Beyond the Human Genome: A Million Person Precision Population Health Project Leroy Hood Institute for Systems Biology
Leroy "Lee" Edward Hood is an American biologist who has served on the faculties at the California Institute of Technology (Caltech) and the University of Washington. He is currently Professor and Chrief Strategy OFficer at the Institute for Systems Biology. Dr Hood has developed ground-breaking scientific instruments which made possible major advances in the biological sciences and the medical sciences. These include the first gas phase protein sequencer (1982), for determining the sequence of amino acids in a given protein; a DNA synthesizer (1983), to synthesize short sections of DNA; a peptide synthesizer (1984), to combine amino acids into longer peptides and short proteins; the first automated DNA sequencer (1986), to identify the order of nucleotides in DNA; ink-jet oligonucleotide technology for synthesizing DNA and nanostring technology for analyzing single molecules of DNA and RNA.
Dr Hood believes that a combination of big data and systems biology has the potential to revolutionize healthcare and create a proactive medical approach focused on maximizing the wellness of the individual. He coined the term "P4 medicine" in 2003.
The vision of this project is that we will develop the infrastructure to employ a data-driven approach to optimizing the health trajectory of individuals for body and brain. We have two large populations (5000 and 10,000) that have validated this approach for body and brain health, respectively. These studies have led to us pioneering the science of wellness and prevention. This project will require the acquisition of key partners for execution, which will be delineated. We are approaching the Federal Government for funding, as we did for the first Human Genome Project. This project will lead to striking new knowledge about medicine, it will catalyze the initiation of start-up companies and it will catalyze a paradigm shift in healthcare from a disease orientation to a wellness and prevention orientation. This will catalyze the largest paradigm shift in medicine, ever.
Tue April 05 @ 16:00 (04:00 PM) in De Anza
The Clinical Laboratory Perspective on Wellness Testing: Let’s Take a Look Under the Hood Geoff Baird University of Washington
Geoffrey Baird, M.D., Ph.D., is a board certified pathologist at UW Medicine, and professor and acting chair of Laboratory Medicine and Pathology. He directs the Clinical Chemistry Laboratory at Harborview Medical Center.
Dr. Baird’s goal is to provide the highest quality lab services to patients in the UW community and Pacific Northwest region.
Dr. Baird earned his M.D. and Ph.D. from UC San Diego. He is board-certified in Anatomic Pathology, Clinical Pathology and Clinical Chemistry. His clinical and research interests include lab test utilization management, proteomics, tissue analysis, general laboratory medicine, pathology and pathophysiology of organ systems and anatomic pathology.
As medical science continues to make gains in the elucidation of disease pathophysiology and the discovery of cures , some have questioned the value of dedicating dwindling financial resources to maintaining wellness rather than to fighting disease per se. While both approaches are meritorious and complementary, neither approach is alone sufficient to ensure the health of a population. One major problem with the focus on wellness is the Bayesian dilemma that the positive predictive value of clinical laboratory testing in apparently healthy people is often low, as the specificities of few clinical tests are high enough to ensure that most positive results are true. The impact of this dilemma on laboratory-based wellness approaches will be discussed.
Tue April 05 @ 16:00 (04:00 PM) in De Anza
Mari DeMarco University of British Columbia
Mari DeMarco, PhD, DABCC, FCACB, is a Clinical Chemist at Providence Health Care, the Research Director of Providence Research, and a Clinical Associate Professor in Pathology and Laboratory Medicine at the University of British Columbia in Vancouver Canada. Dr. DeMarco completed her PhD in the Biomolecular Structure and Design program at the University of Washington, and a clinical chemistry fellowship at Washington University School of Medicine.
With a strong interest in bridging basic biomedical science, analytical chemistry and laboratory medicine, Dr. DeMarco’s research group focuses on building new biofluid tests for direct translation into patient care. A particular area of interest is advancing protein-based clinical diagnostics for neurodegenerative disorders, such as Alzheimer’s disease. The goal of this program of research is to ensure that these new tools make the challenging jump from research into healthcare.
