BioByte 092: reversing diabetes with cell therapy, the effect of mislocalization of proteins within a cell, DNA methylation in the brain, NIH-wide exposome research centre launch
Welcome to Decoding Bio’s BioByte: each week our writing collective highlight notable news—from the latest scientific papers to the latest funding rounds—and everything in between. All in one place.
What we read
Blogs
Stem cells reverse woman’s diabetes — a world first [Smriti Mallapaty, Nature News, Sept 2024]
In the paper “Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient”, the authors describe how a Tiajin, China-based 25-year-old woman with type 1 diabetes (T1D) started producing insulin within three months after receiving a transplant of reprogrammed stem cells.
Deng Hongkui and his colleagues from Peking University extracted cells from three people with T1D and reverted them into a pluripotent state using small molecules instead of transcription factors (aka CiPSCs). The CiPSCs were then used to create 3D clusters of islets. 1.5m islets were then injected into the woman's abdominal muscles. Typically islet transplants occur in the liver, but abdominal injections improve monitoring and safety, as they can be removed if needed. The two other participants will reach the one-year mark in November, but the authors mention the results are very positive.
First NIH-wide exposome research coordinating center launched
The National Institutes of Health (NIH) has launched the first NIH-wide exposome research coordinating center, called NEXUS (Network for Exposomics in the U.S.). This $7.7 million initiative aims to transform how environmental drivers of health and disease are studied.
NEXUS will be led by researchers from Columbia University, Harvard University, and the University of Southern California, and will work to establish exposomics as a core part of scientific and biomedical research across the U.S.
The center's goals include building a global community of practice, developing standardized tools for measuring the exposome, pioneering transdisciplinary education methods, and building data science infrastructure to support large-scale exposome-wide association studies.
Exposomics, the study of the exposome (the integrated compilation of physical, chemical, biological, and social influences on health), is seen as a critical complement to genomics in developing better approaches for preventing and treating a broad range of human diseases.
The initiative is supported by multiple NIH Institutes and Offices, including NIEHS, and aims to integrate comprehensive environmental exposure assessments into biomedical research.
NEXUS seeks to identify the balance between genetic and environmental influences on health, potentially leading to more personalized prevention and treatment strategies for complex diseases like heart disease, cancer, and diabetes.
Can we bring drug discovery back to future [Mihir Trivedi, Resync Bio, October 2024]
ReSync Bio, which launched publicly last week with a focus on addressing inefficiencies in drug discovery operations, has taken to their blog to highlight their response to a broader industry challenge: despite advances in AI and computational technologies, drug development remains a lengthy and costly process. This reality is captured by Eroom’s Law, the inverse of Moore’s Law, which shows that drug development costs have been doubling every decade, despite increased technological innovation—a paradox of sorts.
ReSync has keyed in on one of the key trends reshaping drug development—the use of Contract Research Organizations (CROs) where organizations perform specialized R&D services so pharma companies can outsource and reduce costs / accelerate stages of development. However, relying on multiple contractors with different methods and practices comes with challenges. A common problem is lack of organization and inconsistent data management, which leads to major delays and mistakes.
This has led to an industry-wide realization that modern computational methods and AI-driven tools need to be better integrated with experimental workflows. Several companies are working on bridging this gap between technology and experimentation, where automation and collaboration are more closely linked. These companies span from wet-lab automation to experimental notebooks and data analysis, to organizational management software. The thesis here is that eliminating inefficiencies will pave a path around Eroom’s law, as ReSync hopes to do.
Global effort to map the human brain releases first data [Allen Institute, October 2024]
On October 1st of this year, BICAN released their first collection of single-cell and single-nucleus transcriptomic and epigenomic data from 12 mammalian species, including humans and mice. These data were collected by the Allen Institute and 17 other global institutions in their efforts to map each of the two billion cells in the brain. The project, which has been dubbed the BRAIN Initiative® Cell Atlas Network (or BICAN for short), has been described as the brain equivalent of the Human Genome Project. Funded by the NIH’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, it combines the efforts of neuroscientists, computational biologists, and software engineers to accelerate scientific progress by creating open source datasets that contain brain cell data from numerous species and developmental stages.
It is the hope of the project that the newly shared data will allow external scientists to map and define brain cell types, piecing apart brain structure and function. BICAN believes that by opting to share data more publicly like this, its value will be maximized and new discoveries expedited, given that traditionally it can take years between data acquisition and publication. With the release of subsequent data, those leading this initiative hope that researchers in other fields will follow suit and work to make their data publicly available.
