Gene Hack, Man - Pacific Standard

Gene Hack, Man

A new treatment for Down Syndrome mirrors genetic evolution by hacking an already-existing hack of our genes.
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(PHOTO: SERGEY NIVENS/SHUTTERSTOCK)

(PHOTO: SERGEY NIVENS/SHUTTERSTOCK)

Like drugs, genes can be harmful at the wrong dose. Down Syndrome is caused by a gene-dose problem: patients carry three copies of chromosome 21, instead of two, giving them toxic levels of hundreds of genes that are best had only in moderation. Last week, a team of scientists made headlines with a technical breakthrough that could potentially solve the gene dose problem in Down Syndrome. They found a way to shut down the entire extra copy of chromosome 21 in cells taken from a Down Syndrome patient. The scientists hacked a natural chromosome shut-down system that is itself an evolutionary hack of a previous system.

Much like the extra chromosome 21 in Down Syndrome, sex chromosomes present a dose problem: Males of nearly all mammal species have one X chromosome, while females have two copies. As shown by comparisons with the platypus genome, our modern mammalian system of sex chromosomes began to develop less than 166 million years ago, when the Y chromosome appeared on the scene.

A team of scientists recently made headlines with a technical breakthrough that could potentially solve the gene dose problem in Down Syndrome.

The Y chromosome is essentially a hacked copy of the X chromosome, created by the accidental acquisition of the male sex determination gene SRY, the master control switch in mammals for creating a male. Once the incipient Y chromosome got its hands on the controls, it hijacked the role of sex determination, demoting the chromosome that was previously in charge of this function and creating what we now know as “the male mammal.” One long-term evolutionary consequence of this reckless highjack is that the Y chromosome eventually became a shriveled-up copy of its former self, shedding most of the genes that aren’t needed for specifically male functions like testis development, and raising questions about its future prospects.

The Y chromosome’s downward spiral left the X chromosome as the sole carrier of Y’s former genetic content, causing a gene dosage problem: Male mammals have only one copy of the roughly 1,700 genes on the X chromosome, while females get two copies.

Genes on the X chromosome are important to the biology of both sexes, and males and females generally need the same gene dose. Nature solved this dose problem using a gene called Xist to create a system, called X inactivation, which, itself a hack, shuts down one of the two X chromosomes in females, leaving them at X chromosome parity with the males of the species.

Scientists were able to hack this X inactivation system—hacking a hack—by engineering a copy of Xist into the extra chromosome 21 in the cells taken from a Down Syndrome patient.

A chromosome is a large feature in a cell, and putting an entire chromosome into storage is no small undertaking. Based on comparisons of X inactivation in marsupials and placental mammals, scientists have suggested that packing away the X chromosome in early mammals was a complicated, piecemeal affair, before the whole process finally fell under the control of the Xist gene. And, naturally, Xist arose as an evolutionary hack of a set of previously existing genes.

This convoluted backstory to last week’s breakthrough in Down Syndrome research illustrates evolution’s modus operandi of creating new systems by hacking existing ones. The approach is spectacularly successful, but the results are nightmarishly complex; this means that, unlike the engineering of inanimate objects, bioengineering succeeds primarily by modifying biological systems that have already been worked out by evolution. And therefore biological engineering aimed at curing diseases, making biofuels, or manufacturing drugs is made possible by research into some of the more obscure corners of biology, like elephant genomes and ocean bacteria, as well as basic principles of evolutionary biology. As is true of many areas of science, the biomedical research that benefits us directly is built on a foundation of basic research whose social benefits only become clear in hindsight.

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