Daily Papers

A central problem in biology is to understand how organisms evolve and adapt to their environment by acquiring variations in the observable characteristics or traits of species across the tree of life. With the growing availability of large-scale image repositories in biology and recent advances in generative modeling, there is an opportunity to accelerate the discovery of evolutionary traits automatically from images. Toward this goal, we introduce Phylo-Diffusion, a novel framework for conditioning diffusion models with phylogenetic knowledge represented in the form of HIERarchical Embeddings (HIER-Embeds). We also propose two new experiments for perturbing the embedding space of Phylo-Diffusion: trait masking and trait swapping, inspired by counterpart experiments of gene knockout and gene editing/swapping. Our work represents a novel methodological advance in generative modeling to structure the embedding space of diffusion models using tree-based knowledge. Our work also opens a new chapter of research in evolutionary biology by using generative models to visualize evolutionary changes directly from images. We empirically demonstrate the usefulness of Phylo-Diffusion in capturing meaningful trait variations for fishes and birds, revealing novel insights about the biological mechanisms of their evolution.

The introduction of genome engineering technology has transformed biomedical research, making it possible to make precise changes to genetic information. However, creating an efficient gene-editing system requires a deep understanding of CRISPR technology, and the complex experimental systems under investigation. While Large Language Models (LLMs) have shown promise in various tasks, they often lack specific knowledge and struggle to accurately solve biological design problems. In this work, we introduce CRISPR-GPT, an LLM agent augmented with domain knowledge and external tools to automate and enhance the design process of CRISPR-based gene-editing experiments. CRISPR-GPT leverages the reasoning ability of LLMs to facilitate the process of selecting CRISPR systems, designing guide RNAs, recommending cellular delivery methods, drafting protocols, and designing validation experiments to confirm editing outcomes. We showcase the potential of CRISPR-GPT for assisting non-expert researchers with gene-editing experiments from scratch and validate the agent's effectiveness in a real-world use case. Furthermore, we explore the ethical and regulatory considerations associated with automated gene-editing design, highlighting the need for responsible and transparent use of these tools. Our work aims to bridge the gap between beginner biological researchers and CRISPR genome engineering techniques, and demonstrate the potential of LLM agents in facilitating complex biological discovery tasks.

Facial parts swapping aims to selectively transfer regions of interest from the source image onto the target image while maintaining the rest of the target image unchanged. Most studies on face swapping designed specifically for full-face swapping, are either unable or significantly limited when it comes to swapping individual facial parts, which hinders fine-grained and customized character designs. However, designing such an approach specifically for facial parts swapping is challenged by a reasonable multiple reference feature fusion, which needs to be both efficient and effective. To overcome this challenge, FuseAnyPart is proposed to facilitate the seamless "fuse-any-part" customization of the face. In FuseAnyPart, facial parts from different people are assembled into a complete face in latent space within the Mask-based Fusion Module. Subsequently, the consolidated feature is dispatched to the Addition-based Injection Module for fusion within the UNet of the diffusion model to create novel characters. Extensive experiments qualitatively and quantitatively validate the superiority and robustness of FuseAnyPart. Source codes are available at https://github.com/Thomas-wyh/FuseAnyPart.

Effective editing of personal content holds a pivotal role in enabling individuals to express their creativity, weaving captivating narratives within their visual stories, and elevate the overall quality and impact of their visual content. Therefore, in this work, we introduce SwapAnything, a novel framework that can swap any objects in an image with personalized concepts given by the reference, while keeping the context unchanged. Compared with existing methods for personalized subject swapping, SwapAnything has three unique advantages: (1) precise control of arbitrary objects and parts rather than the main subject, (2) more faithful preservation of context pixels, (3) better adaptation of the personalized concept to the image. First, we propose targeted variable swapping to apply region control over latent feature maps and swap masked variables for faithful context preservation and initial semantic concept swapping. Then, we introduce appearance adaptation, to seamlessly adapt the semantic concept into the original image in terms of target location, shape, style, and content during the image generation process. Extensive results on both human and automatic evaluation demonstrate significant improvements of our approach over baseline methods on personalized swapping. Furthermore, SwapAnything shows its precise and faithful swapping abilities across single object, multiple objects, partial object, and cross-domain swapping tasks. SwapAnything also achieves great performance on text-based swapping and tasks beyond swapping such as object insertion.

