Bayesian Optimization of Antibodies Informed by a Generative Model of Evolving Sequences

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.

Unlocking Tokens as Data Points for Generalization Bounds on Larger Language Models

Large language models (LLMs) with billions of parameters excel at predicting the next token in a sequence. Recent work computes non-vacuous compression-based generalization bounds for LLMs, but these bounds are vacuous for large models at the billion-parameter scale. Moreover, these bounds are obtained through restrictive compression techniques, bounding compressed models that generate low-quality text. Additionally, the tightness of these existing bounds depends on the number of IID documents in a training set rather than the much larger number of non-IID constituent tokens, leaving untapped potential for tighter bounds. In this work, we instead use properties of martingales to derive generalization bounds that benefit from the vast number of tokens in LLM training sets. Since a dataset contains far more tokens than documents, our generalization bounds not only tolerate but actually benefit from far less restrictive compression schemes. With Monarch matrices, Kronecker factorizations, and post-training quantization, we achieve non-vacuous generalization bounds for LLMs as large as LLaMA2-70B. Unlike previous approaches, our work achieves the first non-vacuous bounds for models that are deployed in practice and generate high-quality text.

Non-Vacuous Generalization Bounds for Large Language Models

Modern language models can contain billions of parameters, raising the question of whether they can generalize beyond the training data or simply regurgitate their training corpora. We provide the first non-vacuous generalization bounds for pretrained large language models (LLMs), indicating that language models are capable of discovering regularities that generalize to unseen data. In particular, we derive a compression bound that is valid for the unbounded log-likelihood loss using prediction smoothing, and we extend the bound to handle subsampling, accelerating bound computation on massive datasets. To achieve the extreme level of compression required for non-vacuous generalization bounds, we devise SubLoRA, a low-dimensional non-linear parameterization. Using this approach, we find that larger models have better generalization bounds and are more compressible than smaller models.

Learning Efficient Coding of Natural Images with Maximum Manifold Capacity Representations

Self-supervised Learning (SSL) provides a strategy for constructing useful representations of images without relying on hand-assigned labels. Many such methods aim to map distinct views of the same scene or object to nearby points in the representation space, while employing some constraint to prevent representational collapse. Here we recast the problem in terms of efficient coding by adopting manifold capacity, a measure that quantifies the quality of a representation based on the number of linearly separable object manifolds it can support, as the efficiency metric to optimize. Specifically, we adapt the manifold capacity for use as an objective function in a contrastive learning framework, yielding a Maximum Manifold Capacity Representation (MMCR). We apply this method to unlabeled images, each augmented by a set of basic transformations, and find that it learns meaningful features using the standard linear evaluation protocol. Specifically, we find that MMCRs support performance on object recognition comparable to or surpassing that of recently developed SSL frameworks, while providing more robustness to adversarial attacks. Empirical analyses reveal differences between MMCRs and representations learned by other SSL frameworks, and suggest a mechanism by which manifold compression gives rise to class separability.