Wed April 06 @ 08:00 (08:00 AM) in De Anza
Glycoproteins as Biomarkers for Cancers Carlito Lebrilla UC Davis
The focus of the group is in the development of analytical tools based on advanced separation and mass spectrometry in two areas—nutrition and diseases. We are developing mass spectrometry based tools for the discovery of markers for cancer including ovarian, breast, and prostate. We are pioneering the glycomic approach for the early diagnosis of cancer. In nutrition we are examining human milk as the model for the perfect food and determining bioactive components in milk.
Wed April 06 @ 09:00 (09:00 AM) in De Anza
How Can Proteomics Fulfill the Unmet Needs of Effective Drug Treatment Stratification for Patients with Ovarian Cancer? Stefani Thomas University of Minnesota
Dr. Stefani Thomas earned her BA in Biological Sciences from Dartmouth College and her PhD in Pharmaceutical Sciences from the University of Southern California. She pursued postdoctoral training in Dr. Robert Cotter’s Middle Atlantic Mass Spectrometry laboratory, conducted clinical proteomics research in the Center for Biomarker Discovery and Translation, and completed a Clinical Chemistry postdoctoral fellowship at Johns Hopkins University. She is currently an Assistant Professor, a faculty member of the Advanced Research and Diagnostics Laboratory (ARDL) and a member of the Masonic Cancer Center at the University of Minnesota. She is also the Associate Medical Director of the M Health Fairview West Bank Laboratory. Stefani's research laboratory applies discovery and targeted mass spectrometry-based proteomics methods to elucidate the biology of ovarian cancer and to identify proteome-level mechanisms of improved ovarian cancer treatment response.
The mutational status of a solid tumor can predict the therapeutic efficacy of a specific drug in a molecularly defined subset of patients. Targeted therapies are available to treat advanced (stage II – IV) ovarian cancer with mutations in BRCA1/2 genes. Unfortunately, there is considerable inter-patient heterogeneity in BRCA1/2–based determinations of drug treatment sensitivity. Determining the proteome-level mechanisms of drug treatment sensitivity could enhance our ability to select the ovarian cancer patient populations that would benefit the most from these targeted therapies, consequently improving survival and overall treatment response. Our laboratory is applying mass spectrometry-based proteomics to identify protein signatures of drug treatment sensitivity and subsequent patient stratification for treatment. This presentation will provide an overview of the experimental models and analytical approaches that we are utilizing toward a long-term goal of identifying prognostic protein biomarkers of drug treatment sensitivity in patients with high-grade serous ovarian cancer.
Wed April 06 @ 09:45 (09:45 AM) in De Anza
N-linked Glycans in Human Disease: From New Tools to Translational and Preclinical Studies Peggi Angel MUSC Proteomics Center
Peggi Angel is Associate Professor at Medical University of South Carolina, where she works on technology advancements in MALDI imaging mass spectrometry (IMS) and biomarker imaging analyses in cancer disparities. Dr. Angel attended graduate school at the University of Georgia’s Complex Carbohydrate Research Center, graduating with a PhD in 2007. Her graduate research was on development of technologies for mapping N-linked glycan sites in mammalian development. After a postdoctoral fellowship at Emory University focused on membrane proteomics of fetal alcohol syndrome, she won a competitive Postdoctoral Fellowship with the Systems-based Consortium for Organ Design and Engineering. With the Fellowship, she worked at Vanderbilt University in the laboratory of Richard Caprioli on methods using MALDI IMS for developmental biology. Dr. Angel has developed IMS methods for increasing sensitivity of protein detection from tissues, analysis and identification of signaling lipids in negative mode, targeted metabolomics on tissue and cell culture, extracellular matrix protein detection in FFPE tissues, and N-glycomic strategies for proteins, cells, and tissue. Dr. Angel is a co-founder of Glycopath, a company that focuses on glycosylation patterns as a prognostic or diagnostic tool. She serves on the board of N-Zyme Scientifics, a company that produces enzymes for mass spectrometry. Dr. Angel is committed to serving the imaging mass spectrometry community and serves as President-Elect for the US Imaging Mass Spectrometry Society.
