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.”
Centenarians essentially won the genetic lottery, says Nir Barzilai of Albert Einstein College of Medicine. He is studying their genes to see how the rest of us can benefit from understanding how they work.
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Centenarians may have essentially won the genetic lottery, but that doesn’t mean the rest of us are predestined to have a specific lifespan and health span, or the amount of time spent living productively and enjoyably. “Aging is a mother of all diseases,” Dr. Barzilai told me. And as a disease, it can be targeted by therapeutics. Dr. Barzilai’s team is already running clinical trials on such therapeutics — and the results are promising.
More about Dr. Barzilai: He is scientific director of AFAR, American Federation for Aging Research. As part of his work, Dr. Barzilai studies families of centenarians and their genetics to learn how the rest of us can learn and benefit from their super-aging. He also organizing a clinical trial to test a specific drug that may slow aging.
Show Links
Age Later: Health Span, Life Span, and the New Science of Longevity https://www.amazon.com/Age-Later-Healthiest-Sharpest-Centenarians/dp/1250230853
American Federation for Aging Research https://www.afar.org
https://www.afar.org/nir-barzilai
https://www.einsteinmed.edu/faculty/484/nir-barzilai/
Metformin as a Tool to Target Aging
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943638/
Benefits of Metformin in Attenuating the Hallmarks of Aging https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347426/
The Longevity Genes Project https://www.einsteinmed.edu/centers/aging/longevity-genes-project/
Often called the window to the soul, the eyes are more sacred than other body parts, at least for some.
Eye transplants are desperately needed, but they're nowhere in sight. About 12.7 million people worldwide need a corneal transplant, which means that only one in 70 people who require them, get them. The gaps are international. Eye banks in the United Kingdom are around 20 percent below the level needed to supply hospitals, while Indian eye banks, which need at least 250,000 corneas per year, collect only around 45 to 50 thousand donor corneas (and of those 60 to 70 percent are successfully transplanted).
As for retinas, it's impossible currently to put one into the eye of another person. Artificial devices can be implanted to restore the sight of patients suffering from severe retinal diseases, but the number of people around the world with such “bionic eyes” is less than 600, while in America alone 11 million people have some type of retinal disease leading to severe vision loss. Add to this an increasingly aging population, commonly facing various vision impairments, and you have a recipe for heavy burdens on individuals, the economy and society. In the U.S. alone, the total annual economic impact of vision problems was $51.4 billion in 2017.
Even if you try growing tissues in the petri dish route into organoids mimicking the function of the human eye, you will not get the physiological complexity of the structure and metabolism of the real thing, according to Cosma. She is a member of a scientific consortium that includes researchers from major institutions from Spain, the U.K., Portugal, Italy and Israel. The consortium has received about $3.8 million from the European Union to pursue innovative eye research. Her team’s goal is to give hope to at least 2.2 billion people across the world afflicted with a vision impairment and 33 million who go through life with avoidable blindness.
Their method? Resuscitating cadaveric eyes for at least a month.
If we succeed, it will be the first intact human model of the eye capable of exploring and analyzing regenerative processes ex vivo. -- Maria Pia Cosma.
“We proposed to resuscitate eyes, that is to restore the global physiology and function of human explanted tissues,” Cosma said, referring to living tissues extracted from the eye and placed in a medium for culture. Their ECaBox is an ex vivo biological system, in which eyes taken from dead donors are placed in an artificial environment, designed to preserve the eye’s temperature and pH levels, deter blood clots, and remove the metabolic waste and toxins that would otherwise spell their demise.
Scientists work on resuscitating eyes in the lab of Maria Pia Cosma.
Courtesy of Maria Pia Cosma.
“One of the great challenges is the passage of the blood in the capillary branches of the eye, what we call long-term perfusion,” Cosma said. Capillaries are an intricate network of very thin blood vessels that transport blood, nutrients and oxygen to cells in the body’s organs and systems. To maintain the garland-shaped structure of this network, sufficient amounts of oxygen and nutrients must be provided through the eye circulation and microcirculation. “Our ambition is to combine perfusion of the vessels with artificial blood," along with using a synthetic form of vitreous, or the gel-like fluid that lets in light and supports the the eye's round shape, Cosma said.
The scientists use this novel setup with the eye submersed in its medium to keep the organ viable, so they can test retinal function. “If we succeed, we will ensure full functionality of a human organ ex vivo. It will be the first intact human model of the eye capable of exploring and analyzing regenerative processes ex vivo,” Cosma added.
A rapidly developing field of regenerative medicine aims to stimulate the body's natural healing processes and restore or replace damaged tissues and organs. But for people with retinal diseases, regenerative medicine progress has been painfully slow. “Experiments on rodents show progress, but the risks for humans are unacceptable,” Cosma said.
