Daily Papers

Analogical reasoning is a unique ability of humans to address unfamiliar challenges by transferring strategies from relevant past experiences. One key finding in psychology is that compared with irrelevant past experiences, recalling relevant ones can help humans better handle new tasks. Coincidentally, the NLP community has also recently found that self-generating relevant examples in the context can help large language models (LLMs) better solve a given problem than hand-crafted prompts. However, it is yet not clear whether relevance is the key factor eliciting such capability, i.e., can LLMs benefit more from self-generated relevant examples than irrelevant ones? In this work, we systematically explore whether LLMs can truly perform analogical reasoning on a diverse set of reasoning tasks. With extensive experiments and analysis, we show that self-generated random examples can surprisingly achieve comparable or even better performance, e.g., 4% performance boost on GSM8K with random biological examples. We find that the accuracy of self-generated examples is the key factor and subsequently design two improved methods with significantly reduced inference costs. Overall, we aim to advance a deeper understanding of LLM analogical reasoning and hope this work stimulates further research in the design of self-generated contexts.

The fields of Origin of Life and Artificial Life both question what life is and how it emerges from a distinct set of "pre-life" dynamics. One common feature of most substrates where life emerges is a marked shift in dynamics when self-replication appears. While there are some hypotheses regarding how self-replicators arose in nature, we know very little about the general dynamics, computational principles, and necessary conditions for self-replicators to emerge. This is especially true on "computational substrates" where interactions involve logical, mathematical, or programming rules. In this paper we take a step towards understanding how self-replicators arise by studying several computational substrates based on various simple programming languages and machine instruction sets. We show that when random, non self-replicating programs are placed in an environment lacking any explicit fitness landscape, self-replicators tend to arise. We demonstrate how this occurs due to random interactions and self-modification, and can happen with and without background random mutations. We also show how increasingly complex dynamics continue to emerge following the rise of self-replicators. Finally, we show a counterexample of a minimalistic programming language where self-replicators are possible, but so far have not been observed to arise.

Many proteins useful in modern medicine or bioengineering are challenging to make in the lab, fuse with other proteins in cells, or deliver to tissues in the body, because their sequences are too long. Shortening these sequences typically involves costly, time-consuming experimental campaigns. Ideally, we could instead use modern models of massive databases of sequences from nature to learn how to propose shrunken proteins that resemble sequences found in nature. Unfortunately, these models struggle to efficiently search the combinatorial space of all deletions, and are not trained with inductive biases to learn how to delete. To address this gap, we propose SCISOR, a novel discrete diffusion model that deletes letters from sequences to generate protein samples that resemble those found in nature. To do so, SCISOR trains a de-noiser to reverse a forward noising process that adds random insertions to natural sequences. As a generative model, SCISOR fits evolutionary sequence data competitively with previous large models. In evaluation, SCISOR achieves state-of-the-art predictions of the functional effects of deletions on ProteinGym. Finally, we use the SCISOR de-noiser to shrink long protein sequences, and show that its suggested deletions result in significantly more realistic proteins and more often preserve functional motifs than previous models of evolutionary sequences.

Modern life sciences research is increasingly relying on artificial intelligence approaches to model biological systems, primarily centered around the use of machine learning (ML) models. Although ML is undeniably useful for identifying patterns in large, complex data sets, its widespread application in biological sciences represents a significant deviation from traditional methods of scientific inquiry. As such, the interplay between these models and scientific understanding in biology is a topic with important implications for the future of scientific research, yet it is a subject that has received little attention. Here, we draw from an epistemological toolkit to contextualize recent applications of ML in biological sciences under modern philosophical theories of understanding, identifying general principles that can guide the design and application of ML systems to model biological phenomena and advance scientific knowledge. We propose that conceptions of scientific understanding as information compression, qualitative intelligibility, and dependency relation modelling provide a useful framework for interpreting ML-mediated understanding of biological systems. Through a detailed analysis of two key application areas of ML in modern biological research - protein structure prediction and single cell RNA-sequencing - we explore how these features have thus far enabled ML systems to advance scientific understanding of their target phenomena, how they may guide the development of future ML models, and the key obstacles that remain in preventing ML from achieving its potential as a tool for biological discovery. Consideration of the epistemological features of ML applications in biology will improve the prospects of these methods to solve important problems and advance scientific understanding of living systems.

The sparsity of labelled data is an obstacle to the development of Relation Extraction models and the completion of databases in various biomedical areas. While being of high interest in drug-discovery, the natural-products literature, reporting the identification of potential bioactive compounds from organisms, is a concrete example of such an overlooked topic. To mark the start of this new task, we created the first curated evaluation dataset and extracted literature items from the LOTUS database to build training sets. To this end, we developed a new sampler inspired by diversity metrics in ecology, named Greedy Maximum Entropy sampler, or GME-sampler (https://github.com/idiap/gme-sampler). The strategic optimization of both balance and diversity of the selected items in the evaluation set is important given the resource-intensive nature of manual curation. After quantifying the noise in the training set, in the form of discrepancies between the input abstracts text and the expected output labels, we explored different strategies accordingly. Framing the task as an end-to-end Relation Extraction, we evaluated the performance of standard fine-tuning as a generative task and few-shot learning with open Large Language Models (LLaMA 7B-65B). In addition to their evaluation in few-shot settings, we explore the potential of open Large Language Models (Vicuna-13B) as synthetic data generator and propose a new workflow for this purpose. All evaluated models exhibited substantial improvements when fine-tuned on synthetic abstracts rather than the original noisy data. We provide our best performing (f1-score=59.0) BioGPT-Large model for end-to-end RE of natural-products relationships along with all the generated synthetic data and the evaluation dataset. See more details at https://github.com/idiap/abroad-re.

In an effort to catalog insect biodiversity, we propose a new large dataset of hand-labelled insect images, the BIOSCAN-Insect Dataset. Each record is taxonomically classified by an expert, and also has associated genetic information including raw nucleotide barcode sequences and assigned barcode index numbers, which are genetically-based proxies for species classification. This paper presents a curated million-image dataset, primarily to train computer-vision models capable of providing image-based taxonomic assessment, however, the dataset also presents compelling characteristics, the study of which would be of interest to the broader machine learning community. Driven by the biological nature inherent to the dataset, a characteristic long-tailed class-imbalance distribution is exhibited. Furthermore, taxonomic labelling is a hierarchical classification scheme, presenting a highly fine-grained classification problem at lower levels. Beyond spurring interest in biodiversity research within the machine learning community, progress on creating an image-based taxonomic classifier will also further the ultimate goal of all BIOSCAN research: to lay the foundation for a comprehensive survey of global biodiversity. This paper introduces the dataset and explores the classification task through the implementation and analysis of a baseline classifier.

We discover that DALLE-2 seems to have a hidden vocabulary that can be used to generate images with absurd prompts. For example, it seems that Apoploe vesrreaitais means birds and Contarra ccetnxniams luryca tanniounons (sometimes) means bugs or pests. We find that these prompts are often consistent in isolation but also sometimes in combinations. We present our black-box method to discover words that seem random but have some correspondence to visual concepts. This creates important security and interpretability challenges.

Natural language inference (NLI) is critical for complex decision-making in biomedical domain. One key question, for example, is whether a given biomedical mechanism is supported by experimental evidence. This can be seen as an NLI problem but there are no directly usable datasets to address this. The main challenge is that manually creating informative negative examples for this task is difficult and expensive. We introduce a novel semi-supervised procedure that bootstraps an NLI dataset from existing biomedical dataset that pairs mechanisms with experimental evidence in abstracts. We generate a range of negative examples using nine strategies that manipulate the structure of the underlying mechanisms both with rules, e.g., flip the roles of the entities in the interaction, and, more importantly, as perturbations via logical constraints in a neuro-logical decoding system. We use this procedure to create a novel dataset for NLI in the biomedical domain, called BioNLI and benchmark two state-of-the-art biomedical classifiers. The best result we obtain is around mid 70s in F1, suggesting the difficulty of the task. Critically, the performance on the different classes of negative examples varies widely, from 97% F1 on the simple role change negative examples, to barely better than chance on the negative examples generated using neuro-logic decoding.

Effective DNA embedding remains crucial in genomic analysis, particularly in scenarios lacking labeled data for model fine-tuning, despite the significant advancements in genome foundation models. A prime example is metagenomics binning, a critical process in microbiome research that aims to group DNA sequences by their species from a complex mixture of DNA sequences derived from potentially thousands of distinct, often uncharacterized species. To fill the lack of effective DNA embedding models, we introduce DNABERT-S, a genome foundation model that specializes in creating species-aware DNA embeddings. To encourage effective embeddings to error-prone long-read DNA sequences, we introduce Manifold Instance Mixup (MI-Mix), a contrastive objective that mixes the hidden representations of DNA sequences at randomly selected layers and trains the model to recognize and differentiate these mixed proportions at the output layer. We further enhance it with the proposed Curriculum Contrastive Learning (C^2LR) strategy. Empirical results on 18 diverse datasets showed DNABERT-S's remarkable performance. It outperforms the top baseline's performance in 10-shot species classification with just a 2-shot training while doubling the Adjusted Rand Index (ARI) in species clustering and substantially increasing the number of correctly identified species in metagenomics binning. The code, data, and pre-trained model are publicly available at https://github.com/Zhihan1996/DNABERT_S.

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.

Many examples of cooperation exist in biology. In chemical systems however, which can sometimes be quite complex, we do not appear to observe intricate cooperative interactions. A key question for the origin of life, is then how can molecular cooperation first arise in an abiotic system prior to the emergence of biological replication. We postulate that selection at the molecular level is a driving force behind the complexification of chemical systems, particularly during the origins of life. In the theory of multilevel selection the two selective forces are: within-group and between-group, where the former tends to favor "selfish" replication of individuals and the latter favor cooperation between individuals enhancing the replication of the group as a whole. These forces can be quantified using the Price equation, which is a standard tool used in evolutionary biology to quantify evolutionary change. Our central claim is that replication and heredity in chemical systems are subject to selection, and quantifiable using the multilevel Price equation. We demonstrate this using the Graded Autocatalysis Replication Domain computer model, describing simple protocell composed out of molecules and its replication, which respectively analogue to the group and the individuals. In contrast to previous treatments of this model, we treat the lipid molecules themselves as replicating individuals and the protocells they form as groups of individuals. Our goal is to demonstrate how evolutionary biology tools and concepts can be applied in chemistry and we suggest that molecular cooperation may arise as a result of group selection. Further, the biological relation of parent-progeny is proposed to be analogue to the reactant-product relation in chemistry, thus allowing for tools from evolutionary biology to be applied to chemistry and would deepen the connection between chemistry and biology.

Designing biological sequences is an important challenge that requires satisfying complex constraints and thus is a natural problem to address with deep generative modeling. Diffusion generative models have achieved considerable success in many applications. Score-based generative stochastic differential equations (SDE) model is a continuous-time diffusion model framework that enjoys many benefits, but the originally proposed SDEs are not naturally designed for modeling discrete data. To develop generative SDE models for discrete data such as biological sequences, here we introduce a diffusion process defined in the probability simplex space with stationary distribution being the Dirichlet distribution. This makes diffusion in continuous space natural for modeling discrete data. We refer to this approach as Dirchlet diffusion score model. We demonstrate that this technique can generate samples that satisfy hard constraints using a Sudoku generation task. This generative model can also solve Sudoku, including hard puzzles, without additional training. Finally, we applied this approach to develop the first human promoter DNA sequence design model and showed that designed sequences share similar properties with natural promoter sequences.

This work investigates descriptive captions as an additional source of supervision for biological multimodal foundation models. Images and captions can be viewed as complementary samples from the latent morphospace of a species, each capturing certain biological traits. Incorporating captions during training encourages alignment with this shared latent structure, emphasizing potentially diagnostic characters while suppressing spurious correlations. The main challenge, however, lies in obtaining faithful, instance-specific captions at scale. This requirement has limited the utilization of natural language supervision in organismal biology compared with many other scientific domains. We complement this gap by generating synthetic captions with multimodal large language models (MLLMs), guided by Wikipedia-derived visual information and taxon-tailored format examples. These domain-specific contexts help reduce hallucination and yield accurate, instance-based descriptive captions. Using these captions, we train BIOCAP (i.e., BIOCLIP with Captions), a biological foundation model that captures rich semantics and achieves strong performance in species classification and text-image retrieval. These results demonstrate the value of descriptive captions beyond labels in bridging biological images with multimodal foundation models.

Practitioners frequently aim to infer an unobserved population trajectory using sample snapshots at multiple time points. For instance, in single-cell sequencing, scientists would like to learn how gene expression evolves over time. But sequencing any cell destroys that cell. So we cannot access any cell's full trajectory, but we can access snapshot samples from many cells. Stochastic differential equations are commonly used to analyze systems with full individual-trajectory access; since here we have only sample snapshots, these methods are inapplicable. The deep learning community has recently explored using Schr\"odinger bridges (SBs) and their extensions to estimate these dynamics. However, these methods either (1) interpolate between just two time points or (2) require a single fixed reference dynamic within the SB, which is often just set to be Brownian motion. But learning piecewise from adjacent time points can fail to capture long-term dependencies. And practitioners are typically able to specify a model class for the reference dynamic but not the exact values of the parameters within it. So we propose a new method that (1) learns the unobserved trajectories from sample snapshots across multiple time points and (2) requires specification only of a class of reference dynamics, not a single fixed one. In particular, we suggest an iterative projection method inspired by Schr\"odinger bridges; we alternate between learning a piecewise SB on the unobserved trajectories and using the learned SB to refine our best guess for the dynamics within the reference class. We demonstrate the advantages of our method via a well-known simulated parametric model from ecology, simulated and real data from systems biology, and real motion-capture data.

