James Lyons-Weiler, research scientist and author of “Cures vs. Profits“, “Environmental and Genetic Causes of Autism“, and  “Ebola:An Evolving Story”, was born on July 4, 1967.

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James grew up in Upstate New York as the youngest of three children.  On Valentine’s Day, 1973, his mom died of breast cancer.  Always a bright student, he sought refuge in school as a respite from stresses at home that sometimes come with a mixed family.  His favorite classes were biology, geometry, history, music, and creative writing.

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He attended State University of New York College at Oswego, intending on becoming a high school biology teacher.  After a course genetics, and another human evolution, he was hooked on research.  In that semester, he immediately applied his problem-solving skills to an early flaw he recognized in DNA-DNA hybridization, a method being used at the time to estimate evolutionary relationships among species of birds.  He called an expert on the matter and offered a mathematical correction to the problem of the assumption of base composition homogeneity.  That expert was Dr. Vincent Sarich, at UC Berkeley.  His advisor, Dr. Peter Rosenbaum, counseled him to be a generalist in science – to learn everything he could, from anyone he could.  He carries this advice with him to this day.

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A lifelong student, he developed a keen interest to the big questions in biology: how new species are formed, why is there so much species diversity in the tropics?  He studied Zoology and Paleoecology at Ohio State University, taking additional courses in Molecular Biology, Molecular Evolution, Plant Biology, Biogeography, and Paleontology, and Population Ecology, and Evolutionary Trends in Flowering Plants.  His research project brought him to the Cuyabeno Faunistic Reserve in lowland Amazonian Ecuador (South America), to study (with Dr. Paul Colinvaux) the effects of global climate change on the Amazonian rainforest ecosystem.  For those projects, he derived new computational methods for integrating species diversity patterns using ordination methods.  He proposed a dynamic environment hypothesis for species diversity in his Master’s Thesis (OSU Link, Google Books Link).

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He studied for a while at The University of Connecticut in Storrs, CT.  His favorite experience there was a research study with Dr. David Wagner.  He honed his computational skills and studied Evolutionary Theory, Multivariate statistics and Plant Systematics.  From there, he traveled to Reno, NV to work on the distribution of rare species in the Intermountain West.  On the side, he developed a new field of inquiry in the area of computational statistics for phylogenetics – the science of estimating species’ evolutionary relationships.  It was well known that different algorithms for phylogenetic analysis could give different results given the same data.  He devised a test of the data set for suitability for phylogenetic inference.  He worked under the tutellage and advisorship of Dr. Guy Hoelzer and Dr. Robin Tausch.  He published twelve papers as a result of his PhD research, and quickly became recognized as a thought leader in the area of complex analysis in biological systems.  His favorite courses were in Classical and Molecular Cytogenetics, Conservation Biology, Population Genetics, Experimental Design.  As another side project, he derived a mathematical explanation for the so-called humped-shape pattern of species diversity across a productivity cline, and made a special visit to Arizona to share his findings with Dr. Michael Rosenzweig.  He was invited shortly thereafter to serve as the Associate Editor of Applied Bioinformatics.

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During his graduate school years, James enjoyed teaching ecology, evolution, genetics, environmental biology, and population genetics.  He studied multivariate statistics, regression theory, and applied statistics.  His mind was always at work in wonder, looking at the world of nature at all scales, both as a biologist and as a graphical mathematician.  Often relating questions in biology, an observational and experimental field, to quantitative system, he could see solutions to complex problems first, only to have work backwards to study their correctness.  He excelled in the areas of permutation and resampling-based methods of hypothesis testing of big questions in science, developing new methods in this area, and new applications in molecular genetics.  His terminal degree is in Ecology, Evolution, and Conservation Biology.

