Theme 1: Research—2017 Update

Note: This is an archived version of the 2017 progress review and update to Leading Change: Strategic Plan 2015–2022 (originally 2015–2020).

Back to current: Theme 1: Research

Progress to 2017

Research is moving forward rapidly under the leadership of William DeGrado, PhD, as demonstrated by two papers in the Journal of the American Chemical Society (2014) and the Journal of Medicinal Chemistry (2016) that describe the design of urgently needed drugs against the flu, including strains that are resistant to current drugs. This work targets an influenza A protein involving the M2 proton channel. The research team designed small molecules that bind to the most prevalent and problematic variants of the M2 protein and demonstrated that they disrupt the ability of the virus to reproduce. Optimization of these promising lead compounds could lead to development of durable flu treatments.

Important progress was noted in a 2016 paper in the Journal of Medicinal Chemistry, reporting success by Danica Fujimori, PhD, of the approach for a specific class of epigenetic factors, the Jumonji Histone Demethylases.

Progress continues under Charles S. Craik, PhD, exemplified by a 2016 ChemMedChem paper reporting inhibitors of a viral protease as a potential drug target for Kaposi’s Sarcoma. The focus has also broadened from “drug leads” to incorporate “biomarkers,” specifically imaging agents to help identify cancer and monitor its response to therapy. A 2016 Cancer Research paper exemplifies the latter, demonstrating the ability to image prostate cancer tumors using anti-protease antibodies. See 1.4.5.

Progress to 2017

Major progress is reported by Adam Renslo, PhD, in a 2016 paper in Nature Chemical Biology describing the approach of designing hybrid antimalarials that target disease while greatly reducing side effects by taking advantage of a chemical reaction inside infected cells that allows drugs to be deposited inside only infected cells and not uninfected cells—and broadening its application to also encompass cancer. Work to specifically target malaria is ongoing.

Zev Gartner, PhD, is now co-directing a new multi-institution, UCSF-administered Center for Cellular Construction, formed in 2016 with a five-year $24 million grant by the National Science Foundation. The center’s research will unite scientists from diverse fields to adapt tools from engineering, the physical sciences, and computer science to design automated machines out of living cells.

Research is under way through a 2014 collaboration, initiated by the California Institute for Quantitative Biosciences between Circle Pharma Inc.—a start-up co-founded by Matthew Jacobson, PhD, with UC Santa Cruz partner Scott Lokey, PhD—and Pfizer Inc. Work is focusing on the large cyclic molecules, called macrocycles, that are able to bypass binding sites on molecules and move directly into cells. This permeability makes macrocycles attractive for attacking “hard-to-drug” targets.

Progress to 2017

The Quantitative Biosciences Institute (QBI) was officially established in spring 2016 as a UCSF Organized Research Unit reporting to the School of Pharmacy dean. In spring 2016, Nevan Krogan, PhD (School of Medicine), was appointed QBI director. An operations team was in place by summer 2016. During 2015 and 2016, QBI implemented three collaborative research initiatives:

1. Cancer Cell Mapping Initiative (CCMI) with UC San Diego

2. Host Pathogen Mapping Initiative (HPMI) with UC Berkeley

3. Psychiatric Cell Mapping Initiative (PCMI) with UCSF Department of Psychiatry

QBI facilitates these cross-campus and multi-institute partnerships by supporting investigators and the application of computation, mathematics, and statistics to drive forward the understanding of cell maps. The integration of physical and genetic maps allows researchers to derive quantitative insights into how the biological functions of cells can be perturbed and restored.

In 2015, QBI formed a partnership with Thermo Fisher Scientific Proteomics Facility for Disease Target Discovery at the Gladstone Institutes.

Progress to 2017

Andrej Sali, PhD, continues the development and application of the open-source /Integrative Modeling Platform/software package for integrative modeling of biomolecular structures and networks. He is a member of a number of National Institutes of Health (NIH)-funded collaborations, including: 1) National Center for Dynamic Interactome Research, 2) Enzyme Function Initiative, 3) Center for HIV Accessory and Regulatory Complexes; and collaborations focusing on: 4) mapping the 3D genome landscape, 5) mapping the yeast centrosome structure, assembly, and function, 6) mapping degenerative and dementing diseases of aging, and 7) mapping the conformational cycle of transmembrane transporters.

