GEN BiotechnologyVol. 1, No. 2 News FeatureFree AccessAhead of the Curve: The Arc Institute Aims to Reshape the Biomedical Research LandscapeJonathan D. GrinsteinJonathan D. Grinstein*Address correspondence to: E-mail Address: jdgrinstein@gmail.comScience correspondent, Genetic Engineering & Biotechnology News.Search for more papers by this authorPublished Online:20 Apr 2022https://doi.org/10.1089/genbio.2022.29017.jgrAboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail A bold new nonprofit research institute in Palo Alto, California, infuses uniquely funded core investigators, biotech-inspired technology centers, and academic partnerships to solve complex diseases.The Arc Institute.Island arcs are long curved chains of oceanic islands associated with intense volcanic and seismic activity often formed over a single “hot spot.” The tips of volcanoes that began emerging from the ocean some millions of years ago are now islands usually teeming with life. Owing to extreme variations in topography, conditions, and distance to the mainland, island arcs are some of the best places in the world to observe evolution by natural selection, often to dramatic effect, in the highly specialized yet bountiful and variegated biomes. Just ask Charles Darwin……Or the co-founders of the Arc Institute—a new (501c3) non-profit, independent research institute—for that is precisely their vision for scientists: a “hot spot” for collaborative, curiosity-driven innovation in diverse disciplines of biomedical science and technology to expedite the understanding of complex disease and bridge the gap between discoveries and impact on patients.The Arc Institute is the brainchild of two talented junior faculty—neuroscientist Silvana Konermann (Stanford University) and genome engineer Patrick Hsu (University of California, Berkeley).Silvana Konermann(Stanford University)Taking root on the Stanford campus in Palo Alto, CA, Arc's research biome, supported by $650 million in initial funding, will consist of four main elements: (1) long-term funded core investigators (not tied to a specific project), (2) multidisciplinary experts in one physical laboratory, (3) biotech-inspired technology centers, and (4) partnerships with academic institutions such as Stanford, University of California San Francisco (UCSF), and UC Berkeley.This is not the first time we have seen a combination of curiosity-driven science (modeled best by the university system), multidisciplinary experts under one roof (institutes such as the Broad do this well today), scientific infrastructure, tools (normally seen in a biotech), and almost unconstrained funding, working together to push the scientific progress pedal to the metal. (There are some similarities to the model of the Howard Hughes Medical Institute [HHMI], which employs ∼270 biomedical investigators in a people-not-projects approach to conduct “risky” research.)Arc aims to flourish by nurturing the early noncommercial preclinical stage of discovery pertaining to complex diseases such as Alzheimer's, as opposed to casting a wider net on human health and treating disease such as the Chan Zuckerberg Initiative or similar recent endeavors that have a broader biology and engineering slant (Box 1).To ensure that discoveries at Arc that are medically relevant (such as key disease pathways and targets) actually make an impact on patients, the nonprofit plans to provide translational support: a faster IP licensing process, finance assistance, and a drug development and expert advisory network. Arc will also form targeted entrepreneurial teams committed to exploring specific concepts, such as a new gene target or effector chemical. Ultimately, the mission is to enable Arc scientists, engineers, and innovators to translate their research into tangible benefits for patients with complex disease.Re-Envisioning Research FundingIt is not the strongest of the species that survives, nor the most intelligent that survives. It is the one that is the most adaptable to change.—Charles DarwinKonermann and Hsu first crossed paths in grad school at the Broad Institute, where Hsu, as one of Feng Zhang's first grad students, coauthored one of the two seminal 2013 articles in Science showing CRISPR gene editing could work in human cells. After Hsu set up his own laboratory at the Salk Institute in 2015, Konermann joined as a postdoc (funded by HHMI). Both are currently assistant professors: Konermann's laboratory at Stanford develops technologies for high-throughput transcriptional perturbations to understand the cellular and molecular pathways in neurodegenerative disease. Hsu's laboratory at the Innovative Genomics institute at Berkeley aims to understand and manipulate genetic circuits that control brain and immune cell function to develop gene and cell therapies.In the early days of the COVID-19 pandemic in 2020, Hsu, who helped lead an effort to assess the accuracy of SARS-CoV-2 antibody tests, teamed up with Konermann and her husband, Irish billionaire Patrick Collison (cofounder and CEO of the online payment giant Stripe), to launch Fast Grants. This project provided rapid seed funding for COVID-19 research at a challenging time when researchers could not go to the laboratory because of lockdowns. Many faculty wanted to help out against