Slowing down metabolism can prevent the harmful effects of genetic mutations

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Slowing down metabolism can prevent the harmful effects of genetic mutations

In a new study from Northwestern University, researchers slowed the metabolism of mutant fruit flies by 50%, and the expected adverse effects of many mutations never materialized. After experimentally testing the many genetic mutations in fruit flies, the researchers found the same result each time.

"When the flies developed at a normal rate, developmental problems appeared," said Richard Carthew of Northwestern, who led the experimental research. "When we slowed the pace, the development problems disappeared. They develop more slowly and grow more slowly, but otherwise they are normal animals."

"This upsets the paradigm of everything we know about development," added Luís Amaral of Northwestern, who led the computational research. We have always thought that if you "break" certain genes, there will be serious consequences for development. It turns out that this is not true for some genes, as long as you also slow down the metabolism of the growing organism."

Research could explain a number of factors, such as why industrial farmed chickens that are raised for hyper growth have more developmental problems or why caloric restriction is related to longevity.

The study published today (July 25) in the journal Cell. Dr. Carthew is Professor of Molecular Biosciences at Weinberg College of Arts and Sciences in the Northwest and Professor of Biochemistry and Molecular Genetics at the Feinberg School of Medicine. Amaral holds the Erastus O. Haven Chair in Chemical and Biological Engineering at the McCormick School of Engineering in Northwestern.

In perhaps the most striking discovery of the study, the researchers discovered that fruit flies - whose metabolism was slowed - could live without microRNAs, which was previously thought impossible. Present in all plant and animal species, microRNAs play a key role in regulating gene expression. In other words: microRNAs control development, physiology and behaviour.

"We know, after 20 years of research, that microRNAs are essential to life. If you didn't have microRNAs, you'd be dead. It's as simple as that," says Carthew. "In our study, we slowed the metabolism of fruit flies that did not produce microRNAs. They survived, grew up and became normal adults.

"Our result concludes that this whole family of genetic regulators is not essential," he added. "All you have to do is slow down the metabolism by about 50%."

Nobel laureate Thomas Hunt Morgan first noted the link between diet and genetic mutations in 1915. When breeding mutant fruit flies on limited amounts of bad food, Morgan noticed that some mutations were never expressed.

"He thought it was interesting, but he had no explanation," says Carthew.

Carthew and Amaral now believe that the answer is feedback control. Common to biology, engineering, economics and many other fields, feedback control allows complex systems to adjust their performance to meet a desired response. After hundreds of experiments over several years, the Northwest duo believes that a slower metabolism gives animal systems time to correct their mistakes.

This upsets the paradigm of everything we know about development."

"When you look at the different proteins and genes that interact within a cell, you can be overwhelmed by all the components and the interactions between them," Amaral said. "If you grow up quickly and something is wrong, it can be catastrophic. You need these complex networks because they increase redundancy to prevent disasters.

"But if your growth is slow, you may not need such a complex system, he said. "You have more time to adapt to mistakes and react to changes."

In other words, if you give the system more time, it will eventually get to where it needs to be. Dr. Carthew, who is also a member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University, said the discovery could eventually be applied to cancer.

"Tumours are extremely active metabolically," he says. "Tumours absorb a huge amount of energy, which is why cancer patients are often exhausted. We could consider ways to target cancer cell metabolism. Perhaps by slowing their metabolism, we could prevent oncogenic mutations in tumor cells from expressing their cancerous phenotype."