He also leads a worldwide Protein Data Bank (PDB) effort on standardizing representations and validations of integrative structures, resulting in an expansion of the PDB archive that now includes integrative structures. Recent highlights include structure and function characterizations of the Nuclear Pore Complex, its subcomplexes, and yeast Spindle Pole Body as well as a new method for modeling molecular networks by satisfaction of network restraints.

Thomas Ferrin, PhD, leads the NIH Resource for Biocomputing, Visualization, and Informatics. He continues the development of the ChimeraX program for visualization of molecular structures and networks, importantly including multi-scale structure representations.

Progress to 2017

All drivers of this objective have active research programs focused on developing new therapeutic strategies for neurodegenerative diseases, including Parkinson’s disease and tauopathies.

Progress to 2017

Designer molecules as scalable biological tools for precise measurement and perturbation of biological systems are becoming increasingly critical in modern biomedical research. They impart the ability to quantitatively characterize both fundamental biological processes and disease mechanisms, which provides critical underpinnings to invent new, more effective, and highly personalized therapies. Considerable progress has been made with two technologies that create biological devices for real-time measurement and perturbations: The first are sensor/actuators that provide new ways to detect molecular signals and respond to them. The second are regulators based on CRISPR developments that have the potential to allow rapid prototyping of not only a large number of precise perturbations to many genes but also the temporal sequence of the changes, towards the development of new engineering platforms for next-generation therapeutic interventions.

Progress to 2017

As detailed in a paper published online in a 2016 paper in Nature, research has developed a new opioid drug candidate that blocks pain as effectively as morphine in mice, without triggering dangerous side effects, and also apparently without the addictive properties of current prescription painkillers.

Progress to 2017

Identification of distant sequence and structural relationships and mapping these data to functional properties continue, and include focused studies on large enzyme superfamilies, each containing tens of thousands of sequences. On-going development of our similarity network technology enhances our ability to address protein structure-function relationships on a large scale. Our Structure-Function Linkage Database has been integrated into the European Bioinformatics Institute’s InterPro Consortium, greatly expanding its user community.

Progress to 2017

There is a high chance that Nadav Ahituv, PhD, will receive funding for and lead one of five National Institutes of Health (NIH) centers to explore parts of DNA that do not encode proteins for proteins but might have biochemical activities suggestive of function. This is part of NIH’s ENCODE project (Encyclopedia of DNA Elements) that is cataloging all the genes and regulatory elements—the parts of the genome that control whether genes are active or not—in humans and select model organisms. ENCODE is funded by the National Human Genome Research Institute.

Research is under way to find the genetic contributors to idiopathic scoliosis. The project is funded by the National Institute for Child Health and Human Development.

Progress to 2017

We developed a mathematical model to describe the role that human evolutionary history has played in shaping the genetic architecture of complex traits, as well as a simulation procedure (PMCID: PMC4270825). We then utilized these tools to describe how modern approaches to studying the impact of rare genetic variants on complex human traits are extremely sensitive to assumptions about human evolutionary history, with dire consequences for statistical power (PMCID: PMC4937562). We also utilized sophisticated computational tools from the field of functional data analysis to better understand how the human adaptive immune system responds to influenza vaccines, and to characterize immunoglobin genes involved in targeting the vaccine (PMCID: PMC4891843). Ongoing projects will expand both of these directions into human disease phenotypes, including diabetes, bipolar disease, and HIV.

Progress to 2017

Through the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we generated whole genome sequencing (WGS) data to study bronchodilator drug response in the most at-risk, yet understudied, admixed minority populations. We have also collaborated with Stanford University and the Icahn School of Medicine at Mount Sinai to become an analysis center in National Human Genome Research Institute’s Genome Sequencing Project. Genetic and pharmacogenetic analyses on admixed populations have been a big challenge due to their complex population substructure. We are currently developing computational tools to analyze big data for admixed populations. Our major goals include improving computational efficiency for inferring global and local genetic ancestry; improving the accuracy of rare variant association methods; and developing a suite of web-based tools for discovery, fine-mapping, and functional prediction of genetic variants.

Progress to 2017

Spectacular progress in this objective is highlighted by the awarding 2016 of a $24M National Science Foundation grant for a new UCSF Center for Cellular Construction, co-directed by Zev Gartner, PhD.