Gradient descent has proven to be a powerful and effective technique for optimization in numerous machine learning applications. Recent advances in computational neuroscience have shown that learning in standard gradient descent optimization formulation is not consistent with learning in biological systems. This has opened up interesting avenues for building biologically inspired learning techniques. One such approach is inspired by Dale's law, which states that inhibitory and excitatory synapses do not swap roles during the course of learning. The resulting exponential gradient descent optimization scheme leads to log-normally distributed synaptic weights. Interestingly, the density that satisfies the Fokker-Planck equation corresponding to the stochastic differential equation (SDE) with geometric Brownian motion (GBM) is the log-normal density. Leveraging this connection, we start with the SDE governing geometric Brownian motion, and show that discretizing the corresponding reverse-time SDE yields a multiplicative update rule, which surprisingly, coincides with the sampling equivalent of the exponential gradient descent update founded on Dale's law. Furthermore, we propose a new formalism for multiplicative denoising score-matching, subsuming the loss function proposed by Hyvaerinen for non-negative data. Indeed, log-normally distributed data is positive and the proposed score-matching formalism turns out to be a natural fit. This allows for training of score-based models for image data and results in a novel multiplicative update scheme for sample generation starting from a log-normal density. Experimental results on MNIST, Fashion MNIST, and Kuzushiji datasets demonstrate generative capability of the new scheme. To the best of our knowledge, this is the first instance of a biologically inspired generative model employing multiplicative updates, founded on geometric Brownian motion.

Human medical data can be challenging to obtain due to data privacy concerns, difficulties conducting certain types of experiments, or prohibitive associated costs. In many settings, data from animal models or in-vitro cell lines are available to help augment our understanding of human data. However, this data is known for having low etiological validity in comparison to human data. In this work, we augment small human medical datasets with in-vitro data and animal models. We use Invariant Risk Minimisation (IRM) to elucidate invariant features by considering cross-organism data as belonging to different data-generating environments. Our models identify genes of relevance to human cancer development. We observe a degree of consistency between varying the amounts of human and mouse data used, however, further work is required to obtain conclusive insights. As a secondary contribution, we enhance existing open source datasets and provide two uniformly processed, cross-organism, homologue gene-matched datasets to the community.

Learning the continuous dynamics of a system from snapshots of its temporal marginals is a problem which appears throughout natural sciences and machine learning, including in quantum systems, single-cell biological data, and generative modeling. In these settings, we assume access to cross-sectional samples that are uncorrelated over time, rather than full trajectories of samples. In order to better understand the systems under observation, we would like to learn a model of the underlying process that allows us to propagate samples in time and thereby simulate entire individual trajectories. In this work, we propose Action Matching, a method for learning a rich family of dynamics using only independent samples from its time evolution. We derive a tractable training objective, which does not rely on explicit assumptions about the underlying dynamics and does not require back-propagation through differential equations or optimal transport solvers. Inspired by connections with optimal transport, we derive extensions of Action Matching to learn stochastic differential equations and dynamics involving creation and destruction of probability mass. Finally, we showcase applications of Action Matching by achieving competitive performance in a diverse set of experiments from biology, physics, and generative modeling.

Noise is a ubiquitous feature of the physical world. As a result, the first prerequisite of life is fault tolerance: maintaining integrity of state despite external bombardment. Recent experimental advances have revealed that biological systems achieve fault tolerance by implementing mathematically intricate error-correcting codes and by organizing in a modular fashion that physically separates functionally distinct subsystems. These elaborate structures represent a vanishing volume in the massive genetic configuration space. How is it possible that the primitive process of evolution, by which all biological systems evolved, achieved such unusual results? In this work, through experiments in Boolean networks, we show that the simultaneous presence of error correction and modularity in biological systems is no coincidence. Rather, it is a typical co-occurrence in noisy dynamic systems undergoing evolution. From this, we deduce the principle of error correction enhanced evolvability: systems possessing error-correcting codes are more effectively improved by evolution than those without.

Beam search is the default decoding strategy for many sequence generation tasks in NLP. The set of approximate K-best items returned by the algorithm is a useful summary of the distribution for many applications; however, the candidates typically exhibit high overlap and may give a highly biased estimate for expectations under our model. These problems can be addressed by instead using stochastic decoding strategies. In this work, we propose a new method for turning beam search into a stochastic process: Conditional Poisson stochastic beam search. Rather than taking the maximizing set at each iteration, we sample K candidates without replacement according to the conditional Poisson sampling design. We view this as a more natural alternative to Kool et. al. 2019's stochastic beam search (SBS). Furthermore, we show how samples generated under the CPSBS design can be used to build consistent estimators and sample diverse sets from sequence models. In our experiments, we observe CPSBS produces lower variance and more efficient estimators than SBS, even showing improvements in high entropy settings.

The aim of this paper is to present an elementary computable theory of probability, random variables and stochastic processes. The probability theory is baed on existing approaches using valuations and lower integrals. Various approaches to random variables are discussed, including the approach based on completions in a Polish space. We apply the theory to the study of stochastic dynamical systems in discrete-time, and give a brief exposition of the Wiener process as a foundation for stochastic differential equations. The theory is based within the framework of type-two effectivity, so has an explicit direct link with Turing computation, and is expressed in a system of computable types and operations, so has a clean mathematical description.

Images of the natural world, collected by a variety of cameras, from drones to individual phones, are increasingly abundant sources of biological information. There is an explosion of computational methods and tools, particularly computer vision, for extracting biologically relevant information from images for science and conservation. Yet most of these are bespoke approaches designed for a specific task and are not easily adaptable or extendable to new questions, contexts, and datasets. A vision model for general organismal biology questions on images is of timely need. To approach this, we curate and release TreeOfLife-10M, the largest and most diverse ML-ready dataset of biology images. We then develop BioCLIP, a foundation model for the tree of life, leveraging the unique properties of biology captured by TreeOfLife-10M, namely the abundance and variety of images of plants, animals, and fungi, together with the availability of rich structured biological knowledge. We rigorously benchmark our approach on diverse fine-grained biology classification tasks, and find that BioCLIP consistently and substantially outperforms existing baselines (by 17% to 20% absolute). Intrinsic evaluation reveals that BioCLIP has learned a hierarchical representation conforming to the tree of life, shedding light on its strong generalizability. Our code, models and data will be made available at https://github.com/Imageomics/bioclip.

In recent years, large language models (LLMs) have achieved state-of-the-art results in various biological sequence analysis tasks, such as sequence classification, structure prediction, and function prediction. Similar to advancements in AI for other scientific fields, deeper research into biological LLMs has begun to focus on using these models to rediscover important existing biological laws or uncover entirely new patterns in biological sequences.This study leverages GPT-like LLMs to utilize language transfer capabilities to rediscover the genetic code rules of the central dogma. In our experimental design, we transformed the central dogma into a binary classification problem of aligning DNA sequences with protein sequences, where positive examples are matching DNA and protein sequences, and negative examples are non-matching pairs.We first trained a GPT-2 model from scratch using a dataset comprising protein sequences, DNA sequences, and sequences from languages such as English and Chinese. Subsequently, we fine-tuned the model using the English similarity judgment dataset from PAWS-X. When tested on a dataset for DNA and protein sequence alignment judgment, the fine-tuned model achieved a classification accuracy of 76%. The study also analyzed factors contributing to this zero-shot capability, including model training stability and types of training data.This research demonstrates that LLMs can, through the transfer of natural language capabilities and solely relying on the analysis of sequences themselves, rediscover the central dogma without prior knowledge of it. This study opens a new door for AI-driven biological research.

A variety of recent papers discuss the application of Shapley values, a concept for explaining coalitional games, for feature attribution in machine learning. However, the correct way to connect a machine learning model to a coalitional game has been a source of controversy. The two main approaches that have been proposed differ in the way that they condition on known features, using either (1) an interventional or (2) an observational conditional expectation. While previous work has argued that one of the two approaches is preferable in general, we argue that the choice is application dependent. Furthermore, we argue that the choice comes down to whether it is desirable to be true to the model or true to the data. We use linear models to investigate this choice. After deriving an efficient method for calculating observational conditional expectation Shapley values for linear models, we investigate how correlation in simulated data impacts the convergence of observational conditional expectation Shapley values. Finally, we present two real data examples that we consider to be representative of possible use cases for feature attribution -- (1) credit risk modeling and (2) biological discovery. We show how a different choice of value function performs better in each scenario, and how possible attributions are impacted by modeling choices.

The study of biological materials and bio-inspired materials science is well established; however, surprisingly little knowledge has been systematically translated to engineering solutions. To accelerate discovery and guide insights, an open-source autoregressive transformer large language model (LLM), BioinspiredLLM, is reported. The model was finetuned with a corpus of over a thousand peer-reviewed articles in the field of structural biological and bio-inspired materials and can be prompted to recall information, assist with research tasks, and function as an engine for creativity. The model has proven that it is able to accurately recall information about biological materials and is further enhanced with enhanced reasoning ability, as well as with retrieval-augmented generation to incorporate new data during generation that can also help to traceback sources, update the knowledge base, and connect knowledge domains. BioinspiredLLM also has been shown to develop sound hypotheses regarding biological materials design and remarkably so for materials that have never been explicitly studied before. Lastly, the model showed impressive promise in collaborating with other generative artificial intelligence models in a workflow that can reshape the traditional materials design process. This collaborative generative artificial intelligence method can stimulate and enhance bio-inspired materials design workflows. Biological materials are at a critical intersection of multiple scientific fields and models like BioinspiredLLM help to connect knowledge domains.

Understanding the galaxy-halo relationship is not only key for elucidating the interplay between baryonic and dark matter, it is essential for creating large mock galaxy catalogues from N-body simulations. High-resolution hydrodynamical simulations are limited to small volumes by their large computational demands, hindering their use for comparisons with wide-field observational surveys. We overcome this limitation by using the First Light and Reionisation Epoch Simulations (FLARES), a suite of high-resolution (M_gas = 1.8 x 10^6 M_Sun) zoom simulations drawn from a large, (3.2 cGpc)^3 box. We use an extremely randomised trees machine learning approach to model the relationship between galaxies and their subhaloes in a wide range of environments. This allows us to build mock catalogues with dynamic ranges that surpass those obtainable through periodic simulations. The low cost of the zoom simulations facilitates multiple runs of the same regions, differing only in the random number seed of the subgrid models; changing this seed introduces a butterfly effect, leading to random differences in the properties of matching galaxies. This randomness cannot be learnt by a deterministic machine learning model, but by sampling the noise and adding it post-facto to our predictions, we are able to recover the distributions of the galaxy properties we predict (stellar mass, star formation rate, metallicity, and size) remarkably well. We also explore the resolution-dependence of our models' performances and find minimal depreciation down to particle resolutions of order M_DM ~ 10^8 M_Sun, enabling the future application of our models to large dark matter-only boxes.

Recent research trends in computational biology have increasingly focused on integrating text and bio-entity modeling, especially in the context of molecules and proteins. However, previous efforts like BioT5 faced challenges in generalizing across diverse tasks and lacked a nuanced understanding of molecular structures, particularly in their textual representations (e.g., IUPAC). This paper introduces BioT5+, an extension of the BioT5 framework, tailored to enhance biological research and drug discovery. BioT5+ incorporates several novel features: integration of IUPAC names for molecular understanding, inclusion of extensive bio-text and molecule data from sources like bioRxiv and PubChem, the multi-task instruction tuning for generality across tasks, and a novel numerical tokenization technique for improved processing of numerical data. These enhancements allow BioT5+ to bridge the gap between molecular representations and their textual descriptions, providing a more holistic understanding of biological entities, and largely improving the grounded reasoning of bio-text and bio-sequences. The model is pre-trained and fine-tuned with a large number of experiments, including 3 types of problems (classification, regression, generation), 15 kinds of tasks, and 21 total benchmark datasets, demonstrating the remarkable performance and state-of-the-art results in most cases. BioT5+ stands out for its ability to capture intricate relationships in biological data, thereby contributing significantly to bioinformatics and computational biology. Our code is available at https://github.com/QizhiPei/BioT5.

Protein modeling is an increasingly popular area of machine learning research. Semi-supervised learning has emerged as an important paradigm in protein modeling due to the high cost of acquiring supervised protein labels, but the current literature is fragmented when it comes to datasets and standardized evaluation techniques. To facilitate progress in this field, we introduce the Tasks Assessing Protein Embeddings (TAPE), a set of five biologically relevant semi-supervised learning tasks spread across different domains of protein biology. We curate tasks into specific training, validation, and test splits to ensure that each task tests biologically relevant generalization that transfers to real-life scenarios. We benchmark a range of approaches to semi-supervised protein representation learning, which span recent work as well as canonical sequence learning techniques. We find that self-supervised pretraining is helpful for almost all models on all tasks, more than doubling performance in some cases. Despite this increase, in several cases features learned by self-supervised pretraining still lag behind features extracted by state-of-the-art non-neural techniques. This gap in performance suggests a huge opportunity for innovative architecture design and improved modeling paradigms that better capture the signal in biological sequences. TAPE will help the machine learning community focus effort on scientifically relevant problems. Toward this end, all data and code used to run these experiments are available at https://github.com/songlab-cal/tape.

The emerging field of Diverse Intelligence seeks to identify, formalize, and understand commonalities in behavioral competencies across a wide range of implementations. Especially interesting are simple systems that provide unexpected examples of memory, decision-making, or problem-solving in substrates that at first glance do not appear to be complex enough to implement such capabilities. We seek to develop tools to help understand the minimal requirements for such capabilities, and to learn to recognize and predict basal forms of intelligence in unconventional substrates. Here, we apply novel analyses to the behavior of classical sorting algorithms, short pieces of code which have been studied for many decades. To study these sorting algorithms as a model of biological morphogenesis and its competencies, we break two formerly-ubiquitous assumptions: top-down control (instead, showing how each element within a array of numbers can exert minimal agency and implement sorting policies from the bottom up), and fully reliable hardware (instead, allowing some of the elements to be "damaged" and fail to execute the algorithm). We quantitatively characterize sorting activity as the traversal of a problem space, showing that arrays of autonomous elements sort themselves more reliably and robustly than traditional implementations in the presence of errors. Moreover, we find the ability to temporarily reduce progress in order to navigate around a defect, and unexpected clustering behavior among the elements in chimeric arrays whose elements follow one of two different algorithms. The discovery of emergent problem-solving capacities in simple, familiar algorithms contributes a new perspective to the field of Diverse Intelligence, showing how basal forms of intelligence can emerge in simple systems without being explicitly encoded in their underlying mechanics.