Clustering non-Euclidean data is difficult, and one of the most used algorithms besides hierarchical clustering is the popular algorithm Partitioning Around Medoids (PAM), also simply referred to as k-medoids. In Euclidean geometry the mean-as used in k-means-is a good estimator for the cluster center, but this does not hold for arbitrary dissimilarities. PAM uses the medoid instead, the object with the smallest dissimilarity to all others in the cluster. This notion of centrality can be used with any (dis-)similarity, and thus is of high relevance to many domains such as biology that require the use of Jaccard, Gower, or more complex distances. A key issue with PAM is its high run time cost. We propose modifications to the PAM algorithm to achieve an O(k)-fold speedup in the second SWAP phase of the algorithm, but will still find the same results as the original PAM algorithm. If we slightly relax the choice of swaps performed (at comparable quality), we can further accelerate the algorithm by performing up to k swaps in each iteration. With the substantially faster SWAP, we can now also explore alternative strategies for choosing the initial medoids. We also show how the CLARA and CLARANS algorithms benefit from these modifications. It can easily be combined with earlier approaches to use PAM and CLARA on big data (some of which use PAM as a subroutine, hence can immediately benefit from these improvements), where the performance with high k becomes increasingly important. In experiments on real data with k=100, we observed a 200-fold speedup compared to the original PAM SWAP algorithm, making PAM applicable to larger data sets as long as we can afford to compute a distance matrix, and in particular to higher k (at k=2, the new SWAP was only 1.5 times faster, as the speedup is expected to increase with k).

Scientific discovery relies on scientists generating novel hypotheses that undergo rigorous experimental validation. To augment this process, we introduce an AI co-scientist, a multi-agent system built on Gemini 2.0. The AI co-scientist is intended to help uncover new, original knowledge and to formulate demonstrably novel research hypotheses and proposals, building upon prior evidence and aligned to scientist-provided research objectives and guidance. The system's design incorporates a generate, debate, and evolve approach to hypothesis generation, inspired by the scientific method and accelerated by scaling test-time compute. Key contributions include: (1) a multi-agent architecture with an asynchronous task execution framework for flexible compute scaling; (2) a tournament evolution process for self-improving hypotheses generation. Automated evaluations show continued benefits of test-time compute, improving hypothesis quality. While general purpose, we focus development and validation in three biomedical areas: drug repurposing, novel target discovery, and explaining mechanisms of bacterial evolution and anti-microbial resistance. For drug repurposing, the system proposes candidates with promising validation findings, including candidates for acute myeloid leukemia that show tumor inhibition in vitro at clinically applicable concentrations. For novel target discovery, the AI co-scientist proposed new epigenetic targets for liver fibrosis, validated by anti-fibrotic activity and liver cell regeneration in human hepatic organoids. Finally, the AI co-scientist recapitulated unpublished experimental results via a parallel in silico discovery of a novel gene transfer mechanism in bacterial evolution. These results, detailed in separate, co-timed reports, demonstrate the potential to augment biomedical and scientific discovery and usher an era of AI empowered scientists.

Genetic engineering of cells has a range of applications in treating incurable diseases. Plasmid DNA is a popular choice of nucleic acid for cell engineering due to its low cost and stability. However, plasmid DNA must survive the protective mechanisms present in the cell's cytoplasm to enter the nucleus for translation. Many of the existing methods for nucleic acid delivery, such as chemical-based and virus-based delivery, suffer from drawbacks induced by the nucleic acid carrier itself. Mechanical methods present an alternative to nucleic acid carriers by physically producing openings in the cell to deliver cargos. However, in most systems, the cell membrane openings are too small to deliver large cargos, or the poration process leads to low cell viability. In this study, we present a microfluidic device with integrated high aspect ratio nanostructures that repeatably rupture the cell membrane and nuclear envelope. These sharp-tipped nanolancets penetrate the cell deep enough to allow direct delivery of cargos into the nucleus, but still allow for cell recovery after treatment. We show the device's ability to deliver cargo to a variety of cell types while maintaining high viability. Then, we demonstrate the rapid onset of plasmid DNA expression that results from direct nuclear delivery of naked DNA, showing expression speeds comparable to microinjection, but with significantly greater throughput. We envision the use of this device as a tool to quickly produce high quantities of genetically engineered cells to treat a myriad of diseases.

