About

Paul Schimmel is the John D. and Catherine T. MacArthur Professor of Biochemistry and Biophysics Emeritus and a Professor of Cell and Molecular Biology at Scripps Research Institute. Throughout his career, he has focused on translating bench-side research into tangible products that improve human health, addressing conditions such as alcoholism, schizophrenia, autism, AIDS, heart disease, and cancer. His research interests have centered on aminoacyl tRNA synthetases, which are ancient and universal enzymes. His laboratory has worked on a universal mechanism for error correction in genetic information interpretation, demonstrating its importance for cellular homeostasis and disease prevention. Additionally, his team discovered what is known as a ‘tRNA synthetase-directed primordial’ or ‘second’ genetic code, which was incorporated into the modern genetic code. In 1983, he developed the concept of expressed sequence tags (ESTs) and the strategy of shotgun sequencing, approaches later adopted into the human genome project. More recently, his laboratory has connected synthetases to disease and reported on the structural and functional metamorphosis of these proteins, revealing their repurposing with novel activities inside and outside the cell in various signaling pathways. Schimmel has been recognized with numerous honors, including membership in the American Academy of Arts and Sciences, the National Academy of Sciences, the American Philosophical Society, the Institute of Medicine, and the National Academy of Inventors. He has served as a former president of the Division of Biological Chemistry of the American Chemical Society and has been an editorial board member on numerous scientific journals.

Research topics

• Genetics
• Business
• Cell biology
• Biology
• Computational biology
• Chemistry

Selected publications

• A human histidyl-tRNA synthetase splice variant therapeutic targets NRP2 to resolve lung inflammation and fibrosis

  Science Translational Medicine · 2025-03-12 · 4 citations

  articleSenior authorCorresponding

  Interstitial lung disease (ILD) consists of a group of immune-mediated disorders that can cause inflammation and progressive fibrosis of the lungs, representing an area of unmet medical need given the lack of disease-modifying therapies and toxicities associated with current treatment options. Tissue-specific splice variants (SVs) of human aminoacyl-tRNA synthetases (aaRSs) are catalytic nulls thought to confer regulatory functions. One example from human histidyl-tRNA synthetase (HARS), termed HARS WHEP because the splicing event resulted in a protein encompassing the WHEP-TRS domain of HARS (a structurally conserved domain found in multiple aaRSs), is enriched in human lung and up-regulated by inflammatory cytokines in lung and immune cells. Structural analysis of HARS WHEP confirmed a well-organized helix-turn-helix motif. This motif bound specifically and selectively to neuropilin-2 (NRP2), a receptor expressed by myeloid cells in active sites of inflammation, to inhibit expression of proinflammatory receptors and cytokines and to down-regulate inflammatory pathways in primary human macrophages. In animal models of lung injury and ILD, including bleomycin treatment, silicosis, sarcoidosis, chronic hypersensitivity pneumonitis, systemic sclerosis, and rheumatoid arthritis–ILD, HARS WHEP reduced lung inflammation, immune cell infiltration, and fibrosis. In patients with sarcoidosis, efzofitimod treatment resulted in down-regulation of gene expression for inflammatory pathways in peripheral immune cells and stabilization of inflammatory biomarkers in serum after steroid tapering. We demonstrate the immunomodulatory activity of HARS WHEP and present preclinical data supporting ongoing clinical development of the biologic efzofitimod based on HARS WHEP in ILD.