Markov jump processes are continuous-time stochastic processes which describe dynamical systems evolving in discrete state spaces. These processes find wide application in the natural sciences and machine learning, but their inference is known to be far from trivial. In this work we introduce a methodology for zero-shot inference of Markov jump processes (MJPs), on bounded state spaces, from noisy and sparse observations, which consists of two components. First, a broad probability distribution over families of MJPs, as well as over possible observation times and noise mechanisms, with which we simulate a synthetic dataset of hidden MJPs and their noisy observation process. Second, a neural network model that processes subsets of the simulated observations, and that is trained to output the initial condition and rate matrix of the target MJP in a supervised way. We empirically demonstrate that one and the same (pretrained) model can infer, in a zero-shot fashion, hidden MJPs evolving in state spaces of different dimensionalities. Specifically, we infer MJPs which describe (i) discrete flashing ratchet systems, which are a type of Brownian motors, and the conformational dynamics in (ii) molecular simulations, (iii) experimental ion channel data and (iv) simple protein folding models. What is more, we show that our model performs on par with state-of-the-art models which are finetuned to the target datasets.

Ocean scientists have been collecting visual data to study marine organisms for decades. These images and videos are extremely valuable both for basic science and environmental monitoring tasks. There are tools for automatically processing these data, but none that are capable of handling the extreme variability in sample populations, image quality, and habitat characteristics that are common in visual sampling of the ocean. Such distribution shifts can occur over very short physical distances and in narrow time windows. Creating models that are able to recognize when an image or video sequence contains a new organism, an unusual collection of animals, or is otherwise out-of-sample is critical to fully leverage visual data in the ocean. The FathomNet2023 competition dataset presents a realistic scenario where the set of animals in the target data differs from the training data. The challenge is both to identify the organisms in a target image and assess whether it is out-of-sample.

Foundation models have revolutionized natural language processing and artificial intelligence, significantly enhancing how machines comprehend and generate human languages. Inspired by the success of these foundation models, researchers have developed foundation models for individual scientific domains, including small molecules, materials, proteins, DNA, and RNA. However, these models are typically trained in isolation, lacking the ability to integrate across different scientific domains. Recognizing that entities within these domains can all be represented as sequences, which together form the "language of nature", we introduce Nature Language Model (briefly, NatureLM), a sequence-based science foundation model designed for scientific discovery. Pre-trained with data from multiple scientific domains, NatureLM offers a unified, versatile model that enables various applications including: (i) generating and optimizing small molecules, proteins, RNA, and materials using text instructions; (ii) cross-domain generation/design, such as protein-to-molecule and protein-to-RNA generation; and (iii) achieving state-of-the-art performance in tasks like SMILES-to-IUPAC translation and retrosynthesis on USPTO-50k. NatureLM offers a promising generalist approach for various scientific tasks, including drug discovery (hit generation/optimization, ADMET optimization, synthesis), novel material design, and the development of therapeutic proteins or nucleotides. We have developed NatureLM models in different sizes (1 billion, 8 billion, and 46.7 billion parameters) and observed a clear improvement in performance as the model size increases.

Large-scale cell microscopy screens are used in drug discovery and molecular biology research to study the effects of millions of chemical and genetic perturbations on cells. To use these images in downstream analysis, we need models that can map each image into a feature space that represents diverse biological phenotypes consistently, in the sense that perturbations with similar biological effects have similar representations. In this work, we present the largest foundation model for cell microscopy data to date, a new 1.9 billion-parameter ViT-G/8 MAE trained on over 8 billion microscopy image crops. Compared to a previous published ViT-L/8 MAE, our new model achieves a 60% improvement in linear separability of genetic perturbations and obtains the best overall performance on whole-genome biological relationship recall and replicate consistency benchmarks. Beyond scaling, we developed two key methods that improve performance: (1) training on a curated and diverse dataset; and, (2) using biologically motivated linear probing tasks to search across each transformer block for the best candidate representation of whole-genome screens. We find that many self-supervised vision transformers, pretrained on either natural or microscopy images, yield significantly more biologically meaningful representations of microscopy images in their intermediate blocks than in their typically used final blocks. More broadly, our approach and results provide insights toward a general strategy for successfully building foundation models for large-scale biological data.

We derive an expression for the variation between parallel trajectories in phenotypic evolution, extending the well known result that predicts the mean evolutionary path in adaptive dynamics or quantitative genetics. We show how this expression gives rise to the notion of fluctuation domains - parts of the fitness landscape where the rate of evolution is very predictable (due to fluctuation dissipation) and parts where it is highly variable (due to fluctuation enhancement). These fluctuation domains are determined by the curvature of the fitness landscape. Regions of the fitness landscape with positive curvature, such as adaptive valleys or branching points, experience enhancement. Regions with negative curvature, such as adaptive peaks, experience dissipation. We explore these dynamics in the ecological scenarios of implicit and explicit competition for a limiting resource.

We investigate the use of randomly generated data for the sake of pre-training a model. We justify this approach theoretically from the perspective of algorithmic complexity, building on recent research that shows that sequence models can be trained to approximate Solomonoff induction. We derive similar, but complementary theoretical results. We show empirically that synthetically generated data can be used to pre-train a model before the data is seen. We replicate earlier results that models trained this way show zero-shot in-context learning across a variety of datasets, and that this performance improves with scale. We extend earlier results to real-world data, and show that finetuning a model after pre-training offers faster convergence and better generalization.

Quantifying similarity between neural representations -- e.g. hidden layer activation vectors -- is a perennial problem in deep learning and neuroscience research. Existing methods compare deterministic responses (e.g. artificial networks that lack stochastic layers) or averaged responses (e.g., trial-averaged firing rates in biological data). However, these measures of _deterministic_ representational similarity ignore the scale and geometric structure of noise, both of which play important roles in neural computation. To rectify this, we generalize previously proposed shape metrics (Williams et al. 2021) to quantify differences in _stochastic_ representations. These new distances satisfy the triangle inequality, and thus can be used as a rigorous basis for many supervised and unsupervised analyses. Leveraging this novel framework, we find that the stochastic geometries of neurobiological representations of oriented visual gratings and naturalistic scenes respectively resemble untrained and trained deep network representations. Further, we are able to more accurately predict certain network attributes (e.g. training hyperparameters) from its position in stochastic (versus deterministic) shape space.

Maintaining genetic diversity as a means to avoid premature convergence is critical in Genetic Programming. Several approaches have been proposed to achieve this, with some focusing on the mating phase from coupling dissimilar solutions to some form of self-adaptive selection mechanism. In nature, genetic diversity can be the consequence of many different factors, but when considering reproduction Sexual Selection can have an impact on promoting variety within a species. Specifically, Mate Choice often results in different selective pressures between sexes, which in turn may trigger evolutionary differences among them. Although some mechanisms of Sexual Selection have been applied to Genetic Programming in the past, the literature is scarce when it comes to mate choice. Recently, a way of modelling mating preferences by ideal mate representations was proposed, achieving good results when compared to a standard approach. These mating preferences evolve freely in a self-adaptive fashion, creating an evolutionary driving force of its own alongside fitness pressure. The inner mechanisms of this approach operate from personal choice, as each individual has its own representation of a perfect mate which affects the mate to be selected. In this paper, we compare this method against a random mate choice to assess whether there are advantages in evolving personal preferences. We conducted experiments using three symbolic regression problems and different mutation rates. The results show that self-adaptive mating preferences are able to create a more diverse set of solutions when compared to the traditional approach and a random mate approach (with statistically significant differences) and have a higher success rate in three of the six instances tested.

Computing in the life sciences has undergone a transformative evolution, from early computational models in the 1950s to the applications of artificial intelligence (AI) and machine learning (ML) seen today. This paper highlights key milestones and technological advancements through the historical development of computing in the life sciences. The discussion includes the inception of computational models for biological processes, the advent of bioinformatics tools, and the integration of AI/ML in modern life sciences research. Attention is given to AI-enabled tools used in the life sciences, such as scientific large language models and bio-AI tools, examining their capabilities, limitations, and impact to biological risk. This paper seeks to clarify and establish essential terminology and concepts to ensure informed decision-making and effective communication across disciplines.

High-throughput screening techniques are commonly used to obtain large quantities of data in many fields of biology. It is well known that artifacts arising from variability in the technical execution of different experimental batches within such screens confound these observations and can lead to invalid biological conclusions. It is therefore necessary to account for these batch effects when analyzing outcomes. In this paper we describe RxRx1, a biological dataset designed specifically for the systematic study of batch effect correction methods. The dataset consists of 125,510 high-resolution fluorescence microscopy images of human cells under 1,138 genetic perturbations in 51 experimental batches across 4 cell types. Visual inspection of the images alone clearly demonstrates significant batch effects. We propose a classification task designed to evaluate the effectiveness of experimental batch correction methods on these images and examine the performance of a number of correction methods on this task. Our goal in releasing RxRx1 is to encourage the development of effective experimental batch correction methods that generalize well to unseen experimental batches. The dataset can be downloaded at https://rxrx.ai.

Protein design, a grand challenge of the day, involves optimization on a fitness landscape, and leading methods adopt a model-based approach where a model is trained on a training set (protein sequences and fitness) and proposes candidates to explore next. These methods are challenged by sparsity of high-fitness samples in the training set, a problem that has been in the literature. A less recognized but equally important problem stems from the distribution of training samples in the design space: leading methods are not designed for scenarios where the desired optimum is in a region that is not only poorly represented in training data, but also relatively far from the highly represented low-fitness regions. We show that this problem of "separation" in the design space is a significant bottleneck in existing model-based optimization tools and propose a new approach that uses a novel VAE as its search model to overcome the problem. We demonstrate its advantage over prior methods in robustly finding improved samples, regardless of the imbalance and separation between low- and high-fitness training samples. Our comprehensive benchmark on real and semi-synthetic protein datasets as well as solution design for physics-informed neural networks, showcases the generality of our approach in discrete and continuous design spaces. Our implementation is available at https://github.com/sabagh1994/PGVAE.

Images are increasingly becoming the currency for documenting biodiversity on the planet, providing novel opportunities for accelerating scientific discoveries in the field of organismal biology, especially with the advent of large vision-language models (VLMs). We ask if pre-trained VLMs can aid scientists in answering a range of biologically relevant questions without any additional fine-tuning. In this paper, we evaluate the effectiveness of 12 state-of-the-art (SOTA) VLMs in the field of organismal biology using a novel dataset, VLM4Bio, consisting of 469K question-answer pairs involving 30K images from three groups of organisms: fishes, birds, and butterflies, covering five biologically relevant tasks. We also explore the effects of applying prompting techniques and tests for reasoning hallucination on the performance of VLMs, shedding new light on the capabilities of current SOTA VLMs in answering biologically relevant questions using images. The code and datasets for running all the analyses reported in this paper can be found at https://github.com/sammarfy/VLM4Bio.

There is widespread optimism that frontier Large Language Models (LLMs) and LLM-augmented systems have the potential to rapidly accelerate scientific discovery across disciplines. Today, many benchmarks exist to measure LLM knowledge and reasoning on textbook-style science questions, but few if any benchmarks are designed to evaluate language model performance on practical tasks required for scientific research, such as literature search, protocol planning, and data analysis. As a step toward building such benchmarks, we introduce the Language Agent Biology Benchmark (LAB-Bench), a broad dataset of over 2,400 multiple choice questions for evaluating AI systems on a range of practical biology research capabilities, including recall and reasoning over literature, interpretation of figures, access and navigation of databases, and comprehension and manipulation of DNA and protein sequences. Importantly, in contrast to previous scientific benchmarks, we expect that an AI system that can achieve consistently high scores on the more difficult LAB-Bench tasks would serve as a useful assistant for researchers in areas such as literature search and molecular cloning. As an initial assessment of the emergent scientific task capabilities of frontier language models, we measure performance of several against our benchmark and report results compared to human expert biology researchers. We will continue to update and expand LAB-Bench over time, and expect it to serve as a useful tool in the development of automated research systems going forward. A public subset of LAB-Bench is available for use at the following URL: https://huggingface.co/datasets/futurehouse/lab-bench

In statistics, independent, identically distributed random samples do not carry a natural ordering, and their statistics are typically invariant with respect to permutations of their order. Thus, an n-sample in a space M can be considered as an element of the quotient space of M^n modulo the permutation group. The present paper takes this definition of sample space and the related concept of orbit types as a starting point for developing a geometric perspective on statistics. We aim at deriving a general mathematical setting for studying the behavior of empirical and population means in spaces ranging from smooth Riemannian manifolds to general stratified spaces. We fully describe the orbifold and path-metric structure of the sample space when M is a manifold or path-metric space, respectively. These results are non-trivial even when M is Euclidean. We show that the infinite sample space exists in a Gromov-Hausdorff type sense and coincides with the Wasserstein space of probability distributions on M. We exhibit Fr\'echet means and k-means as metric projections onto 1-skeleta or k-skeleta in Wasserstein space, and we define a new and more general notion of polymeans. This geometric characterization via metric projections applies equally to sample and population means, and we use it to establish asymptotic properties of polymeans such as consistency and asymptotic normality.

In the modern world, technology is at its peak. Different avenues in programming and technology have been explored for data analysis, automation, and robotics. Machine learning is key to optimize data analysis, make accurate predictions, and hasten/improve existing functions. Thus, presently, the field of machine learning in artificial intelligence is being developed and its uses in varying fields are being explored. One field in which its uses stand out is that of microbial biosynthesis. In this paper, a comprehensive overview of the differing machine learning programs used in biosynthesis is provided, alongside brief descriptions of the fields of machine learning and microbial biosynthesis separately. This information includes past trends, modern developments, future improvements, explanations of processes, and current problems they face. Thus, this paper's main contribution is to distill developments in, and provide a holistic explanation of, 2 key fields and their applicability to improve industry/research. It also highlights challenges and research directions, acting to instigate more research and development in the growing fields. Finally, the paper aims to act as a reference for academics performing research, industry professionals improving their processes, and students looking to understand the concept of machine learning in biosynthesis.

