Agent in Genome Science

• SlideDeck: 2026-SP-W3.5-LifeScience-ProteinLLM.pdf
• Version: current
• Notes: 2026-SP-W3.7-LifeScience-genomeLLM

Perception Healthcare

In this session, our readings cover:

Required Readings:

Understanding how agents perceive and process actions in a special domain like healthcare

Key Concepts: Domain-specific perception, multimodal input processing, specialized domain understanding (bio, healthcare, robotics)

Here are the related slide deck from the previous two course offerings:

Topic	Slide Deck	Previous Semester
Survey - BioScience LLMs	W2.2-bioLM	25course
Survey - FMs in Healthcare	W3.1-GenAI-healthcare	25course
Agent - In Healthcare	W9.1-HealthAI-agenticHealth	25course

2025 HIGH-IMPACT PAPERS on this topic

Advancing regulatory variant effect prediction with AlphaGenome

• Nature 2026 / from Google DeepMind
• Model shared https://github.com/google-deepmind/alphagenome_research
• Abstract: Deep learning models that predict functional genomic measurements from DNA sequences are powerful tools for deciphering the genetic regulatory code. Existing methods involve a trade-off between input sequence length and prediction resolution, thereby limiting their modality scope and performance1,2,3,4,5. We present AlphaGenome, a unified DNA sequence model, which takes as input 1 Mb of DNA sequence and predicts thousands of functional genomic tracks up to single-base-pair resolution across diverse modalities. The modalities include gene expression, transcription initiation, chromatin accessibility, histone modifications, transcription factor binding, chromatin contact maps, splice site usage and splice junction coordinates and strength. Trained on human and mouse genomes, AlphaGenome matches or exceeds the strongest available external models in 25 of 26 evaluations of variant effect prediction. The ability of AlphaGenome to simultaneously score variant effects across all modalities accurately recapitulates the mechanisms of clinically relevant variants near the TAL1 oncogene6. To facilitate broader use, we provide tools for making genome track and variant effect predictions from sequence.

Genome modeling and design across all domains of life with Evo 2

• Garyk Brixi, Matthew G. Durrant, Jerome Ku, Michael Poli, Greg Brockman, Daniel Chang, Gabriel A. Gonzalez, Samuel H. King, David B. Li, View ORCID ProfileAditi T. Merchant, Mohsen Naghipourfar, Eric Nguyen, Chiara Ricci-Tam, David W. Romero, Gwanggyu Sun, Ali Taghibakshi, Anton Vorontsov, Brandon Yang, Myra Deng, Liv Gorton, Nam Nguyen, Nicholas K. Wang, Etowah Adams, Stephen A. Baccus, Steven Dillmann, Stefano Ermon, Daniel Guo, Rajesh Ilango, Ken Janik, Amy X. Lu, Reshma Mehta, View ORCID ProfileMohammad R.K. Mofrad, Madelena Y. Ng, Jaspreet Pannu, Christopher Ré, Jonathan C. Schmok, John St. John, Jeremy Sullivan, Kevin Zhu, Greg Zynda, Daniel Balsam, Patrick Collison, Anthony B. Costa, Tina Hernandez-Boussard, Eric Ho, Ming-Yu Liu, Thomas McGrath, Kimberly Powell, Dave P. Burke, View ORCID ProfileHani Goodarzi, View ORCID ProfilePatrick D. Hsu, View ORCID ProfileBrian L. Hie
• doi: https://doi.org/10.1101/2025.02.18.638918
• All of life encodes information with DNA. While tools for sequencing, synthesis, and editing of genomic code have transformed biological research, intelligently composing new biological systems would also require a deep understanding of the immense complexity encoded by genomes. We introduce Evo 2, a biological foundation model trained on 9.3 trillion DNA base pairs from a highly curated genomic atlas spanning all domains of life. We train Evo 2 with 7B and 40B parameters to have an unprecedented 1 million token context window with single-nucleotide resolution. Evo 2 learns from DNA sequence alone to accurately predict the functional impacts of genetic variation—from noncoding pathogenic mutations to clinically significant BRCA1 variants—without task-specific finetuning. Applying mechanistic interpretability analyses, we reveal that Evo 2 autonomously learns a breadth of biological features, including exon–intron boundaries, transcription factor binding sites, protein structural elements, and prophage genomic regions. Beyond its predictive capabilities, Evo 2 generates mitochondrial, prokaryotic, and eukaryotic sequences at genome scale with greater naturalness and coherence than previous methods. Guiding Evo 2 via inference-time search enables controllable generation of epigenomic structure, for which we demonstrate the first inference-time scaling results in biology. We make Evo 2 fully open, including model parameters, training code, inference code, and the OpenGenome2 dataset, to accelerate the exploration and design of biological complexity.