  PublisherDOI

• Metabolic regulation of mRNA splicing

  Trends in Cell Biology · 2024-03-01 · 14 citations

  reviewSenior authorCorresponding
  PublisherDOI

• Cytoplasmic isoleucyl tRNA synthetase as an attractive multistage antimalarial drug target

  Science Translational Medicine · 2023-03-08 · 26 citations

  articleOpen access

  Development of antimalarial compounds into clinical candidates remains costly and arduous without detailed knowledge of the target. As resistance increases and treatment options at various stages of disease are limited, it is critical to identify multistage drug targets that are readily interrogated in biochemical assays. Whole-genome sequencing of 18 parasite clones evolved using thienopyrimidine compounds with submicromolar, rapid-killing, pan–life cycle antiparasitic activity showed that all had acquired mutations in the P. falciparum cytoplasmic isoleucyl tRNA synthetase (cIRS). Engineering two of the mutations into drug-naïve parasites recapitulated the resistance phenotype, and parasites with conditional knockdowns of cIRS became hypersensitive to two thienopyrimidines. Purified recombinant P. vivax cIRS inhibition, cross-resistance, and biochemical assays indicated a noncompetitive, allosteric binding site that is distinct from that of known cIRS inhibitors mupirocin and reveromycin A. Our data show that Plasmodium cIRS is an important chemically and genetically validated target for next-generation medicines for malaria.

  PublisherOA PDFDOI

• tRNA renovatio: Rebirth through fragmentation

  Molecular Cell · 2023-10-05 · 93 citations

  reviewOpen accessSenior authorCorresponding

  tRNA function is based on unique structures that enable mRNA decoding using anticodon trinucleotides. These structures interact with specific aminoacyl-tRNA synthetases and ribosomes using 3D shape and sequence signatures. Beyond translation, tRNAs serve as versatile signaling molecules interacting with other RNAs and proteins. Through evolutionary processes, tRNA fragmentation emerges as not merely random degradation but an act of recreation, generating specific shorter molecules called tRNA-derived small RNAs (tsRNAs). These tsRNAs exploit their linear sequences and newly arranged 3D structures for unexpected biological functions, epitomizing the tRNA "renovatio" (from Latin, meaning renewal, renovation, and rebirth). Emerging methods to uncover full tRNA/tsRNA sequences and modifications, combined with techniques to study RNA structures and to integrate AI-powered predictions, will enable comprehensive investigations of tRNA fragmentation products and new interaction potentials in relation to their biological functions. We anticipate that these directions will herald a new era for understanding biological complexity and advancing pharmaceutical engineering.

  PublisherDOI

• Structural basis for a degenerate tRNA identity code and the evolution of bimodal specificity in human mitochondrial tRNA recognition

  Nature Communications · 2023-08-09 · 4 citations

  articleOpen accessSenior author

  Abstract Animal mitochondrial gene expression relies on specific interactions between nuclear-encoded aminoacyl-tRNA synthetases and mitochondria-encoded tRNAs. Their evolution involves an antagonistic interplay between strong mutation pressure on mtRNAs and selection pressure to maintain their essential function. To understand the molecular consequences of this interplay, we analyze the human mitochondrial serylation system, in which one synthetase charges two highly divergent mtRNA Ser isoacceptors. We present the cryo-EM structure of human mSerRS in complex with mtRNA Ser(UGA) , and perform a structural and functional comparison with the mSerRS-mtRNA Ser(GCU) complex. We find that despite their common function, mtRNA Ser(UGA) and mtRNA Ser(GCU) show no constrain to converge on shared structural or sequence identity motifs for recognition by mSerRS. Instead, mSerRS evolved a bimodal readout mechanism, whereby a single protein surface recognizes degenerate identity features specific to each mtRNA Ser . Our results show how the mutational erosion of mtRNAs drove a remarkable innovation of intermolecular specificity rules, with multiple evolutionary pathways leading to functionally equivalent outcomes.