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His energy, drive and quantitative skills brought a fellowship from the Alfred P. Sloan Foundation, which he took to Penn State University.  While studying Molecular Evolutionary Genetics under Dr. Masatoshi Nei and Dr. Webb Miller at Penn State University during his postdoctoral years, James became a father.  He continued to study statistical properties of methods for studying molecular evolution, and also developed a new method for detecting purifying selection in evolving protein sequences.  He continued to study biological systems (proteins, biological pathways).  One day, Dr. Mark Boguski came to visit.  He presented data on cancer research using partial genome microarrays.  In these platforms, one can interrogate >40,000 genes in cancer, and, compared to tumors, determine which genes are turned on, and off, in cancer tissue relative to normal.  Because James had his own funding, he requested permission from Dr. Nei to move into the area of computational statistics for microarray data analysis.  James had recognized that, as in phylogenetics, people might derive arbitrary conclusions from these new, important ways of studying cancer.

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James then found a position at UMASS Lowell, where he founded one of the world’s first Centers for Bioinformatics.  He helped develop that institutions’ undergraduate and graduate studies curriculum in Bioinformatics.  He routinely had 20 or more students performing analyses for research projects, asking questions about the impact of algorithm selection on the biological inferences being made in many types of diseases.  He produced online software that implemented numerous methods of microarray data analysis – and that provided objective performance evaluation measures to aid in the selection of the optimal methods.  He studied gene expression in cancer, publishing a paper on overcoming experimental design flaws such as confounded controls.  He taught courses in biology, genetics, and bioinformatics, and set up a sequencing lab for the Department of Biological Sciences.

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He was then invited to relocate to Pittsburgh, PA to work in the then-new Hillman Cancer Center and the University of Pittsburgh Cancer Institute, where Dr. Ronald Herberman was Director.  James worked with oncologists, surgeons, and other cancer researchers applied his methods of analysis to prostate cancer, ovarian cancer, renal cell carcinoma, astrocytoma, melanoma, and lung cancer.  There he met Dr. Sam Weiand, who took him under his wing and advised him on the use of matching methods for accrual of patients to randomized clinical trials.  He was selected to serve on numerous large grants, and managed a multi-institutional consortium focused on the optimization of laboratory and computational methods in proteomics.  He participated in the NCI’s Early Detection Research Network (EDRN) and their caBIG (Cancer Biomedical Informatics Grid) initiatives.  He served as the founding Editor-in-Chief of his brainchild journal, the open access, rigorously peer-reviewed journal, Cancer Informatics.  He published numerous papers on new ways of looking at cancer that have helped set the stage for research in individualized medicine. He taught two full courses a year, one on research design, and the other on the analysis of high dimensional genomic and proteomic data.

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His favorite moment from these years was when five-time melanoma survivor Dr. Andy von Eschenbach, then Director of the National Cancer Institute, and future Commissioner of the Food and Drug Administration, gave him a hug at one of NCI’s meeting for creating the journal Cancer Informatics.

Throughout this time period, and to the present day,  he is a popular favorite speaker at many public speaking engagements.  Because he has a keen eye for important open questions in science, his presentations often draw crowds, and some make news.  As an advocate for the public trust in science, he has always kept a keen eye on translational potential in biomedical research.

 

Here Dr. Lyons-Weiler is seen at a national meeting in Philadelphia, PA, leading a discussion on whether existing information scores such as Phred and Phrap contain sufficient information to be used to assess confidence in Next Generation Sequencing applications. 

 

Given the immense potential for knowledge from biomedical research to reduce human pain and suffering, he does not tolerate unethical or lazy practices in research, and believes that senior faculty members should see junior faculty not as competitors, but as their progeny: their legacy.  His popularity with students and researchers from all walks of biomedicine and biology allowed him to branch out from cancer to offer bioinformatics data analysis services to investigators across the campus.  Working closely with senior administrators Dr. Arthur S. Levine and Dr. Michelle Broido at the University of Pittsburgh, he founded the Bioinformatics Analysis Core as a three-year pilot project. His enthusiasm for translational research and his love of helping others helped the core project last for seven years, and he and his staff members provided data analysis and study design consultations to over 100 research projects.

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His methodological research had continued over this time period, and he created improved methods for survivorship analysis, for identifying differentially expressed genes, for selected optimal methods for the normalization of high dimensional data, and for estimating the risk of false discovery.  He devised a novel statistical framework for modeling the incorporation of new biomarkers into existing clinical diagnostic workflows (Clinical Decision Modeling System, or CDMS software available from The University of Pittsburgh).

