BioByte 099: Ferroptosis across disease, adipose retains epigenetic memory, Cephalopod-inspired drug delivery, and predicting RNA 3D structures
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
Ferroptosis—disease perils and therapeutic promise [Brown, Hirschhorn, and Stockwell, Science, 2024]
Ferroptosis, a form of iron-dependent cell death driven by the oxidation of lipids in cellular membranes, has emerged as a promising mechanism in various diseases. When lipids containing polyunsaturated fatty acids oxidize, they compromise membrane integrity, leading to cell death unless mitigated by repair systems such as the enzyme GPX4. Ferroptosis has been linked toe conditions like neurodegeneration, cancer, and organ damage, where hallmarks like iron buildup and lipid oxidation are prevalent. Targeting these pathways could provide new therapeutic avenues for diseases associated with ferroptosis.
Neurodegenerative diseases such as Alzheimer's, Parkinson's, and ALS are increasingly associated with ferroptosis. In Alzheimer’s, iron accumulation in regions of the brain correlates with disease progression and cognitive decline. Existing treatments targeting amyloid and tau proteins offer limited success, highlighting the need for innovative approaches like ferroptosis regulation. Drugs like CuII(atsm) show promise in reducing oxidative damage and protecting neurons. This strategy could potentially extend to diseases such as Huntington's and Friedreich’s ataxia, where ferroptosis appears to play a role.
In cancer therapy, inducing ferroptosis selectively has shown potential against resistant tumors like lung and colorectal cancers. These cancers often exhibit heightened sensitivity to ferroptosis-inducing mechanisms. Additionally, targeting lipid metabolism and modulating fatty acid incorporation in cancer cells can enhance the efficacy of treatments. Hormone-dependent cancers such as breast and prostate cancer may benefit from combining antihormone therapies with ferroptosis-promoting agents, highlighting the versatility of this therapeutic approach.
Beyond neurodegeneration and cancer, ferroptosis is implicated in other organ-specific disorders. Conditions like COPD, Crohn’s disease, and rheumatoid arthritis reveal the role of impaired antioxidant defenses and lipid peroxidation in tissue damage. Ferroptosis inhibitors could mitigate damage in these contexts, while selective induction might address localized issues like damaged cartilage. As understanding of ferroptosis deepens, it offers a dual pathway for therapeutic innovations: halting cell death in degenerative diseases while inducing it in malignancies, presenting significant promise for therapeutic advancements.
Adipose tissue retains an epigenetic memory of obesity after weight loss [Hinte et al., Nature, November 2024]
This study provides the first direct evidence that fat tissue (adipose tissue) retains a "memory" of obesity even after significant weight loss. This memory is primarily stored in the form of epigenetic changes - modifications to how genes are regulated without changing the DNA sequence itself. This finding helps explain why it's so difficult for many people to maintain weight loss and why weight often returns rapidly when dieting stops.
Using advanced molecular techniques, they identified specific alterations in gene regulatory regions and histone modifications that persist after weight loss, explaining how this memory is maintained at a molecular level. This finding has significant implications for treating obesity, suggesting that current approaches - including bariatric surgery and newer drugs like semaglutide - may not address these underlying epigenetic changes. The research indicates that truly effective long-term weight management might require developing new strategies to "reset" fat tissue to its pre-obese state. This breakthrough helps explain the notorious difficulty of maintaining weight loss and the common "yo-yo" effect experienced by many people who diet. Importantly, while the study primarily focused on bariatric surgery patients and mouse models, it opens new therapeutic avenues that could revolutionize obesity treatment by addressing not just weight loss itself, but the persistent biological memory that makes that loss so difficult to maintain.
Cephalopod-inspired jetting devices for gastrointestinal drug delivery [Arrick et al., Nature, November 2024]
Injection via needle has been a vital drug delivery method for centuries, despite the often unpleasant experience endured by the recipient during subcutaneous administration as well as the burdens of handling, training, and disposal that accompany the use of sharps. To mitigate this burden and facilitate the accessibility of traditionally injected therapies, the work in this study delved into the powerful arsenal of natural processes ripe for biomimicry, taking inspiration from the jet propulsion mechanisms of cephalopods to develop a new, needle-free method of administering macromolecules in the gastrointestinal tract.