Progress to 2017

We are developing new materials for regenerative medicine and tissue engineering applications, including gels to mitigate cardiac fibrosis and materials to facilitate vascular healing. The Desai Lab and the Gartner Lab are developing methods to pattern and assemble cells to form more tissue-like structures. By combining cellular biology and computational analytics, Stephen Altschuler, PhD, and Lani Wu, PhD, have developed a way to perform cell-based drug screening more efficiently. They have already formed some partnerships with industry and are exploring others.

Progress to 2017

The UCSF Pediatric Device Consortium, co-directed by Shuvo Roy, PhD, and Michael Harrison MD, (Department of Surgery) is now in its 7th year of U.S. Food and Drug Administration sponsorship and is continuing to support collaborative medical device development between engineers, clinicians, and trainees for unmet needs in pediatric medicine. Since the program’s inception in 2009, seven devices have been brought into clinical trials at UCSF, seven faculty startups have launched, $23 million in follow-on funding has been raised, and one device is now commercially available. We are now scaling up this program by establishing a new cross-campus center to promote technological innovation for pediatrics that will bring in UC Berkeley engineers and expand clinical collaborations with UCSF Benioff Children’s Hospital and Children’s Hospital Oakland Research Institute investigators. We are planning a launch symposium in January 2017.

The Surgical Innovations program, co-directed by Shuvo Roy, PhD, and Hanmin Lee MD, (Department of Surgery) was launched in 2013 as an expansion of the PDC and is now successfully established as an interdepartmental resource for facilitating medical device innovation by surgeons and residents through collaboration with bioengineering faculty and students. Ten projects have been supported through our accelerator program and six surgery trainees have completed our Innovation Pathway, over 60 bioengineering students have been involved on projects, and five faculty startups have launched. We submitted an R25 training grant to the National Institute of Biomedical Imaging and Bioengineering in May 2016 to fund surgery residents completing our Innovation Pathway and will be scored in early November 2016. We are preparing a complementary training grant to train bioengineering master’s and doctoral students in biomedical device innovation and will submit that application to the National Science Foundation in February 2017.

For FY 2017, we received Medical Center Strategic Initiative funding ($650K) to pilot the Chancellor’s Office’s ‘BioSilicon Collaboratory’ concept using the Department of Surgery’s Surgical Innovations initiative and School of Pharmacy’s Kidney Project as vehicles. The goal of this effort is to develop best practices for attracting and sustaining high-impact external partnerships with the tech industry as well as for facilitating homegrown technological innovation within UCSF. To this end, we are in the process of rolling out Surgical Innovations services to other clinical departments and setting up partnership agreements with interested medical technology companies.

Progress to 2017

The Abate Lab has been extremely successful in gaining grant support (Examples: National Institutes of Health Innovator Award, National Science Foundation Career Award) to develop microfluidic platforms for high throughput screening and DNA sequencing.

Progress to 2017

In a major boost for this project, Celgene signed a three-year (2015-2018), $25M agreement with the Recombinant Antibody Network (co-founded by James Wells PhD, and including two other universities) to develop next-generation, antibody-based cancer therapies. As of 2015, the network had already generated more than 700 antibodies that can be used by anyone.

Progress to 2017

A number of new bioengineering projects have been started with UCSF School of Medicine departments including surgery, ophthalmology, medicine, and dermatology. We have several active research efforts around disease detection and treatment monitoring: Contactless Bioimpedance Sensing for Transplant Rejection Detection and Monitoring (Clinical collaborator: Georg Wieselthaler, Department of Surgery); SmartDerm: Real-time Monitoring and Management for Pressure Ulcer Prevention (Clinical collaborator: Hanmin Lee, Department of Surgery); Sentinel Bandage: Monitoring Wounds with Non-Invasive Impedance Mapping (Clinical collaborator: David Young, Department of Surgery); Roboimplant (Clinical collaborator: Michael Harrison, Department of Surgery).

Progress to 2017

As part of the U.S. Food and Drug Administration fast track program, we identified that the feasibility of the implantable bioartificial kidney depends on the success of the hemofilter component, which filters the blood using silicon nanopore membranes. Testing the hemofilter is thus our first priority, and its performance will be evaluated through a first-in-human clinical trial to demonstrate safety.

We conducted a small proof-of-concept study to develop the surgical implantation procedure and to evaluate the blood-flow path of our hemofilter. A swine model was selected because of the comparably sized vasculature and hematologic similarities with humans. Minimizing the weight of a well-anchored device and utilizing a two-layered polyester and polytetrafluoroethylene graft as the blood conduit appear key to the successful implantation.

