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Single gene knockout causes ‘unprecedented body shut-down’

Scientists at the Medical Research Council’s Institute of Genetics and Molecular Medicine (IGMM) have identified a gene that if removed can cause many essential body systems to shut down in a matter of days.

New research published in the journal PLoS Genetics shows that removing the Wilms’ Tumour gene (WT1) in mice leads to extremely rapid and widespread deterioration of many essential tissues and organs. Within a few days, the animals lose most of their body fat, their bones become brittle, they stop producing red blood cells that carry oxygen to tissues and organs, and their kidneys and pancreas cease to function.

The researchers say the results are unprecedented in the field of genetics and could open the door to a raft of future treatments for human diseases from kidney failure and osteoporosis to a variety of cancers. The findings could also help to alleviate the tissue damage experienced as we age.

Dr You-Ying Chau from IGMM, who carried out the research, said:

“The deletion of this gene is the most dramatic discovery we’ve ever made in terms of the severity and speed of the effect on nearly all major body systems. It’s astonishing to think that the removal of just a single gene can tip the delicate balance keeping the body’s organs and tissues functioning into almost total shut down.

“In the long-term, we expect our findings to inform new treatments for a wide variety of common diseases. In addition, we have identified a major new player in the maintenance of a stable environment in the body – a process known as tissue homeostasis.”

Over the course of our lives, our tissues undergo a process of continuous turnover, whereby old cells die and are replaced with new ones produced by adult stem cells. It is important for scientists to understand this process as tissue maintenance often goes awry in disease. For example, cancer occurs when this process spirals out of control leading to unregulated cell growth and division and the formation of a tumour.

The WT1 gene was previously thought to be involved only during development of the fetus, where it helps make kidneys, reproductive organs and blood vessels. This study sheds light on a new role for this gene in tissue maintenance and suggests that the turnover of adult tissue may work differently to the process in the womb. It also points to the importance of a particular type of cell called the mesenchymal cell, which is vital for the production of new tissue.

Professor Nick Hastie, director of IGMM, and a co-author on the study, said:

“While previous research has suggested a role for WT1 in some forms of adult cancer and kidney disease, the level of destruction seen here is unprecedented. By exploring how individual genes affect physical characteristics in mice, we will eventually gain a deeper understanding of the human disease process and identify potential targets for new treatments.”

Dr Lara Bennett, Scientific Advisor at the Association for International Cancer Research which co-funded the research along with the MRC said:

“This is a perfect example of how basic research is vital for the development of new treatments in the future.”

Though the experiments were carried out in mice, the researchers are confident the effect will be similar in humans. They will now work on human tissue in the lab to try to replicate and expand on their findings, however, they stress that any potential new treatment is likely to be 10-20 years away at the earliest.

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