In this paper, we propose a novel diffusion-based multi-condition controllable framework for video head swapping, which seamlessly transplant a human head from a static image into a dynamic video, while preserving the original body and background of target video, and further allowing to tweak head expressions and movements during swapping as needed. Existing face-swapping methods mainly focus on localized facial replacement neglecting holistic head morphology, while head-swapping approaches struggling with hairstyle diversity and complex backgrounds, and none of these methods allow users to modify the transplanted head expressions after swapping. To tackle these challenges, our method incorporates several innovative strategies through a unified latent diffusion paradigm. 1) Identity-preserving context fusion: We propose a shape-agnostic mask strategy to explicitly disentangle foreground head identity features from background/body contexts, combining hair enhancement strategy to achieve robust holistic head identity preservation across diverse hair types and complex backgrounds. 2) Expression-aware landmark retargeting and editing: We propose a disentangled 3DMM-driven retargeting module that decouples identity, expression, and head poses, minimizing the impact of original expressions in input images and supporting expression editing. While a scale-aware retargeting strategy is further employed to minimize cross-identity expression distortion for higher transfer precision. Experimental results demonstrate that our method excels in seamless background integration while preserving the identity of the source portrait, as well as showcasing superior expression transfer capabilities applicable to both real and virtual characters.

Despite promising progress in face swapping task, realistic swapped images remain elusive, often marred by artifacts, particularly in scenarios involving high pose variation, color differences, and occlusion. To address these issues, we propose a novel approach that better harnesses diffusion models for face-swapping by making following core contributions. (a) We propose to re-frame the face-swapping task as a self-supervised, train-time inpainting problem, enhancing the identity transfer while blending with the target image. (b) We introduce a multi-step Denoising Diffusion Implicit Model (DDIM) sampling during training, reinforcing identity and perceptual similarities. (c) Third, we introduce CLIP feature disentanglement to extract pose, expression, and lighting information from the target image, improving fidelity. (d) Further, we introduce a mask shuffling technique during inpainting training, which allows us to create a so-called universal model for swapping, with an additional feature of head swapping. Ours can swap hair and even accessories, beyond traditional face swapping. Unlike prior works reliant on multiple off-the-shelf models, ours is a relatively unified approach and so it is resilient to errors in other off-the-shelf models. Extensive experiments on FFHQ and CelebA datasets validate the efficacy and robustness of our approach, showcasing high-fidelity, realistic face-swapping with minimal inference time. Our code is available at https://github.com/Sanoojan/REFace.

Current face reenactment and swapping methods mainly rely on GAN frameworks, but recent focus has shifted to pre-trained diffusion models for their superior generation capabilities. However, training these models is resource-intensive, and the results have not yet achieved satisfactory performance levels. To address this issue, we introduce Face-Adapter, an efficient and effective adapter designed for high-precision and high-fidelity face editing for pre-trained diffusion models. We observe that both face reenactment/swapping tasks essentially involve combinations of target structure, ID and attribute. We aim to sufficiently decouple the control of these factors to achieve both tasks in one model. Specifically, our method contains: 1) A Spatial Condition Generator that provides precise landmarks and background; 2) A Plug-and-play Identity Encoder that transfers face embeddings to the text space by a transformer decoder. 3) An Attribute Controller that integrates spatial conditions and detailed attributes. Face-Adapter achieves comparable or even superior performance in terms of motion control precision, ID retention capability, and generation quality compared to fully fine-tuned face reenactment/swapping models. Additionally, Face-Adapter seamlessly integrates with various StableDiffusion models.

