Di Carlo Lab 2023 Year in Review

Season's Greetings! This year we celebrated our 15th anniversary of the founding of our lab at UCLA. One striking take home was how different our research is compared to 15 years ago. Unlike many labs that continue the detailed study of a specific protein or refinement of an engineering process, becoming the world-experts in the domain, our lab has the tradition of changing research directions every 5 years or so. Bringing a technology to a sufficient level of readiness for it to be commercialized and then starting from scratch with a completely new technology. Our trajectory: Inertial microfluidics, deformability cytometry, mechanomedicine, microparticle gels, lab on a particle, ferrobotics.

Starting from scratch every 5 years doesn't make it easy. Obtaining grant funding to explore a new research direction is so much more challenging than sticking to the same field where your peers already trust your demonstrated competency. But where is the fun in retreading well-worn paths? Breaking new trails is where we grow the most and creativity thrives on scarcity of resources.

SEC-seq with Lab on a Particle Technology. One new trail that has been opening up many more paths on its own is "Lab on a Particle" technology - with 2023 marking some substantial milestones. One example breakthrough for 2023 is Secretion-encoded Single-cell Sequencing (SEC-seq). This technique introduces the ability to link cell secretory function to underlying transcriptomes for thousands of single cells. Secreted proteins, extracellular vesicles, or other biomolecules are critical across almost all body functions - immunity, digestion, wound healing. Our collaborators, Rich James and Rene Cheng used SEC-seq to study how plasma cell secretion of antibodies, such as IgG, were linked to mRNA transcripts, publishing their findings in Nature Communications. They uncovered a number of new paths to explore including new surface marker proteins that defined highly-secreting human plasma cells.

My student, Shreya Udani , along with Justin Langerman from Kathrin Plath 's lab led another study published in Nature Nanotechnology that used SEC-seq to link the secretion of vascular endothelial growth factor (VEGF) with gene expression for individual cells. Surprisingly, the amount of gene expression for VEGF was not the main correlate with increase secretion. Another surface marker was discovered for the highly secreting cells, opening up new opportunities to enrich these cells with more therapeutic potential. We anticipate this type of tool can help bioengineers modulate cell secretory function directly and uncover the right gene programs to elicit a desired function.

The accessibility of the technology (all using off the shelf approaches and no new instruments) was a key design constraint and should enable more rapid adoption. Along this line Partillion Bioscience launched new products this year to accelerate Antibody Discovery, using nanovials to capture cells and link secreted antibody bound to antigen to gene sequences for those useful antibodies.

In parallel, we worked with Andrea Bertozzi 's lab to explore the formation of nanovials using the phase separation of aqueous two-phase systems (ATPS) under fluid flow. The findings, published in the Proceedings of the National Academy of Sciences, highlighted the importance of buoyancy differences and fluid flow to drive rapid phase separation and final configurations that approach the configurations observed experimentally. These findings can assist with engineering ATPS systems for manufacturing of microparticles or understanding phase separation and condensates in enclosed biological systems, such as cells.

Deformability Cytometry Matures. Deformability cytometry technology, which uses microfluidics and high-speed imaging to measure mechanical properties of thousands of individual cells, has matured over the last year. Cytovale's FDA clearance of the IntelliSep test and first hospitals adopting the technology for early diagnosis of sepsis, along with an $84M funding round exemplify the maturity for this research path. A <10 minute test is possible since the purely mechanical properties of cells are measured as a metric of immune activation signaling sepsis. This is the first test to be used in the clinic that uses mechanical properties of cells as a distinguishing feature of disease, and represents a culmination of the "mechanomedicine" field.

Some minor trails of our academic work continues in this space, with publications from Hector Enrique Mu?oz, Ph.D. in the first volume of the new translational journal Med-X. Quique's work was the first to be published using a fluorescence imaging cytometer from Omega Biosystems, that uses the FIRE technology which is now the basis for the BD FACSDiscover that was launched this year. Congratulations to lab alumni Eric Diebold, Ph.D. and Keegan Owsley on bringing this new instrument to market. We also explored the origins of mechanical signatures of sepsis with the formation of neutrophil extracellular traps (NETs), published in Diagnostics.

Long-lasting Vaccines from Microparticle Gels. Our collaborative work with Philip Scumpia and Jason Weinstein led by Hiromi M. demonstrates the potential for using microparticle gels that anneal in situ to form porous scaffolds in the sustained presentation of encapsulated antigen that lead to a robust immune response. Notably, the technique did not require danger signal "adjuvants" that are used in traditional vaccines to generate a lasting immune response. Notably the microparticle vaccines protected mice from death from influenza infection at similar levels compared to traditional vaccines with adjuvants (aluminum hydroxide). The work was published in Advanced Science.

Impact of Large Language Models on Scientific Practice. About a year ago I spoke to an audience at the IEEE EMBS Micro & Nanotechnology in Medicine Conference, and used ChatGPT to write an introduction, as a way to share with the audience how this technology represented a step change in capability of foundation models. Capabilities have continued to improve over the last year and are changing the way we communicate and do science in fundamental ways. Although these models are good partners, they have not yet reached the capabilities to replace scientists and engineers who are exploring the boundaries of thought. Some of the thoughts of the ACS Nano editors on best practices for using AI in academic writing is available here.

That's all for now! For a sneak peek of what to expect in 2024 from our lab, please take a look at our many pre-prints on biorxiv. These range from new single-tier tests for Lyme disease, sorting cells based on production of extracellular vesicles, to discovering new T-cell receptors based on cytokine release function.