Artificial neural networks provide a powerful paradigm for nonbiological information processing. To understand whether similar principles could enable computation within living cells, we combined de novo-designed protein...Artificial neural networks provide a powerful paradigm for nonbiological information processing. To understand whether similar principles could enable computation within living cells, we combined de novo-designed protein heterodimers and engineered viral proteases to implement a synthetic protein circuit that performs winner-take-all neural network classification. This "perceptein" circuit combines weighted input summation through reversible binding interactions with self-activation and mutual inhibition through irreversible proteolytic cleavage. These interactions collectively generate a large repertoire of distinct protein species stemming from up to eight coexpressed starting protein species. The complete system achieves multi-output signal classification with tunable decision boundaries in mammalian cells and can be used to conditionally control cell death. These results demonstrate how engineered protein-based networks can enable programmable signal classification in living cells.
Immune cells can be programmed to deliver targeted therapies in models of brain and inflammatory disease.Immune cells can be programmed to deliver targeted therapies in models of brain and inflammatory disease.
A genomic foundation model broadly enables sequence modeling, prediction, and design.A genomic foundation model broadly enables sequence modeling, prediction, and design.
Uniting life's seen and unseen realms guides a conceptual advance in research.Uniting life's seen and unseen realms guides a conceptual advance in research.
Advances in genomics, proteomics, and metabolomics have revealed associations between specific microbiota species in health and disease. However, the precise mechanism(s) of action for many microbiota species and molecul...Advances in genomics, proteomics, and metabolomics have revealed associations between specific microbiota species in health and disease. However, the precise mechanism(s) of action for many microbiota species and molecules have not been fully elucidated, limiting the development of microbiota-based diagnostics and therapeutics. In this Review, we highlight innovative chemical and genetic approaches that are enabling the dissection of microbiota mechanisms and providing causation in health and disease. Although specific microbiota molecules and mechanisms have begun to emerge, new approaches are still needed to go beyond phenotypic associations and translate microbiota discoveries into actionable targets and therapeutic leads to prevent and treat diseases.
Nguyen E, Poli M, Durrant MG
… +17 more, Kang B, Katrekar D, Li DB, Bartie LJ, Thomas AW, King SH, Brixi G, Sullivan J, Ng MY, Lewis A, Lou A, Ermon S, Baccus SA, Hernandez-Boussard T, Ré C, Hsu PD, Hie BL
The genome is a sequence that encodes the DNA, RNA, and proteins that orchestrate an organism's function. We present Evo, a long-context genomic foundation model with a frontier architecture trained on millions of prokar...The genome is a sequence that encodes the DNA, RNA, and proteins that orchestrate an organism's function. We present Evo, a long-context genomic foundation model with a frontier architecture trained on millions of prokaryotic and phage genomes, and report scaling laws on DNA to complement observations in language and vision. Evo generalizes across DNA, RNA, and proteins, enabling zero-shot function prediction competitive with domain-specific language models and the generation of functional CRISPR-Cas and transposon systems, representing the first examples of protein-RNA and protein-DNA codesign with a language model. Evo also learns how small mutations affect whole-organism fitness and generates megabase-scale sequences with plausible genomic architecture. These prediction and generation capabilities span molecular to genomic scales of complexity, advancing our understanding and control of biology.
Li L, Ge Z, Liu S
… +33 more, Zheng K, Li Y, Chen K, Fu Y, Lei X, Cui Z, Wang Y, Huang J, Liu Y, Duan M, Sun Z, Chen J, Li L, Shen P, Wang G, Chen J, Li R, Li C, Yang Z, Ning Y, Luo A, Chen B, Seim I, Liu X, Wang F, Yao Y, Guo F, Yang M, Liu CH, Fan G, Wang L, Yang D, Zhang L
Tardigrades are captivating organisms known for their resilience in extreme environments, including ultra-high-dose radiation, but the underlying mechanisms of this resilience remain largely unknown. Using genome, transc...Tardigrades are captivating organisms known for their resilience in extreme environments, including ultra-high-dose radiation, but the underlying mechanisms of this resilience remain largely unknown. Using genome, transcriptome, and proteome analysis of , we explored the molecular basis contributing to radiotolerance in this organism. A putatively horizontally transferred gene, DOPA dioxygenase 1 (), responds to radiation and confers radiotolerance by synthesizing betalains-a type of plant pigment with free radical-scavenging properties. A tardigrade-specific radiation-induced disordered protein, TRID1, facilitates DNA damage repair through a mechanism involving phase separation. Two mitochondrial respiratory chain complex assembly proteins, BCS1 and NDUFB8, accumulate to accelerate nicotinamide adenine dinucleotide (NAD) regeneration for poly(adenosine diphosphate-ribosyl)ation (PARylation) and subsequent poly(adenosine diphosphate-ribose) polymerase 1 (PARP1)-mediated DNA damage repair. These three observations expand our understanding of mechanisms of tardigrade radiotolerance.
The first era of genomics started with the publication of Watson and Crick's notable work on the description of the DNA double helix in 1953. This era lasted 50 years, until the publication of the human genome in April 2...The first era of genomics started with the publication of Watson and Crick's notable work on the description of the DNA double helix in 1953. This era lasted 50 years, until the publication of the human genome in April 2003. The second era is associated with the period between the completion of the human genome and the present day. I argue that, with the discontinuity caused by the COVID-19 pandemic and the spread and increased use of genomics to every corner of the world, we are entering a new, third era of genomics that provides major opportunities to advance the health of humans, animals, and the planet. However, this can only happen if the capacity that has greatly expanded in recent years is maintained and expanded further rather than left to atrophy, particularly across the global south.