A hallmark of human innovation is the process of recombination -- creating original ideas by integrating elements of existing mechanisms and concepts. In this work, we automatically mine the scientific literature and build CHIMERA: a large-scale knowledge base (KB) of recombination examples. CHIMERA can be used to empirically explore at scale how scientists recombine concepts and take inspiration from different areas, or to train supervised machine learning models that learn to predict new creative cross-domain directions. To build this KB, we present a novel information extraction task of extracting recombination from scientific paper abstracts, collect a high-quality corpus of hundreds of manually annotated abstracts, and use it to train an LLM-based extraction model. The model is applied to a large corpus of papers in the AI domain, yielding a KB of over 28K recombination examples. We analyze CHIMERA to explore the properties of recombination in different subareas of AI. Finally, we train a scientific hypothesis generation model using the KB, which predicts new recombination directions that real-world researchers find inspiring. Our data and code are available at https://github.cs.huji.ac.il/tomhope-lab/CHIMERA

In an era where images and visual content dominate our digital landscape, the ability to manipulate and personalize these images has become a necessity. Envision seamlessly substituting a tabby cat lounging on a sunlit window sill in a photograph with your own playful puppy, all while preserving the original charm and composition of the image. We present Photoswap, a novel approach that enables this immersive image editing experience through personalized subject swapping in existing images. Photoswap first learns the visual concept of the subject from reference images and then swaps it into the target image using pre-trained diffusion models in a training-free manner. We establish that a well-conceptualized visual subject can be seamlessly transferred to any image with appropriate self-attention and cross-attention manipulation, maintaining the pose of the swapped subject and the overall coherence of the image. Comprehensive experiments underscore the efficacy and controllability of Photoswap in personalized subject swapping. Furthermore, Photoswap significantly outperforms baseline methods in human ratings across subject swapping, background preservation, and overall quality, revealing its vast application potential, from entertainment to professional editing.

Current diffusion-based video editing primarily focuses on structure-preserved editing by utilizing various dense correspondences to ensure temporal consistency and motion alignment. However, these approaches are often ineffective when the target edit involves a shape change. To embark on video editing with shape change, we explore customized video subject swapping in this work, where we aim to replace the main subject in a source video with a target subject having a distinct identity and potentially different shape. In contrast to previous methods that rely on dense correspondences, we introduce the VideoSwap framework that exploits semantic point correspondences, inspired by our observation that only a small number of semantic points are necessary to align the subject's motion trajectory and modify its shape. We also introduce various user-point interactions (\eg, removing points and dragging points) to address various semantic point correspondence. Extensive experiments demonstrate state-of-the-art video subject swapping results across a variety of real-world videos.

Face swapping aims to seamlessly transfer a source facial identity onto a target while preserving target attributes such as pose and expression. Diffusion models, known for their superior generative capabilities, have recently shown promise in advancing face-swapping quality. This paper addresses two key challenges in diffusion-based face swapping: the prioritized preservation of identity over target attributes and the inherent conflict between identity and attribute conditioning. To tackle these issues, we introduce an identity-constrained attribute-tuning framework for face swapping that first ensures identity preservation and then fine-tunes for attribute alignment, achieved through a decoupled condition injection. We further enhance fidelity by incorporating identity and adversarial losses in a post-training refinement stage. Our proposed identity-constrained diffusion-based face-swapping model outperforms existing methods in both qualitative and quantitative evaluations, demonstrating superior identity similarity and attribute consistency, achieving a new state-of-the-art performance in high-fidelity face swapping.

Recent studies have demonstrated the strong empirical performance of diffusion models on discrete sequences across domains from natural language to biological sequence generation. For example, in the protein inverse folding task, conditional diffusion models have achieved impressive results in generating natural-like sequences that fold back into the original structure. However, practical design tasks often require not only modeling a conditional distribution but also optimizing specific task objectives. For instance, we may prefer protein sequences with high stability. To address this, we consider the scenario where we have pre-trained discrete diffusion models that can generate natural-like sequences, as well as reward models that map sequences to task objectives. We then formulate the reward maximization problem within discrete diffusion models, analogous to reinforcement learning (RL), while minimizing the KL divergence against pretrained diffusion models to preserve naturalness. To solve this RL problem, we propose a novel algorithm, DRAKES, that enables direct backpropagation of rewards through entire trajectories generated by diffusion models, by making the originally non-differentiable trajectories differentiable using the Gumbel-Softmax trick. Our theoretical analysis indicates that our approach can generate sequences that are both natural-like and yield high rewards. While similar tasks have been recently explored in diffusion models for continuous domains, our work addresses unique algorithmic and theoretical challenges specific to discrete diffusion models, which arise from their foundation in continuous-time Markov chains rather than Brownian motion. Finally, we demonstrate the effectiveness of DRAKES in generating DNA and protein sequences that optimize enhancer activity and protein stability, respectively, important tasks for gene therapies and protein-based therapeutics.

