news IN this section Tools to visualize Pediatric hospital What’s happened gene expression spinout lands in biotech around in situ p490 $4.8 billion deal the world p494 p492 Unicorn startup trawls databases for protective genetic modifers Startup aims to identify disease modifying genes in people with milder than expected phenotypes as starting points for drug discovery programs. fter two-and-a-half years in stealth mode, Maze Therapeutics unveiled a A$191 million series A funding round and a stellar line-up of scientists who aim to discover new biology and new drug targets by systematically mining human genetic databases for genetic modifiers that reduce the impact of disease-causing mutations. The company is, at the same time, establishing a functional genomics platform to study the phenotypic consequences of disrupting the genome. Combining these two types of data will, it hopes, lead to new insights into disease biology that can be translated into starting points for drug discovery programs. The general concept is not new, but Maze’s founding team and its backers hold that this is an opportune time to pursue such a strategy at scale because of the simultaneous availability of large volumes of human genomic and associated clinical data and the tools and technologies for conducting detailed phenotypic analyses. The hunt for such genetic exceptions At DeCode in Reykjavik, blood samples from Icelanders are stored for genetic testing. Credit: dpa picture came to prominence in 2016 when a group alliance / Alamy Stock Photo of researchers—headed by Stephen Friend, founder of Sage Bionetworks, and Eric Schadt of Mount Sinai under the collective the other 3.199 billion base pairs in your forms the basis of gene editing programs umbrella of the Resilience Project— genome are irrelevant to your disease,” underway at CRISPR Therapeutics and announced they had identified 13 people says Nicholas Katsanis, professor of cell Sangamo Biosciences. Each firm has who should have had serious childhood biology at Duke University. However, some disrupted the gene encoding BCL11A, a diseases, but didn’t (Nat. Biotechnol. 34, protective variants may only operate within transcriptional repressor of fetal hemoglobin 531–538, 2016). The study confirmed why, very specific genetic contexts. “One question production, which normally switches on in human monogenic disorders, individuals is whether the effects seen are sufficiently as soon as the adult form of hemoglobin with the same disease-causing variant often generalizable to be captured in a drug starts to be produced in early childhood. have a different course of disease, in terms of therapy,” says Stephen Friend, now professor Understanding the underlying biology has time of onset or degree of severity, because of connected medicine at Oxford University. opened up an additional—and potentially modifiers can alter the disease phenotype. Several firms are already developing more easily druggable—route to achieving The very term ‘monogenic disorder’ is therapies based on well-known genetic the same effect. A group at the University actually a gross simplification of what is modifiers. For instance, fetal hemoglobin of Pennsylvania recently identified a invariably a far more complex picture. “The expressed in adulthood is known to have a translational repressor of fetal hemoglobin moment that we say that one mutation is protective effect in sickle cell disease and using a CRISPR–Cas9 screen to knock the cause of your disease, we’re saying that in some forms of β-thalassemia; as such, it out 482 kinase domains in turn from a NATURE BIOTECHNOLOGY | VOL 37 | MAY 2019 | 487–496 | www.nature.com/naturebiotechnology 487 news Table 1 | Selected population genetics initiatives Project (year Goal Funders Partners, participants established) DeCode Genetics, DeCode has whole-genome sequence Amgen SomaLogic a subsidiary of data on about 15% of Iceland’s population Amgen (1996) and genotype data from about 50%, which it combines with clinical and genealogical data from Iceland and open-source data from around the globe for biological discovery China Kadoorie Blood samples collected from over Kadoorie Charitable Foundation, Chinese Academy of Medical Sciences, Biobank (2004) 510,000 individuals from 2004–2008; Wellcome Trust, Chinese Natural Science Oxford University analyses combined with clinical and Foundation, Chinese Ministry of Science mortality data, as well as biological data and Technology, British Heart Foundation, from periodic follow-up studies Cancer Research UK UK Biobank (2006) Prospective cohort study involving Medical Research Council, Wellcome Trust Regeneron is leading exome sequencing, collection and analysis of genetic, with support from AbbVie, Alnylam physical and health data