COVID-19 but were frustrated because they could not redirect their existing grants and found the process too slow to get fresh funding.Fast Grants was inspired by Vannevar Bush's proposal for the National Defense Research Committee to coordinate scientific research during World War II, which was integral for the generation of the Manhattan Project. Konermann, Hsu, and Collison created a model wherein researchers could apply for extremely low overhead grants and get a decision within 48 h. They received thousands of high-quality grant applications in just a few weeks, and distributed>$50 million over the next 12 months to some 200 laboratories and projects. When Fast Grant recipients were asked how having unconstrained permanent funding could impact their research, ∼80% said they would change their research program “a lot” if their existing funding could be spent in an unconstrained manner.Patrick Hsu(University of California, Berkeley)Box 1. A Whole New Biotech WorldThe Arc Institute is not the only new establishment looking to shake up the research funding landscape. Here are two others.Petri: Feeding Tectonic Bioscience in a VC DishIn Boston, Petri is a new model for seed funding that supports early stage companies working on discoveries at the intersection of biology and engineering. Pillar VC—a venture firm cofounded by the CEOs of Exact Sciences, Ginkgo Bioworks, Iora Health, and 22 Boston firms—created and backs this accelerator. Petri was cofounded by Pillar VC and academics who are leading bioengineering basic science.The accelerator invests in preseed and seed money and works with startups one-on-one for at least a year. Petri assists entrepreneurs in forming world-class teams, developing intellectual property, identifying clients, and raising a later round of funding. Their approach is built on a 12-month program with a $250,000 equity commitment for each team (sometimes more) and gives access to business development and corporate venture capital organizations as well as to a talent network from leading universities.Petri has invested in everything from food laboratory-grown cotton (Daly), plant-based cheese (Tea), beanless coffee (Compound Foods), and biomaterial solutions for the fashion industry (Modern Synthesis) to microbiome modulators (Vulcan Biologics), supernatural protein engineering (Nabla Bio), drug candidate discovery (New Equilibrium Biosciences), and disposable wound sensors (Medsix). Between their summits and the Petri Podcast, they shine a spotlight on inspiring founders, women, and under-represented genders in bio at the free and virtual Wave Summit.Arcadia Sciences: Evolving the Research Organism BiomeArcadia Sciences is a for-profit research and development firm that is putting a novel scientific discovery paradigm to the test in developing research organisms. Arcadia aims to enable scientists to research and explore what interests them without fear of failure by providing resources, an open platform, and collaborative partnerships at a physical laboratory space (currently Berkeley, CA). The ultimate goal is to pursue translational opportunities that emerge from their research and discovery.The research institution was cofounded by two female scientists: Seemay Chou, assistant professor at University of California San Francisco, and Prachee Avasthi, associate professor at Dartmouth. Backed by Chou's life partner Jed McCaleb (Stellar Development Foundation cofounder) and investor Sam Altman (CEO of Open.AI), Arcadia offers novel techniques to investigate the biology of various organisms for whom there are few instruments and resources. With intent on fast-tracking work on emerging research organisms, Arcadia stresses and invests extensively in the creation of research instruments, in addition to supporting an intramural research program. Access to essential enabling technologies is a major stumbling block to further research in this field.Arcadia claims that study on nonmodel organisms is both intellectually and financially valuable. By combining fundamental research, tool, and translational development under one roof and providing adequate runway, scientists with technical expertise can be trained to pilot and lead translational activities sparked by their own work. Arcadia's employees are also given shares in the company, with the percentage ownership not dependent on whether specific initiatives are exploratory or translational, successful or not.“Nearly 80% said they would change their research program ‘a lot’ if their existing funding could be spent in an unconstrained fashion.”But Konermann and Hsu say they were already nurturing the idea for Arc. Once Fast Grants showed how impactful alternative funding mechanisms could be, they sought to develop a new funding model to solving complex diseases such as neurodegeneration, cancer, and immune dysfunction. So, when donors from Collison's network asked what they would like to do next, Konermann and Hsu were ready: why not apply this science funding model to solving complex diseases such as neurodegeneration, cancer, and immune dysfunction?Letting Principal Investigators Principally InvestigateI love fools' experiments. I am always making them.