The New England Journal of Medicine January 7, 2021 pp1-4 “A Half-Century of Progress in Health: The National Academy of Medicine at 50”. “Human Molecular Genetics and Genomics-Important Advances and Exciting Possibilities” By Francis S. Collins, M.D., Ph.D., Jennifer A Doudna, Ph.D., Eric S. Lander, Ph.D., and Charles N. Rotimi, Ph.D.
Image from science.institut-curie.org
See the full article and audio at NEJM.org for all details (Free)
Summary of Article
See the table below “Highlights in Human Molecular Genetics and Genomes.”
In summary solid basic and medical science has set the foundation to increasingly use molecular methods to diagnose and treat disease.
· “genes responsible for more than 5000 rare mendelian diseases “ have been identified facilitating “genetic diagnostics for many patients, pregnancy-related counseling, new drug treatments and in some cases, gene therapies.”
· 100,000 robust [gene] associations between genomic regions and common diseases has pointed to new biologic mechanisms, such as the role of microglia in Alzheimer’s disease, autophagy in inflammatory bowel disease, and synaptic pruning in schizophrenia.”
· Advances have “enabled the development of polygenic risk scores to identify patients at increased risk for heart disease, breast cancer, and other conditions…”
· “Studies of cancer genomes have revealed hundreds of genes in which somatic mutations propel tumor initiation and growth.” This information is aiding the development of new targeted therapies.
· Genomic studies are also helping to understand “why some people have responses to certain therapies or survive certain infections” while other don’t.
· Studies now are increasingly focusing on “patterns of gene expression in individual cells”. “Tens of millions of cells have been characterized thus far in route to a complete cells atlas of the human body.” These data are illuminating new cell types and how cells “differ between healthy people and people with various diseases.”
· Over time the cost of “sequencing a complete genome” have decreased from $3B during the human genomic project (1990-2003) to only $600 now. Biobanks are being developed consisting of “complete genome-sequencing and phenotype information from hundreds of thousands of people.” See U.K. Biobank (https://www.ukbiobank.ac.uk/) and in the U.S. “All of Us” (https://allofus.nih.gov/). It is correctly noted that these banks so far suffer from being predominately from European Ancestry and efforts are being focused rightfully on diversifying the banks because it’s well known that disease prevalence etc. can vary depending on ancestry. Examples are APOL1 gene “variants that protect against African sleeping sickness but increase the risk of kidney failure,…”for type 2 diabetes in SLC16A11 that is present in about half of Indigenous peoples of the Americans and rare in people of European or African ancestry explains about 20% of the increase type 2 diabetes prevalence among Mexican Americans as compared with European Americans” and others. See “The Human Heredity and Health in Africa (H3Africa) initiative (https://h3africa.org/) as an example of a genome database focused on African ancestry.
· Sequencing technology has now greatly enabled the diagnosis of certain diseases “but developing and validating treatments have been more challenging.” Examples of treatments include “CFTR gene, for example, safe and effective molecularly targeted drugs can be offered to 90% of people with cystic fibrosis” but this approach based on identifying disease genes on a gene-by-gene basis is too slow and won't scale. New technologies are enabling a more exciting approach. Some treatments based on studies focused directly “at the gene” level have now yielded some successes for “spinal muscular atrophy and hemophilia.” “Over the past 8 years, CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) technologies have emerged as accessible and adaptable tools for studying and altering genomes.” The technology can be “used to induce genome edits”…”as these technologies continue to mature, it will become increasingly possible to alter genomes efficiently and accurately.” “Although Cas9-engineered cells haven’t yet demonstrated efficacy at scale, early trial results suggest that such cells are stable and don’t cause acute adverse reactions in humans.”
· Disease maps are being constructed see the “International Common Disease Alliance’s Maps to Mechanisms to Medicine vision (https://www.icda.bio/)
· Going forward further advances must ensure equitable and inclusive access, “balance scientific progress with emerging ethical issues” and “sustain data-sharing ethos.”