To build effective therapeutics, biologists iteratively mutate antibody sequences to improve binding and stability. Proposed mutations can be informed by previous measurements or by learning from large antibody databases to predict only typical antibodies. Unfortunately, the space of typical antibodies is enormous to search, and experiments often fail to find suitable antibodies on a budget. We introduce Clone-informed Bayesian Optimization (CloneBO), a Bayesian optimization procedure that efficiently optimizes antibodies in the lab by teaching a generative model how our immune system optimizes antibodies. Our immune system makes antibodies by iteratively evolving specific portions of their sequences to bind their target strongly and stably, resulting in a set of related, evolving sequences known as a clonal family. We train a large language model, CloneLM, on hundreds of thousands of clonal families and use it to design sequences with mutations that are most likely to optimize an antibody within the human immune system. We propose to guide our designs to fit previous measurements with a twisted sequential Monte Carlo procedure. We show that CloneBO optimizes antibodies substantially more efficiently than previous methods in realistic in silico experiments and designs stronger and more stable binders in in vitro wet lab experiments.

When using large language models (LLMs) in high-stakes applications, we need to know when we can trust their predictions. Some works argue that prompting high-performance LLMs is sufficient to produce calibrated uncertainties, while others introduce sampling methods that can be prohibitively expensive. In this work, we first argue that prompting on its own is insufficient to achieve good calibration and then show that fine-tuning on a small dataset of correct and incorrect answers can create an uncertainty estimate with good generalization and small computational overhead. We show that a thousand graded examples are sufficient to outperform baseline methods and that training through the features of a model is necessary for good performance and tractable for large open-source models when using LoRA. We also investigate the mechanisms that enable reliable LLM uncertainty estimation, finding that many models can be used as general-purpose uncertainty estimators, applicable not just to their own uncertainties but also the uncertainty of other models. Lastly, we show that uncertainty estimates inform human use of LLMs in human-AI collaborative settings through a user study.

We propose fine-tuning large language models for generation of stable materials. While unorthodox, fine-tuning large language models on text-encoded atomistic data is simple to implement yet reliable, with around 90% of sampled structures obeying physical constraints on atom positions and charges. Using energy above hull calculations from both learned ML potentials and gold-standard DFT calculations, we show that our strongest model (fine-tuned LLaMA-2 70B) can generate materials predicted to be metastable at about twice the rate (49% vs 28%) of CD-VAE, a competing diffusion model. Because of text prompting's inherent flexibility, our models can simultaneously be used for unconditional generation of stable material, infilling of partial structures and text-conditional generation. Finally, we show that language models' ability to capture key symmetries of crystal structures improves with model scale, suggesting that the biases of pretrained LLMs are surprisingly well-suited for atomistic data. Large language models (LLMs) are trained to compress large text datasets, but can also act as strong foundations for non-text data (Delétang et al., 2023). As compressors, LLMs extract common patterns and find simple programs that can produce them (Goldblum et al., 2023; Sutskever, 2023), regardless of the data's origin. Alongside generality, LLM pre-training also gives rise to sample efficiency, as in-context learning and fine-tuning require far fewer training examples to identify salient patterns than training a model from scratch (Brown et al., 2020). The generality and sample efficiency of LLMs make them particular promising for scientific problems, where data are often limited, collected from diverse sources, or challenging for non-experts to interpret. In materials science, for example, the number of known stable materials is relatively small, and the data describing each material are diverse, including composition, structure, and complex properties. LLMs can learn generalizable rules from a small number of examples (Zhu et al., 2023), combine modalities into a single model (Moon et al., 2023), and provide users with a text-based interface. A text interface, in particular, has the potential to improve access to scientific discovery (White, 2023); LLMs can use text to describe new observations, or, in design applications (e.g. In this work, we show that fine-tuned LLMs can generate the three-dimensional structure of stable crystals as text (Figure 1).

A popular approach to protein design is to combine a generative model with a discriminative model for conditional sampling. The generative model samples plausible sequences while the discriminative model guides a search for sequences with high fitness. Given its broad success in conditional sampling, classifier-guided diffusion modeling is a promising foundation for protein design, leading many to develop guided diffusion models for structure with inverse folding to recover sequences. In this work, we propose diffusioN Optimized Sampling (NOS), a guidance method for discrete diffusion models that follows gradients in the hidden states of the denoising network. NOS makes it possible to perform design directly in sequence space, circumventing significant limitations of structure-based methods, including scarce data and challenging inverse design. Moreover, we use NOS to generalize LaMBO, a Bayesian optimization procedure for sequence design that facilitates multiple objectives and edit-based constraints. The resulting method, LaMBO-2, enables discrete diffusions and stronger performance with limited edits through a novel application of saliency maps. We apply LaMBO-2 to a real-world protein design task, optimizing antibodies for higher expression yield and binding affinity to several therapeutic targets under locality and developability constraints, attaining a 99% expression rate and 40% binding rate in exploratory in vitro experiments.

