The digital and analog worlds of protein engineering

Access through your institution Buy or subscribe Over the past decades of protein design research, computational algorithms for studying proteins were often explored for novelty rather than

their utility in designing functional proteins — yielding heaps of unvalidated and untranslated research. Marked by the success of AlphaFold, trained on structural databases, only recently

have the predictive power of these models become robust enough to start reliably integrating them into workflows of protein engineering companies. Seeing models become an increasing

component of a protein engineer’s toolkit, some started to wonder: will models become the primary drivers of value creation, and what role will the wet lab play? We propose that, while

models have already been tightly integrated in company engineering workflows, most of their economic value is yet to be realized. State-of-the-art computational protein design is usually

open sourced, with authors openly publishing the model code and parameters for its accessibility and reuse. With architectures like transformers and diffusion-based generation becoming

commonplace, it is challenging to establish unique, proprietary advantages based solely on model design. As such, platforms centered around acquiring data, improving the quality of the

acquired data, building a diversity of assays to characterize the designed proteins and accessing new variants that normally do not appear in nature started to emerge. Some companies, such

as Basecamp Research, are heavily investing in mining proteins from extremophile organisms in hard-to-access parts of the world. Others, such as Ginkgo Bioworks, are using their

years-in-development metagenomic libraries and automation to collect large amounts of data on enzyme functions. In the therapeutic realm, A-Alpha Bio centered their thesis on generating wet

lab screens for millions of protein–protein interactions. This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Access Nature

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taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support REFERENCES * Kaplan, J. et

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notes * These authors contributed equally: Lada Nuzhna, Tess van Stekelenburg. AUTHORS AND AFFILIATIONS * Impetus Grants, San Francisco, CA, USA Lada Nuzhna * Crick Institute, London, UK

Lada Nuzhna * Lux Capital, New York, NY, USA Tess van Stekelenburg Authors * Lada Nuzhna View author publications You can also search for this author inPubMed Google Scholar * Tess van

Stekelenburg View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHORS Correspondence to Lada Nuzhna or Tess van Stekelenburg. ETHICS

DECLARATIONS COMPETING INTERESTS T.v.S. works at Lux Capital, which has invested in A-Alpha Bio and Dyno Therapeutics. L.N. funds aging research, which may involve some of the techniques

discussed in the article, through Impetus Grants. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Nuzhna, L., van Stekelenburg, T. The digital and analog

worlds of protein engineering. _Nat Biotechnol_ 41, 1513–1514 (2023). https://doi.org/10.1038/s41587-023-01938-x Download citation * Published: 25 August 2023 * Issue Date: November 2023 *

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