Papers
Multivariate genomic analysis of 5 million people elucidates the genetic architecture of shared components of the metabolic syndrome [Park et al., Nature Genetics, September 2024]
Researchers conducted a large-scale genetic study of metabolic syndrome (MetS) using data from nearly 5 million people. They identified 1,307 genetic loci associated with MetS using advanced statistical methods. The study revealed a hierarchical genetic structure of MetS, with three main factors: obesity, insulin resistance/hypertension, and dyslipidemia. Genetic signals for MetS were found to be enriched primarily in brain tissues, suggesting a neurological component to the condition. The researchers also identified 11 genes strongly associated with MetS that could serve as potential therapeutic targets. A polygenic risk score for MetS showed promise in predicting cardiovascular disease risk in both European and East Asian populations. The study also found causal relationships between MetS and various health outcomes beyond traditional cardiometabolic diseases. This research provides new insights into the complex genetic architecture of MetS and its relationship with diverse health outcomes, potentially guiding future studies and therapeutic interventions.
Pervasive mislocalization of pathogenic coding variants underlying human disorders [Lacoste et al., Cell, Sep 2024]
Missense mutations are genetic alterations where a single nucleotide change results in the substitution of one amino acid for another in the encoded protein. This can potentially affect the protein's structure and function, depending on the location and nature of the amino acid change. An additional, underappreciated effect of missense mutations is the mislocalization of proteins within a cell. Anne Carpenter and Mikko Taipale’s groups used high-content screens to study the subcellular localization of 3500 missense mutations of 1000 disease-associated genes, and discovered that ⅙ of ll pathogenic variants were mislocalized to the wrong cellular compartment. Mislocalizaton was primarily driven by effects on protein stability and membrane insertion. Phenotypic screens focusing on correcting these trafficking defects have already yielded successful treatments, such as those for cystic fibrosis. This approach offers the potential to develop therapies that could address entire classes of disorders caused by protein mislocalization, particularly for membrane and secreted proteins, opening up new avenues for treating rare diseases.
DNA methylation: durability and what's unique about the brain [Eric Minikel, CureFFI, 2024]
DNA methylation, a crucial process in gene regulation, plays a unique role in the brain compared to other organs. This blog post delves into the intricacies of DNA methylation, focusing on its durability and distinctive features in neurons. Here, Eric discusses the key players involved in writing, erasing, and reading DNA methylation, including enzymes like DNMT3A/B, DNMT1, and TET, as well as methylation readers such as MeCP2.
One of the most fascinating aspects of DNA methylation in the brain is its unique pattern compared to other tissues. Neurons exhibit lower levels of methylated CpG sites but higher levels of hydroxymethylated CpG sites and methylated non-CpG sites. This distinctive methylation profile develops gradually during brain maturation and is associated with synaptic density and DNMT3A expression. Eric highlights how these patterns are highly conserved across individuals and primarily affect genes involved in learning and memory.
He concludes by addressing a critical question: will DNA methylation introduced by CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase) therapeutics remain durable over a human lifetime? Eric presents arguments for both optimism and pessimism regarding the long-term stability of induced methylation in neurons. Factors such as the post-mitotic nature of neurons, the expression of demethylation enzymes, and the specificity of methylation patterns all play a role in this issue. The field is still searching for answers; the level of confidence in methylation durability could heavily influence decisions about the design of methylation therapeutics in the brain and whether they’re feasible for pushing forward.
Notable deals
Kailera Therapeutics Launches with $400M and Licensed Obesity Assets
Backed by Atlas Venture, Bain Capital, and RTW, Kailera Therapeutics has successfully launched with a significant $400 million in funding. The company has secured four experimental obesity therapies licensed from Jiangsu Hengrui for $110 million upfront, including a promising GLP-1/GIP/glucagon tri-agonist. These assets, having already completed Phase II trials, will now proceed directly to a global Phase III. With growing investor interest in the obesity space—fueled by the recent success of Eli Lilly’s Versanis acquisition of a Novartis asset - Kailera is looking to be a potential acquisition target.
DCVC Bio Raises $400M to Drive Computational Biology Innovations
DCVC Bio has announced the closing of a new $400 million fund aimed at advancing companies at the intersection of biology and computation. With a focus on leveraging cutting-edge computational approaches to unlock new biological insights, the firm is expanding its scope beyond its current areas of expertise. New focus areas include pain, metabolism, endocrinology, and inflammation. DCVC Bio is well-positioned to accelerate breakthrough innovations in these fields, potentially reshaping the future of healthcare through data-driven biology.
CAMP4 Therapeutics Eyes IPO, Partners with BioMarin
In the wake of renewed IPO activity in the biotech space, RNA-focused biotech CAMP4 has set its sights on going public. The company has also announced a partnership with BioMarin, securing $1 million in upfront capital with potential future milestone payments of up to $370 million. As the company prepares for its public debut, this collaboration with BioMarin signals confidence in CAMP4’s proprietary RNA platform and its potential to drive long-term value in precision medicine.
What we liked on socials channels
Field Trip
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