By encoding time series as a string of numerical digits, we can frame time series forecasting as next-token prediction in text. Developing this approach, we find that large language models (LLMs) such as GPT-3 and LLaMA-2 can surprisingly zero-shot extrapolate time series at a level comparable to or exceeding the performance of purpose-built time series models trained on the downstream tasks. To facilitate this performance, we propose procedures for effectively tokenizing time series data and converting discrete distributions over tokens into highly flexible densities over continuous values. We argue the success of LLMs for time series stems from their ability to naturally represent multimodal distributions, in conjunction with biases for simplicity, and repetition, which align with the salient features in many time series, such as repeated seasonal trends. We also show how LLMs can naturally handle missing data without imputation through non-numerical text, accommodate textual side information, and answer questions to help explain predictions. While we find that increasing model size generally improves performance on time series, we show GPT-4 can perform worse than GPT-3 because of how it tokenizes numbers, and poor uncertainty calibration, which is likely the result of alignment interventions such as RLHF.

Bayesian optimization (BayesOpt) is a gold standard for query-efficient continuous optimization. However, its adoption for drug design has been hindered by the discrete, high-dimensional nature of the decision variables. We develop a new approach (LaMBO) which jointly trains a denoising autoencoder with a discriminative multi-task Gaussian process head, allowing gradient-based optimization of multi-objective acquisition functions in the latent space of the autoencoder. These acquisition functions allow LaMBO to balance the explore-exploit tradeoff over multiple design rounds, and to balance objective tradeoffs by optimizing sequences at many different points on the Pareto frontier. We evaluate LaMBO on two small-molecule design tasks, and introduce new tasks optimizing \emph{in silico} and \emph{in vitro} properties of large-molecule fluorescent proteins. In our experiments LaMBO outperforms genetic optimizers and does not require a large pretraining corpus, demonstrating that BayesOpt is practical and effective for biological sequence design.

Physics-inspired neural networks (NNs), such as Hamiltonian or Lagrangian NNs, dramatically outperform other learned dynamics models by leveraging strong inductive biases. These models, however, are challenging to apply to many real world systems, such as those that don't conserve energy or contain contacts, a common setting for robotics and reinforcement learning. In this paper, we examine the inductive biases that make physics-inspired models successful in practice. We show that, contrary to conventional wisdom, the improved generalization of HNNs is the result of modeling acceleration directly and avoiding artificial complexity from the coordinate system, rather than symplectic structure or energy conservation. We show that by relaxing the inductive biases of these models, we can match or exceed performance on energy-conserving systems while dramatically improving performance on practical, non-conservative systems. We extend this approach to constructing transition models for common Mujoco environments, showing that our model can appropriately balance inductive biases with the flexibility required for model-based control.

Adaptive Informative Path Planning (AIPP) problems model an agent tasked with obtaining information subject to resource constraints in unknown, partially observable environments. Existing work on AIPP has focused on representing observations about the world as a result of agent movement. We formulate the more general setting where the agent may choose between different sensors at the cost of some energy, in addition to traversing the environment to gather information. We call this problem AIPPMS (MS for Multimodal Sensing). AIPPMS requires reasoning jointly about the effects of sensing and movement in terms of both energy expended and information gained. We frame AIPPMS as a Partially Observable Markov Decision Process (POMDP) and solve it with online planning. Our approach is based on the Partially Observable Monte Carlo Planning framework with modifications to ensure constraint feasibility and a heuristic rollout policy tailored for AIPPMS. We evaluate our method on two domains: a simulated search-and-rescue scenario and a challenging extension to the classic RockSample problem. We find that our approach outperforms a classic AIPP algorithm that is modified for AIPPMS, as well as online planning using a random rollout policy.

Understanding large-scale patterns in student course enrollment is a problem of great interest to university administrators and educational researchers. Yet important decisions are often made without a good quantitative framework of the process underlying student choices. We propose a probabilistic approach to modelling course enrollment decisions, drawing inspiration from multilabel classification and mixture models. We use ten years of anonymized student transcripts from a large university to construct a Gaussian latent variable model that learns the joint distribution over course enrollments. The models allow for a diverse set of inference queries and robustness to data sparsity. We demonstrate the efficacy of this approach in comparison to others, including deep learning architectures, and demonstrate its ability to infer the underlying student interests that guide enrollment decisions.

This document provides an overview of the material covered in a course taught at Stanford in the spring quarter of 2018. The course draws upon insight from cognitive and systems neuroscience to implement hybrid connectionist and symbolic reasoning systems that leverage and extend the state of the art in machine learning by integrating human and machine intelligence. As a concrete example we focus on digital assistants that learn from continuous dialog with an expert software engineer while providing initial value as powerful analytical, computational and mathematical savants. Over time these savants learn cognitive strategies (domain-relevant problem solving skills) and develop intuitions (heuristics and the experience necessary for applying them) by learning from their expert associates. By doing so these savants elevate their innate analytical skills allowing them to partner on an equal footing as versatile collaborators - effectively serving as cognitive extensions and digital prostheses, thereby amplifying and emulating their human partner's conceptually-flexible thinking patterns and enabling improved access to and control over powerful computing resources.