Our laboratory uses tools from pharmacology, genomics, and cell signaling to identify new precision anticancer therapeutic strategies. Under this broad heading, our work involves three key areas of emphasis. First, we use custom functional and structural genomic tools to define the landscape of signaling pathways capable of driving resistance to therapy (for example, Science Signaling 2012, 5, rs4; Science Signaling 2014, 7, ra121; and Cell Reports 2017, 20, 999). Second, we utilize knowledge of resistance landscapes to identify new therapeutic strategies that have the potential to circumvent resistance evolution (for example, Science Signaling 2014, 7, ra122; Nature Communications 2017, 8, 15617; Cell Reports 2017, 21, 2796; Nature Communications 2018, 9, 4274; Science Advances 2019, 5, eaaw9162; and Nature Genetics 2020, 52, 408). Finally, we use unbiased approaches to define mechanism-based, targetable vulnerabilities in human cancers for application to malignancies characterized by “undruggable” genetic drivers or immunologically “cold” microenvironments, where in many cases these vulnerabilities center on the dysregulated structure and function of tumor mitochondria (for example, Science Translational Medicine 2016, 8, ra175; Nature Communications 2018, 9, 1677; Nature Communications 2018, 9, 3513; and Cell Metabolism 2019, 29, 1217). Collectively, these studies are leading to both fundamental new insights into the core survival circuitry operating in defined human tumor subsets as well as novel translational therapeutics. In this talk, I will provide an overview of our work, with a particular focus on studies that have identified mechanisms of convergent tumor evolution and associated strategies to leverage this phenomenon to build combination therapies that select against resistance.

Learning Objectives:
1. Understand strategies for designing mechanism-based combination therapies to overcome resistance

2. Learn examples of convergent resistance evolution

3. Use functional genomics and pharmacological screening to identify therapeutic targets

Recent technological advances as well as longitudinal monitoring not only have the potential to improve the treatment of disease (Precision Medicine) but also empower people to stay healthy (Precision Health). We have profiled 109 participants using multiomics technologies (genomics, immunomics, transcriptomics, proteomics, metabolomics, microbiomics and wearables etc) for up to 9.5 years and made 49 major health discoveries. We have also profiled people after an acute bout of exercise and found that thousands of blood molecules change after a short bout of exercise. Lastly, we demonstrate that individuals have distinct aging patterns that can be measured in a period of time that is actionable. We conclude that deep longitudinal profiling can lead to actionable health discoveries and provide relevant information for precision health.

Learning Objectives:

1. What is wrong with healthcare today

2. What kinds of omics and wearables data can be used to best predict disease risk and manage health

The development of automated DNA sequencers using fluorescent di-deoxy nucleotide sequencing and capillary electrophoresis made it possible to generate the first draft sequences of the human genome about 20 years ago. This information revolutionized our understanding of the organization of the human genome, but the cost for doing this was several hundred million dollars. The solution to dramatically decreasing the cost of sequencing was the development of technologies that all depended upon the simultaneous sequencing of a very large number of DNA molecules which was termed massively parallel sequencing (MPS). There are two generations of these technologies. The first generation depended upon amplifying individual DNA fragments and then determining the sequence of those amplified fragments. The amplification process and the subsequent sequencing of those fragments could only be performed on very short fragments and thus all first generation MPS are short-read technologies. There are two strengths to these approaches and that is sequence accuracy and ultimately tremendous sequence output. In my talk I will focus on the various first generation MPS technologies that were developed and their strengths and weaknesses. I will also describe how with the use of these technologies it became possible to increase sequence output (and correspondingly decrease sequence costs) from hundreds of millions of dollars two what is now approaching $100 per genome. I will also describe how this will change just about everything in our society. Other speakers in this session will then describe some of the second generation MPS technologies which can obtain very long DNA sequences and are thus long read sequencing technologies. We will also hear about some of the clinical applications of both first and second generation MPS technologies as well.

Learning Objectives:

1. To understand about the different short read MPS technologies and their strengths and weaknesses

2. To understand how being able to characterize the complete genome sequence for an individual for $100, or less, will completely transform just about everything

Resolving the genetics of underlying Mendelian diseases as well as host immune responses to infectious diseases is an important prerequisite for understanding their biology and for ultimate treatment options. A number of affected genomic loci are difficult to fully characterize due to underlying sequence complexities. The introduction of long and accurate, single-molecule (HiFi) sequence reads by PacBio has allowed for an improved resolution of many of these genomic regions, resulting in highly accurate, full-length gene sequencing with allelic phasing. The associated workflows are efficient and allow for cost effective scaling to large sample volumes. I will highlight several examples of recent advances in clinical research applications, with a particular emphasis on COVID-19 host response relevant targets, including HLA typing, pharmacogenetics, B Cell repertoire sequencing and resolution of the IGH locus.