on 500,000 Pharmaceuticals, AstraZeneca, Biogen, people aged 40–69 at time of GlaxoSmithKline and Pfizer; data are recruitment available to 10,000 approved industry and academic researchers Million Veteran Collecting blood samples, health, military US Department of Veterans Affairs Office Veterans Affairs-affiliated researchers Program (2009) experience and lifestyle information from of Research & Development one million US military veterans to study the genetic factors that influence health Regeneron Genetics Has sequenced 400,000 exomes of Regeneron Pharmaceutica Geisinger Health System, US National Center (2014) 500,000-exome target; combining Institutes of Health, academic medical genetic data with electronic health centers record data Genomics Medicine Combining medical and health data with Arch Venture Partners, Ireland Strategic AbbVie, University College Dublin, Ireland (Dublin), sequence data from 400,000 genomes Investment Initiative, Polaris Partners, University of Cambridge, hospitals in a subsidiary of (>10,000 completed so far); studies in Temasek Holdings, Yunfeng Capital, Ireland and Northern Ireland, UK WuXi NextCode rare and chronic diseases ongoing Sequoia Capital (Shanghai) (2015) All of Us (formerly Building a research database containing US National Institutes of Health; US Accredited academic and industry Precision Medicine biological, physiological, environmental National Cancer Institute researchers, as well as interested Initiative Cohort and health data from over one million citizen scientists, will have access to a Program) (2016) people who reflect the diversity of research portal the US population Kaiser Permanente Aims to collect biological samples from Kaiser Permanante Kaiser Permanante and accredited Research Bank 500,000 members, which it will combine researchers (2016) with electronic health records, lifestyle and environmental data FinnGen (2017) The University of Helsinki is responsible Business Finland, industry partners AbbVie, AstraZeneca (Cambridge, for the study, which involves the collection UK), Biogen, Celgene, Genentech, of genome and longitudinal clinical GlaxoSmithKline (London), Merck, Sanofi data from 500,000 individuals through (Paris), Pfizer a nationwide network of biobanks, universities and hospitals Sources: organization websites, PubMed human cell line that expresses high levels and MIT, and Harvard Medical School, a number of addressable targets that can of adult hemoglobin and low levels of fetal points to the work of his Harvard and delay or accelerate disease onset. “The genes hemoglobin (Science 361, 285–290, 2018). Massachusetts General colleague James are basically involved in repair of DNA,” Their screen uncovered an erythroid- Gusella in identifying genetic factors says Kathiresan. specific kinase, called heme-regulated that alter the age of onset of Huntington’s Maze is agnostic both in terms of inhibitor, that is required to produce the disease as “an example of how all this therapeutic modality and in terms of BCL11A repressor. might work.” The CAG trinucleotide repeats therapeutic focus. It already has discovery Maze cofounder Sekar Kathiresan, in the gene encoding huntingtin protein programs underway in rare metabolic, who holds posts at Massachusetts General cause the condition but are not easily neurodegenerative and kidney diseases, Hospital, the Broad Institute of Harvard druggable. Instead, Gusella has identified based on known genetic effects. Whether 488 NATURE BIOTECHNOLOGY | VOL 37 | MAY 2019 | 487–496 | www.nature.com/naturebiotechnology news Maze’s approach is distinctive is debatable. motor function in a TDP-43-based mouse Regeneron,” says Aris Baras, senior vice “The basic notion that it is something model of ALS. Although Maze is not president at the biotech firm and head of the different to go after modifiers is a bit funny,” commenting publicly on the question, it Regeneron Genetics Center. Not only has says Kári Stefánsson, the CEO and founder represents an obvious drug target for the it led to a flood of new discoveries—about of Reykjavik, Iceland-based DeCode company to pursue. 50 novel findings have already advanced Genetics, who pioneered the use of large- into formal target biology programs—it scale human genetic studies to unlock new Some genetic fndings are has deepened the company’s biological biology. Everyone is looking for genetic so obvious and compelling understanding of ongoing clinical programs, variants that affect disease phenotypes, he such as those targeting interleukin-33 in says. “You use exactly the same approach, that they are immediately autoimmune disease and angiopoietin- no matter whether you’re looking for translated into a drug like 3 in familial hypercholesterolemia. major genes or genes that have