Raymond C Stevens

Biography

Stevens was born into a military family. In 1969 his father died in the Air Force, and his mother took several part-time jobs to support the family. He was raised in Auburn, Maine.

In 1980, Stevens joined the Army under their split option training program and conducted basic training at Fort Dix, New Jersey and advanced individual training at Fort Sam Houston, Texas. While engaged in his military service, Stevens entered the University of Southern Maine in the Computer Science program in 1981. However, an enthusiastic professor (John Ricci) converted him to the study of Chemistry. He spent two summers working as an intern at the Brookhaven National Laboratory in Long Island with Professor Ricci, and Drs. Thomas Koetzle and Dick McMullan, where he first learned how to determine the molecular structure of compounds by X-ray and neutron diffraction. While there he also met a University of Southern California research team led by Dr. Robert Bau; after he obtained a Bachelor of Science degree in Chemistry at USM, he entered the University of Southern California in pursuit of a Doctor of Philosophy degree in Chemistry working with Professors Robert Bau and George Olah. He completed his Ph.D. in 26 months, graduating in 1988.

Although science is a major part of his life, Stevens climbs mountains with his wife and children and runs ultramarathons including the Vermont 100 Mile Endurance Run and American River 50 Mile Endurance Run, and in 2011 he successfully completed the 156 mile Marathon des Sables across the Moroccan Sahara Desert.

Scientific career

After obtaining his Ph.D., Stevens accepted a postdoctoral position in 1988 in the lab of Nobel Laureate William N. Lipscomb, Jr. in the chemistry department at Harvard University where he focused on the large allosteric enzyme aspartate carbamoyltransferase. In 1991, he accepted a tenure-track position at the University of California, Berkeley in the chemistry department with a joint appointment in neurobiology. His initial research as an assistant professor focused on structural neurobiology and immunology, combining chemistry, structural biology and protein chemistry with a specific biological interest in understanding how the G protein-coupled receptor (GPCR) superfamily works. A seminal collaboration for Stevens was with Professor Peter G. Schultz where they jointly published a series of Science and Nature papers describing the immunological evolution of antibodies through careful structural studies. In 1999, Stevens left Berkeley to take a tenured position at The Scripps Research Institute. While at The Scripps Research Institute, Stevens has helped to found and establish the Joint Center for Structural Genomics, Joint Center for Innovative Membrane Protein Technologies, and the GPCR Network, all funded by the National Institutes of Health with direct guidance from NIGMS. In 2012, Stevens was recruited to found the iHuman Institute at ShanghaiTech University. In 2014, Stevens moved his lab from The Scripps Research Institute to the University of Southern California, where he is currently the Provost Professor of Biological Sciences and Chemistry and he founded the Bridge Institute to converge the arts and sciences.

Stevens is known for obtaining the structures of many biologically significant proteins and his technological innovations. He is considered a pioneer of high-throughput x-ray crystallography and structural genomics. His laboratory has led to the contribution of over 500 protein structure entries in the Protein Data Bank www.pdb.org. Stevens has withdrawn two different structures of ligand-bound clostridial neurotoxins.

In October 2007, Stevens and colleagues published the first high-resolution structure of a human GPCR. The β₂-adrenergic receptor work was quickly followed up 9 months later by the determination of the structure of the human A_2A adenosine receptor structure, also known as the caffeine receptor. In 2010, the structures of the human chemokine CXCR4 receptor (HIV co-receptor), the human dopamine D3 receptor and the human Histamine H1 receptor were published. In addition to these inactive-state structures, Stevens and colleagues solved the structure of an agonist-bound A_2A adenosine receptor.

Subsequent novel human receptor structures include:

2012: The first structure of a lipid-activated GPCR, the sphingolipid, the human kappa-opioid receptor and the human nociceptin/orphanin FQ peptide.

2013: Serotonin receptors 5-HT1B and 5-HT2B, the second HIV co-receptor, C-C chemokine receptor type 5 (CCR5) and the first structure of a class C GPCR, the transmembrane domain of the human Metabotropic glutamate receptor 1 (mGluR1) and the first structures of non-class A GPCRs, the transmembrane domain of the human Smoothened receptor from the Frizzled/Taste2 family and the transmembrane domain of the human glucagon receptor (GCGR) from the adhesion family.

2014: The human P2Y receptor 12 (P2Y12) bound to antagonist or agonist; the human Delta opioid receptor at 1.8A and the first structure of a class C GPCR, the transmembrane domain of the human Metabotropic glutamate receptor 1 (mGluR1).

2015: The human Lysophosphatidic acid receptor 1 (LPAR1), the human angiotensin II receptor type 1 (AT1R), human P2Y receptor 1 (P2Y1); and the human Rhodopsin-Arrestin complex.

2016: The marijuana receptor—human Cannabinoid receptor type 1 (CB1) and the human C-C chemokine receptor type 2 (CCR2)

In combination with the structural studies, working with the computational biology community to conduct GPCR Dock 2008 and GPCR Dock 2010 has helped to evaluate where the field is at, and functional studies using HDX and NMR are conducted by Stevens and collaborators to understand how the receptors work at the molecular level, and what fundamental and basic insights can be gained towards developing therapeutic drugs.

Structure based drug discovery

In 1992, Stevens worked with researchers at Gilead on the structural studies of neuraminidase inhibitors that eventually became Tamiflu, and later partnered with Roche. After the initial experience with structure based drug discovery from 1992–1997 with Gilead and Tamiflu, Stevens focused on understanding the basic mechanism of how Botox^TM (botulinum toxin) works, and on ways to use this scaffold for next generation protein therapeutics. In parallel to the work on botulinum toxin, Stevens worked on the enzymes involved in the catecholamine biosynthetic pathway, specifically the three aromatic amino acid hydroxylases including phenylalanine hydroxylase. From 1999-2004 Stevens was involved in the startup of Syrrx that developed the marketed drug Nesina for type II diabetes. From 2000–2010, Stevens has worked with BioMarin Pharmaceutical to develop Kuvan^TM (tetrahydrobiopterin) and assisted in the design and development of PEG-PAL (pegylated Phenylalanine ammonia-lyase) as treatments for mild and classical phenylketonuria (PKU). In 2008 Stevens started Receptos that developed an S1P1 agonist for multiple sclerosis and inflammatory bowel disease and in 2011 he started RuiYi that developed an anti-CB1 antibody for liver fibrosis.

Biotechnology Startups

Stevens has started four biotechnology companies (Syrrx (1999), MemRx (2002), Receptos (2009), and RuiYi (2011)), all focused on structure based drug discovery and each company started with one of his former Ph.D. students.

Awards

The Professor Emeritus John Ricci Undergraduate Fellowships

Established by Stevens to honor USM Professor Emeritus John Ricci and his innovative educational program at Brookhaven National Laboratory, these fellowships offer a unique opportunity for USM undergraduates to pursue research at The University of Southern California in Los Angeles, California, one of the oldest private research universities.

The Robert Bau Endowed Graduate Fellowship

Established by Stevens and Charles McKenna in 2010 to honor USC distinguished professor Robert Bau after his death in December 2008, the fellowship proposes to help celebrate Professor Bau's life and honor his extraordinary mentorship by linking him to new generations of young chemists at USC.