In order to propel themselves through water or to disperse clouds of ink to hide their escape, cephalopods use a maneuverable siphon to eject pressurized liquid, directing the force in a direction of their choosing. The authors of this paper used the cephalopod’s mechanism as inspiration for their microjet delivery (MiDe) systems, of which they designed two versions with different angles of ejection relative to the orientation of the robot with the goal of utilizing the systems to target different administration locations: axial and radial. Both systems could either be ingested freely or attached to an endoscope for more precise targeting.
After a series of in vitro and ex vivo tests on porcine tissue samples, the authors found that neither direct contact nor a perpendicular angle of incidence were necessary for successful delivery, although deviations from ideal resulted in 20% and 40% losses respectively. The devices were then translated to dogs and pigs, using insulin, a long-acting inactive GLP-1, and a small interfering RNA (siRNA) as probe therapies. Although met with varying degrees of success, all methods of administration resulted in double-digit bioavailabilities. They also confirmed that the devices exited safely, and that the vast majority were activated in the correct location.
The authors point to several problems that must be resolved before this technology will be commercially viable: the size of the devices will need to be decreased to meet the FDA standards, and the variability will need to be addressed. Despite these shortcomings, the robots in this study have the potential to reduce the dependency of many larger therapies on needles–ideally decreasing costs–and increase treatment accessibility and patient comfort.
Accurate RNA 3D structure prediction using a language model-based deep learning approach [Shen et al., Nature Methods, Nov 2024]
A new RNA structure prediction model published in Nature Methods last week introduces RhoFold+, a novel deep learning method that accurately predicts 3D structures of single-chain RNAs directly from their sequences. The method combines a large RNA language model pretrained on ~23.7 million RNA sequences with multiple deep learning modules to enable end-to-end structure prediction. RhoFold+ outperforms existing computational methods and even human experts on standard benchmarks. The model demonstrates strong generalizability across different RNA families and types, achieving sub-4Å mean RMSD accuracy, while being computationally efficient (predictions typically complete within ~0.14 seconds).
RNA structure determination is crucial for understanding RNA function and developing RNA-targeted therapeutics, but historically has been a more difficult task than protein structure prediction. While over 85% of the human genome is transcribed into RNA, only about 3% codes for proteins, leaving many RNAs with unknown structures and functions. Traditional experimental methods for determining RNA structures like X-ray crystallography and cryo-EM are low-throughput, and therefore there is a lack of large training sets for ML models. RhoFold+ provides a fast, accurate computational alternative that could accelerate RNA biology research and RNA-targeted drug development by predicting structures of both known and newly discovered RNAs. Additionally, the model can predict secondary structures and interhelical angles, providing experimentally verifiable features that broaden its applicability in RNA structure-function studies and rational drug design.
Notable deals
Enveda raises an $130M Series C to progress to clinical proof-of-concept in three of its drug candidates. The Colorado-based biotech draws inspiration from plant chemistry and uses machine learning to develop first and best-in-class therapeutics across inflammation, obesity, fibrosis, pain and neuroscience. Investors include Kinnevik, FPV and Ballie Gifford.
Aizen Therapeutics has emerged from stealth with $13 million in seed funding to develop synthetic “mirror peptides,” drugs composed of D-amino acids that resist degradation and evade immune detection as only L-amino acids are found in the body naturally. The company is a spin-out from Caltech and is based on generative AI technology trained on ligand-receptor data that forms the basis of the company’s DaX platform. Investors include Wilson Hill Ventures and Madrona.
Nobel Laureate Carolyn Bertozzi launches her next start-up, Valora Therapeutics, with $30M in funding. This time, the focus is the development of antibody-lectin chimeras (AbLecs) which target lectins implicated in cancer’s evasion of the immune system.
Struggling 23andMe enters a strategic collaboration with Mirador Therapeutics. Mirador will use 23andMe’s genetic and phenotypic health database to mine new target. No financial details have been disclosed.
More:
Novartis and Ratio partner on radiopharma for $745M in biobucks.
Jupiter Bioventures launches with a $70M fund targeting early science.
Novartis acquires neuroscience biotech Kate Therapeutics for $1.1B in biobucks.
iMicrobes raises $10M to develop bio-based chemicals for scalable bioprocesses.
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Field Trip
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