Basecamp Research is using portable labs like this one to gather samples from ecosystems around the world.
Clark works for Basecamp Research, a biotech company headquartered in London, and his job is to collect samples from ecosystems around the world. By extracting DNA from soil, water, plants, microbes and other organisms, Basecamp is building an extensive database of the Earth’s proteins. While DNA itself isn’t a protein, the information stored in DNA is used to create proteins, so extracting, sequencing, and annotating DNA allows for the discovery of unique protein sequences.
Using what they’re finding in the middle of the Atlantic and beyond, Basecamp’s detailed database is constantly growing. The outputs could be essential for cleaning up the damage done by toxic chemicals and finding alternatives to these chemicals.
Catalysts for change
Proteins provide structure and function in all living organisms. Some of these functional proteins are enzymes, which quite literally make things happen.
“Industrial chemistry is heavily polluting, especially the chemistry done in pharmaceutical drug development. Biocatalysis is providing advantages, both to make more complex drugs and to be more sustainable, reducing the pollution and toxicity of conventional chemistry," says Ahir Pushpanath, who heads partnerships for Basecamp.
“Enzymes are perfectly evolved catalysts,” says Ahir Pushpanath, a partnerships lead at Basecamp. ”Enzymes are essentially just a polymer, and polymers are made up of amino acids, which are nature’s building blocks.” He suggests thinking about it like Legos — if you have a bunch of Lego pieces and use them to build a structure that performs a function, “that’s basically how an enzyme works. In nature, these monuments have evolved to do life’s chemistry. If we didn’t have enzymes, we wouldn’t be alive.”
In our own bodies, enzymes catalyze everything from vision to digesting food to regrowing muscles, and these same types of enzymes are necessary in the pharmaceutical, agrochemical and fine chemical industries. But industrial conditions differ from those inside our bodies. So, when scientists need certain chemical reactions to create a particular product or substance, they make their own catalysts in their labs — generally through the use of petroleum and heavy metals.
These petrochemicals are effective and cost-efficient, but they’re wasteful and often hazardous. With growing concerns around sustainability and long-term public health, it's essential to find alternative solutions to toxic chemicals. “Industrial chemistry is heavily polluting, especially the chemistry done in pharmaceutical drug development,” Pushpanath says.
Basecamp is trying to replace lab-created catalysts with enzymes found in the wild. This concept is called biocatalysis, and in theory, all scientists have to do is find the right enzymes for their specific need. Yet, historically, researchers have struggled to find enzymes to replace petrochemicals. When they can’t identify a suitable match, they turn to what Pushpanath describes as “long, iterative, resource-intensive, directed evolution” in the laboratory to coax a protein into industrial adaptation. But the latest scientific advances have enabled these discoveries in nature instead.
Marlon Clark, a research scientist at Basecamp Research, looks for novel biochemistries in the Azores.
Glen Gowers
Enzyme hunters
Whether it’s Clark and a colleague setting off on an expedition, or a local, on-the-ground partner gathering and processing samples, there’s a lot to be learned from each collection. “Microbial genomes contain complete sets of information that define an organism — much like how letters are a code allowing us to form words, sentences, pages, and books that contain complex but digestible knowledge,” Clark says. He thinks of the environmental samples as biological libraries, filled with thousands of species, strains, and sequence variants. “It’s our job to glean genetic information from these samples.”
“We can actually dream up new proteins using generative AI," Pushpanath says.
Basecamp researchers manage this feat by sequencing the DNA and then assembling the information into a comprehensible structure. “We’re building the ‘stories’ of the biota,” Clark says. The more varied the samples, the more valuable insights his team gains into the characteristics of different organisms and their interactions with the environment. Sequencing allows scientists to examine the order of nucleotides — the organic molecules that form DNA — to identify genetic makeups and find changes within genomes. The process used to be too expensive, but the cost of sequencing has dropped from $10,000 a decade ago to as low as $100. Notably, biocatalysis isn’t a new concept — there have been waves of interest in using natural enzymes in catalysis for over a century, Pushpanath says. “But the technology just wasn’t there to make it cost effective,” he explains. “Sequencing has been the biggest boon.”