The ECaBox could boost progress with regenerative medicine for people with retinal diseases, which has been painfully slow because human experiments involving their eyes are too risky. “We will test emerging treatments while reducing animal research, and greatly accelerate the discovery and preclinical research phase of new possible treatments for vision loss at significantly reduced costs,” Cosma explained. Much less time and money would be wasted during the drug discovery process. Their work may even make it possible to transplant the entire eyeball for those who need it.
“It is a very exciting project,” said Sanjay Sharma, a professor of ophthalmology and epidemiology at Queen's University, in Kingston, Canada. “The ability to explore and monitor regenerative interventions will increasingly be of importance as we develop therapies that can regenerate ocular tissues, including the retina.”
Seemingly, there's no sacred religious text or a holy book prohibiting the practice of eye donation.
But is the world ready for eye transplants? “People are a bit weird or very emotional about donating their eyes as compared to other organs,” Cosma said. And much can be said about the problem of eye donor shortage. Concerns include disfigurement and healthcare professionals’ fear that the conversation about eye donation will upset the departed person’s relatives because of cultural or religious considerations. As just one example, Sharma noted the paucity of eye donations in his home country, Canada.
Yet, experts like Sharma stress the importance of these donations for both the recipients and their family members. “It allows them some psychological benefit in a very difficult time,” he said. So why are global eye banks suffering? Is it because the eyes are the windows to the soul?
Seemingly, there's no sacred religious text or a holy book prohibiting the practice of eye donation. In fact, most major religions of the world permit and support organ transplantation and donation, and by extension eye donation, because they unequivocally see it as an “act of neighborly love and charity.” In Hinduism, the concept of eye donation aligns with the Hindu principle of daan or selfless giving, where individuals donate their organs or body after death to benefit others and contribute to society. In Islam, eye donation is a form of sadaqah jariyah, a perpetual charity, as it can continue to benefit others even after the donor's death.
Meanwhile, Buddhist masters teach that donating an organ gives another person the chance to live longer and practice dharma, the universal law and order, more meaningfully; they also dismiss misunderstandings of the type “if you donate an eye, you’ll be born without an eye in the next birth.” And Christian teachings emphasize the values of love, compassion, and selflessness, all compatible with organ donation, eye donation notwithstanding; besides, those that will have a house in heaven, will get a whole new body without imperfections and limitations.
The explanation for people’s resistance may lie in what Deepak Sarma, a professor of Indian religions and philosophy at Case Western Reserve University in Cleveland, calls “street interpretation” of religious or spiritual dogmas. Consider the mechanism of karma, which is about the causal relation between previous and current actions. “Maybe some Hindus believe there is karma in the eyes and, if the eye gets transplanted into another person, they will have to have that karmic card from now on,” Sarma said. “Even if there is peculiar karma due to an untimely death–which might be interpreted by some as bad karma–then you have the karma of the recipient, which is tremendously good karma, because they have access to these body parts, a tremendous gift,” Sarma said. The overall accumulation is that of good karma: “It’s a beautiful kind of balance,” Sarma said.
For the Jews, Christians, and Muslims who believe in the physical resurrection of the body that will be made new in an afterlife, the already existing body is sacred since it will be the basis of a new refashioned body in an afterlife.---Omar Sultan Haque.
With that said, Sarma believes it is a fallacy to personify or anthropomorphize the eye, which doesn’t have a soul, and stresses that the karma attaches itself to the soul and not the body parts. But for scholars like Omar Sultan Haque—a psychiatrist and social scientist at Harvard Medical School, investigating questions across global health, anthropology, social psychology, and bioethics—the hierarchy of sacredness of body parts is entrenched in human psychology. You cannot equate the pinky toe with the face, he explained.
“The eyes are the window to the soul,” Haque said. “People have a hierarchy of body parts that are considered more sacred or essential to the self or soul, such as the eyes, face, and brain.” In his view, the techno-utopian transhumanist communities (especially those in Silicon Valley) have reduced the totality of a person to a mere material object, a “wet robot” that knows no sacredness or hierarchy of human body parts. “But for the Jews, Christians, and Muslims who believe in the physical resurrection of the body that will be made new in an afterlife, the [already existing] body is sacred since it will be the basis of a new refashioned body in an afterlife,” Haque said. “You cannot treat the body like any old material artifact, or old chair or ragged cloth, just because materialistic, secular ideologies want so,” he continued.
For Cosma and her peers, however, the very definition of what is alive or not is a bit semantic. “As soon as we die, the electrophysiological activity in the eye stops,” she said. “The goal of the project is to restore this activity as soon as possible before the highly complex tissue of the eye starts degrading.” Cosma’s group doesn’t yet know when they will be able to keep the eyes alive and well in the ECaBox, but the consensus is that the sooner the better. Hopefully, the taboos and fears around the eye donations will dissipate around the same time.