—Charles DarwinAddressing research funding is just one piece of the mission for the Arc Institute, which is to understand and systematically solve various issues that impede biomedical progress. Although the current funding and organizational system driving academic research have been successful on the whole, there is a lot of what Hsu calls “friction.” Konermann, who is the founding executive director and a core investigator at the institute, says that one of the main motivations behind establishing Arc is to provide a research environment for scientists to focus without restraining their curiosity, helping them pursue the science they are most passionate about.For example, it can be difficult for principal investigators (PIs) to choose the problems they work on, which can be dictated by funding availability, technical capabilities, and the knowledgebase used to start a laboratory. Hsu, who is also an Arc core investigator, says this leads to cultural or sociological challenges with academic research laboratories, where the research is dictated by the need for grant funding success and research groups to grow to a specific size to maintain internal platforms and long-term knowhow. This also has skewed the way that researchers strategize their research, which, in many ways, is optimized for high-impact publications and not necessarily to solve the questions PIs find most exciting or important.“The problems you solve for emerge from that initial seed [funding] and are predicated based on what you know how to do, as opposed to the problems that you may really want to go after,” Hsu says. “Then you have to follow that path because of feasibility, which tracks with you for the rest of your career.” In addition, PIs are tasked with administrative and managerial responsibilities that they never trained for. “We're called PIs—principal investigators—but most PIs would probably tell you that they do much less investigating than they had expected before becoming one!” Hsu says.But Hsu argues there is no need to continue down this path. “We are thinking intentionally from the very beginning about the kind of culture and institution that we want to set up and the incentive structure that we'd like to develop. We'd like to give science back to the scientist to work on their best ideas with long-term funding.”“We'd like to give science back to the scientist to work on their best ideas with long-term funding.”Arc will provide funding support for 8 years, allowing PIs to have laboratories of 10–20 researchers, where they can freely set their research agenda. Eight years is a long time and will provide investigators with research agility and a welcome release from excessive grant writing. “This funding strategy actually lets PIs take some real risks and pursue some projects that are very worthwhile but may actually fail,” says Konermann. “We want the core faculty to pursue the science that they would like to pursue more freely and with a longer-term lens.”Infusing Academia with BiotechI have called this principle, by which each slight variation, if useful, is preserved, by the term of natural selection.—Charles DarwinThe Arc Institute also wants to bring the spirit of biotech to academic research. Hsu says that industrial expertise is needed to really solve something and create new therapeutic proofs of concept for accelerating new biological insights into actionable targets or affecting molecules or pathways to make an impact on disease.Arc's mission “is to try to understand and treat complex disease,” says Hsu. “We realize that this will require multiple things to get at it: fundamental new biological basic science, really focused goal-directed technology development, and an effective path to commercialization, which we think is challenging the academic system today.”The technology centers also get at another sociocultural issue in academic research—what happens to the careers and livelihoods of the 90-plus percent of researchers who do not become faculty? Hsu says, “These people are just as talented, but the type of work that you have to do often to do technology development—careful comparisons, benchmarking, the refinement beyond the initial innovation—sometimes even that initial innovation may not be heavily incentivized. It's quite hard to then have a stable, long-term career.” By setting one of its pillars in technology development, Arc hopes to provide career options for scientists interested in biomedical technology development and prioritize the development of trail-blazing tools as well as improving the nuts and bolts for biomedical science.“Arc hopes to provide career options for scientists interested in biomedical technology development and prioritize the development of trail-blazing tools as well as improving the nuts and bolts for biomedical science.”