Background Readings:

Highly accurate protein structure prediction with AlphaFold

• Proteins are essential to life, and understanding their structure can facilitate a mechanistic understanding of their function. Through an enormous experimental effort1,2,3,4, the structures of around 100,000 unique proteins have been determined5, but this represents a small fraction of the billions of known protein sequences6,7. Structural coverage is bottlenecked by the months to years of painstaking effort required to determine a single protein structure. Accurate computational approaches are needed to address this gap and to enable large-scale structural bioinformatics. Predicting the three-dimensional structure that a protein will adopt based solely on its amino acid sequence—the structure prediction component of the ‘protein folding problem’8—has been an important open research problem for more than 50 years9. Despite recent progress10,11,12,13,14, existing methods fall far short of atomic accuracy, especially when no homologous structure is available. Here we provide the first computational method that can regularly predict protein structures with atomic accuracy even in cases in which no similar structure is known. We validated an entirely redesigned version of our neural network-based model, AlphaFold, in the challenging 14th Critical Assessment of protein Structure Prediction (CASP14)15, demonstrating accuracy competitive with experimental structures in a majority of cases and greatly outperforming other methods. Underpinning the latest version of AlphaFold is a novel machine learning approach that incorporates physical and biological knowledge about protein structure, leveraging multi-sequence alignments, into the design of the deep learning algorithm.

Evolutionary-scale prediction of atomic-level protein structure with a language model

• Speedy structures from single sequences: Machine learning methods for protein structure prediction have taken advantage of the evolutionary information present in multiple sequence alignments to derive accurate structural information, but predicting structure accurately from a single sequence is much more difficult. Lin et al. trained transformer protein language models with up to 15 billion parameters on experimental and high-quality predicted structures and found that information about atomic-level structure emerged in the model as it was scaled up. They created ESMFold, a sequence-to-structure predictor that is nearly as accurate as alignment-based methods and considerably faster. The increased speed permitted the generation of a database, the ESM Metagenomic Atlas, containing more than 600 million metagenomic proteins. —MAF
• Recent advances in machine learning have leveraged evolutionary information in multiple sequence alignments to predict protein structure. We demonstrate direct inference of full atomic-level protein structure from primary sequence using a large language model. As language models of protein sequences are scaled up to 15 billion parameters, an atomic-resolution picture of protein structure emerges in the learned representations. This results in an order-of-magnitude acceleration of high-resolution structure prediction, which enables large-scale structural characterization of metagenomic proteins. We apply this capability to construct the ESM Metagenomic Atlas by predicting structures for >617 million metagenomic protein sequences, including >225 million that are predicted with high confidence, which gives a view into the vast breadth and diversity of natural proteins.

Accurate prediction of protein structures and interactions using a three-track neural network

• Science 19 Aug 2021

• Deep learning takes on protein folding: In 1972, Anfinsen won a Nobel prize for demonstrating a connection between a protein’s amino acid sequence and its three-dimensional structure. Since 1994, scientists have competed in the biannual Critical Assessment of Structure Prediction (CASP) protein-folding challenge. Deep learning methods took center stage at CASP14, with DeepMind’s Alphafold2 achieving remarkable accuracy. Baek et al. explored network architectures based on the DeepMind framework. They used a three-track network to process sequence, distance, and coordinate information simultaneously and achieved accuracies approaching those of DeepMind. The method, RoseTTA fold, can solve challenging x-ray crystallography and cryo–electron microscopy modeling problems and generate accurate models of protein-protein complexes. —VV

• DeepMind presented notably accurate predictions at the recent 14th Critical Assessment of Structure Prediction (CASP14) conference. We explored network architectures that incorporate related ideas and obtained the best performance with a three-track network in which information at the one-dimensional (1D) sequence level, the 2D distance map level, and the 3D coordinate level is successively transformed and integrated. The three-track network produces structure predictions with accuracies approaching those of DeepMind in CASP14, enables the rapid solution of challenging x-ray crystallography and cryo–electron microscopy structure modeling problems, and provides insights into the functions of proteins of currently unknown structure. The network also enables rapid generation of accurate protein-protein complex models from sequence information alone, short-circuiting traditional approaches that require modeling of individual subunits followed by docking. We make the method available to the scientific community to speed biological research.