N-glycosylation plays a significant role in immune cell recruitment, influences disease progression and outcome and response to therapy. Here, we discuss simplified workflows capable of reporting N-glycan expression patterns in tissues, cells and biofluids. We present translational and pre-clinical work investigating glycosylation patterns in cardiovascular disease, cancer risk and cancer. A long-term goal is to leverage glycosylation patterns to non-invasively monitor disease status and therapeutic efficacy.
Thu April 07 @ 08:00 (08:00 AM) in De Anza
Barbara Engelhardt Princeton University
Barbara E. Engelhardt, an associate professor, joined the Princeton Computer Science Department in 2014 from Duke University, where she had been an assistant professor in Biostatistics and Bioinformatics and Statistical Sciences. She graduated from Stanford University and received her Ph.D. from the University of California, Berkeley, advised by Professor Michael Jordan. She did postdoctoral research at the University of Chicago, working with Professor Matthew Stephens, and three years at Duke University as an assistant professor. Interspersed among her academic experiences, she spent two years working at the Jet Propulsion Laboratory, a summer at Google Research, and a year at 23andMe, a DNA ancestry service. Professor Engelhardt received an NSF Graduate Research Fellowship, the Google Anita Borg Memorial Scholarship, and the Walter M. Fitch Prize from the Society for Molecular Biology and Evolution. As a faculty member, she received the NIH NHGRI K99/R00 Pathway to Independence Award, a Sloan Faculty Fellowship, and an NSF CAREER Award. Professor Engelhardt’s research interests involve developing statistical models and methods for the analysis of high-dimensional biomedical data, with a goal of understanding the underlying biological mechanisms of complex phenotypes and human disease.
Thu April 07 @ 09:00 (09:00 AM) in De Anza
Meena Choi Genentech
Extensive experience for the development of statistical methods, tools, and software for the analysis of mass spectrometry-based proteomics and metabolomics data. Highly effective statisticians with over eight years of experience communicating statistical and technical concepts to researchers and clinicians. 5+ years’ experience creating and implementing training programs for chemists, biologists, clinicians and bioinformaticians in Mass Spectrometry-based proteomics community.
Fri April 08 @ 09:00 (09:00 AM) in De Anza
Addressing Hurdles in Clinical Translation of Targeted Proteomics Jeffrey Whiteaker Fred Hutchinson Cancer Research Center
Quantifying proteins and post-translational modifications will improve precision medicine, but several hurdles remain to adopting proteomics to the clinical laboratory. Dr. Whiteaker will discuss successes and remaining challenges for incorporating targeted proteomic measurements in clinical trials and other clinical applications.
Fri April 08 @ 10:00 (10:00 AM) in De Anza
Newborn Screening by Mass Spec Meets Newborn Screening by DNA Sequencing Michael Gelb University of Washington
Michael H. Gelb is Professor of Chemistry and Barbara L. Weinstein Endowed Chair in Chemistry, Adjunct Professor of Biochemistry at the University of Washington. Major developments in the Gelb lab include discovery of protein prenylation, development of ICAT proteomic reagents, identification of phospholipases involved in lipid mediator generation, development of anti-parasite drugs, and development of mass spectrometry for newborn screening. Awards include: Repligen Award in Chemistry of Biological Processes (Amer. Chem. Soc.), Univ.of Washington Faculty Lecture Award, Gustavus John Esselen Award (Harvard Univ.), AAAS Fellow, NIH Merit Award, Medicines for Malaria Project of the Year Award, Pfizer Award in Enzyme Chemistry, ICI Pharmaceuticals Award for Excellence in Chemistry. The Gelb lab has published more than 500 papers and 100 patents in biological chemistry. The Gelb laboratory has developed mass spectrometry for worldwide newborn screening of lysosomal storage diseases (the latest expansion of newborn screening panels).
Our laboratory has been developing tandem mass spectrometry (MS/MS) for worldwide expansion of newborn screening (NBS) panels to include an ever-increasing collection of treatable genetic diseases. There is widespread discussion on the use of whole genome and whole exome DNA sequencing in population-wide NBS. The intersection of biochemical- and DNA-based NBS is an interesting topic now under heavy discussion.
