Developments in whole genome sequencing technologies have catalysed incredible progress in the diagnosis of rare disease and the discovery of novel disease-associated genes. However, large-scale sequencing of population cohorts has revealed that many healthy individuals carry the same disease-causing variants as patients. The extent of this incomplete penetrance in individuals not ascertained on the basis of a family history or clinical diagnosis is neither well understood nor widely appreciated. In this talk, Professor Caroline Wright, Professor of Genomic Medicine at the Department of Clinical and Biomedical Sciences at the University of Exeter, outlines recent research into penetrance of different diseases across different populations, and discusses the broader implications of these findings for genomic screening. This is the 2024 Dr Stanley Ho Memorial Lecture, in collaboration with the Oxford Martin School, and it took place on 29 May 2024.

Can we do better than small blue pills with overly broad effects in the brain? Just as people and populations are diverse – motivating ideas of personalised medicine, nerve cells – or neurons – of the brain are immensely diverse in their types and “individual” circuits that become diseased or damaged in humans. This lecture considers newly accessible molecular routes to more specific future therapies. The long-term goals of the research to be discussed in this Stanley Ho Memorial Lecture are to understand, at a “subcellular” molecular level, controls over the initial growth – the “development” – and diversity of cerebral cortex function-specific circuitry, and diversity of mature function. The work aims to identify causes, mechanisms, and thus potential “circuit-customised” therapeutic approaches to developmental, neuropsychiatric and degenerative disease, and to elucidate and potentially overcome blocks to brain and spinal cord regeneration in disorders like spinal cord injury. The specificity, modification, and function of quite diverse brain circuitry underlies how the brain-nervous system senses, integrates, moves the body, thinks, functions with precision, malfunctions with specificity in disease, degenerates with circuit specificity, might be regenerated, and/or might be better modeled in the laboratory. However, many relevant aspects of this neuronal circuit diversity and distinctness have been inaccessible in multiple core aspects until quite recently. Understanding what actually implements and maintains circuit specificity is a key issue regarding childhood developmental nervous system abnormalities and disease, proper function vs. dysfunction in neuropsychiatric disorders, selective neuron type vulnerability of degeneration (e.g. in motor neuron disease (MND-ALS), Huntington’s, Parkinson’s diseases), regeneration (or typical lack thereof) for spinal cord injury, and investigations of disease using human pluripotent stem cell (hiPS)-derived neurons. Professor Jeffrey D. Macklis’ talk will consider possibilities of taking the idea of “personalised medicine”- tailored to an individual based on individual information – in a complementary direction– tailoring therapies to specific diseased or damaged brain circuitry. This is the Dr Stanley Ho Memorial Lecture organised by the Oxford Martin School, Oxford Martin Programme on 3D Printing for Brain Repair and the Centre for Personalised Medicine.

This lecture was given on 3 February 2022 as the second Dr Stanley Ho Memorial Lecture. Heidi Rehm, a human geneticist and genomic medicine researcher, is co-director of the Program in Medical and Population Genetics and an institute member at the Broad Institute. She is the chief genomics officer in the Department of Medicine at Massachusetts General Hospital (MGH), working to integrate genomics into medical practice with standardized approaches. She is also a professor of pathology at Harvard Medical School and faculty member of the Center for Genomic Medicine at MGH. As a board-certified laboratory geneticist and medical director of the Clinical Research Sequencing Platform, she is guiding genomic testing for clinical and clinical research use. She is a leader in defining standards for the interpretation of sequence variants and a principal investigator of a major NIH-funded effort called ClinGen (Clinical Genome Resource), providing free and publicly accessible resources to support the interpretation of genes and variants. Professor Rehm also co-leads the Broad Center for Mendelian Genomics with Anne O’Donnell-Luria focused on discovering novel rare disease genes and co-leads the Matchmaker Exchange to aid in gene discovery. She is a strong advocate and pioneer of open science and data sharing, working to extend these approaches through her role as a vice chair of the Global Alliance for Genomics and Health. Rehm is also a principal investigator of the Broad-LMM-Color All of Us Genome Center, supporting the sequencing and return of results to a cohort of one million individuals in the U.S. and co-leading gnomAD, the Genome Aggregation Database. She is a board member of the American College of Medical Genetics and Genomics and the National Library of Medicine. She serves as an editor of the Cold Spring Harbor Molecular Case Studies journal and as an associate editor of the American Journal of Human Genetics. Among Rehm’s honors are the BWH Physician Recognition Award for Clinical Innovation and the Boston Business Journal’s 40 Under 40 Award for Civic Leadership. She was also a member of the team that won the 2012 CLARITY Challenge run by Boston Children’s Hospital and the 2013 Bio-IT World Editors’ Prize for the GeneInsight software system. Professor Rehm received her B.A. degree in molecular biology and biochemistry from Middlebury College before earning her M.S. in biomedical science from Harvard Medical School and Ph.D. in genetics from Harvard University. She completed her post-doctoral training with David Corey in neurobiology and a fellowship in clinical molecular genetics at Harvard Medical School.

Professor Jennifer Doudna is an American biochemist. She is Li Ka Shing Chancellor Chair Professor in the Department of Chemistry and the Department of Molecular and Cell Biology at the University of California, Berkeley. Doudna has been an investigator with the Howard Hughes Medical Institute since 1997, and since 2018 she has held the position of senior investigator at the Gladstone Institutes, as well as that of professor at the University of California, San Francisco. Professor Doudna has been a leading figure in what is referred to as the”CRISPR revolution” for her fundamental work and leadership in developing CRISPR-mediated genome editing. In 2012, Professor Doudna and Emmanuelle Charpentier were the first to propose that CRISPR-Cas9 could be used for programmable editing of genomes, which is now considered one of the most significant discoveries in the history of biology. They were awarded the 2020 Nobel Prize in Chemistry for their pioneering work. This is the CPM Dr Stanley Ho Memorial Lecture.