For the bioreactor component, which houses renal epithelial cells, we have demonstrated immunoprotection against proinflammatory cytokines and antibodies. Primary human and immortalized human and animal cell lines were successfully grown on silicon nanopore membranes, which also resisted passage of TNFα.

Progress to 2017

We have developed several platforms that are moving towards translation, including thin film devices for age-related macular degeneration and glaucoma; oral microdevices for protein delivery, and an implantable device for HIV prep. New funding has come from industry partnerships, the National Institutes of Health, U.S. Agency for International Development, and the Bill and Melinda Gates Foundation.

Progress to 2017

The U.S. Food and Drug Administration awarded the UCSF-Stanford Center of Excellence in Regulatory Science and Innovation a five-year grant (September 1, 2016 to August 31, 2021) with up to $25 million in funding.

Progress to 2017

Research by Dorie Apollonio, PhD, in tobacco control has expand into local and state marijuana laws. She is a co-investigator on a Tobacco Related Disease and Research Program grant, funded August 2016, on measuring combined tobacco, e-cigarette, and marijuana use. Since December 2015, she is part of the San Francisco Cancer Initiative with Lisa Kroon, PharmD, to reduce the burden of tobacco in vulnerable populations, including the homeless, in San Francisco.

Recent publications include:

• Realist review of policy intervention studies aimed at reducing exposures to environmental hazards in the United States

• Minimum Ages of Legal Access for Tobacco in the United States From 1863 to 2015, which was used by Governor Brown’s office and cited in recent Michigan legislation on Tobacco 21.

• Challenges to generating evidence-informed policy and the role of systematic reviews and (perceived) conflicts of interest

Progress to 2017

Leslie Wilson, PhD, continues to be very productive in this research. She is a co-investigator on a Center for Medicare Services project. Investigators are initiating a new model of care for dementia patients and determining its economic impact on Medicare. She is actively working with Bret Brodowy, PharmD, and Kevin Rodondi, PharmD, on a UCSF strategic initiatives grant to evaluate a new framework for high-cost oncolytics; an abstract and manuscript have been submitted to the American Managed Care Pharmacy.

Select publications include:

• Ting J, Tien Ho P, Xiang P, Sugay A, Abdel-Sattar M, Wilson L. Cost-effectiveness and value of information of erlotinib, afatinib, and cisplatin-pemetrexed for first-line treatment of advanced EGFR mutation-positive non-small lung cancer in the United States. Value Health. 2015 Sep; 18(6):774-82. doi: 10.1016/j.jval.2015.04.008. Epub 2015 Jun 22./> PMID: 26409604

• Li Y, Bare LA, Bender RA, Sninsky JJ, Wilson LS, Devlin JJ, Waldman FM. Cost-effectiveness of sequencing 34 cancer-associated genes as an aid for treatment selection in patients with metastatic melanoma. Mol Diagn Ther 2015 19(3):169-77. PMID: 25955535.

• Shih V, Ten Ham RM, Bui CT, Tran DN, Ting J, Wilson L. Targeted therapies compared to dacarbazine for treatment of BRAF (V600E) Metastatic melanoma: A cost-effectiveness analysis. J Skin Cancer. 2015;2015:505302. doi: 10.1155/2015/505302. Epub 2015 Jun 10. PMID: 26171248

• Zaid UB, Hawkins M, Wilson L, Ting J, Harris C, Alwaal A, Zhao LC, Morey AF, Breyer BN. The cost of surveillance after urethroplasty. Urology. 2015. 85(5):1195-9. PMID 25819624

• Ting J, Wilson L, Schwarzenberg SJ, et al. Direct costs of acute recurrent and chronic pancreatitis in children in the INSPPIRE registry. J Pediatr. Gastroenterol. Nutr. 2016. 62(3):443-9 PMID: 26704866

Progress to 2017

Kathryn Phillips, PhD, continues her research in the Center for Translational and Policy Research on Personalized Medicine assessing the current state of insurer coverage of various types of genetic testing. Payer coverage of new genomic tests—such as multigene panels, whole exome sequencing, and whole genome sequencing—will be critical if these tests are to be more widely adopted. She recently published a study in Genetics in Medicine about a specific type of testing called cell-free DNA prenatal screening, which has likely had the most rapid insurer coverage of any genetic test.