Can we learn more from data than existed in the generating process itself? Can new and useful information be constructed from merely applying deterministic transformations to existing data? Can the learnable content in data be evaluated without considering a downstream task? On these questions, Shannon information and Kolmogorov complexity come up nearly empty-handed, in part because they assume observers with unlimited computational capacity and fail to target the useful information content. In this work, we identify and exemplify three seeming paradoxes in information theory: (1) information cannot be increased by deterministic transformations; (2) information is independent of the order of data; (3) likelihood modeling is merely distribution matching. To shed light on the tension between these results and modern practice, and to quantify the value of data, we introduce epiplexity, a formalization of information capturing what computationally bounded observers can learn from data. Epiplexity captures the structural content in data while excluding time-bounded entropy, the random unpredictable content exemplified by pseudorandom number generators and chaotic dynamical systems. With these concepts, we demonstrate how information can be created with computation, how it depends on the ordering of the data, and how likelihood modeling can produce more complex programs than present in the data generating process itself. We also present practical procedures to estimate epiplexity which we show capture differences across data sources, track with downstream performance, and highlight dataset interventions that improve out-of-distribution generalization. In contrast to principles of model selection, epiplexity provides a theoretical foundation for data selection, guiding how to select, generate, or transform data for learning systems.

Straight line equation y=mx with slope m, when singularly perturbed as ay^3+y=mx with a positive parameter a, results in S-shaped curves or S-curves on a real plane. As arightarrow 0, we get back y=mx which is a cumulative distribution function of a continuous uniform distribution that describes the occurrence of every event in an interval to be equally probable. As arightarrowinfty, the derivative of y has finite support only at y=0 resembling a degenerate distribution. Based on these arguments, in this work, we propose that these S-curves can represent maximum entropy uniform distribution to a zero entropy single value. We also argue that these S-curves are superposable as they are only parametrically nonlinear but fundamentally linear. So far, the superposed forms have been used to capture the patterns of natural systems such as nonlinear dynamics of biological growth and kinetics of enzyme reactions. Here, we attempt to use the S-curve and its superposed form as statistical models. We fit the models on a classical dataset containing flower measurements of iris plants and analyze their usefulness in pattern recognition. Based on these models, we claim that any non-uniform pattern can be represented as a singular perturbation to uniform distribution. However, our parametric estimation procedure have some limitations such as sensitivity to initial conditions depending on the data at hand.

Discovering evolutionary traits that are heritable across species on the tree of life (also referred to as a phylogenetic tree) is of great interest to biologists to understand how organisms diversify and evolve. However, the measurement of traits is often a subjective and labor-intensive process, making trait discovery a highly label-scarce problem. We present a novel approach for discovering evolutionary traits directly from images without relying on trait labels. Our proposed approach, Phylo-NN, encodes the image of an organism into a sequence of quantized feature vectors -- or codes -- where different segments of the sequence capture evolutionary signals at varying ancestry levels in the phylogeny. We demonstrate the effectiveness of our approach in producing biologically meaningful results in a number of downstream tasks including species image generation and species-to-species image translation, using fish species as a target example.

Numerous biological and physical processes can be modeled as systems of interacting entities evolving continuously over time, e.g. the dynamics of communicating cells or physical particles. Learning the dynamics of such systems is essential for predicting the temporal evolution of populations across novel samples and unseen environments. Flow-based models allow for learning these dynamics at the population level - they model the evolution of the entire distribution of samples. However, current flow-based models are limited to a single initial population and a set of predefined conditions which describe different dynamics. We argue that multiple processes in natural sciences have to be represented as vector fields on the Wasserstein manifold of probability densities. That is, the change of the population at any moment in time depends on the population itself due to the interactions between samples. In particular, this is crucial for personalized medicine where the development of diseases and their respective treatment response depends on the microenvironment of cells specific to each patient. We propose Meta Flow Matching (MFM), a practical approach to integrating along these vector fields on the Wasserstein manifold by amortizing the flow model over the initial populations. Namely, we embed the population of samples using a Graph Neural Network (GNN) and use these embeddings to train a Flow Matching model. This gives MFM the ability to generalize over the initial distributions unlike previously proposed methods. We demonstrate the ability of MFM to improve prediction of individual treatment responses on a large scale multi-patient single-cell drug screen dataset.

The challenge of replicating research results has posed a significant impediment to the field of molecular biology. The advent of modern intelligent systems has led to notable progress in various domains. Consequently, we embarked on an investigation of intelligent monitoring systems as a means of tackling the issue of the reproducibility crisis. Specifically, we first curate a comprehensive multimodal dataset, named ProBio, as an initial step towards this objective. This dataset comprises fine-grained hierarchical annotations intended for the purpose of studying activity understanding in BioLab. Next, we devise two challenging benchmarks, transparent solution tracking and multimodal action recognition, to emphasize the unique characteristics and difficulties associated with activity understanding in BioLab settings. Finally, we provide a thorough experimental evaluation of contemporary video understanding models and highlight their limitations in this specialized domain to identify potential avenues for future research. We hope ProBio with associated benchmarks may garner increased focus on modern AI techniques in the realm of molecular biology.

Recent advancements in specialized large-scale architectures for training image and language have profoundly impacted the field of computer vision and natural language processing (NLP). Language models, such as the recent ChatGPT and GPT4 have demonstrated exceptional capabilities in processing, translating, and generating human languages. These breakthroughs have also been reflected in protein research, leading to the rapid development of numerous new methods in a short time, with unprecedented performance. Language models, in particular, have seen widespread use in protein research, as they have been utilized to embed proteins, generate novel ones, and predict tertiary structures. In this book chapter, we provide an overview of the use of protein generative models, reviewing 1) language models for the design of novel artificial proteins, 2) works that use non-Transformer architectures, and 3) applications in directed evolution approaches.

Likelihood-free inference methods typically make use of a distance between simulated and real data. A common example is the maximum mean discrepancy (MMD), which has previously been used for approximate Bayesian computation, minimum distance estimation, generalised Bayesian inference, and within the nonparametric learning framework. The MMD is commonly estimated at a root-m rate, where m is the number of simulated samples. This can lead to significant computational challenges since a large m is required to obtain an accurate estimate, which is crucial for parameter estimation. In this paper, we propose a novel estimator for the MMD with significantly improved sample complexity. The estimator is particularly well suited for computationally expensive smooth simulators with low- to mid-dimensional inputs. This claim is supported through both theoretical results and an extensive simulation study on benchmark simulators.

Understanding the world and explaining it with scientific theories is a central aspiration of artificial intelligence research. Proposing theories, designing experiments to test them, and then revising them based on data are fundamental to scientific discovery. Despite the significant promise of LLM-based scientific agents, no benchmarks systematically test LLM's ability to propose scientific models, collect experimental data, and revise them in light of new data. We introduce BoxingGym, a benchmark with 10 environments for systematically evaluating both experimental design (e.g. collecting data to test a scientific theory) and model discovery (e.g. proposing and revising scientific theories). To enable tractable and quantitative evaluation, we implement each environment as a generative probabilistic model with which a scientific agent can run interactive experiments. These probabilistic models are drawn from various real-world scientific domains ranging from psychology to ecology. To quantitatively evaluate a scientific agent's ability to collect informative experimental data, we compute the expected information gain (EIG), an information-theoretic quantity which measures how much an experiment reduces uncertainty about the parameters of a generative model. A good scientific theory is a concise and predictive explanation. Therefore, to quantitatively evaluate model discovery, we ask a scientific agent to explain their model and then assess whether this explanation enables another scientific agent to make reliable predictions about this environment. In addition to this explanation-based evaluation, we compute standard model evaluation metrics such as prediction errors. We find that current LLMs, such as GPT-4o, struggle with both experimental design and model discovery. We find that augmenting the LLM-based agent with an explicit statistical model does not reliably improve these results.

Complex hierarchical structures composed of simple nanoscale building blocks form the basis of most biological materials. Here we demonstrate how analogies between seemingly different fields enable the understanding of general principles by which functional properties in hierarchical systems emerge, similar to an analogy learning process. Specifically, natural hierarchical materials like spider silk exhibit properties comparable to classical music in terms of their hierarchical structure and function. As a comparative tool here we apply hierarchical ontology logs (olog) that follow a rigorous mathematical formulation based on category theory to provide an insightful system representation by expressing knowledge in a conceptual map. We explain the process of analogy creation, draw connections at several levels of hierarchy and identify similar patterns that govern the structure of the hierarchical systems silk and music and discuss the impact of the derived analogy for nanotechnology.

Early warning signals have been proposed to forecast the possibility of a critical transition, such as the eutrophication of a lake, the collapse of a coral reef, or the end of a glacial period. Because such transitions often unfold on temporal and spatial scales that can be difficult to approach by experimental manipulation, research has often relied on historical observations as a source of natural experiments. Here we examine a critical difference between selecting systems for study based on the fact that we have observed a critical transition and those systems for which we wish to forecast the approach of a transition. This difference arises by conditionally selecting systems known to experience a transition of some sort and failing to account for the bias this introduces -- a statistical error often known as the Prosecutor's Fallacy. By analysing simulated systems that have experienced transitions purely by chance, we reveal an elevated rate of false positives in common warning signal statistics. We further demonstrate a model-based approach that is less subject to this bias than these more commonly used summary statistics. We note that experimental studies with replicates avoid this pitfall entirely.

Consider a random uniform sample of n points in a compact region A of Euclidean d-space, d geq 2, with a smooth or (when d=2) polygonal boundary. Fix k bf N. Let T_{n,k} be the threshold r at which the geometric graph on these n vertices with distance parameter r becomes k-connected. We show that if d=2 then n (pi/|A|) T_{n,1}^2 - log n is asymptotically standard Gumbel. For (d,k) neq (2,1), it is n (theta_d/|A|) T_{n,k}^d - (2-2/d) log n - (4-2k-2/d) log log n that converges in distribution to a nondegenerate limit, where theta_d is the volume of the unit ball. The limit is Gumbel with scale parameter 2 except when (d,k)=(2,2) where the limit is two component extreme value distributed. The different cases reflect the fact that boundary effects are more more important in some cases than others. We also give similar results for the largest k-nearest neighbour link U_{n,k} in the sample, and show T_{n,k}=U_{n,k} with high probability. We provide estimates on rates of convergence and give similar results for Poisson samples in A. Finally, we give similar results even for non-uniform samples, with a less explicit sequence of centring constants.

In the development of science, accurate and reproducible documentation of the experimental process is crucial. Automatic recognition of the actions in experiments from videos would help experimenters by complementing the recording of experiments. Towards this goal, we propose FineBio, a new fine-grained video dataset of people performing biological experiments. The dataset consists of multi-view videos of 32 participants performing mock biological experiments with a total duration of 14.5 hours. One experiment forms a hierarchical structure, where a protocol consists of several steps, each further decomposed into a set of atomic operations. The uniqueness of biological experiments is that while they require strict adherence to steps described in each protocol, there is freedom in the order of atomic operations. We provide hierarchical annotation on protocols, steps, atomic operations, object locations, and their manipulation states, providing new challenges for structured activity understanding and hand-object interaction recognition. To find out challenges on activity understanding in biological experiments, we introduce baseline models and results on four different tasks, including (i) step segmentation, (ii) atomic operation detection (iii) object detection, and (iv) manipulated/affected object detection. Dataset and code are available from https://github.com/aistairc/FineBio.

Discrete diffusion or flow models could enable faster and more controllable sequence generation than autoregressive models. We show that na\"ive linear flow matching on the simplex is insufficient toward this goal since it suffers from discontinuities in the training target and further pathologies. To overcome this, we develop Dirichlet flow matching on the simplex based on mixtures of Dirichlet distributions as probability paths. In this framework, we derive a connection between the mixtures' scores and the flow's vector field that allows for classifier and classifier-free guidance. Further, we provide distilled Dirichlet flow matching, which enables one-step sequence generation with minimal performance hits, resulting in O(L) speedups compared to autoregressive models. On complex DNA sequence generation tasks, we demonstrate superior performance compared to all baselines in distributional metrics and in achieving desired design targets for generated sequences. Finally, we show that our classifier-free guidance approach improves unconditional generation and is effective for generating DNA that satisfies design targets. Code is available at https://github.com/HannesStark/dirichlet-flow-matching.

Motivation: The gut microbiota has recently emerged as a key factor that underpins certain connections between diet and human health. A tremendous amount of knowledge has been amassed from experimental studies on diet, human metabolism and microbiome. However, this evidence remains mostly buried in scientific publications, and biomedical literature mining in this domain remains scarce. We developed DiMB-RE, a comprehensive corpus annotated with 15 entity types (e.g., Nutrient, Microorganism) and 13 relation types (e.g., increases, improves) capturing diet-microbiome associations. We also trained and evaluated state-of-the-art natural language processing (NLP) models for named entity, trigger, and relation extraction as well as factuality detection using DiMB-RE. Results: DiMB-RE consists of 14,450 entities and 4,206 relationships from 165 articles. While NLP models performed reasonably well for named entity recognition (0.760 F_{1}), end-to-end relation extraction performance was modest (0.356 F_{1}), partly due to missed entities and triggers as well as cross-sentence relations. Conclusions: To our knowledge, DiMB-RE is largest and most diverse dataset focusing on diet-microbiome interactions. It can serve as a benchmark corpus for biomedical literature mining. Availability: DiMB-RE and the NLP models are available at https://github.com/ScienceNLP-Lab/DiMB-RE.

Data of sequential nature arise in many application domains in forms of, e.g. textual data, DNA sequences, and software execution traces. Different research disciplines have developed methods to learn sequence models from such datasets: (i) in the machine learning field methods such as (hidden) Markov models and recurrent neural networks have been developed and successfully applied to a wide-range of tasks, (ii) in process mining process discovery techniques aim to generate human-interpretable descriptive models, and (iii) in the grammar inference field the focus is on finding descriptive models in the form of formal grammars. Despite their different focuses, these fields share a common goal - learning a model that accurately describes the behavior in the underlying data. Those sequence models are generative, i.e, they can predict what elements are likely to occur after a given unfinished sequence. So far, these fields have developed mainly in isolation from each other and no comparison exists. This paper presents an interdisciplinary experimental evaluation that compares sequence modeling techniques on the task of next-element prediction on four real-life sequence datasets. The results indicate that machine learning techniques that generally have no aim at interpretability in terms of accuracy outperform techniques from the process mining and grammar inference fields that aim to yield interpretable models.