Large language models (LLMs) trained on text demonstrated remarkable results on natural language processing (NLP) tasks. These models have been adapted to decipher the language of DNA, where sequences of nucleotides act as "words" that encode genomic functions. However, the genome differs fundamentally from natural language, as it lacks clearly defined words or a consistent grammar. Although DNA language models (DNALMs) such as DNABERT, GENA-LM have achieved high level of performance on genome-related biological tasks, these models do not encode biological functions in the presence of sequence variations. To address this problem, we pre-train foundation models that effectively integrate sequence variations, in particular Single Nucleotide Polymorphisms (SNPs), as they underlie important biological functions. Specifically, we use ModernBERT to pre-train two different Biomedical Foundation Models (BMFM), namely, BMFM-DNA-REF in which the model is trained with sequences of varying lengths along with their reverse complements derived from the reference genome and BMFM-DNA-SNP in which the model is trained with sequences created using a novel representation scheme that encodes sequence variations. Our findings indicate that integrating sequence variations into DNALMs helps capture the biological functions as seen in improvements on all fine-tuning tasks. To explore the model's practical utility, we experimented with various strategies for SNP imputation on promoter detection task introduced in DNABERT-2. However, we acknowledge that the current benchmarks are limited in their ability to fully evaluate these models. To enable more comprehensive assessment in the future and encourage community contributions, we release our models through HuggingFace and the code to reproduce the results at https://github.com/BiomedSciAI/biomed-multi-omic

Face swapping is a task that changes a facial identity of a given image to that of another person. In this work, we propose a novel face-swapping framework called Megapixel Facial Identity Manipulation (MFIM). The face-swapping model should achieve two goals. First, it should be able to generate a high-quality image. We argue that a model which is proficient in generating a megapixel image can achieve this goal. However, generating a megapixel image is generally difficult without careful model design. Therefore, our model exploits pretrained StyleGAN in the manner of GAN-inversion to effectively generate a megapixel image. Second, it should be able to effectively transform the identity of a given image. Specifically, it should be able to actively transform ID attributes (e.g., face shape and eyes) of a given image into those of another person, while preserving ID-irrelevant attributes (e.g., pose and expression). To achieve this goal, we exploit 3DMM that can capture various facial attributes. Specifically, we explicitly supervise our model to generate a face-swapped image with the desirable attributes using 3DMM. We show that our model achieves state-of-the-art performance through extensive experiments. Furthermore, we propose a new operation called ID mixing, which creates a new identity by semantically mixing the identities of several people. It allows the user to customize the new identity.

Building a general-purpose task model similar to ChatGPT has been an important research direction for gene large language models. Instruction fine-tuning is a key component in building ChatGPT, but existing instructions are primarily based on natural language. Natural language and gene sequences have significant differences in tokenization and encoding. Therefore, constructing a multilingual model that can handle both natural language and gene sequences is crucial for solving this problem.In this paper, we expand the capabilities of the LLaMA large language model to include gene language. This involves expanding the vocabulary using the Byte Pair Encoding (BPE) method, specifically tailored for DNA and protein sequences, and conducting further pre-training on these sequences. We then convert various downstream gene task data into a unified format for instruction fine-tuning and further fine-tune the model on this data.Our study demonstrates that a mixed model of gene and natural language, fine-tuned with instructions, achieves results comparable to the current state-of-the-art (SOTA) in tasks such as gene classification and gene sequence interaction. This provides a promising direction for building a unified large language model for gene tasks.