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• Clinical and molecular characterization of novel FARS2 variants causing neonatal mitochondrial disease

  Molecular Genetics and Metabolism · 2023-07-24 · 9 citations

  articleOpen access
  PublisherOA PDFDOI

• Arg-tRNA synthetase links inflammatory metabolism to RNA splicing and nuclear trafficking via SRRM2

  Nature Cell Biology · 2023-04-01 · 35 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Domain collapse and active site ablation generate a widespread animal mitochondrial seryl-tRNA synthetase

  Nucleic Acids Research · 2023-08-28 · 2 citations

  articleOpen access

  Through their aminoacylation reactions, aminoacyl tRNA-synthetases (aaRS) establish the rules of the genetic code throughout all of nature. During their long evolution in eukaryotes, additional domains and splice variants were added to what is commonly a homodimeric or monomeric structure. These changes confer orthogonal functions in cellular activities that have recently been uncovered. An unusual exception to the familiar architecture of aaRSs is the heterodimeric metazoan mitochondrial SerRS. In contrast to domain additions or alternative splicing, here we show that heterodimeric metazoan mitochondrial SerRS arose from its homodimeric ancestor not by domain additions, but rather by collapse of an entire domain (in one subunit) and an active site ablation (in the other). The collapse/ablation retains aminoacylation activity while creating a new surface, which is necessary for its orthogonal function. The results highlight a new paradigm for repurposing a member of the ancient tRNA synthetase family.