Often we wish to predict a large number of variables that depend on each other as well as on other observed variables. Structured prediction methods are essentially a combination of classification and graphical modeling, combining the ability of graphical models to compactly model multivariate data with the ability of classification methods to perform prediction using large sets of input features. This tutorial describes conditional random fields, a popular probabilistic method for structured prediction. CRFs have seen wide application in natural language processing, computer vision, and bioinformatics. We describe methods for inference and parameter estimation for CRFs, including practical issues for implementing large scale CRFs. We do not assume previous knowledge of graphical modeling, so this tutorial is intended to be useful to practitioners in a wide variety of fields.

Despite its widespread use in neural networks, error backpropagation has faced criticism for its lack of biological plausibility, suffering from issues such as the backward locking problem and the weight transport problem. These limitations have motivated researchers to explore more biologically plausible learning algorithms that could potentially shed light on how biological neural systems adapt and learn. Inspired by the counter-current exchange mechanisms observed in biological systems, we propose counter-current learning (CCL), a biologically plausible framework for credit assignment in neural networks. This framework employs a feedforward network to process input data and a feedback network to process targets, with each network enhancing the other through anti-parallel signal propagation. By leveraging the more informative signals from the bottom layer of the feedback network to guide the updates of the top layer of the feedforward network and vice versa, CCL enables the simultaneous transformation of source inputs to target outputs and the dynamic mutual influence of these transformations. Experimental results on MNIST, FashionMNIST, CIFAR10, and CIFAR100 datasets using multi-layer perceptrons and convolutional neural networks demonstrate that CCL achieves comparable performance to other biologically plausible algorithms while offering a more biologically realistic learning mechanism. Furthermore, we showcase the applicability of our approach to an autoencoder task, underscoring its potential for unsupervised representation learning. Our work presents a direction for biologically inspired and plausible learning algorithms, offering an alternative mechanism of learning and adaptation in neural networks.

We investigate the expressive power of depth-2 bandlimited random neural networks. A random net is a neural network where the hidden layer parameters are frozen with random assignment, and only the output layer parameters are trained by loss minimization. Using random weights for a hidden layer is an effective method to avoid non-convex optimization in standard gradient descent learning. It has also been adopted in recent deep learning theories. Despite the well-known fact that a neural network is a universal approximator, in this study, we mathematically show that when hidden parameters are distributed in a bounded domain, the network may not achieve zero approximation error. In particular, we derive a new nontrivial approximation error lower bound. The proof utilizes the technique of ridgelet analysis, a harmonic analysis method designed for neural networks. This method is inspired by fundamental principles in classical signal processing, specifically the idea that signals with limited bandwidth may not always be able to perfectly recreate the original signal. We corroborate our theoretical results with various simulation studies, and generally, two main take-home messages are offered: (i) Not any distribution for selecting random weights is feasible to build a universal approximator; (ii) A suitable assignment of random weights exists but to some degree is associated with the complexity of the target function.

Irregularly sampled time series data arise naturally in many application domains including biology, ecology, climate science, astronomy, and health. Such data represent fundamental challenges to many classical models from machine learning and statistics due to the presence of non-uniform intervals between observations. However, there has been significant progress within the machine learning community over the last decade on developing specialized models and architectures for learning from irregularly sampled univariate and multivariate time series data. In this survey, we first describe several axes along which approaches to learning from irregularly sampled time series differ including what data representations they are based on, what modeling primitives they leverage to deal with the fundamental problem of irregular sampling, and what inference tasks they are designed to perform. We then survey the recent literature organized primarily along the axis of modeling primitives. We describe approaches based on temporal discretization, interpolation, recurrence, attention and structural invariance. We discuss similarities and differences between approaches and highlight primary strengths and weaknesses.

Colloids play an important role in fundamental science as well as in nature and technology. They have had a strong impact on the fundamental understanding of statistical physics. For example, colloids have helped to obtain a better understanding of collective phenomena, ranging from phase transitions and glass formation to the swarming of active Brownian particles. Yet the success of colloidal systems hinges crucially on the specific physical and chemical properties of the colloidal particles, i.e. particles with the appropriate characteristics must be available. Here we present an idea to create particles with freely selectable properties. The properties might depend, for example, on the presence of other particles (hence mimicking specific pair or many-body interactions), previous configurations (hence introducing some memory or feedback), or a directional bias (hence changing the dynamics). Without directly interfering with the sample, each particle is fully controlled and can receive external commands through a predefined algorithm that can take into account any input parameters. This is realized with computer-controlled colloids, which we term cybloids - short for cybernetic colloids. The potential of cybloids is illustrated by programming a time-delayed external potential acting on a single colloid and interaction potentials for many colloids. Both an attractive harmonic potential and an annular potential are implemented. For a single particle, this programming can cause subdiffusive behavior or lend activity. For many colloids, the programmed interaction potential allows to select a crystal structure at wish. Beyond these examples, we discuss further opportunities which cybloids offer.

We study the problem of optimizing biological sequences, e.g., proteins, DNA, and RNA, to maximize a black-box score function that is only evaluated in an offline dataset. We propose a novel solution, bootstrapped training of score-conditioned generator (BootGen) algorithm. Our algorithm repeats a two-stage process. In the first stage, our algorithm trains the biological sequence generator with rank-based weights to enhance the accuracy of sequence generation based on high scores. The subsequent stage involves bootstrapping, which augments the training dataset with self-generated data labeled by a proxy score function. Our key idea is to align the score-based generation with a proxy score function, which distills the knowledge of the proxy score function to the generator. After training, we aggregate samples from multiple bootstrapped generators and proxies to produce a diverse design. Extensive experiments show that our method outperforms competitive baselines on biological sequential design tasks. We provide reproducible source code: https://github.com/kaist-silab/bootgen{https://github.com/kaist-silab/bootgen}.

Biological nervous systems are created in a fundamentally different way than current artificial neural networks. Despite its impressive results in a variety of different domains, deep learning often requires considerable engineering effort to design high-performing neural architectures. By contrast, biological nervous systems are grown through a dynamic self-organizing process. In this paper, we take initial steps toward neural networks that grow through a developmental process that mirrors key properties of embryonic development in biological organisms. The growth process is guided by another neural network, which we call a Neural Developmental Program (NDP) and which operates through local communication alone. We investigate the role of neural growth on different machine learning benchmarks and different optimization methods (evolutionary training, online RL, offline RL, and supervised learning). Additionally, we highlight future research directions and opportunities enabled by having self-organization driving the growth of neural networks.

Bayesian models of cognition have gained considerable traction in computational neuroscience and psychiatry. Their scopes are now expected to expand rapidly to artificial intelligence, providing general inference frameworks to support embodied, adaptable, and energy-efficient autonomous agents. A central theory in this domain is predictive coding, which posits that learning and behaviour are driven by hierarchical probabilistic inferences about the causes of sensory inputs. Biological realism constrains these networks to rely on simple local computations in the form of precision-weighted predictions and prediction errors. This can make this framework highly efficient, but its implementation comes with unique challenges on the software development side. Embedding such models in standard neural network libraries often becomes limiting, as these libraries' compilation and differentiation backends can force a conceptual separation between optimization algorithms and the systems being optimized. This critically departs from other biological principles such as self-monitoring, self-organisation, cellular growth and functional plasticity. In this paper, we introduce pyhgf: a Python package backed by JAX and Rust for creating, manipulating and sampling dynamic networks for predictive coding. We improve over other frameworks by enclosing the network components as transparent, modular and malleable variables in the message-passing steps. The resulting graphs can implement arbitrary computational complexities as beliefs propagation. But the transparency of core variables can also translate into inference processes that leverage self-organisation principles, and express structure learning, meta-learning or causal discovery as the consequence of network structural adaptation to surprising inputs. The code, tutorials and documentation are hosted at: https://github.com/ilabcode/pyhgf.

In this report, we introduce SciFive, a domain-specific T5 model that has been pre-trained on large biomedical corpora. Our model outperforms the current SOTA methods (i.e. BERT, BioBERT, Base T5) on tasks in named entity relation, relation extraction, natural language inference, and question-answering. We show that text-generation methods have significant potential in a broad array of biomedical NLP tasks, particularly those requiring longer, more complex outputs. Our results support the exploration of more difficult text generation tasks and the development of new methods in this area

Many cellular processes involve information processing and decision making. We can probe these processes at increasing molecular detail. The analysis of heterogeneous data remains a challenge that requires new ways of thinking about cells in quantitative, predictive, and mechanistic ways. We discuss the role of mathematical models in the context of cell-fate decision making systems across the tree of life. Complex multi-cellular organisms have been a particular focus, but single celled organisms also have to sense and respond to their environment. We center our discussion around the idea of design principles which we can learn from observations and modeling, and exploit in order to (re)-design or guide cellular behavior.

Pre-trained large language models demonstrate potential in extracting information from DNA sequences, yet adapting to a variety of tasks and data modalities remains a challenge. To address this, we propose DNAGPT, a generalized DNA pre-training model trained on over 200 billion base pairs from all mammals. By enhancing the classic GPT model with a binary classification task (DNA sequence order), a numerical regression task (guanine-cytosine content prediction), and a comprehensive token language, DNAGPT can handle versatile DNA analysis tasks while processing both sequence and numerical data. Our evaluation of genomic signal and region recognition, mRNA abundance regression, and artificial genomes generation tasks demonstrates DNAGPT's superior performance compared to existing models designed for specific downstream tasks, benefiting from pre-training using the newly designed model structure.

Advancements in DNA sequencing technologies have significantly improved our ability to decode genomic sequences. However, the prediction and interpretation of these sequences remain challenging due to the intricate nature of genetic material. Large language models (LLMs) have introduced new opportunities for biological sequence analysis. Recent developments in genomic language models have underscored the potential of LLMs in deciphering DNA sequences. Nonetheless, existing models often face limitations in robustness and application scope, primarily due to constraints in model structure and training data scale. To address these limitations, we present GENERator, a generative genomic foundation model featuring a context length of 98k base pairs (bp) and 1.2B parameters. Trained on an expansive dataset comprising 386B bp of eukaryotic DNA, the GENERator demonstrates state-of-the-art performance across both established and newly proposed benchmarks. The model adheres to the central dogma of molecular biology, accurately generating protein-coding sequences that translate into proteins structurally analogous to known families. It also shows significant promise in sequence optimization, particularly through the prompt-responsive generation of promoter sequences with specific activity profiles. These capabilities position the GENERator as a pivotal tool for genomic research and biotechnological advancement, enhancing our ability to interpret and predict complex biological systems and enabling precise genomic interventions.

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.

A great deal of effort has been devoted to reducing the risk of spurious scientific discoveries, from the use of sophisticated validation techniques, to deep statistical methods for controlling the false discovery rate in multiple hypothesis testing. However, there is a fundamental disconnect between the theoretical results and the practice of data analysis: the theory of statistical inference assumes a fixed collection of hypotheses to be tested, or learning algorithms to be applied, selected non-adaptively before the data are gathered, whereas in practice data is shared and reused with hypotheses and new analyses being generated on the basis of data exploration and the outcomes of previous analyses. In this work we initiate a principled study of how to guarantee the validity of statistical inference in adaptive data analysis. As an instance of this problem, we propose and investigate the question of estimating the expectations of m adaptively chosen functions on an unknown distribution given n random samples. We show that, surprisingly, there is a way to estimate an exponential in n number of expectations accurately even if the functions are chosen adaptively. This gives an exponential improvement over standard empirical estimators that are limited to a linear number of estimates. Our result follows from a general technique that counter-intuitively involves actively perturbing and coordinating the estimates, using techniques developed for privacy preservation. We give additional applications of this technique to our question.

In recent years, diffusion models trained on equilibrium molecular distributions have proven effective for sampling biomolecules. Beyond direct sampling, the score of such a model can also be used to derive the forces that act on molecular systems. However, while classical diffusion sampling usually recovers the training distribution, the corresponding energy-based interpretation of the learned score is often inconsistent with this distribution, even for low-dimensional toy systems. We trace this inconsistency to inaccuracies of the learned score at very small diffusion timesteps, where the model must capture the correct evolution of the data distribution. In this regime, diffusion models fail to satisfy the Fokker--Planck equation, which governs the evolution of the score. We interpret this deviation as one source of the observed inconsistencies and propose an energy-based diffusion model with a Fokker--Planck-derived regularization term to enforce consistency. We demonstrate our approach by sampling and simulating multiple biomolecular systems, including fast-folding proteins, and by introducing a state-of-the-art transferable Boltzmann emulator for dipeptides that supports simulation and achieves improved consistency and efficient sampling. Our code, model weights, and self-contained JAX and PyTorch notebooks are available at https://github.com/noegroup/ScoreMD.

Generative Flow Networks (GFlowNets) are amortized sampling methods that learn a distribution over discrete objects proportional to their rewards. GFlowNets exhibit a remarkable ability to generate diverse samples, yet occasionally struggle to consistently produce samples with high rewards due to over-exploration on wide sample space. This paper proposes to train GFlowNets with local search, which focuses on exploiting high-rewarded sample space to resolve this issue. Our main idea is to explore the local neighborhood via backtracking and reconstruction guided by backward and forward policies, respectively. This allows biasing the samples toward high-reward solutions, which is not possible for a typical GFlowNet solution generation scheme, which uses the forward policy to generate the solution from scratch. Extensive experiments demonstrate a remarkable performance improvement in several biochemical tasks. Source code is available: https://github.com/dbsxodud-11/ls_gfn.