Transformer protein language models are unsupervised structure learners

• https://doi.org/10.1101/2020.12.15.422761
• Unsupervised contact prediction is central to uncovering physical, structural, and functional constraints for protein structure determination and design. For decades, the predominant approach has been to infer evolutionary constraints from a set of related sequences. In the past year, protein language models have emerged as a potential alternative, but performance has fallen short of state-of-the-art approaches in bioinformatics. In this paper we demonstrate that Transformer attention maps learn contacts from the unsupervised language modeling objective. We find the highest capacity models that have been trained to date already outperform a state-of-the-art unsupervised contact prediction pipeline, suggesting these pipelines can be replaced with a single forward pass of an end-to-end model.1

PEER: A Comprehensive and Multi-Task Benchmark for Protein Sequence Understanding

• [Submitted on 5 Jun 2022 (v1), last revised 19 Sep 2022 (this version, v2)]
• Minghao Xu, Zuobai Zhang, Jiarui Lu, Zhaocheng Zhu, Yangtian Zhang, Chang Ma, Runcheng Liu, Jian Tang
• We are now witnessing significant progress of deep learning methods in a variety of tasks (or datasets) of proteins. However, there is a lack of a standard benchmark to evaluate the performance of different methods, which hinders the progress of deep learning in this field. In this paper, we propose such a benchmark called PEER, a comprehensive and multi-task benchmark for Protein sEquence undERstanding. PEER provides a set of diverse protein understanding tasks including protein function prediction, protein localization prediction, protein structure prediction, protein-protein interaction prediction, and protein-ligand interaction prediction. We evaluate different types of sequence-based methods for each task including traditional feature engineering approaches, different sequence encoding methods as well as large-scale pre-trained protein language models. In addition, we also investigate the performance of these methods under the multi-task learning setting. Experimental results show that large-scale pre-trained protein language models achieve the best performance for most individual tasks, and jointly training multiple tasks further boosts the performance. The datasets and source codes of this benchmark are all available at this https URL Comments: Accepted by NeurIPS 2022 Dataset and Benchmark Track. a

More Readings:

Structure-based drug design with geometric deep learning

• https://doi.org/10.1016/j.sbi.2023.102548

• Structure-based drug design uses three-dimensional geometric information of macromolecules, such as proteins or nucleic acids, to identify suitable ligands. Geometric deep learning, an emerging concept of neural-network-based machine learning, has been applied to macromolecular structures. This review provides an overview of the recent applications of geometric deep learning in bioorganic and medicinal chemistry, highlighting its potential for structure-based drug discovery and design. Emphasis is placed on molecular property prediction, ligand binding site and pose prediction, and structure-based de novo molecular design. The current challenges and opportunities are highlighted, and a forecast of the future of geometric deep learning for drug discovery is presented. Questions answered in this article

• Structure-based drug design is based on methods that leverage three-dimensional (3D) structures of macromolecular targets, such as proteins and nucleic acids, for decision-making in medicinal chemistry [1,2]. Structure-based modeling is well established throughout the drug discovery process, aiming to rationalize non-covalent interactions between ligands and their target macromolecule(s) [3]. The questions addressed with structure-based approaches include molecular property prediction, ligand binding site recognition, binding pose estimation, as well as de novo design [4, 5, 6, 7]. For such tasks, detailed knowledge of the 3D structure of the investigated macromolecular surfaces and ligand–receptor interfaces is essential. Recently, an emerging concept of neural-network-based “artificial intelligence”, geometric deep learning, has been introduced to solve numerous problems in the molecular sciences, including structure-based drug discovery and design [8].

Generative models for molecular discovery: Recent advances and challenges

• Camille Bilodeau, Wengong Jin, Tommi Jaakkola, Regina Barzilay, Klavs F. Jensen
• 05 March 2022 https://doi.org/10.1002/wcms.1608Citations
• Development of new products often relies on the discovery of novel molecules. While conventional molecular design involves using human expertise to propose, synthesize, and test new molecules, this process can be cost and time intensive, limiting the number of molecules that can be reasonably tested. Generative modeling provides an alternative approach to molecular discovery by reformulating molecular design as an inverse design problem. Here, we review the recent advances in the state-of-the-art of generative molecular design and discusses the considerations for integrating these models into real molecular discovery campaigns. We first review the model design choices required to develop and train a generative model including common 1D, 2D, and 3D representations of molecules and typical generative modeling neural network architectures. We then describe different problem statements for molecular discovery applications and explore the benchmarks used to evaluate models based on those problem statements. Finally, we discuss the important factors that play a role in integrating generative models into experimental workflows. Our aim is that this review will equip the reader with the information and context necessary to utilize generative modeling within their domain.