  PublisherOA PDFDOI

• Richard A. Lerner: Memories and Reflections

  Israel Journal of Chemistry · 2023-10-01

  articleOpen access1st authorCorresponding

  Richard Lerner was a singularity. During his tenure, Scripps Research was transformed into a biomedical powerhouse. He rapidly built remarkable strength in chemical and structural biology, immunology, cell and molecular biology, and molecular medicine. Not to stop there, he also instituted a new graduate program that consistently ranked in the top ten in the US. At the same time, he was a prolific author of scientific papers, which poured out of his own laboratory with colleagues at Scripps Research and collaborators throughout the world. These and many other aspects of his brilliant career and contributions are well documented and discussed elsewhere. Here I chose to avoid redundancy and focus instead on a few of the personal encounters, which give some sense of Richard's character and spirit. An essential part of Richard's success was his wife Nicola (Nicky), herself an MD, who worked tirelessly to enable him to achieve what he did. Early on, my wife Cleo and Nicky became close friends. This relationship facilitated social occasions, where we would be with the Lerner's at a dinner or event, sometimes at our home or at theirs, but also with guests at various restaurants in La Jolla. As a result, my understanding of Richard was broadened beyond that received from the many discussions and meetings at Scripps Research. This understanding was helpful during those times when we faced serious challenges and he, like all of us when under stress, needed support. In what is written below, I have used plain language to relate some of my memories and reflections. Richard was a friend and colleague and taught me much, especially the power of a vision, of belief in that vision and of the will to make the effort to bring it to pass. How did Richard search for people to add to the Institute? During the years of growth, he had raised funds from the Skaggs Family and from Novartis, among others. While his vision was to build an enterprise in which chemistry would flourish and be a bridge to the life sciences, his priority was the quality of the individual and his/her science. It was hard to define the parameters, if any, that he used. But in a Chemical and Engineering piece that appeared around 1997, Barry Sharples was quoted as saying “Richard smells the horse leather”. That was his approach – intuitive. When I first met Richard, my single outstanding thought was: “this man is on a nonstop adventure”. His time was somewhat unstructured, and ‘organized’ around the most interesting thought or conversation of the moment. He only spoke of big ideas, those that were ‘out of the box’ and, if fulfilled, would transform a segment of science by opening new areas. Those ideas were often connected to people he felt he could recruit to help with implementation. I recall one afternoon he called me and Julius Rebek, and insistently asked us to come as soon as possible to his office. There was really no need for a rush to his office. But to him, this was the big idea of the moment, which had suddenly come to him and demanded immediate attention and discussion. After Julius and I arrived, he described a top professor on the east coast who he wanted to recruit. He felt the amount of funding he would need was, as I recall, several tens of millions. That amount did not seem to concern him – it was, after all, just a detail and the big picture was the essence. What did we think? The spontaneous interruptions by Richard were not just calls to his office. When I was absorbed in writing papers or grants in my office, I closed my unlocked door. In order to access mine, a visitor had to pass through the abutting office of my administrative assistant. The Assistant knew that I did not want visitors when I was writing. She was quite conscientious about making that clear to anyone who came by wishing to speak to me. However, Richard disregarded all of this. Suddenly, as I am in midst of typing a sentence, he would walk by the assistant and burst into my office, whereupon he sat down and immediately poured out a stream of ideas. What did I think of this, or that, which had just come to his mind? These abrupt interruptions happened over and over. His mind would not let a new, over the top, idea be suppressed or unshared. He had to let it out and get into a discussion about it. Once I was able to accept the interruption and redirect my mind to his insistent presence, I was struck that he shared with me his unabashed enthusiasm and sought my input. To be sure, some of his ‘out of the box’ ideas had to be put back into a box. But that was not the point. To me, a nonstop adventure meant you were a free and unstoppable spirit, with a rich and diverse mind, which in our nerdy academic world was refreshing. After my laboratory moved to Scripps Research from MIT in 1997, my wife Cleo and I hosted a dinner at our newly built home on La Jolla Farms Road. We had a long and cordial relationship with then MIT President, Chuck Vest, and his wife Becky, who on at least two occasions stayed with us at the LJFR home. Vest was considered one of the greatest fund raisers ever at MIT, who among other achievements transformed the face of the campus with multiple building projects. He also gained fame with his famous statement that ‘gender discrimination within universities is more reality than perception’. We felt a dinner party with the Vest's would be meaningful for Richard, given their mutual interests in building great academic institutions. Richard and Nicky came to the dinner, along with Floyd Bloom and the Vest's. Chuck and Becky brought a gift – a handmade painted plaque that showed an image that labeled Scripps Research as “MIT West”. This did not set well with Richard, who did not see the spirit or humor in the plaque. As a consequence, the dinner did not go well, at least as far as Cleo and I saw it. The problem was, and typical of Richard's deep pride and feeling for Scripps Research, he saw MIT as “Scripps East”. New people in a group or at a dinner had to pass through his critical filters. They might induce conversation and he would respond if he felt a conversation would be of interest. Some succeeded but many failed. For example, through a board I served on I became acquainted with a former member of the cabinet of one of the US presidents. He at one time had also headed up a major corporation. His mind was sharp and clear, and that led to free and easy conversations. He had a winter home in Florida and, as it turned out, Richard and Nicky were by then homeowners also in Florida. Because Cleo and I often spent time at our home there, we felt it would be a stimulating evening to have dinner with Richard and Nicky and the CM and his wife at our home. That dinner also could have gone better. The problem was that, after applying his filters, Richard had no interest in talking to the CM. This kind reaction happened on other occasions as well, whether people were in science or business. I felt Richard could do better on this point, and could perhaps realize that not everyone was gifted with his free-flowing imagination and enormous capacity for deep and fascinating conversations. But then, his time was precious. He craved serious intellectual conversations, which would enlighten him and stimulate the kind of new thinking that he cherished. When he lit up a big cigar, I knew Richard was preparing to relax and to go into his contemplative state. He often was seen on the porch of his Florida home – which faced the crashing waves of the Atlantic – looking out and, while lost in thought, smoking his cigar. This contemplative side of Richard was his mind's private place, which was tied to his deep thinking and the endless and demanding decision-making he was subjected to. And yet, while immersed in thought, and without warning, he would blurt out a question or an idea. And then he would relax back to go on enjoying his cigar. I learned at MIT that, when a small department is given the opportunity to grow into a powerhouse, you do this by paying the cost to first hire top established people. Nucleated with these faculty, you can perpetuate and empower the excellence, with these faculty working together to find the best younger ones. Once you establish a first-rate faculty, they, and the people they hired, will self-perpetuate the quality and culture. In this way the legacy of the initial top people endures as the years pass and new faculty replace those that wind down. The same approach was used by Richard. He hired top people early in his administration and, in a short period of time, had created a top research institute. This effort was joined to his vision of a graduate program, patterned initially in some ways after the one at the Rockefeller Institute. The Scripps Research program rapidly became top-ranked in all disciplines in which it was represented. It also enormously magnified the reputation of Scripps Research. For example, as I recollect, after the early-years ratings came out on the graduate program, a distinguished Harvard professor asked a distinguished colleague at MIT “who is Scripps Research, and how can they outrank us in some disciplines?”. While I was at MIT in the Department of Biology, Richard managed to recruit Barry Sharples from the Chemistry Department. I recall Barry telling me in some detail about Richard and his phenomenal vision, and capacity to inspire him (Barry) to relocate. This happened before Barry had won the first of his two Nobel Prizes. But there was no mistake that Richard foresaw this possibility in the clearest way, and therefore set out to bring in Barry. Similarly, other carefully chosen names were added before and after Barry's appointment. With this core of outstanding people, Richard knew that, long after he was no longer the leader, his legacy was established and would continue well into the future.

