Biology subjects

Dobbs, K.

Publications and source records attributed to Dobbs, K..

3 recordsLinked to original sources

bioRxiv2024

Manufacturing-Aware Generative Model Architectures Enable Biological Sequence Design and Synthesis at Petascale

We introduce a method to reduce the cost of synthesizing proteins and other biological sequences designed by a generative model by as much as a trillion-fold. In particular, we make our generative models manufacturing-aware, such that model-designed sequences can be efficiently synthesized in the real world with extreme parallelism. We demonstrate by training and synthesizing samples from generative models of antibodies, T cell antigens and DNA polymerases. For example, we train a manufacturing-aware generative model on 300 million observed human antibodies and synthesize[~] 1017 generated designs from the model, achieving a sample quality comparable to a state-of-the-art protein language model, at a cost of 103 dollars. Using previous methods, synthesis of a library of the same accuracy and size would cost roughly a quadrillion (1015) dollars.

bioengineering↗

bioRxiv2023

Embryonic lymphocytes contribute to a genetic form of autoimmune inflammation

Omenn Syndrome (OS) is a rare hematological disorder, caused by hypomorphic mutations in genes involved in B-/T-cell receptor (BCR/TCR) rearrangement that result in impaired lymphocyte development and immunodeficiency. Notwithstanding, few T-cell clones enriched in self-reactive specificities expand in peripheral tissues, where they trigger severe inflammation and autoimmune reactions. Interestingly, residual OS lymphocytes display characteristics proper of embryonic lymphocytes that emerge before, and independently from, hematopoietic stem cells (HSCs). This prompted us to hypothesize whether OS autoreactive T-cells are generated in the embryo independently from HSCs. Here we show that in the Rag2R229Q/R229Q OS mouse model, embryonic but not adult bone marrow-derived hematopoietic progenitors can generate T-cells. T-lymphopoiesis can be rescued in adult OS blood progenitors via their Lin28-mediated reprogramming to an embryonic-like state. Remarkably, when transplanted in immunodeficient mice, embryonic-like OS progenitors trigger tissue morphological alterations and inflammation in the large intestine of the recipients, recapitulating the typical OS inflammatory phenotype. Our study describes the previously unappreciated contribution of embryonic progenitors to the pool of autoreactive infilitrating T-cells, providing a novel platform for both the detailed study of human autoimmune disorders and the design of more targeted therapies.

developmental biology↗

bioRxiv2022

Autoantibody discovery across monogenic, acquired, and COVID19-associated autoimmunity with scalable PhIP-Seq

Phage Immunoprecipitation-Sequencing (PhIP-Seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-Seq for autoantigen discovery, including our previous work (Vazquez et al. 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki Disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C), and finally, mild and severe forms of COVID19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as PDYN in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in 2 patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-Seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID19, including the endosomal protein EEA1. Together, scaled PhIP-Seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.

immunology↗