Comparative genomic analyses provide mechanistic clues to cardiac muscle regulation.Comparative genomic analyses provide mechanistic clues to cardiac muscle regulation.
The recent capability to measure thousands of plasma proteins from a tiny blood sample has provided a new dimension of expansive data that can advance our understanding of human health. For example, the company SomaLogic...The recent capability to measure thousands of plasma proteins from a tiny blood sample has provided a new dimension of expansive data that can advance our understanding of human health. For example, the company SomaLogic has developed the means to measure more than 10,000 proteins and Thermo Fisher's Olink assays over 5400 proteins from as little as 2 μl. When these rich data are integrated with other layers of information from large patient cohorts, such as the UK Biobank's genetic, health, and lifestyle information from half a million participants, we get new insights about the underpinnings of disease, the aging process, and the potential ability to forecast an individual's health trajectory.
Trove of data-mining resources on malaria and other killers will need donations to stay alive.Trove of data-mining resources on malaria and other killers will need donations to stay alive.
Humanities and social sciences help advance "cultures of care" around laboratory animal science and welfare.Humanities and social sciences help advance "cultures of care" around laboratory animal science and welfare.
With vision and a big personality, Christian Happi has built a world-class genomics center so Africans can help Africa.With vision and a big personality, Christian Happi has built a world-class genomics center so Africans can help Africa.
Earlier this year, an international group of scientists published a paper in on the draft genome of the little bush moa (), one of about nine species of extinct flightless birds endemic to Aotearoa (New Zealand). The ge...Earlier this year, an international group of scientists published a paper in on the draft genome of the little bush moa (), one of about nine species of extinct flightless birds endemic to Aotearoa (New Zealand). The genome was sequenced from the ancient DNA of a "poorly provenanced" fossil bone acquired by the Royal Ontario Museum. It held important clues about the moa's evolutionary history and aspects of its biology.
The rapid global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the beginning of 2020 presented the world with its greatest health challenge in decades. It soon became clear that governments we...The rapid global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the beginning of 2020 presented the world with its greatest health challenge in decades. It soon became clear that governments were unprepared to respond appropriately to this crisis. National and international public health authorities were confused about the transmission routes of the virus and the control measures required to protect against it. In particular, the need to reduce the risk of infection through sufficient and effective ventilation of indoor spaces was given little attention. In this review, we discuss insights and key lessons learned from the COVID-19 pandemic regarding the role of ventilation as an effective means against airborne transmission of pathogens and, more broadly, for supporting good indoor air quality.
Genomic data from different populations will improve understanding of complex diseases.Genomic data from different populations will improve understanding of complex diseases.
Proximity labeling proteomics (PLP) strategies are powerful approaches to yield snapshots of protein neighborhoods. Here, we describe a multiscale PLP method with adjustable resolution that uses a commercially available...Proximity labeling proteomics (PLP) strategies are powerful approaches to yield snapshots of protein neighborhoods. Here, we describe a multiscale PLP method with adjustable resolution that uses a commercially available photocatalyst, Eosin Y, which upon visible light illumination activates different photo-probes with a range of labeling radii. We applied this platform to profile neighborhoods of the oncogenic epidermal growth factor receptor and orthogonally validated more than 20 neighbors using immunoassays and AlphaFold-Multimer prediction. We further profiled the protein neighborhoods of cell-cell synapses induced by bispecific T cell engagers and chimeric antigen receptor T cells. This integrated multiscale PLP platform maps local and distal protein networks on and between cell surfaces, which will aid in the systematic construction of the cell surface interactome, revealing horizontal signaling partners and reveal new immunotherapeutic opportunities.
Winnikoff JR, Milshteyn D, Vargas-Urbano SJ
… +9 more, Pedraza-Joya MA, Armando AM, Quehenberger O, Sodt A, Gillilan RE, Dennis EA, Lyman E, Haddock SHD, Budin I
Hydrostatic pressure increases with depth in the ocean, but little is known about the molecular bases of biological pressure tolerance. We describe a mode of pressure adaptation in comb jellies (ctenophores) that also co...Hydrostatic pressure increases with depth in the ocean, but little is known about the molecular bases of biological pressure tolerance. We describe a mode of pressure adaptation in comb jellies (ctenophores) that also constrains these animals' depth range. Structural analysis of deep-sea ctenophore lipids shows that they form a nonbilayer phase at pressures under which the phase is not typically stable. Lipidomics and all-atom simulations identified phospholipids with strong negative spontaneous curvature, including plasmalogens, as a hallmark of deep-adapted membranes that causes this phase behavior. Synthesis of plasmalogens enhanced pressure tolerance in , whereas low-curvature lipids had the opposite effect. Imaging of ctenophore tissues indicated that the disintegration of deep-sea animals when decompressed could be driven by a phase transition in their phospholipid membranes.
Comparative genomics elucidates the steps enabling heat production in fat tissue.Comparative genomics elucidates the steps enabling heat production in fat tissue.