Image-based head swapping task aims to stitch a source head to another source body flawlessly. This seldom-studied task faces two major challenges: 1) Preserving the head and body from various sources while generating a seamless transition region. 2) No paired head swapping dataset and benchmark so far. In this paper, we propose a semantic-mixing diffusion model for head swapping (HS-Diffusion) which consists of a latent diffusion model (LDM) and a semantic layout generator. We blend the semantic layouts of source head and source body, and then inpaint the transition region by the semantic layout generator, achieving a coarse-grained head swapping. Semantic-mixing LDM can further implement a fine-grained head swapping with the inpainted layout as condition by a progressive fusion process, while preserving head and body with high-quality reconstruction. To this end, we propose a semantic calibration strategy for natural inpainting and a neck alignment for geometric realism. Importantly, we construct a new image-based head swapping benchmark and design two tailor-designed metrics (Mask-FID and Focal-FID). Extensive experiments demonstrate the superiority of our framework. The code will be available: https://github.com/qinghew/HS-Diffusion.

Gene expression analysis holds the key to many biomedical discoveries, yet extracting insights from raw transcriptomic data remains formidable due to the complexity of multiple large, semi-structured files and the need for extensive domain expertise. Current automation approaches are often limited by either inflexible workflows that break down in edge cases or by fully autonomous agents that lack the necessary precision for rigorous scientific inquiry. GenoMAS charts a different course by presenting a team of LLM-based scientists that integrates the reliability of structured workflows with the adaptability of autonomous agents. GenoMAS orchestrates six specialized LLM agents through typed message-passing protocols, each contributing complementary strengths to a shared analytic canvas. At the heart of GenoMAS lies a guided-planning framework: programming agents unfold high-level task guidelines into Action Units and, at each juncture, elect to advance, revise, bypass, or backtrack, thereby maintaining logical coherence while bending gracefully to the idiosyncrasies of genomic data. On the GenoTEX benchmark, GenoMAS reaches a Composite Similarity Correlation of 89.13% for data preprocessing and an F_1 of 60.48% for gene identification, surpassing the best prior art by 10.61% and 16.85% respectively. Beyond metrics, GenoMAS surfaces biologically plausible gene-phenotype associations corroborated by the literature, all while adjusting for latent confounders. Code is available at https://github.com/Liu-Hy/GenoMAS.

Face swapping transfers the identity of a source face to a target face while retaining the attributes like expression, pose, hair, and background of the target face. Advanced face swapping methods have achieved attractive results. However, these methods often inadvertently transfer identity information from the target face, compromising expression-related details and accurate identity. We propose a novel method DynamicFace that leverages the power of diffusion models and plug-and-play adaptive attention layers for image and video face swapping. First, we introduce four fine-grained facial conditions using 3D facial priors. All conditions are designed to be disentangled from each other for precise and unique control. Then, we adopt Face Former and ReferenceNet for high-level and detailed identity injection. Through experiments on the FF++ dataset, we demonstrate that our method achieves state-of-the-art results in face swapping, showcasing superior image quality, identity preservation, and expression accuracy. Our framework seamlessly adapts to both image and video domains. Our code and results will be available on the project page: https://dynamic-face.github.io/

Recent advancements in diffusion models (DMs) have been propelled by alignment methods that post-train models to better conform to human preferences. However, these approaches typically require computation-intensive training of a base model and a reward model, which not only incurs substantial computational overhead but may also compromise model accuracy and training efficiency. To address these limitations, we propose Inversion-DPO, a novel alignment framework that circumvents reward modeling by reformulating Direct Preference Optimization (DPO) with DDIM inversion for DMs. Our method conducts intractable posterior sampling in Diffusion-DPO with the deterministic inversion from winning and losing samples to noise and thus derive a new post-training paradigm. This paradigm eliminates the need for auxiliary reward models or inaccurate appromixation, significantly enhancing both precision and efficiency of training. We apply Inversion-DPO to a basic task of text-to-image generation and a challenging task of compositional image generation. Extensive experiments show substantial performance improvements achieved by Inversion-DPO compared to existing post-training methods and highlight the ability of the trained generative models to generate high-fidelity compositionally coherent images. For the post-training of compostitional image geneation, we curate a paired dataset consisting of 11,140 images with complex structural annotations and comprehensive scores, designed to enhance the compositional capabilities of generative models. Inversion-DPO explores a new avenue for efficient, high-precision alignment in diffusion models, advancing their applicability to complex realistic generation tasks. Our code is available at https://github.com/MIGHTYEZ/Inversion-DPO

