate has been put out by a Russian scientist Sergey Zimov, the creator of the Pleistocene Park. The 20-square-kilometer nature preserve has been established in an effort to restore the health of the mammoth steppe ecosystem. This massive real-world experiment includes the repopulation of the ecosystem with ice-age animals to keep the arctic soil frozen.
Colossal’s founders share that ambitious vision and are working to tackle it from the synthetic biology side. Their plan is not to clone the woolly mammoth, as some have suggested, but rather to introduce the cold-tolerant traits into its closest living relative, the Asian elephant, to create a genetically modified version with twenty or so genome edits. Even a few years ago, this task seemed impossible to accomplish. However, last year scientists have demonstrated that this could be done in pigs engineered for human organ transplantation. The science to edit genomes is already there. It is the computational part that remained rather difficult. Now, the advances in bioinformatics tools are bringing these science fiction-like projects closer to reality.
With the help of Form Bio’s platform, Colossal is sequencing the genomes of different mammoth species, as well as other cold-adapted animals, such as polar bears and penguins, and looking for clues as to what makes them resistant to the frigid temperature. Scientists could then use that information to edit the DNA taken from an elephant nucleus, put the nucleus back into an egg, and develop an embryo of the edited elephant. After two years of gestation, extensive testing of behavioral and physiological effects would have to be done. It would take at least a decade until we know whether the animal can survive in the cold and help us freeze the effects of climate change.
But until then, there are plenty of other problems that synthetic biology can focus on solving: from removing plastics from our environment to making drought-resistant crops. Just like the mammoth de-extinction project, these are not trivial tasks; but at least the computational side of it is going to be much easier thanks to Form Bio’s software.
Thank you to Katia Tarasava for additional research and reporting on this article. I’m the founder of SynBioBeta and some of the companies I write about, such as Form Bio, are sponsors of the SynBioBeta conference and weekly digest.
