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Crispr is not enough. Get ready for genetic editing 2.0
Material posted: Publication date: 31-12-2017
In less than five years, the technology for editing genes known as Crispr, has revolutionized modern biology. Since 2012, when its ability to find, remove and replace the genetic material was registered for the first time, scientists have published more than 5000 papers mentioning Crispr. Researchers biomedical master it, to better simulate various diseases. And countless companies began to attempt to extract a commercial benefit at the expense of new drugs, therapies, food products, chemicals and materials based on this technology.

Usually when we refer to Crispr, we mean Crispr/Cas9 — riboprotein complex, consisting of short chains of RNA and enzyme cutting DNA. It did for biology and medicine that "Model T" made for production and transport in the process democratizarea access to revolutionary technology and breaking the status quo (we are talking about a car from Henry Ford, also known as the "Tin Lizzie" — the first car in the world, produced millions of series from 1908 to 1927 years. She became a symbol of how Ford "put America on wheels", making the car relatively affordable for the American middle class — ed M. K.).

Crispr is already used to improve the condition of cancer patients, and next year he may be admitted to the clinical trials for the treatment of genetic diseases such as sickle cell anemia and beta-thalassemia.

But, like the "Model T", Crispr Classic little clunky, unreliable and a bit dangerous. He is unable to communicate simply with any place in the genome. Sometimes he corrects in the wrong place. And he doesn't have a switch. If the "Model T" was prone to overheating, and susceptible to Crispr Classic "overeating".

Even with these limitations Crispr Classic will remain the workhorse for science in 2018 and later. But this year on the production line began producing new, more brilliant tools for editing genes, promising to outshine their brother of the first generation. So if you only began to think about Crispr — buckle up, because the genetic make-edit 2.0 is here.

Aiming cutting impact Crispr is its defining feature. But when Cas9 cuts the two strands of DNA in an organism, introduced an element of risk — if you restore the sudden trauma of the genome of the cells may start to make mistakes. That's why scientists are developing ways to achieve the same results more safely.

One approach is to create a mutation of the enzyme Cas9 is such that it could still bind to DNA but that it "scissors" didn't work. Then other proteins that activate the expression of genes can be combined with this Cas9, allowing them to turn on and off genes (sometimes using light or chemical signals) without changing the DNA sequence. Such "epigenetic editing" can be used to resolve situations arising if all genetic factors — as opposed to mere isolated breaches, the most suitable for Crispr Classic (earlier this month, researchers from the Salk Institute used one such system for the treatment of several diseases in mice, including diabetes, acute renal failure and muscular dystrophy).

Other scientists at Harvard and the Brodsky Institute, working on even more ambitious setting of the Crispr system: editing of individual base pairs, one at a time. To do this they had to develop an entirely new enzyme — not taken from natural which could chemically convert the pairing of nucleotides at in G-C. This is a small change with potentially huge consequences. David Liu, a chemist from Harvard, whose lab did this work, estimated that about half of the 32 000 known pathogenic point mutations in humans can be corrected to this single transformation.

"I don't want the public come to the mistaken idea that we can replace any part of the DNA of any other part of the DNA of any person or any animal or even any cell in the Cup," says Liu. "But finding, even where we are now, is a heavy responsibility. The big question is how effectively will become this approach? And how quickly can we translate these technological advances for the benefit of society?"

Crispr evolved in bacteria as a primitive protection mechanism. His task was to find the enemy of viral DNA and cut it up as long as it does not remain. This is the accelerator without the brakes, and this can make it dangerous, especially for clinical applications. The longer Crispr will remain in the cell, the higher the chance that he will find something similar to its target gene and make the incision.

To minimize these "non-targeted" effects, scientists have developed a number of new tools for closer monitoring of the activity of Crispr.

At the moment, researchers have identified 21 unique family of natural Crispr-proteins — small molecules that turn off the genetic editor. But they know how to operate only a portion of them: some communicate directly with Cas9, not allowing it to bind to DNA; others include enzymes that displace Cas9 for genome space. Currently, researchers from the University of California at Berkeley, UCSF, Harvard, Ford and the University of Toronto are working hard to turn these natural "circuit breakers" to those that can be programmed.

In addition to medical applications, it will be crucial for the further development of gene drive technology to edit genes, which can quickly spread desired variation in the population.

The ability to push evolution in one way or another will become a powerful tool to combat many challenges — from disease to climate change. It is regarded as a tool for the destruction of mosquitoes and extermination of other harmful species. But released, she can get out of control and may lead to serious consequences. Only this year, Darpa has invested $ 65 million for the search of safer gene drives, including "switches" anti-Crispr.

Despite years of progress, scientists still don't know much about how mistakes in DNA can cause disease. They know what genes are involved in cellular "guides to action", but it is difficult to understand where these commands are delivered and how they are translated (including wrong) in the process. That is why the group at Harvard and the Brodsky Institute, led by co-discoverer Crispr Feng Zhang working with a new class of enzymes Cas, which focused on RNA instead of DNA.

Since they are instructions that the mechanisms cells use to create proteins they carry more information about the genetic bases of specific diseases. And since RNA comes and goes, changes in it will be useful for the treatment of short-term problems, such as acute inflammation or wound. System they called the Repair (which stands for "Programmable for RNA Editing A to I Replacement" — "edit the RNA for the programmed replacement of A by I"), while working to convert only a single nucleotide. The next step is to figure out how to create the other 11 possible combinations.

Scientists are constantly finding new enzymes Cas. Team Brodsky Institute are also working to describe cpf1 version of Cas, which leaves sticky ends is defosfaurilirovnie when it cuts DNA. In February a group from UC Berkeley found CasY and CasX, the most compact of the Crispr system. And researchers expect that in the coming months and years will bring many others.

Only time will tell whether Crispr-Cas9 the best of them, or just the first one who has captured the minds of one generation of scientists. "We don't know what will work best in different applications," says Megan Hochstrasser, who did his PhD in the laboratory of co-discoverer Crispr Jennifer Doudna and now works in the Innovative Genomics Institute. — "So at the moment I believe that all need to rely on all these tools together."

It will take many years of work to the current generation of gene editors moved from the lab to the real patients, the lines of vegetables and pests carrying disease.

If genetic edit 3.0 won't make it obsolete first.


Source: https://www.wired.com/story/whats-next-for-crispr/

Tags: science


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