This paper introduces a novel framework for DNA sequence generation, comprising two key components: DiscDiff, a Latent Diffusion Model (LDM) tailored for generating discrete DNA sequences, and Absorb-Escape, a post-training algorithm designed to refine these sequences. Absorb-Escape enhances the realism of the generated sequences by correcting `round errors' inherent in the conversion process between latent and input spaces. Our approach not only sets new standards in DNA sequence generation but also demonstrates superior performance over existing diffusion models, in generating both short and long DNA sequences. Additionally, we introduce EPD-GenDNA, the first comprehensive, multi-species dataset for DNA generation, encompassing 160,000 unique sequences from 15 species. We hope this study will advance the generative modelling of DNA, with potential implications for gene therapy and protein production.

We consider controllable DNA sequence design, where sequences are generated by conditioning on specific biological properties. While language models (LMs) such as GPT and BERT have achieved remarkable success in natural language generation, their application to DNA sequence generation remains largely underexplored. In this work, we introduce ATGC-Gen, an Automated Transformer Generator for Controllable Generation, which leverages cross-modal encoding to integrate diverse biological signals. ATGC-Gen is instantiated with both decoder-only and encoder-only transformer architectures, allowing flexible training and generation under either autoregressive or masked recovery objectives. We evaluate ATGC-Gen on representative tasks including promoter and enhancer sequence design, and further introduce a new dataset based on ChIP-Seq experiments for modeling protein binding specificity. Our experiments demonstrate that ATGC-Gen can generate fluent, diverse, and biologically relevant sequences aligned with the desired properties. Compared to prior methods, our model achieves notable improvements in controllability and functional relevance, highlighting the potential of language models in advancing programmable genomic design. The source code is released at (https://github.com/divelab/AIRS/blob/main/OpenBio/ATGC_Gen).

Large language models (LLMs) such as those embedded in 'chatbots' are accelerating and democratizing research by providing comprehensible information and expertise from many different fields. However, these models may also confer easy access to dual-use technologies capable of inflicting great harm. To evaluate this risk, the 'Safeguarding the Future' course at MIT tasked non-scientist students with investigating whether LLM chatbots could be prompted to assist non-experts in causing a pandemic. In one hour, the chatbots suggested four potential pandemic pathogens, explained how they can be generated from synthetic DNA using reverse genetics, supplied the names of DNA synthesis companies unlikely to screen orders, identified detailed protocols and how to troubleshoot them, and recommended that anyone lacking the skills to perform reverse genetics engage a core facility or contract research organization. Collectively, these results suggest that LLMs will make pandemic-class agents widely accessible as soon as they are credibly identified, even to people with little or no laboratory training. Promising nonproliferation measures include pre-release evaluations of LLMs by third parties, curating training datasets to remove harmful concepts, and verifiably screening all DNA generated by synthesis providers or used by contract research organizations and robotic cloud laboratories to engineer organisms or viruses.

Recent advancements in conversational large language models (LLMs), such as ChatGPT, have demonstrated remarkable promise in various domains, including drug discovery. However, existing works mainly focus on investigating the capabilities of conversational LLMs on chemical reaction and retrosynthesis. While drug editing, a critical task in the drug discovery pipeline, remains largely unexplored. To bridge this gap, we propose ChatDrug, a framework to facilitate the systematic investigation of drug editing using LLMs. ChatDrug jointly leverages a prompt module, a retrieval and domain feedback (ReDF) module, and a conversation module to streamline effective drug editing. We empirically show that ChatDrug reaches the best performance on 33 out of 39 drug editing tasks, encompassing small molecules, peptides, and proteins. We further demonstrate, through 10 case studies, that ChatDrug can successfully identify the key substructures (e.g., the molecule functional groups, peptide motifs, and protein structures) for manipulation, generating diverse and valid suggestions for drug editing. Promisingly, we also show that ChatDrug can offer insightful explanations from a domain-specific perspective, enhancing interpretability and enabling informed decision-making. This research sheds light on the potential of ChatGPT and conversational LLMs for drug editing. It paves the way for a more efficient and collaborative drug discovery pipeline, contributing to the advancement of pharmaceutical research and development.