Double Trouble


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Chromosome pairs: Does doubling them help or hurt? Image: Wikimedia commons
When we are under heavy stress, our reactions can sometimes be excessive, even if we know our actions carry a price. Once we have the time to stop and reflect, we are likely to come up with a more moderate solution. When a cell is exposed to harsh stress, it can also engage in a radical response involving the wholesale doubling of chromosomes. This mechanism is quick and effective, but it also comes at a heavy price for the cell. Recent Weizmann Institute research on yeast shows that stressed cells can behave like people: Given time, they are likely to adopt a different coping mechanism that is more specific, carries a lower cost and is more effective in the long run.

The change in chromosome numbers called aneuploidy has been well studied. In general, it results from an error taking place during cell division; when that mistake turns out to be to the cell’s advantage, it can be passed on to future generations. This “fast and dirty” response to environmental stress boosts the expression of most of the genes in the duplicated chromosome – including those that help the cell cope with stress. But there is also a great deal of waste: Cells must expend extra energy and resources on the extra genes, and so they develop more slowly and exhibit imbalances in their protein production schedules. In humans, aneuploidy in developing embryos can lead to miscarriages or, in the case of chromosome 21, to Down syndrome. Many tumor cells also have irregular numbers of chromosomes.

So is a non-standard number of chromosomes a “Dr. Jekyll” that helps cells survive stress or a “Mr. Hyde” that destroys them? This question, known as the aneuploidy paradox, is the subject of a long-standing scientific controversy.
(l-r) Dr. Orna Dahan, Avihu Yona and Prof. Yitzhak Pilpel
To approach the question, Prof. Yitzhak Pilpel and his team in the Molecular Genetics Department, including Avihu Yona and Dr. Orna Dahan, created an evolutionary process in the lab: For over a year, they grew baker’s yeast cells and followed their progress over thousands of generations. Though a year may seem a long time to watch yeast grow, it is a quick flash compared to the millions it takes for an organism to evolve in nature. The controlled experiment enabled the team to speed things up enough to observe the process of evolution instead of just viewing the end results. As the cells were exposed to heat or acidity – stress factors that acted as means of “natural” selection – the yeast adapted to survive. Every few generations, the researchers checked the genomes of their yeast, hoping to pinpoint the changes that contributed to their adaptation to the harsh conditions.

The results showed that the yeast adapted to heat by adding another copy of a certain chromosome. Growth in acidic conditions led to the doubling of a different chromosome. Clearly, the extra chromosomes were helping the yeast cells to improve their coping abilities in the face of the various stress factors. When the scientists tested cells with artificially inserted extra chromosomes and then exposed them to stress, these fared as well as the yeast that had evolved to do so in the lab.

But the scientists did not stop there: They continued to follow the evolution of the yeast cells as they kept growing and dividing. This persistence led the team to a surprising discovery: As time passed, the extra chromosome tended to disappear. In its place, new mechanisms arose that took longer to develop but were more focused and carried a lower cost to the cell. In particular, the expression of the genes for dealing with the stress remained as high as it had been with the extra chromosome. “The quick solution is not optimal, but in sudden, overwhelming stress conditions, it is worthwhile to the cell to pay the price,” says Pilpel. “When there is time to adapt, the cell will exchange that solution for another that is more precise.”

The research team demonstrated this principle by applying “gradual evolution” – worsening the yeast’s conditions slowly rather than all at once. Now, there was no aneuploidy, apparently because the yeast cells could take their time to adapt. In other words, says Pilpel, “The outcome depends on the pace of the evolutionary regime.”

The scientists believe that their findings may be relevant to understanding cancer, especially the ways in which cancer cells rid themselves of genetic mechanisms that suppress unchecked growth. For example, a cancer cell with a mutation in a tumor suppressor gene might double the damaged chromosome and then usurp the intact one, thus removing the “brakes” holding back cell division. Also, understanding how the coping ability of a cell is affected by extreme versus gradual environmental challenges might help doctors and biomedical researchers plan chemotherapy protocols in a way that will not encourage cancer cells to develop resistance.  
Prof.  Yitzhak Pilpel's research is supported by the Sharon Zuckerman Laboratory for Research in Systems Biology; the Braginsky Center for the Interface between Science and Humanities; and the European Research Council. Prof. Pilpel is the incumbent of the Ben May Professorial Chair.