“While novelty is important, I think we over incentivize novelty for novelty's sake,” says Hsu. “For many important biotechnologies, it's important for things to be really robust and really work. One of the major impacts that technological tools do in biology is to decrease the friction of doing things. There are certain types of technologies that are hot and widely appreciated. Still, many others are just as important that get comparatively less attention, less funding, or require a very high capital scale.”To accelerate biomedical technology development, Arc plans to create five initial technology centers: genome engineering, complex ex vivo models, mammalian disease models, multiomics, and computation. Genome engineering will be split into two categories: vector development (including the discovery of new enzymes, not just CRISPR, useful for any genome trans prescriptive integration) and functional genomics (applications of engineering tools such as perturb-seq). With ex vivo disease modeling, the intention is to develop primarily multiple cell-type disease models. The multiomics technology center will support the newest generation of sequencing and spatial readouts of gene expression, and the in vivo disease modeling technology platform will generate new animal models.Finally, there is computational biology. “It's tough to attract real computational scientists or engineers to work in bio or at least non-profit biology,” says Konermann. “The hope is by being able to set more competitive salary scales relative to industry, we can actually hire computer scientists and engineers. There's plenty of potential to bring some of the latest tools in computation to biological problems. I think right now that's mostly just happening in a for-profit setting, and I've decided to bring that to a non-profit setting.”Naturally Selecting Scientific ProgressIn the long history of humankind (and animal kind, too) those who learned to collaborate and improvise most effectively have prevailed.—Charles DarwinArc's brain trust has been working on this plan quietly for the past 2 years, setting up the physical colocation of researchers and technology centers into its new headquarters while developing close partnership with major research universities. Collaborating with Stanford, UCSF, and UC Berkeley will benefit the Arc Institute through the broader intellectual network of those universities and help the nonprofit integrate into the Bay area's research ecosystem. Konermann says: “Most of my energy has gone into building the relationships with the three universities and figuring out the model that will work for them and the details of collaborating.”She has spent less time worrying about funding. Konermann says donors came to her and then spread the word themselves. Arc's group of founding donors will contribute >$650 million to support scientists and their research for renewable 8-year terms. The founding donors include Arc cofounder Patrick Collison (who has no operating role at the institute) and his younger brother John (also a billionaire).Other notable investors include Vitalik Buterin, the 28-year old founder of the open-source blockchain Ethereum, and Daniel Gross, who cofounded the search engine Cue (bought by Apple). Cari Tuna and her husband, Dustin Moskovitz, a cofounder of Facebook who later cofounded the venture capital firm VC Good Ventures, are also in the fold. Other contributing power couples include Jessica Taneja and her husband Hemant Taneja of the VC General Catalyst, as well as Jennifer Huang Gil and her husband Elad Gil, the most prominent solo VC in Silicon Valley.Arc has set up an operational team and space on the Stanford campus and is hiring for many positions across the technology centers and core laboratories. Hsu says they will likely open a call for core investigator applications and joint searches with the primary universities in the second half of 2022. In phase I, Arc will scale up to ∼150 people in 3–4 years. Although the core faculty can hold positions at Stanford, UCSF, or UC Berkeley, they do not have to.Initially the Arc Institute has four laboratories—joining Konermann and Hsu are Lingyin Li, an associate professor at Stanford studying the treatment of diseases rooted in autoimmunity, neurodegeneration, and sterile inflammation (e.g., myocardial infarction, atherosclerosis), and Luke Gilbert, an assistant professor at UCSF building new CRISPR tools using synthetic biology and functional genomics to model and overcome drug resistance in cancer. That will provide an initial critical mass to house a team of scientists who can interact and create a productive environment. From there, Arc will add about two laboratories per year.Clearly the Arc Institute will not solve all the problems that impede biomedical progress or devise therapies for all complex diseases. Konermann knows it is not a one-and-all solution and hopes for corporate and nonprofit spinoffs to join the march toward complex disease therapies. “I'm hoping that, ten years down the road, not only will we have come up with some unique insights or therapeutic solutions but also we'll potentially spawn a few more non-profit research institutes, each with a unique combination of factors and distinct models,” she says.As the tectonic elements of the Arc Institute converge over the next few years, we will have to wait and see how much new scientific terrain will be laid.FiguresReferencesRelatedDetails Volume 1Issue 2Apr 2022 InformationCopyright 2022, Mary Ann Liebert, Inc., publishersTo cite this article:Jonathan D. Grinstein.Ahead of the Curve: The Arc Institute Aims to Reshape the Biomedical Research Landscape.GEN Biotechnology.Apr 2022.115-119.http://doi.org/10.1089/genbio.2022.29017.jgrPublished in Volume: 1 Issue 2: April 20, 2022PDF download
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