The Shaw Prize in Life Science and Medicine 2019 is awarded to Maria Jasin, Member at the Memorial Sloan Kettering Cancer Centre (MSK) and Professor at the Weill Cornell Graduate School of Medical Sciences, Cornell University, USA, for her work showing that localized double strand breaks in DNA stimulate recombination in mammalian cells. This seminal work was essential for and led directly to the tools enabling editing at specific sites in mammalian genomes.
We stand at a moment of great promise in the ability to modify the genomes of virtually all organisms on Earth using the precision tools of gene editing. In the near future, it will be possible to treat human and animal genetic diseases and to improve agricultural productivity by the introduction of specific changes at precise locations within chromosomes. The preferred tool of this revolution is called CRISPR/Cas9, and its development has been attributed to many investigators around the world. But, the origin of this technological advance relies upon a crucial discovery that was made by Maria Jasin in 1994 when she showed that the site-specific introduction of a double-stand break in a mammalian chromosome may be repaired by two different normal cellular process of recombination and chromosome end-joining.
Human chromosomes often undergo breakage due to agents that damage the DNA. It is critical to repair such breaks, to maintain genome integrity and to prevent mutations that can give rise to cancer. All cells have the capacity to repair such breaks by a process called homologous recombination, which restores the continuity of the genome without introducing mutations. Another recombination process, called non-homologous end-joining, often introduces mutations and thus is only used by a cell when homologous recombination is not possible. Maria Jasin pioneered genetic and physical assays for recombination in human cells and she was the first scientist to directly demonstrate the importance of both homologous recombination and non-homologous end-joining for repair of chromosomal breaks. Her discovery has important implications for both normal cellular function and for the etiology of diseases such as cancer. In the course of this work, Jasin demonstrated that breaks in chromosomes greatly increase the frequency of recombination at the site of the break. This important discovery laid the groundwork for efficient modification of mammalian genomes by site-specific nucleases, an approach that is currently being widely exploited for gene therapy and basic research.
In Jasin’s groundbreaking 1994 work, her laboratory devised an ingenious method to create a double strand break in the mouse genome. To do this, she used a specialized nuclease enzyme from yeast that had a well characterized unique 18 nucleotide long DNA recognition sequence. The gene encoding the yeast enzyme was introduced into the mouse genome and the companion recognition sequence, which is not normally present in any mouse chromosome, was genetically engineered into another mouse gene that could be scored for its function or loss of function in the animal. When the recognition sequence is cut by the yeast enzyme, the mouse gene loses its function unless the damage is patched up by the normal cellular process of repair.
Using this strategy, Jasin performed the first specific genome editing and most importantly, she showed that introduction of a site-specific double strand break into the genome of mammalian cells produced a 1000-fold increase in the targeting of a homologous fragment of DNA to that site. This groundbreaking work laid the foundation for all subsequent gene editing studies, because now it was clear that a double strand break is the critical step in gene targeting for homologous recombination.
Jasin’s discovery forms the basis for subsequent work on more highly specific nucleases — Zinc fingers, TALENs, and CRISPR — that are currently being used for genome modification. All of these methods describe new and increasingly refined ways to introduce enzymes and double strand breaks into DNA. Nonetheless, they all rely fundamentally on Jasin’s discovery of the stimulation of homologous recombination by a double strand DNA break and the strategy to introduce a DNA cleaving enzyme to make the precise break. In her visionary 1994 paper, Jasin modestly concluded: “This could facilitate the creation of subtle genetic alterations at targeted loci”.
Using the methods developed in her lab and now applied worldwide, Jasin also discovered that the two major familial breast/ovarian tumor suppressor genes, BRCA1 and BRCA2, are required for homologous recombination, a finding that explained how the loss of either of these two genes increases the frequency of potentially carcinogenic genetic alterations (note the 2018 Shaw Prize in Life Science and Medicine to Mary-Claire King for the discovery of the BRCA1 and 2 genes in breast cancer). The importance of these results cannot be overstated, and they are being exploited in novel therapies for the treatment of breast, ovarian, and other cancers with BRCA1 and BRCA2 mutations, and potentially cancers with mutations in other homologous recombination genes.
Maria Jasin’s research has contributed to the textbook view of how cells survive breaks in their chromosomes, which is critical for the life of all cells. Equally important, her insights paved the way for today’s current revolution in genome editing.
Life Science and Medicine Selection Committee
The Shaw Prize
21 May 2019 Hong Kong (Revised)