Learning Objectives:

1. Become familiar with HiFi sequence reads which are both long and accurate at the individual sequence read level

2. Learn about the benefits of full-length, phased gene sequencing with efficient and cost effective workflows allowing for large numbers of samples

3. Learn about improved resolution of previously difficult to resolve clinical research genomic targets, with a particular emphasis on COVID-19 research related loci

The introduction of improved, more cost efficient target capture technologies has accelerated the adoption of Whole Exome Sequencing (WES) in clinical diagnostics. The ability to provide more complete answers to patients with rare diseases in turn has increased the interest of physicians in genetic testing. Clinical genetic testing today is generating more real world evidence than any large scale research sequencing project has or will ever have. However, this valuable real world evidence remains underutilized due to the lack of proper technology and due to legal obstacles. In practice WES generates large amounts of information that need to be processed and interpreted. If used in routine diagnostics, the data processing and the interpretation must be standardized, clinically validated and ultimately automated to a high degree. The hands-on time of creating a diagnosis must be a matter of minutes and not of days or weeks. Taking together the genotype and phenotype information from a large number of patients can improve the success rate in diagnostic testing significantly. Healthcare institutions address these challenges to a variable degree by creating and maintaining proprietary in-house software or by using a patchwork of third-party solutions. A single, streamlined solution for these challenges is varvis, a diagnostic software that covers the entire workflow from raw data to interpretation and reporting. Using varvis, diagnostic laboratories across Europe, Canada and the USA are aggregating and sharing real-world evidence and improving patient care in compliance with data privacy regulations. The aggregated database now contains information about 19,000,000 unique variants from 35,000 cases. I will present case examples how patients benefit from this knowledgebase and how it enables clinical labs to quickly scale up WES diagnostics.

Learning Objectives:

1. How Whole Exome Sequencing has matured to become a first-line diagnostic method in clinical genetics and what its benefit is for the patient

2. Which tools and processes are necessary to successfully deploy this powerful method in routine diagnostics at scale

3. How every data point from every single patient can be leveraged to continuously improve the quality and success of the diagnostic process.

Estrogen metabolism is the ability to favorably excrete potentially toxic estrogens through urine and sweat. Impaired estrogen metabolism is associated with Endometriosis and Polycystic Ovarian Syndrome as well as Breast and other cancers. For women with suboptimal function, excess estrogen exposures such as estrogen-based medications and environmental phytoestrogens may result in greater risk of sporadic breast cancer. Improving a woman’s ability to excrete estrogens along optimal pathways may lessen these risks.

The objective is to improve estrogen health through individualized nutritional supplementation.

Tests available in commercial labs examine modifiable genes with the goal of providing individualized nutritional interventions to improve estrogen health. Genes frequently tested are: CYP1A1, CYP1B1, CYP3A4, GSTM1, & COMT. Each gene may have 2 mutations or a deletion.

Information about a patient’s genetic mutations provides a critical understanding of each woman’s lifelong disposition to excrete estrogens. This guidance allows physicians more precision in prescribing estrogen medications such as birth control pills, hormone replacement and fertility treatments. Test results also advise physicians which supplements may improve estrogen health and which patients require stricter oversight.

TOWARD PERSONALIZED TREATMENT PROTOCOLS

Personalized treatment requires:

1. Estrogen Metabolism Genetic Testing to provide data on lifelong capability to excrete estrogens

2. Physician Intake of Estrogen Metabolism related disease, Exogenous Estrogen Exposure and Extended Family History of Estrogen Metabolism related conditions

3. Nutritional Supplementation to Improve Estrogen Health

4. Metabolite Testing for Supplement Dosing Adjustment

Learning Objectives:

1. Overview of Estrogen Metabolism & Sporadic Breast Cancer Risk Factors

2. Discussion of how Estrogen Metabolism Genetic mutations or health can guide precision interventions and prescribing estrogenic medications

3. Review of case studies

Realizing the promise of Precision Medicine requires both a deep understanding of the landscape of genomic evidence and an understanding of the molecular drivers that influence all aspects of the drug development pipeline. Advances in genomic sequencing technology provide incredible opportunities for the use of genetics to drive drug discovery, but the lack of organized empirical data and the challenge of manually interpreting and annotating genomic evidence has limited its enormous potential. Using real-world examples, Dr. Kiel will demonstrate how Genomenon has overcome these obstacles and is being used by pharmaceutical companies to provide invaluable insight into the genomic drivers of disease. Drawing from its exhaustive database of empirical evidence and a unique combination of AI and expert curation, Genomenon’s Mastermind® produces comprehensive genomic landscapes to validate candidate targets, inform downstream research and discovery, and segregate patients for enrollment in clinical trials. Dr. Kiel will also discuss how Genomenon is pursuing its vision of curating the entire human genome to advance the drug discovery process and maximize the efficiency of clinical diagnosis.