AI is probably the second biggest boon.
“We can actually dream up new proteins using generative AI,” Pushpanath says, which means that biocataylsis now has real potential to scale.
Glen Gowers, the co-founder of Basecamp, compares the company’s AI approach to that of social networks and streaming services. Consider how these platforms suggest connecting with the friends of your friends, or how watching one comedy film from the 1990s leads to a suggestion of three more.
“They’re thinking about data as networks of relationships as opposed to lists of items,” says Gowers. “By doing the same, we’re able to link the metadata of the proteins — by their relationships to each other, the environments in which they’re found, the way those proteins might look similar in sequence and structure, their surrounding genome context — really, this just comes down to creating a searchable network of proteins.”
On an Azores island, this volcanic opening may harbor organisms that can help scientists identify enzymes for biocatalysis to replace toxic chemicals.
Emma Bolton
Uwe Bornscheuer, professor at the Institute of Biochemistry at the University of Greifswald, and co-founder of Enzymicals, another biocatalysis company, says that the development of machine learning is a critical component of this work. “It’s a very hot topic, because the challenge in protein engineering is to predict which mutation at which position in the protein will make an enzyme suitable for certain applications,” Bornscheuer explains. These predictions are difficult for humans to make at all, let alone quickly. “It is clear that machine learning is a key technology.”
Benefiting from nature’s bounty
Biodiversity commonly refers to plants and animals, but the term extends to all life, including microbial life, and some regions of the world are more biodiverse than others. Building relationships with global partners is another key element to Basecamp’s success. Doing so in accordance with the access and benefit sharing principles set forth by the Nagoya Protocol — an international agreement that seeks to ensure the benefits of using genetic resources are distributed in a fair and equitable way — is part of the company's ethos. “There's a lot of potential for us, and there’s a lot of potential for our partners to have exactly the same impact in building and discovering commercially relevant proteins and biochemistries from nature,” Clark says.
Bornscheuer points out that Basecamp is not the first company of its kind. A former San Diego company called Diversa went public in 2000 with similar work. “At that time, the Nagoya Protocol was not around, but Diversa also wanted to ensure that if a certain enzyme or microorganism from Costa Rica, for example, were used in an industrial process, then people in Costa Rica would somehow profit from this.”
An eventual merger turned Diversa into Verenium Corporation, which is now a part of the chemical producer BASF, but it laid important groundwork for modern companies like Basecamp to continue to scale with today’s technologies.
“To collect natural diversity is the key to identifying new catalysts for use in new applications,” Bornscheuer says. “Natural diversity is immense, and over the past 20 years we have gained the advantages that sequencing is no longer a cost or time factor.”
This has allowed Basecamp to rapidly grow its database, outperforming Universal Protein Resource or UniProt, which is the public repository of protein sequences most commonly used by researchers. Basecamp’s database is three times larger, totaling about 900 million sequences. (UniProt isn’t compliant with the Nagoya Protocol, because, as a public database, it doesn’t provide traceability of protein sequences. Some scientists, however, argue that Nagoya compliance hinders progress.)
“Eventually, this work will reduce chemical processes. We’ll have cleaner processes, more sustainable processes," says Uwe Bornscheuer, a professor at the University of Greifswald.
With so much information available, Basecamp’s AI has been trained on “the true dictionary of protein sequence life,” Pushpanath says, which makes it possible to design sequences for particular applications. “Through deep learning approaches, we’re able to find protein sequences directly from our database, without the need for further laboratory-directed evolution.”
Recently, a major chemical company was searching for a specific transaminase — an enzyme that catalyzes a transfer of amino groups. “They had already spent a year-and-a-half and nearly two million dollars to evolve a public-database enzyme, and still had not reached their goal,” Pushpanath says. “We used our AI approaches on our novel database to yield 10 candidates within a week, which, when validated by the client, achieved the desired target even better than their best-evolved candidate.”