We will highlight the development of liquid chromatography-MS/MS (LC-MS/MS) for multiplex NBS of a large panel of treatable genetic diseases in newborns. Next generation sequencing (NGS) is also employed currently as a second-tier analysis after LC-MS/MS assays. We will also illustrate how it is possible to carry out first-tier NGS followed by second-tier LC-MS/MS NBS.
LC-MS/MS is used together with enzyme substrates and biomarkers to monitor the activity of a large collection of enzymes and to measure the abundance of biomarkers in dried blood spots on NBS cards. We will focus on multiplex methods and then zoom in one a more detailed analysis of one disease called metachromatic leukodystrophy (MLD). We carried out a pilot MLD NBS study and determined that the rate of false positives out of 28,000 newborns screened is essentially zero showing the power of LC-MS/MS for NBS of this lysosomal storage disorder. In the second arm of the study, we have been measuring the activity of the enzyme relevant to MLD on a large collection of gene variants that are found in allele databases and for which no pathogenic information is reported. We show how we can integrate these efforts to provide for a highly efficient NBS program for MLD.
We screened ~28,000 newborns for elevated sulfatide lipid, the biomarker that is relevant to MLD and found 180 high sulfatide newborns. These were submitted to an assay of the activity of the relevant enzyme, arylsulfatase A, and all but two showed normal levels of activity. DNA sequencing was carried out on 2 newborns, one with 0% and one with 8% of normal ARSA activity. The newborn with 0% activity was confirmed to have MLD, the other was shown to not have MLD. On the DNA front, we created a phenotype matrix that allows one to input the ARSA enzymatic activity of each variant to provide a composite genotype, and to make a prediction of the phenotype associated with this genotype. We show that this method is 83% accurate at predicting the true set of phenotypes observed in MLD patients.
Massively multiplexed NBS of genetic diseases in newborns is possible using LC-MS/MS, and when used with second-tier NGS leads to a successful NBS platform. We show that it is also possible to carry out NGS as a first-tier NBS step and to clarify the results with second-tier biochemical assays based on LC-MS/MS. Thus LC-MS/MS meets DNA and DNA meets LC-MS/MS, and this provides a framework for the future employment of both LC-MS/MS and NGS in expansion of population based NBS.
Fri April 08 @ 10:50 (10:50 AM) in De Anza
Utilization of Mass Spectrometry to Discover and Develop Novel Biomarkers to Support Drug Development Veronica Anania Genentech
Experienced researcher with Ph. D. in Molecular and Cell biology with over 10 years experience in immunology, protein biochemistry, and methods development. Strong neuroimmunology biomarker strategist and mass spectrometry group leader.
Biomarkers play an important role in the drug development process including providing necessary insights into target engagement, dose selection and mechanism of action of candidate therapeutics. LC-MS is uniquely positioned to enable accurate quantitation of both small and large molecule biomarker candidates, however, the process of going from biomarker discovery to a multiplexed targeted MRM panel in clinical samples is long and resource intensive. Moreover, biomarker candidates often fail to replicate when tested in large clinical cohorts. Recent advances in data-independent MS (DIA-MS) have made this technology more accessible and certain benefits of DIA-MS including reproducible label-free analysis of hundreds of samples, ability to capture low abundance ions over a high dynamic range, and deep proteome coverage makes this technology well suited to streamline translational proteomics. One major hurdle for using DIA-MS to support drug development is that the quantitative range for most DIA-MS methods has not been well characterized and thus, quantitative conclusions drawn by prior studies that have employed this approach have been controversial. Here, we describe challenges associated with applying DIA-MS methods to address questions associated with clinical development and introduce best practices for establishing quantitative criteria for DIA-MS approaches in clinical trial samples. Results and lessons learned from both discovery and targeted clinical biomarker studies will be discussed and a model for a more streamlined biomarker development workflow that conserves resources and provides more comprehensive proteomic information from clinical trial samples will be discussed.