Diffusion models excel at capturing the natural design spaces of images, molecules, DNA, RNA, and protein sequences. However, rather than merely generating designs that are natural, we often aim to optimize downstream reward functions while preserving the naturalness of these design spaces. Existing methods for achieving this goal often require ``differentiable'' proxy models (e.g., classifier guidance or DPS) or involve computationally expensive fine-tuning of diffusion models (e.g., classifier-free guidance, RL-based fine-tuning). In our work, we propose a new method to address these challenges. Our algorithm is an iterative sampling method that integrates soft value functions, which looks ahead to how intermediate noisy states lead to high rewards in the future, into the standard inference procedure of pre-trained diffusion models. Notably, our approach avoids fine-tuning generative models and eliminates the need to construct differentiable models. This enables us to (1) directly utilize non-differentiable features/reward feedback, commonly used in many scientific domains, and (2) apply our method to recent discrete diffusion models in a principled way. Finally, we demonstrate the effectiveness of our algorithm across several domains, including image generation, molecule generation, and DNA/RNA sequence generation. The code is available at https://github.com/masa-ue/SVDD{https://github.com/masa-ue/SVDD}.

The use of machine learning (ML) based techniques has become increasingly popular in the field of bioacoustics over the last years. Fundamental requirements for the successful application of ML based techniques are curated, agreed upon, high-quality datasets and benchmark tasks to be learned on a given dataset. However, the field of bioacoustics so far lacks such public benchmarks which cover multiple tasks and species to measure the performance of ML techniques in a controlled and standardized way and that allows for benchmarking newly proposed techniques to existing ones. Here, we propose BEANS (the BEnchmark of ANimal Sounds), a collection of bioacoustics tasks and public datasets, specifically designed to measure the performance of machine learning algorithms in the field of bioacoustics. The benchmark proposed here consists of two common tasks in bioacoustics: classification and detection. It includes 12 datasets covering various species, including birds, land and marine mammals, anurans, and insects. In addition to the datasets, we also present the performance of a set of standard ML methods as the baseline for task performance. The benchmark and baseline code is made publicly available at https://github.com/earthspecies/beans in the hope of establishing a new standard dataset for ML-based bioacoustic research.

Biomedical text mining and question-answering are essential yet highly demanding tasks, particularly in the face of the exponential growth of biomedical literature. In this work, we present our participation in the 13th edition of the BioASQ challenge, which involves biomedical semantic question-answering for Task 13b and biomedical question-answering for developing topics for the Synergy task. We deploy a selection of open-source large language models (LLMs) as retrieval-augmented generators to answer biomedical questions. Various models are used to process the questions. A majority voting system combines their output to determine the final answer for Yes/No questions, while for list and factoid type questions, the union of their answers in used. We evaluated 13 state-of-the-art open source LLMs, exploring all possible model combinations to contribute to the final answer, resulting in tailored LLM pipelines for each question type. Our findings provide valuable insight into which combinations of LLMs consistently produce superior results for specific question types. In the four rounds of the 2025 BioASQ challenge, our system achieved notable results: in the Synergy task, we secured 1st place for ideal answers and 2nd place for exact answers in round 2, as well as two shared 1st places for exact answers in round 3 and 4.

Machine learning has achieved remarkable success in many applications. However, existing studies are largely based on the closed-world assumption, which assumes that the environment is stationary, and the model is fixed once deployed. In many real-world applications, this fundamental and rather naive assumption may not hold because an open environment is complex, dynamic, and full of unknowns. In such cases, rejecting unknowns, discovering novelties, and then incrementally learning them, could enable models to be safe and evolve continually as biological systems do. This paper provides a holistic view of open-world machine learning by investigating unknown rejection, novel class discovery, and class-incremental learning in a unified paradigm. The challenges, principles, and limitations of current methodologies are discussed in detail. Finally, we discuss several potential directions for future research. This paper aims to provide a comprehensive introduction to the emerging open-world machine learning paradigm, to help researchers build more powerful AI systems in their respective fields, and to promote the development of artificial general intelligence.

In this work, we introduce ChemBFN, a language model that handles chemistry tasks based on Bayesian flow networks working on discrete data. A new accuracy schedule is proposed to improve the sampling quality by significantly reducing the reconstruction loss. We show evidence that our method is appropriate for generating molecules with satisfied diversity even when a smaller number of sampling steps is used. A classifier-free guidance method is adapted for conditional generation. It is also worthwhile to point out that after generative training, our model can be fine-tuned on regression and classification tasks with the state-of-the-art performance, which opens the gate of building all-in-one models in a single module style. Our model has been open sourced at https://github.com/Augus1999/bayesian-flow-network-for-chemistry.

In October 2007, a Research Proposal for the University of Sydney, Australia, the author suggested that biovie-physical phenomenon as `electrodynamic dependant biological vision', is governed by relativistic quantum laws and biovision. The phenomenon on the basis of `biovielectroluminescence', satisfies man/microbio/megabio/computer vision (MMMCV), as a robust candidate for physical and visual sciences. The general aim of this addendum is to present a refined text of Sections 1-3 of that proposal and highlighting the contents of its Appendix in form of a `Mechanisms' Section. We then briefly remind in an article aimed for December 2007, by appending two more equations into Section 3, a theoretical II-time scenario as a time model well-proposed for the phenomenon. The time model within the core of the proposal, plays a significant role in emphasizing the principle points on Objectives no. 1-8, Sub-hypothesis 3.1.2, mentioned in Article [arXiv:0710.0410]. It also expresses the time concept in terms of causing quantized energy f(|E|) of time |t|, emit in regard to shortening the probability of particle loci as predictable patterns of particle's un-occurred motion, a solution to Heisenberg's uncertainty principle (HUP) into a simplistic manner. We conclude that, practical frames via a time algorithm to this model, fixates such predictable patterns of motion of scenery bodies onto recordable observation points of a MMMCV system. It even suppresses/predicts superposition phenomena coming from a human subject and/or other bio-subjects for any decision making event, e.g., brainwave quantum patterns based on vision. Maintaining the existential probability of Riemann surfaces of II-time scenarios in the context of biovielectroluminescence, makes motion-prediction a possibility.

Background. In the last decades, several life science resources have structured data using the same framework and made these accessible using the same query language to facilitate interoperability. Knowledge graphs have seen increased adoption in bioinformatics due to their advantages for representing data in a generic graph format. For example, yummydata.org catalogs more than 60 knowledge graphs accessible through SPARQL, a technical query language. Although SPARQL allows powerful, expressive queries, even across physically distributed knowledge graphs, formulating such queries is a challenge for most users. Therefore, to guide users in retrieving the relevant data, many of these resources provide representative examples. These examples can also be an important source of information for machine learning, if a sufficiently large number of examples are provided and published in a common, machine-readable and standardized format across different resources. Findings. We introduce a large collection of human-written natural language questions and their corresponding SPARQL queries over federated bioinformatics knowledge graphs (KGs) collected for several years across different research groups at the SIB Swiss Institute of Bioinformatics. The collection comprises more than 1000 example questions and queries, including 65 federated queries. We propose a methodology to uniformly represent the examples with minimal metadata, based on existing standards. Furthermore, we introduce an extensive set of open-source applications, including query graph visualizations and smart query editors, easily reusable by KG maintainers who adopt the proposed methodology. Conclusions. We encourage the community to adopt and extend the proposed methodology, towards richer KG metadata and improved Semantic Web services.

Solving complex real-world tasks requires cycles of actions and observations. This is particularly true in science, where tasks require many cycles of analysis, tool use, and experimentation. Language agents are promising for automating intellectual tasks in science because they can interact with tools via natural language or code. Yet their flexibility creates conceptual and practical challenges for software implementations, since agents may comprise non-standard components such as internal reasoning, planning, tool usage, as well as the inherent stochasticity of temperature-sampled language models. Here, we introduce Aviary, an extensible gymnasium for language agents. We formalize agents as policies solving language-grounded partially observable Markov decision processes, which we term language decision processes. We then implement five environments, including three challenging scientific environments: (1) manipulating DNA constructs for molecular cloning, (2) answering research questions by accessing scientific literature, and (3) engineering protein stability. These environments were selected for their focus on multi-step reasoning and their relevance to contemporary biology research. Finally, with online training and scaling inference-time compute, we show that language agents backed by open-source, non-frontier LLMs can match and exceed both frontier LLM agents and human experts on multiple tasks at up to 100x lower inference cost.

The rapid growth of biomedical knowledge has outpaced our ability to efficiently extract insights and generate novel hypotheses. Large language models (LLMs) have emerged as a promising tool to revolutionize knowledge interaction and potentially accelerate biomedical discovery. In this paper, we present a comprehensive evaluation of LLMs as biomedical hypothesis generators. We construct a dataset of background-hypothesis pairs from biomedical literature, carefully partitioned into training, seen, and unseen test sets based on publication date to mitigate data contamination. Using this dataset, we assess the hypothesis generation capabilities of top-tier instructed models in zero-shot, few-shot, and fine-tuning settings. To enhance the exploration of uncertainty, a crucial aspect of scientific discovery, we incorporate tool use and multi-agent interactions in our evaluation framework. Furthermore, we propose four novel metrics grounded in extensive literature review to evaluate the quality of generated hypotheses, considering both LLM-based and human assessments. Our experiments yield two key findings: 1) LLMs can generate novel and validated hypotheses, even when tested on literature unseen during training, and 2) Increasing uncertainty through multi-agent interactions and tool use can facilitate diverse candidate generation and improve zero-shot hypothesis generation performance. However, we also observe that the integration of additional knowledge through few-shot learning and tool use may not always lead to performance gains, highlighting the need for careful consideration of the type and scope of external knowledge incorporated. These findings underscore the potential of LLMs as powerful aids in biomedical hypothesis generation and provide valuable insights to guide further research in this area.

A Recurrent Neural Network (RNN) was used to perform video frame prediction of microbial growth for a population of two mutants of Pseudomonas aeruginosa. The RNN was trained on videos of 20 frames that were acquired using fluorescence microscopy and microfluidics. The network predicted the last 10 frames of each video, and the accuracy's of the predictions was assessed by comparing raw images, population curves, and the number and size of individual colonies. Overall, we found the predictions to be accurate using this approach. The implications this result has on designing autonomous experiments in microbiology, and the steps that can be taken to make the predictions even more accurate, are discussed.

Many have observed that the development and deployment of generative machine learning (ML) and artificial intelligence (AI) models follow a distinctive pattern in which pre-trained models are adapted and fine-tuned for specific downstream tasks. However, there is limited empirical work that examines the structure of these interactions. This paper analyzes 1.86 million models on Hugging Face, a leading peer production platform for model development. Our study of model family trees -- networks that connect fine-tuned models to their base or parent -- reveals sprawling fine-tuning lineages that vary widely in size and structure. Using an evolutionary biology lens to study ML models, we use model metadata and model cards to measure the genetic similarity and mutation of traits over model families. We find that models tend to exhibit a family resemblance, meaning their genetic markers and traits exhibit more overlap when they belong to the same model family. However, these similarities depart in certain ways from standard models of asexual reproduction, because mutations are fast and directed, such that two `sibling' models tend to exhibit more similarity than parent/child pairs. Further analysis of the directional drifts of these mutations reveals qualitative insights about the open machine learning ecosystem: Licenses counter-intuitively drift from restrictive, commercial licenses towards permissive or copyleft licenses, often in violation of upstream license's terms; models evolve from multi-lingual compatibility towards english-only compatibility; and model cards reduce in length and standardize by turning, more often, to templates and automatically generated text. Overall, this work takes a step toward an empirically grounded understanding of model fine-tuning and suggests that ecological models and methods can yield novel scientific insights.

Recent advancements in biological research leverage the integration of molecules, proteins, and natural language to enhance drug discovery. However, current models exhibit several limitations, such as the generation of invalid molecular SMILES, underutilization of contextual information, and equal treatment of structured and unstructured knowledge. To address these issues, we propose BioT5, a comprehensive pre-training framework that enriches cross-modal integration in biology with chemical knowledge and natural language associations. BioT5 utilizes SELFIES for 100% robust molecular representations and extracts knowledge from the surrounding context of bio-entities in unstructured biological literature. Furthermore, BioT5 distinguishes between structured and unstructured knowledge, leading to more effective utilization of information. After fine-tuning, BioT5 shows superior performance across a wide range of tasks, demonstrating its strong capability of capturing underlying relations and properties of bio-entities. Our code is available at https://github.com/QizhiPei/BioT5{Github}.

Suppose Alice trains an open-weight language model and Bob uses a blackbox derivative of Alice's model to produce text. Can Alice prove that Bob is using her model, either by querying Bob's derivative model (query setting) or from the text alone (observational setting)? We formulate this question as an independence testing problem--in which the null hypothesis is that Bob's model or text is independent of Alice's randomized training run--and investigate it through the lens of palimpsestic memorization in language models: models are more likely to memorize data seen later in training, so we can test whether Bob is using Alice's model using test statistics that capture correlation between Bob's model or text and the ordering of training examples in Alice's training run. If Alice has randomly shuffled her training data, then any significant correlation amounts to exactly quantifiable statistical evidence against the null hypothesis, regardless of the composition of Alice's training data. In the query setting, we directly estimate (via prompting) the likelihood Bob's model gives to Alice's training examples and order; we correlate the likelihoods of over 40 fine-tunes of various Pythia and OLMo base models ranging from 1B to 12B parameters with the base model's training data order, achieving a p-value on the order of at most 1e-8 in all but six cases. In the observational setting, we try two approaches based on estimating 1) the likelihood of Bob's text overlapping with spans of Alice's training examples and 2) the likelihood of Bob's text with respect to different versions of Alice's model we obtain by repeating the last phase (e.g., 1%) of her training run on reshuffled data. The second approach can reliably distinguish Bob's text from as little as a few hundred tokens; the first does not involve any retraining but requires many more tokens (several hundred thousand) to achieve high power.

The integration of biomolecular modeling with natural language (BL) has emerged as a promising interdisciplinary area at the intersection of artificial intelligence, chemistry and biology. This approach leverages the rich, multifaceted descriptions of biomolecules contained within textual data sources to enhance our fundamental understanding and enable downstream computational tasks such as biomolecule property prediction. The fusion of the nuanced narratives expressed through natural language with the structural and functional specifics of biomolecules described via various molecular modeling techniques opens new avenues for comprehensively representing and analyzing biomolecules. By incorporating the contextual language data that surrounds biomolecules into their modeling, BL aims to capture a holistic view encompassing both the symbolic qualities conveyed through language as well as quantitative structural characteristics. In this review, we provide an extensive analysis of recent advancements achieved through cross modeling of biomolecules and natural language. (1) We begin by outlining the technical representations of biomolecules employed, including sequences, 2D graphs, and 3D structures. (2) We then examine in depth the rationale and key objectives underlying effective multi-modal integration of language and molecular data sources. (3) We subsequently survey the practical applications enabled to date in this developing research area. (4) We also compile and summarize the available resources and datasets to facilitate future work. (5) Looking ahead, we identify several promising research directions worthy of further exploration and investment to continue advancing the field. The related resources and contents are updating in https://github.com/QizhiPei/Awesome-Biomolecule-Language-Cross-Modeling.