Basecamp’s other huge potential is in bioremediation, where natural enzymes can help to undo the damage caused by toxic chemicals. “Biocatalysis impacts both sides,” says Gowers. “It reduces the usage of chemicals to make products, and at the same time, where contamination sites do exist from chemical spills, enzymes are also there to kind of mop those up.”
So far, Basecamp's round-the-world sampling has covered 50 percent of the 14 major biomes, or regions of the planet that can be distinguished by their flora, fauna, and climate, as defined by the World Wildlife Fund. The other half remains to be catalogued — a key milestone for understanding our planet’s protein diversity, Pushpanath notes.
There’s still a long road ahead to fully replace petrochemicals with natural enzymes, but biocatalysis is on an upward trajectory. "Eventually, this work will reduce chemical processes,” Bornscheuer says. “We’ll have cleaner processes, more sustainable processes.”
Doctors used new eye drops to treat a rare genetic disorder.
The gene therapy: In May 2023, the FDA approved Vyjuvek, the first gene therapy to treat DEB.
Vyjuvek uses an inactivated herpes simplex virus to deliver working copies of the gene for collagen 7 to the body’s cells. In small trials, 65 percent of DEB-caused wounds sprinkled with it healed completely, compared to just 26 percent of wounds treated with a placebo.
“It was like looking through thick fog.” -- Antonio Vento Carvajal.
The patient: Antonio Vento Carvajal, a 14 year old living in Florida, was one of the trial participants to benefit from Vyjuvek, which was developed by Pittsburgh-based pharmaceutical company Krystal Biotech.
While the topical gene therapy could help his skin, though, it couldn’t do anything to address the severe vision loss Antonio experienced due to his DEB. He’d undergone multiple surgeries to have scar tissue removed from his eyes, but due to his condition, the blisters keep coming back.
“It was like looking through thick fog,” said Antonio, noting how his impaired vision made it hard for him to play his favorite video games. “I had to stand up from my chair, walk over, and get closer to the screen to be able to see.”
The idea: Encouraged by how Antonio’s skin wounds were responding to the gene therapy, Alfonso Sabater, his doctor at the Bascom Palmer Eye Institute, reached out to Krystal Biotech to see if they thought an alternative formula could potentially help treat his patient’s eyes.
The company was eager to help, according to Sabater, and after about two years of safety and efficacy testing, he had permission, under the FDA’s compassionate use protocol, to treat Antonio’s eyes with a version of the topical gene therapy delivered as eye drops.
The results: In August 2022, Sabater once again removed scar tissue from Antonio’s right eye, but this time, he followed up the surgery by immediately applying eye drops containing the gene therapy.
“I would send this message to other families in similar situations, whether it’s DEB or another condition that can benefit from genetic therapy. Don’t be afraid.” -- Yunielkys “Yuni” Carvajal.
The vision in Antonio’s eye steadily improved. By about eight months after the treatment, it was just slightly below average (20/25) and stayed that way. In March 2023, Sabater performed the same procedure on his young patient’s other eye, and the vision in it has also steadily improved.
“I’ve seen the transformation in Antonio’s life,” said Sabater. “He’s always been a happy kid. Now he’s very happy. He can function pretty much normally. He can read, he can study, he can play video games.”
Looking ahead: The topical gene therapy isn’t a permanent fix — it doesn’t alter Antonio’s own genes, so he has to have the eye drops reapplied every month. Still, that’s far less invasive than having to undergo repeated surgeries.
Sabater is now working with Krystal Biotech to launch trials of the eye drops in other patients, and not just those with DEB. By changing the gene delivered by the therapy, he believes it could be used to treat other eye disorders that are far more common — Fuchs’ dystrophy, for example, affects the vision of an estimated 300 million people over the age of 30.
Antonio’s mother, Yunielkys “Yuni” Carvajal, meanwhile, has said that having her son be the first to receive the eye drops was “very scary,” but she’s hopeful others will take a chance on new gene therapies if given the opportunity.
“I would send this message to other families in similar situations, whether it’s DEB or another condition that can benefit from genetic therapy,” she said. “Don’t be afraid.”
This article originally appeared on Freethink, home of the brightest minds and biggest ideas of all time.