  PublisherOA PDFDOI

• Supporting data associated with the manuscript: "A widespread metazoan heterodimeric mitochondrial seryl-tRNA synthetase evolved through asymmetric domain loss."

  Figshare · 2023-01-01

  datasetOpen access

  Contents: <strong>Clustal_X species and raw alignment: </strong> clustal_x_aln_species.fa clustal_aligment_supplementary.docx <br> <br> <strong>Data for phylogenetic pipeline:</strong> <em><strong>Species included in the eukaryotic database with download link </strong></em> eukaryotic_database__data.xlsx <em><strong>Query for blastsearch</strong></em> HOMSAP007601_serrs.fa <em><strong>Raw blastoutput</strong></em> SRS2_SLIMP_blastoutput.txt <em><strong>Fasta sequences of all sequences used in the phylogenetic analyses</strong></em> SRS2_SLIMP_species.fa <em><strong>Raw alignment of blasthits</strong></em> SRS2_SLIMP.aln <em><strong>Trimmed alignment</strong></em> SRS2_SLIMP_trim10.aln <em><strong>Raw tree files </strong></em> SRS2_SLIMP_trim10.aln.ckp.gz SRS2_SLIMP_trim10.aln.contree SRS2_SLIMP_trim10.aln.iqtree SRS2_SLIMP_trim10.aln.log SRS2_SLIMP_trim10.aln.mldist SRS2_SLIMP_trim10.aln.model.gz SRS2_SLIMP_trim10.aln.nex SRS2_SLIMP_trim10.aln.treefile SRS2_SLIMP_trim10.aln.uniqueseq.phy SRS2_SLIMP_trim10.newick.txt <br>

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Recent grants

• NIH Grant R01GM034366

  NIH · $449k · 1989

• NIH Grant R01GM015539

  NIH · $8.0M · 2012

• NIH Grant R01GM023562

  NIH · $8.5M · 2013

• Stablization of Fragile Human Transfer RNAs

  NIH · $1.5M · 2018–2022

• Components of Translation in Signal Transduction

  NIH · $4.5M · 2001–2017

Frequent coauthors

• Xiang‐Lei Yang

  Scripps Research Institute

  148 shared

• Tamara L. Hendrickson

  Wayne State University

  63 shared

• Shigeyuki Yokoyama

  56 shared

• Shuya Fukai

  Kyoto University

  53 shared

• Osamu Nureki

  The University of Tokyo

  52 shared

• Atsushi Shimada

  Okinawa Institute of Science and Technology Graduate University

  51 shared

• Masaru Tateno

  Japan Tobacco (Japan)

  50 shared

• Dmitry G. Vassylyev

  University of Alabama at Birmingham

  50 shared

Awards & honors

• Member of the American Academy of Arts and Sciences
• Member of the National Academy of Sciences
• Member of the American Philosophical Society
• Member of the Institute of Medicine (National Academy of Med…
• Member of the National Academy of Inventors