Diffusion models have been successful on a range of conditional generation tasks including molecular design and text-to-image generation. However, these achievements have primarily depended on task-specific conditional training or error-prone heuristic approximations. Ideally, a conditional generation method should provide exact samples for a broad range of conditional distributions without requiring task-specific training. To this end, we introduce the Twisted Diffusion Sampler, or TDS. TDS is a sequential Monte Carlo (SMC) algorithm that targets the conditional distributions of diffusion models through simulating a set of weighted particles. The main idea is to use twisting, an SMC technique that enjoys good computational efficiency, to incorporate heuristic approximations without compromising asymptotic exactness. We first find in simulation and in conditional image generation tasks that TDS provides a computational statistical trade-off, yielding more accurate approximations with many particles but with empirical improvements over heuristics with as few as two particles. We then turn to motif-scaffolding, a core task in protein design, using a TDS extension to Riemannian diffusion models. On benchmark test cases, TDS allows flexible conditioning criteria and often outperforms the state of the art.

Pre-trained language models (PLMs) have been the de facto paradigm for most natural language processing (NLP) tasks. This also benefits biomedical domain: researchers from informatics, medicine, and computer science (CS) communities propose various PLMs trained on biomedical datasets, e.g., biomedical text, electronic health records, protein, and DNA sequences for various biomedical tasks. However, the cross-discipline characteristics of biomedical PLMs hinder their spreading among communities; some existing works are isolated from each other without comprehensive comparison and discussions. It expects a survey that not only systematically reviews recent advances of biomedical PLMs and their applications but also standardizes terminology and benchmarks. In this paper, we summarize the recent progress of pre-trained language models in the biomedical domain and their applications in biomedical downstream tasks. Particularly, we discuss the motivations and propose a taxonomy of existing biomedical PLMs. Their applications in biomedical downstream tasks are exhaustively discussed. At last, we illustrate various limitations and future trends, which we hope can provide inspiration for the future research of the research community.

Normalizing flows are a promising tool for modeling probability distributions in physical systems. While state-of-the-art flows accurately approximate distributions and energies, applications in physics additionally require smooth energies to compute forces and higher-order derivatives. Furthermore, such densities are often defined on non-trivial topologies. A recent example are Boltzmann Generators for generating 3D-structures of peptides and small proteins. These generative models leverage the space of internal coordinates (dihedrals, angles, and bonds), which is a product of hypertori and compact intervals. In this work, we introduce a class of smooth mixture transformations working on both compact intervals and hypertori. Mixture transformations employ root-finding methods to invert them in practice, which has so far prevented bi-directional flow training. To this end, we show that parameter gradients and forces of such inverses can be computed from forward evaluations via the inverse function theorem. We demonstrate two advantages of such smooth flows: they allow training by force matching to simulation data and can be used as potentials in molecular dynamics simulations.

Self-replication is a key aspect of biological life that has been largely overlooked in Artificial Intelligence systems. Here we describe how to build and train self-replicating neural networks. The network replicates itself by learning to output its own weights. The network is designed using a loss function that can be optimized with either gradient-based or non-gradient-based methods. We also describe a method we call regeneration to train the network without explicit optimization, by injecting the network with predictions of its own parameters. The best solution for a self-replicating network was found by alternating between regeneration and optimization steps. Finally, we describe a design for a self-replicating neural network that can solve an auxiliary task such as MNIST image classification. We observe that there is a trade-off between the network's ability to classify images and its ability to replicate, but training is biased towards increasing its specialization at image classification at the expense of replication. This is analogous to the trade-off between reproduction and other tasks observed in nature. We suggest that a self-replication mechanism for artificial intelligence is useful because it introduces the possibility of continual improvement through natural selection.

Predicting gene function from its DNA sequence is a fundamental challenge in biology. Many deep learning models have been proposed to embed DNA sequences and predict their enzymatic function, leveraging information in public databases linking DNA sequences to an enzymatic function label. However, much of the scientific community's knowledge of biological function is not represented in these categorical labels, and is instead captured in unstructured text descriptions of mechanisms, reactions, and enzyme behavior. These descriptions are often captured alongside DNA sequences in biological databases, albeit in an unstructured manner. Deep learning of models predicting enzymatic function are likely to benefit from incorporating this multi-modal data encoding scientific knowledge of biological function. There is, however, no dataset designed for machine learning algorithms to leverage this multi-modal information. Here we propose a novel dataset and benchmark suite that enables the exploration and development of large multi-modal neural network models on gene DNA sequences and natural language descriptions of gene function. We present baseline performance on benchmarks for both unsupervised and supervised tasks that demonstrate the difficulty of this modeling objective, while demonstrating the potential benefit of incorporating multi-modal data types in function prediction compared to DNA sequences alone. Our dataset is at: https://hoarfrost-lab.github.io/BioTalk/.

We study the relationship between vocabulary size and text length in a corpus of 75 literary works in English, authored by six writers, distinguishing between the contributions of three grammatical classes (or ``tags,'' namely, {\it nouns}, {\it verbs}, and {\it others}), and analyze the progressive appearance of new words of each tag along each individual text. While the power-law relation prescribed by Heaps' law is satisfactorily fulfilled by total vocabulary sizes and text lengths, the appearance of new words in each text is on the whole well described by the average of random shufflings of the text, which does not obey a power law. Deviations from this average, however, are statistically significant and show a systematic trend across the corpus. Specifically, they reveal that the appearance of new words along each text is predominantly retarded with respect to the average of random shufflings. Moreover, different tags are shown to add systematically distinct contributions to this tendency, with {\it verbs} and {\it others} being respectively more and less retarded than the mean trend, and {\it nouns} following instead this overall mean. These statistical systematicities are likely to point to the existence of linguistically relevant information stored in the different variants of Heaps' law, a feature that is still in need of extensive assessment.

Agents based on large language models have shown great potential in accelerating scientific discovery by leveraging their rich background knowledge and reasoning capabilities. In this paper, we introduce BioDiscoveryAgent, an agent that designs new experiments, reasons about their outcomes, and efficiently navigates the hypothesis space to reach desired solutions. We demonstrate our agent on the problem of designing genetic perturbation experiments, where the aim is to find a small subset out of many possible genes that, when perturbed, result in a specific phenotype (e.g., cell growth). Utilizing its biological knowledge, BioDiscoveryAgent can uniquely design new experiments without the need to train a machine learning model or explicitly design an acquisition function as in Bayesian optimization. Moreover, BioDiscoveryAgent, using Claude 3.5 Sonnet, achieves an average of 21% improvement in predicting relevant genetic perturbations across six datasets, and a 46% improvement in the harder task of non-essential gene perturbation, compared to existing Bayesian optimization baselines specifically trained for this task. Our evaluation includes one dataset that is unpublished, ensuring it is not part of the language model's training data. Additionally, BioDiscoveryAgent predicts gene combinations to perturb more than twice as accurately as a random baseline, a task so far not explored in the context of closed-loop experiment design. The agent also has access to tools for searching the biomedical literature, executing code to analyze biological datasets, and prompting another agent to critically evaluate its predictions. Overall, BioDiscoveryAgent is interpretable at every stage, representing an accessible new paradigm in the computational design of biological experiments with the potential to augment scientists' efficacy.

The objective of personalized medicine is to tailor interventions to an individual patient's unique characteristics. A key technology for this purpose involves medical digital twins, computational models of human biology that can be personalized and dynamically updated to incorporate patient-specific data collected over time. Certain aspects of human biology, such as the immune system, are not easily captured with physics-based models, such as differential equations. Instead, they are often multi-scale, stochastic, and hybrid. This poses a challenge to existing model-based control and optimization approaches that cannot be readily applied to such models. Recent advances in automatic differentiation and neural-network control methods hold promise in addressing complex control problems. However, the application of these approaches to biomedical systems is still in its early stages. This work introduces dynamics-informed neural-network controllers as an alternative approach to control of medical digital twins. As a first use case for this method, the focus is on agent-based models, a versatile and increasingly common modeling platform in biomedicine. The effectiveness of the proposed neural-network control method is illustrated and benchmarked against other methods with two widely-used agent-based model types. The relevance of the method introduced here extends beyond medical digital twins to other complex dynamical systems.

In this paper, we provide a finite random iterated function system satisfying the open set condition, for which the random version of Bowen's formula fails to hold. This counterexample shows that analogous results established for random recursive constructions are not always obtained for random iterated function systems.

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 a striking neuroscience study, the authors placed a dead salmon in an MRI scanner and showed it images of humans in social situations. Astonishingly, standard analyses of the time reported brain regions predictive of social emotions. The explanation, of course, was not supernatural cognition but a cautionary tale about misapplied statistical inference. In AI interpretability, reports of similar ''dead salmon'' artifacts abound: feature attribution, probing, sparse auto-encoding, and even causal analyses can produce plausible-looking explanations for randomly initialized neural networks. In this work, we examine this phenomenon and argue for a pragmatic statistical-causal reframing: explanations of computational systems should be treated as parameters of a (statistical) model, inferred from computational traces. This perspective goes beyond simply measuring statistical variability of explanations due to finite sampling of input data; interpretability methods become statistical estimators, and findings should be tested against explicit and meaningful alternative computational hypotheses, with uncertainty quantified with respect to the postulated statistical model. It also highlights important theoretical issues, such as the identifiability of common interpretability queries, which we argue is critical to understand the field's susceptibility to false discoveries, poor generalizability, and high variance. More broadly, situating interpretability within the standard toolkit of statistical inference opens promising avenues for future work aimed at turning AI interpretability into a pragmatic and rigorous science.

Machine learning is widely used to analyze biological sequence data. Non-sequential models such as SVMs or feed-forward neural networks are often used although they have no natural way of handling sequences of varying length. Recurrent neural networks such as the long short term memory (LSTM) model on the other hand are designed to handle sequences. In this study we demonstrate that LSTM networks predict the subcellular location of proteins given only the protein sequence with high accuracy (0.902) outperforming current state of the art algorithms. We further improve the performance by introducing convolutional filters and experiment with an attention mechanism which lets the LSTM focus on specific parts of the protein. Lastly we introduce new visualizations of both the convolutional filters and the attention mechanisms and show how they can be used to extract biological relevant knowledge from the LSTM networks.

RNA is a vital biomolecule with numerous roles and functions within cells, and interest in targeting it for therapeutic purposes has grown significantly in recent years. However, fully understanding and predicting RNA behavior, particularly for applications in drug discovery, remains a challenge due to the complexity of RNA structures and interactions. While foundational models in biology have demonstrated success in modeling several biomolecules, especially proteins, achieving similar breakthroughs for RNA has proven more difficult. Current RNA models have yet to match the performance observed in the protein domain, leaving an important gap in computational biology. In this work, we present ChaRNABERT, a suite of sample and parameter-efficient RNA foundational models, that through a learnable tokenization process, are able to reach state-of-the-art performance on several tasks in established benchmarks. We extend its testing in relevant downstream tasks such as RNA-protein and aptamer-protein interaction prediction. Weights and inference code for ChaRNABERT-8M will be provided for academic research use. The other models will be available upon request.

Diffusion models are a class of generative models that learn to synthesize samples by inverting a diffusion process that gradually maps data into noise. While these models have enjoyed great success recently, a full theoretical understanding of their observed properties is still lacking, in particular, their weak sensitivity to the choice of noise family and the role of adequate scheduling of noise levels for good synthesis. By identifying a correspondence between diffusion models and a well-known paradigm in cognitive science known as serial reproduction, whereby human agents iteratively observe and reproduce stimuli from memory, we show how the aforementioned properties of diffusion models can be explained as a natural consequence of this correspondence. We then complement our theoretical analysis with simulations that exhibit these key features. Our work highlights how classic paradigms in cognitive science can shed light on state-of-the-art machine learning problems.

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

Star-convex shapes arise across bio-microscopy and radiology in the form of nuclei, nodules, metastases, and other units. Existing instance segmentation networks for such structures train on densely labeled instances for each dataset, which requires substantial and often impractical manual annotation effort. Further, significant reengineering or finetuning is needed when presented with new datasets and imaging modalities due to changes in contrast, shape, orientation, resolution, and density. We present AnyStar, a domain-randomized generative model that simulates synthetic training data of blob-like objects with randomized appearance, environments, and imaging physics to train general-purpose star-convex instance segmentation networks. As a result, networks trained using our generative model do not require annotated images from unseen datasets. A single network trained on our synthesized data accurately 3D segments C. elegans and P. dumerilii nuclei in fluorescence microscopy, mouse cortical nuclei in micro-CT, zebrafish brain nuclei in EM, and placental cotyledons in human fetal MRI, all without any retraining, finetuning, transfer learning, or domain adaptation. Code is available at https://github.com/neel-dey/AnyStar.

Drug discovery typically consists of multiple steps, including identifying a target protein key to a disease's etiology, validating that interacting with this target could prevent symptoms or cure the disease, discovering a small molecule or biologic therapeutic to interact with it, and optimizing the candidate molecule through a complex landscape of required properties. Drug discovery related tasks often involve prediction and generation while considering multiple entities that potentially interact, which poses a challenge for typical AI models. For this purpose we present MAMMAL - Molecular Aligned Multi-Modal Architecture and Language - a method that we applied to create a versatile multi-task foundation model ibm/biomed.omics.bl.sm.ma-ted-458m that learns from large-scale biological datasets (2 billion samples) across diverse modalities, including proteins, small molecules, and genes. We introduce a prompt syntax that supports a wide range of classification, regression, and generation tasks. It allows combining different modalities and entity types as inputs and/or outputs. Our model handles combinations of tokens and scalars and enables the generation of small molecules and proteins, property prediction, and transcriptomic lab test predictions. We evaluated the model on 11 diverse downstream tasks spanning different steps within a typical drug discovery pipeline, where it reaches new SOTA in 9 tasks and is comparable to SOTA in 2 tasks. This performance is achieved while using a unified architecture serving all tasks, in contrast to the original SOTA performance achieved using tailored architectures. The model code and pretrained weights are publicly available at https://github.com/BiomedSciAI/biomed-multi-alignment and https://huggingface.co/ibm/biomed.omics.bl.sm.ma-ted-458m.

