Bike Brakes, Cancer and Mutated Genes: The Analogies Become More Complex With More Focus on Interact
Deeply understanding interactions between genes is one of the next frontiers for molecular researchers. As a result of 15 years of work, researchers have now accomplished another big step for genetic understanding, and the result is being published this month. This new study establishes the general fact of links between high importance genes, and serves as proof of principle for the next generation of research to understand inter-relationships between genes. The project was accomplished because of brains, bots, and computers. The next 20 years of new genetic and epigenetic knowledge will be both stunning and transformative for medicine and litigation.
For the shorter term, the “bike brake” analogy for defective genes is now undergoing modification as researchers look for back-ups to defective genes, and relationships. The theories and arguments matter for toxic tort claims as more and more cases include evidence about mutations and individual variability, including bike brake analogies. Thus, the universe of relevant information continues to expand, but most parties to litigation are unaware of the changes. Science Daily included the following explanation in its September 23, 2016 article about the new paper by Costanzo et al.
“Andrews, Boone and Myers led the pioneering work in yeast cells by deleting two genes at a time in pair combinations. They were trying to look for gene pairs that are essential for survival. This called for custom-built robots and a state-of-the-art automated pipeline to analyse almost all of the mind-blowing 18 million different combinations.
The yeast map identified genes that work together in a cell. It shows how, if a gene function is lost, there’s another gene in the genome to fill its role. Consider a bicycle analogy: a wheel is akin to an essential gene — without it, you couldn’t ride the bike. But front brakes? Well, as long as the back brakes are working, you might be able to get by. But if you were to lose both sets of brakes, you are heading for trouble.
Geneticists say that front and back brakes are “synthetic lethal,” meaning that losing both — but not one — spells doom. Synthetic lethal gene pairs are relatively rare, but because they tend to control the same process in the cell, they reveal important information about genes we don’t know much about. For example, scientists can predict what an unexplored gene does in the cell simply based on its genetic interaction patterns.
It’s becoming increasingly clear that human genes also have one or more functional backups. So researchers believe that instead of searching for single genes underlying diseases, we should be looking for gene pairs. That is a huge challenge because it means examining about 200 million possible gene pairs in the human genome for association with a disease.
Fortunately, with the know-how from the yeast map, researchers can now begin to map genetic interactions in human cells and even expand it to different cell types. Together with whole-genome sequences and health parameters measured by new personal devices, it should finally become possible to find combinations of genes that underlie human physiology and disease.
“Without our many years of genetic network analysis with yeast, you wouldn’t have known the extent to which genetic interactions drive cellular life or how to begin mapping a global genetic network in human cells,” said Boone, who is also a professor in U of T’s molecular genetics department and a co-director of the Genetic Networks program at the Canadian Institute for Advanced Research (CIFAR) and holds Canada Research Chair in Proteomics, Bioinformatics and Functional Genomics. We have tested the method to completion in a model system to provide the proof of principle for how to approach this problem in human cells. There’s no doubt it will work and generate a wealth of new information.”
The concept of synthetic lethality is already changing cancer treatment because of its potential to identify drug targets that exist only in tumour cells. Cancer cells differ from normal cells in that they have scrambled genomes littered with mutations. They’re like a bicycle without a set of brakes. If scientists could find the highly vulnerable back-up genes in cancer, they could target specific drugs at them to destroy only the cells that are sick, leaving the healthy ones untouched.”
The new paper is online at Science magazine (paywall).