Learning Objectives:

1. Why a deep understanding of genomic evidence is critical at each stage of the drug development process

2. How genomic evidence can be used in each stage using real-world examples

3. How Mastermind Curated Genomic Datasets are being used to increase the success rate of drug candidates, broaden patient populations, and identify new disease indications

Complex genomes, including the human genome, contain ‘dark’ regions that standard short-read sequencing technologies do not adequately resolve—overlooking many variants that may be relevant to disease. We systematically characterized these regions in genomes with high short-read coverage, identifying more than 6000 gene bodies that are at least partially dark, and more than 100 protein-coding genes are 100% ‘camouflaged’. Many known disease-relevant genes are also camouflaged, including CR1, a top Alzheimer’s disease gene. Other disease-relevant genes include NEB, SMN1 and SMN2, and ARX. Long-read technologies resolve major portions of these regions. We specifically compared 10x Genomics, PacBio’s Sequel, and Oxford Nanopore Technologies’ PromethION, demonstrating potential long-term benefits of using long-read technologies. We are also utilizing optical DNA mapping from the Bionano Genomics’ Saphyr System to construct full individual haplotypes across challenging genomic regions that are strongly implicated in disease, including the C9orf72 ‘GGGGCC’ repeat expansion, CR1, and major histocompatibility locus, which harbors the human leukocyte antigen (HLA) genes.

Learning Objectives:

1. Identify types of genetic variants that are overlooked with standard short-read sequencing approaches, including ‘dark’ and ‘camouflaged’ genes

2. Identify specific genes that are ‘dark’ or ‘camouflaged’, including 76 disease-associated genes

3. Demonstrate how long-range technologies resolve these regions

In recent years Nanotherapeutics has revolutionized the healthcare strategies and envisioned to have a tremendous impact to offer better health facilities. It involves design, fabrication, regulation, and application of therapeutic drugs and devices having a size in nano-range (1–100 nm). Owing to the revolutionary implications in drug delivery and gene therapy, lipid nanoparticles has gained increasing research interest in the current medical sector of the modern world. Current clinical efforts are focused on vaccination, protein replacement therapies, and treatment of genetic diseases. Since the first pre-clinical studies in the 1990s, significant progress in the clinical translation of mRNA therapeutics has been made through advances in the design of mRNA manufacturing and intracellular delivery methods. The growth of such powerful biologic therapeutics has gone hand in hand with the progress in delivery systems technology, which is absolutely required to improve their safety and effectiveness.

One of the most developed methods for RNA delivery is co-formulation into lipid nanoparticles (LNP). LNP as drug delivery vehicles is becoming more attractive because it can pack drug product more efficiently, enhance its bioavailability, and target specific cells. In this presentation, we discuss the revolution of lipid nanoparticles into precision medicine and recent advances in biomaterials and drug delivery strategies, challenges for clinical translations of RNA based therapeutics with an overview of the future clinical applications in protein therapy, gene editing, and vaccination.

Learning Objectives:

1. What current Nanomedicine are being developed for drug delivery

2. Why use lipid nanoparticles for RNA delivery

3. Recent advances and clinical applications

With the completion of the human genome nearly two decades ago, consumers, patients, and physicians are wondering when genetic testing will go PRIME TIME.  While the diagnostic utility of genetic testing continues to steadily increase, the idea of population health driven genetic testing is just getting started.  This talk will explore how genetic testing can be used to better manage the healthcare of large populations, the challenges and concerns with launching such a program, and how it is different than diagnostic genetic testing.

Learning Objectives:

1. Define how genetic testing fits into population health management strategies

2. Understand how genetic testing for screening purposes is different than that used for diagnostic purposes

3. Describe the value of population health genetic screening to society

As genomics plays an ever expanding role in healthcare and research, educational programs focused on applied genomics have not kept pace with the demand for trained students.  In this talk, we will discuss some of the challenges and opportunities in training the next generation of genomics scientists, particularly in the field of clinical genomics.  Special attention will be paid to the knowledge domains and skills in highest demand in academic, industry, and healthcare settings.  We will also discuss delivery platforms and program modalities, especially considering the disruption to higher education institutions due to the COVID-19 social distancing efforts.

Learning Objectives:

1. To identify the primary skills and knowledge domains in applied genomics training programs

2. To recognize challenges in applied genomics education in the current environment

3. To appreciate opportunities to expand the genomics expertise pipeline

In this presentation Dr. Kevin Halling describes the use of RNA-seq testing for identifying clinically significant gene fusions in tumors that can be used to help establish diagnosis and guide therapy.  The methodology used to perform the testing and the bioinformatic analyses that are used to interpret the data are explained.  A case study is used to illustrate the identification of a gene fusion in a sarcoma.

Learning Objectives:

1. Describe the clinical utility of gene fusion detection in tumors

2. Explain how clinically significant gene fusions are distinguished from clinically insignificant gene fusions that are identified by RNA-seq

Achieving a diagnosis in rare disease patients can be challenging for even the most experienced clinician or scientist, creating a barrier to delivering truly personalised care. An exome sequencing approach in these patients provides a balance between cost and benefit, allowing for all disease-causing genes to be analysed simultaneously and therefore reducing the need for sequential testing whilst optimizing diagnostic yield. In this talk state-registered Clinical Scientist Louisa Ive will present real-world cases that exemplify how exome sequencing is being used to end the diagnostic odyssey for rare disease patients and their families.

Learning Objectives:

1. Why is exome sequencing of particular clinical utility for patients with neurodevelopmental disorders?

2. What was the diagnostic yield following exome sequencing in this cohort (prenatal and postnatal)?

3. Discuss the clinical utility of achieving a diagnosis for one of the patients presented