 

Dr. Lyons-Weiler breaks the news of the severity of the inherent bias in Fold-Change (Ratio) compared to Delta (Difference) to an audience in Boston, MA (2014).  He also introduced an application of the use of Boltzmann entropy to measure genotypic signal in Next Generation Sequence variant data to avoid spurious genotype calls.

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One of the methods devised was a test for differentially expressed genes called the J5 test, which he then improved with the world’s first nonlinear thresholding method called G-thresholding.  He and his staff studied so many data sets that they noticed a serious bias in the commonly used fold-change measure (ratio).  Time and again his staff demonstrated that the J5 test, which he named after his mother, Joan, was less biased and more informative than fold-change.  J5 is a simple function of delta, a difference score, and is more reproducible in repeated studies than fold-change.  In 2013, he demonstrated that the widespread use of fold-change was an absolute bias that led to hundreds if not thousands of researchers throwing away significant portions of their high- and low-dimensional data.  He considers this unintentional practice more harmful to biomedical science than any fraud perpetuated to date, or any funding cut.  In the final year at the University (2014), he devised measures of genotypic signal, to identify sites in next generation sequencing data where different genotype calling algorithms are likely to disagree, and to provide measures of uncertainty for individual base calls.

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When the core closed in 2014 due to state budget cuts, the Ebola outbreak in Guinea had become an epidemic, spreading to Liberia, Sierra Leone.  James decided to use his expertise to help society better understand the outbreak, so he began reading research papers, and interviewing experts to sort out the confusing mess of public policy.  During a drive through the hills of Western PA, it dawned on him that a powerful way to help shut down transmission was pre-symptomatic diagnosis.  He created the Ebola Rapid Assay Development Consortium, enlisting the help of colleagues from Penn State University (Dr. Costas Maranas), University of Illinois Urbana-Champaign (Prof. Klaus Schulten), The Scripps Research Institute (Dr. Erica Ollman-Sapphire), and University of California Santa Barbara (Dr. Kevin Plaxco).  The group focused on the computational development of anti-body like binding proteins able to bind to Ebola Gp1Gp2 protein complex on the viral coat.  The synthetic antibodies were also optimized to undergo a large conformational state change upon binding to facilitate use in a rapid colorimetric assay.

As the situation in Africa worsened, James felt that his cumulative research experience and knowledge could benefit those in the front lines, and the general public, if they had a better understood the virus, especially its modes of transmission.  He spoke with experts in epidemiology, public health, policy makers, evolutionary psychologists, emergency responders, truck drivers and every day people, and researchers at the very cutting edge of drug development targeting Ebola.  He wrote his first book “Ebola: An Evolving Story” (World Scientific) to not only inform people of the details of the outbreak and how it became an epidemic, but also to sort out how policy should be based on logic, science, and evidence, and not on fear, superstition, belief, or dogma.  His research on Ebola allowed him to discover and catalog a number of important new research directions and open questions surrounding Ebola.

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In the process of his career, James got more than he bargained for.  Always looking to improve ways of doing science, he discovered numerous fundamental flaws in the methods for analyzing data.  He always strived to provide improved solutions to these problems.   Over the years, given his extensive knowledge of cutting-edge research in cancer and cancer treatments, James helped his sister, his uncle, his future father-in-law, and several close friends find optimal routes to treatment of their cancer.  Close friends and family would, on a regular basis, challenge him with statements like “They already have a cure for cancer.  They don’t want cures, they want treatments!”  While conducting research for “Ebola: An Evolving Story”, it became apparent to him that important and significant improvements could be made to FDA’s approach to gold standard randomized clinical trials.   To help sort out these perspectives, using the cumulative benefit of all of these experiences, he is now writing a second book “Cures vs. Profits: Success Stories in Translational Research”, published in May, 2016.

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Today, James on a national tour with his latest book, “The Environmental and Genetic Causes of Autism“, directing analysis of studies of many types at the Institute for Pure and Applied Knowledge where scientists work to reduce human pain and suffering through knowledge without profit motive.