Neo-Darwinian evolutionary theory explains how the appearance of purposive design in the sophisticated adaptations of living organisms can have come about without their intentionally being designed. The explanation relies crucially on the possibility of certain physical processes: mainly, gene replication and natural selection. In this paper I show that for those processes to be possible without the design of biological adaptations being encoded in the laws of physics, those laws must have certain other properties. The theory of what these properties are is not part of evolution theory proper, and has not been developed, yet without it the neo-Darwinian theory does not fully achieve its purpose of explaining the appearance of design. To this end I apply Constructor Theory's new mode of explanation to provide an exact formulation of the appearance of design, of no-design laws, and of the logic of self-reproduction and natural selection, within fundamental physics. I conclude that self-reproduction, replication and natural selection are possible under no-design laws, the only non-trivial condition being that they allow digital information to be physically instantiated. This has an exact characterisation in the constructor theory of information. I also show that under no-design laws an accurate replicator requires the existence of a "vehicle" constituting, together with the replicator, a self-reproducer.

This paper presents a reinforced genetic approach to a defined d-resource system optimization problem. The classical evolution schema was ineffective due to a very strict feasibility function in the studied problem. Hence, the presented strategy has introduced several modifications and adaptations to standard genetic routines, e.g.: a migration operator which is an analogy to the biological random genetic drift.

Large language models (LLMs) trained on huge corpora of text datasets demonstrate intriguing capabilities, achieving state-of-the-art performance on tasks they were not explicitly trained for. The precise nature of LLM capabilities is often mysterious, and different prompts can elicit different capabilities through in-context learning. We propose a framework that enables us to analyze in-context learning dynamics to understand latent concepts underlying LLMs' behavioral patterns. This provides a more nuanced understanding than success-or-failure evaluation benchmarks, but does not require observing internal activations as a mechanistic interpretation of circuits would. Inspired by the cognitive science of human randomness perception, we use random binary sequences as context and study dynamics of in-context learning by manipulating properties of context data, such as sequence length. In the latest GPT-3.5+ models, we find emergent abilities to generate seemingly random numbers and learn basic formal languages, with striking in-context learning dynamics where model outputs transition sharply from seemingly random behaviors to deterministic repetition.

We introduce MABe22, a large-scale, multi-agent video and trajectory benchmark to assess the quality of learned behavior representations. This dataset is collected from a variety of biology experiments, and includes triplets of interacting mice (4.7 million frames video+pose tracking data, 10 million frames pose only), symbiotic beetle-ant interactions (10 million frames video data), and groups of interacting flies (4.4 million frames of pose tracking data). Accompanying these data, we introduce a panel of real-life downstream analysis tasks to assess the quality of learned representations by evaluating how well they preserve information about the experimental conditions (e.g. strain, time of day, optogenetic stimulation) and animal behavior. We test multiple state-of-the-art self-supervised video and trajectory representation learning methods to demonstrate the use of our benchmark, revealing that methods developed using human action datasets do not fully translate to animal datasets. We hope that our benchmark and dataset encourage a broader exploration of behavior representation learning methods across species and settings.

Motivation The genotype assignment problem consists of predicting, from the genotype of an individual, which of a known set of populations it originated from. The problem arises in a variety of contexts, including wildlife forensics, invasive species detection and biodiversity monitoring. Existing approaches perform well under ideal conditions but are sensitive to a variety of common violations of the assumptions they rely on. Results In this article, we introduce Mycorrhiza, a machine learning approach for the genotype assignment problem. Our algorithm makes use of phylogenetic networks to engineer features that encode the evolutionary relationships among samples. Those features are then used as input to a Random Forests classifier. The classification accuracy was assessed on multiple published empirical SNP, microsatellite or consensus sequence datasets with wide ranges of size, geographical distribution and population structure and on simulated datasets. It compared favorably against widely used assessment tests or mixture analysis methods such as STRUCTURE and Admixture, and against another machine-learning based approach using principal component analysis for dimensionality reduction. Mycorrhiza yields particularly significant gains on datasets with a large average fixation index (FST) or deviation from the Hardy-Weinberg equilibrium. Moreover, the phylogenetic network approach estimates mixture proportions with good accuracy.

Active learning (AL) is a promising ML paradigm that has the potential to parse through large unlabeled data and help reduce annotation cost in domains where labeling data can be prohibitive. Recently proposed neural network based AL methods use different heuristics to accomplish this goal. In this study, we demonstrate that under identical experimental settings, different types of AL algorithms (uncertainty based, diversity based, and committee based) produce an inconsistent gain over random sampling baseline. Through a variety of experiments, controlling for sources of stochasticity, we show that variance in performance metrics achieved by AL algorithms can lead to results that are not consistent with the previously reported results. We also found that under strong regularization, AL methods show marginal or no advantage over the random sampling baseline under a variety of experimental conditions. Finally, we conclude with a set of recommendations on how to assess the results using a new AL algorithm to ensure results are reproducible and robust under changes in experimental conditions. We share our codes to facilitate AL evaluations. We believe our findings and recommendations will help advance reproducible research in AL using neural networks. We open source our code at https://github.com/PrateekMunjal/TorchAL

Evolvability is an important feature that impacts the ability of evolutionary processes to find interesting novel solutions and to deal with changing conditions of the problem to solve. The estimation of evolvability is not straightforward and is generally too expensive to be directly used as selective pressure in the evolutionary process. Indirectly promoting evolvability as a side effect of other easier and faster to compute selection pressures would thus be advantageous. In an unbounded behavior space, it has already been shown that evolvable individuals naturally appear and tend to be selected as they are more likely to invade empty behavior niches. Evolvability is thus a natural byproduct of the search in this context. However, practical agents and environments often impose limits on the reach-able behavior space. How do these boundaries impact evolvability? In this context, can evolvability still be promoted without explicitly rewarding it? We show that Novelty Search implicitly creates a pressure for high evolvability even in bounded behavior spaces, and explore the reasons for such a behavior. More precisely we show that, throughout the search, the dynamic evaluation of novelty rewards individuals which are very mobile in the behavior space, which in turn promotes evolvability.

Large participatory biomedical studies, studies that recruit individuals to join a dataset, are gaining popularity and investment, especially for analysis by modern AI methods. Because they purposively recruit participants, these studies are uniquely able to address a lack of historical representation, an issue that has affected many biomedical datasets. In this work, we define representativeness as the similarity to a target population distribution of a set of attributes and our goal is to mirror the U.S. population across distributions of age, gender, race, and ethnicity. Many participatory studies recruit at several institutions, so we introduce a computational approach to adaptively allocate recruitment resources among sites to improve representativeness. In simulated recruitment of 10,000-participant cohorts from medical centers in the STAR Clinical Research Network, we show that our approach yields a more representative cohort than existing baselines. Thus, we highlight the value of computational modeling in guiding recruitment efforts.

Generative modeling of single-cell RNA-seq data has shown invaluable potential in community-driven tasks such as trajectory inference, batch effect removal and gene expression generation. However, most recent deep models generating synthetic single cells from noise operate on pre-processed continuous gene expression approximations, ignoring the inherently discrete and over-dispersed nature of single-cell data, which limits downstream applications and hinders the incorporation of robust noise models. Moreover, crucial aspects of deep-learning-based synthetic single-cell generation remain underexplored, such as controllable multi-modal and multi-label generation and its role in the performance enhancement of downstream tasks. This work presents Cell Flow for Generation (CFGen), a flow-based conditional generative model for multi-modal single-cell counts, which explicitly accounts for the discrete nature of the data. Our results suggest improved recovery of crucial biological data characteristics while accounting for novel generative tasks such as conditioning on multiple attributes and boosting rare cell type classification via data augmentation. By showcasing CFGen on a diverse set of biological datasets and settings, we provide evidence of its value to the fields of computational biology and deep generative models.

We introduce a new predator-prey model by replacing the growth and predation constant by a square matrix, and the population density as a population vector. The classical Lotka-Volterra model describes a population that either modulates or converges. Stability analysis of such models have been extensively studied by the works of Merdan (https://doi.org/10.1016/j.chaos.2007.06.062). The new model adds complexity by introducing an age group structure where the population of each age group evolves as prescribed by the Leslie matrix. The added complexity changes the behavior of the model such that the population either displays roughly an exponential growth or decay. We first provide an exact equation that describes a time evolution and use analytic techniques to obtain an approximate growth factor. We also discuss the variants of the Leslie model, i.e., the complex value predator-prey model and the competitive model. We then prove the Last Species Standing theorem that determines the dominant population in the large time limit. The recursive structure of the model denies the application of simple regression. We discuss a machine learning scheme that allows an admissible fit for the population evolution of Paramecium Aurelia and Paramecium Caudatum. Another potential avenue to simplify the computation is to use the machinery of quantum operators. We demonstrate the potential of this approach by computing the Hamiltonian of a simple Leslie system.

Compression is at the heart of intelligence. A theoretically optimal way to compress any sequence of data is to find the shortest program that outputs that sequence and then halts. However, such 'Kolmogorov compression' is uncomputable, and code generating LLMs struggle to approximate this theoretical ideal, as it requires reasoning, planning and search capabilities beyond those of current models. In this work, we introduce the KoLMogorov-Test (KT), a compression-as-intelligence test for code generating LLMs. In KT a model is presented with a sequence of data at inference time, and asked to generate the shortest program that produces the sequence. We identify several benefits of KT for both evaluation and training: an essentially infinite number of problem instances of varying difficulty is readily available, strong baselines already exist, the evaluation metric (compression) cannot be gamed, and pretraining data contamination is highly unlikely. To evaluate current models, we use audio, text, and DNA data, as well as sequences produced by random synthetic programs. Current flagship models perform poorly - both GPT4-o and Llama-3.1-405B struggle on our natural and synthetic sequences. On our synthetic distribution, we are able to train code generation models with lower compression rates than previous approaches. Moreover, we show that gains on synthetic data generalize poorly to real data, suggesting that new innovations are necessary for additional gains on KT.

Insects comprise millions of species, many experiencing severe population declines under environmental and habitat changes. High-throughput approaches are crucial for accelerating our understanding of insect diversity, with DNA barcoding and high-resolution imaging showing strong potential for automatic taxonomic classification. However, most image-based approaches rely on individual specimen data, unlike the unsorted bulk samples collected in large-scale ecological surveys. We present the Mixed Arthropod Sample Segmentation and Identification (MassID45) dataset for training automatic classifiers of bulk insect samples. It uniquely combines molecular and imaging data at both the unsorted sample level and the full set of individual specimens. Human annotators, supported by an AI-assisted tool, performed two tasks on bulk images: creating segmentation masks around each individual arthropod and assigning taxonomic labels to over 17 000 specimens. Combining the taxonomic resolution of DNA barcodes with precise abundance estimates of bulk images holds great potential for rapid, large-scale characterization of insect communities. This dataset pushes the boundaries of tiny object detection and instance segmentation, fostering innovation in both ecological and machine learning research.

Many real-world problems require reasoning across multiple scales, demanding models which operate not on single data points, but on entire distributions. We introduce generative distribution embeddings (GDE), a framework that lifts autoencoders to the space of distributions. In GDEs, an encoder acts on sets of samples, and the decoder is replaced by a generator which aims to match the input distribution. This framework enables learning representations of distributions by coupling conditional generative models with encoder networks which satisfy a criterion we call distributional invariance. We show that GDEs learn predictive sufficient statistics embedded in the Wasserstein space, such that latent GDE distances approximately recover the W_2 distance, and latent interpolation approximately recovers optimal transport trajectories for Gaussian and Gaussian mixture distributions. We systematically benchmark GDEs against existing approaches on synthetic datasets, demonstrating consistently stronger performance. We then apply GDEs to six key problems in computational biology: learning representations of cell populations from lineage-tracing data (150K cells), predicting perturbation effects on single-cell transcriptomes (1M cells), predicting perturbation effects on cellular phenotypes (20M single-cell images), modeling tissue-specific DNA methylation patterns (253M sequences), designing synthetic yeast promoters (34M sequences), and spatiotemporal modeling of viral protein sequences (1M sequences).

The Brownian sphere is a random metric space, homeomorphic to the two-dimensional sphere, which arises as the universal scaling limit of many types of random planar maps. The direct construction of the Brownian sphere is via a continuous analogue of the Cori--Vauquelin--Schaeffer (CVS) bijection. The CVS bijection maps labeled trees to planar maps, and the continuous version maps Aldous' continuum random tree with Brownian labels (the Brownian snake) to the Brownian sphere. In this work, we describe the inverse of the continuous CVS bijection, by constructing the Brownian snake as a measurable function of the Brownian sphere. Special care is needed to work with the orientation of the Brownian sphere.

Space biology research aims to understand fundamental effects of spaceflight on organisms, develop foundational knowledge to support deep space exploration, and ultimately bioengineer spacecraft and habitats to stabilize the ecosystem of plants, crops, microbes, animals, and humans for sustained multi-planetary life. To advance these aims, the field leverages experiments, platforms, data, and model organisms from both spaceborne and ground-analog studies. As research is extended beyond low Earth orbit, experiments and platforms must be maximally autonomous, light, agile, and intelligent to expedite knowledge discovery. Here we present a summary of recommendations from a workshop organized by the National Aeronautics and Space Administration on artificial intelligence, machine learning, and modeling applications which offer key solutions toward these space biology challenges. In the next decade, the synthesis of artificial intelligence into the field of space biology will deepen the biological understanding of spaceflight effects, facilitate predictive modeling and analytics, support maximally autonomous and reproducible experiments, and efficiently manage spaceborne data and metadata, all with the goal to enable life to thrive in deep space.