Explanation: How CRISPR works (2023)

Scientists usually avoid using the wordmiracle. Unless they're talking about a gene-editing tool called CRISPR. "You can do anything with CRISPR," some say. Others call it simply amazing.

Indeed, it surprised so many people and so quickly that only eight years after discovering it Jennifer Doudna and Emmanuelle Charpentier took it homeNobel Prize in Chemistry 2020.

CRISPR stands for "clustered regularly arranged short".reciprocalrepeats." These repeats are found in the DNA of bacteria. They are actually copies of small parts of the virus. Bacteria use them as picture collections to recognize bad viruses. Cas9 isenzymewhich can cut DNA. Bacteria fight viruses by sending the Cas9 enzyme to break up viruses that have a mug in their collection. Scientists have recently discovered how bacteria do this. Now, in the lab, researchers are using a similar approach to turn a microbial virus-fighting system into the latest new lab tool.

This CRISPR/Cas9 tool was first described in 2012 and 2013. Scientific laboratories around the world soon began using it to alter an organism's genome—its entire set of DNA instructions.

This tool can quickly and efficiently modify almost any gene in any plant or animal. Researchers have already used it to correct genetic diseases in animals, fight viruses and sterilize animalsmosquitoes. It has also been used to prepare pig organs for human transplants and to strengthen musclesto the heart.

So far, the biggest impact of CRISPR has been felt in basic biology laboratories. This inexpensive gene editor is easy to use. This allowed researchers to delve into the basic mysteries of life. And they can do it in ways that were once difficult, if not impossible.

Robert Reed is a developmental biologist at Cornell University in Ithaca, New York. He compares CRISPR to a computer mouse. "You can just point it at a point in the genome and you can do whatever you want up to that point."

At first this meant anything that involved cutting DNA. CRISPR/Cas9 in its original form is a host device (CRISPR segment) that guides molecular scissors (Cas9 enzyme) to the target DNA segment. Together, they act like a genetic engineering cruise missile that turns off or repairs a gene or inserts something new where the scissors of Cas9 have made some cuts. Newer versions of CRISPR are called "base editors." They can process the genetic material one base at a time, without cutting. They look more like a pencil than scissors.

That's how it works

Scientists start with RNA. This is a molecule that can read the genetic information in DNA. RNA finds a point atcorethe station where some processing activity should take place. (The nucleus is the compartment in the cell where most of the genetic material is stored.) This RNA guides Cas9 to the exact spot on the DNA where the cut is needed. Cas9 then latches onto the double-stranded DNA and unwinds it.

This allows the guide RNA to pair with the region of DNA it has targeted. Cas9 cuts the DNA at this point. This creates a break in both strands of the DNA molecule. The station, sensing a problem, repairs the interruption.

Repairing the defect can turn off the gene (which is the easiest thing to do). Alternatively, this repair may correct the error or even insert a new gene (a much more difficult process).

Cells usually repair a break in their DNA by gluing the loose pieces together. This is a sloppy process. It often comes down to a mistake that turns off a gene. This may not sound helpful - but sometimes it is.

Scientists cut DNA with CRISPR/Cas9 to make gene changes ormutations. By comparing cells with and without the mutation, scientists can sometimes discover what the protein's normal role is. Or a new mutation could help them understand genetic diseases. CRISPR/Cas9 can also be useful in human cells by turning off certain genes — those that play a role in inherited diseases, for example.

"The original Cas9 is like a Swiss army knife with only one application: it's a knife," says Gene Yeo. He is an RNA biologist at the University of California, San Diego. But Yeo and others have inserted other proteins and chemicals into the blunt blades. This turned this knife into a multi-purpose tool.

CRISPR/Cas9 and related tools can now be used in new ways, such as changing a single nucleotide base — a single letter in the genetic code — or adding a fluorescent protein to mark a point in the DNA that scientists want to track. Scientists can also use this cut-and-paste genetic technology to turn genes on or off.

This explosion of new ways to use CRISPR is far from over. Feng Zhang is a molecular biologist at the Massachusetts Institute of Technology in Cambridge. He was one of the first scientists to use Cas9 scissors. "The field is moving so fast," he says. "Just looking at how far we've come ... I think what we're going to see in the next few years is just going to be amazing."

This story was updated on October 8, 2020 to highlight the Nobel Committee's decision to award the 2020 Chemistry Prize to the discovery of CRISPR.

Strong words

More about Power Words

applicationA special use or function of something.

the base(in genetics) A shortened version of the term nucleobase. These bases are the building blocks of DNA and RNA molecules.

biologyThe study of living things. Scientists who study them are known asbiologists.

Cas9An enzyme that geneticists now use to help edit genes. It can cut DNA, allowing it to repair damaged genes, splice in new ones, or turn certain genes off. Cas9 has been moved to where it should make the cuts from CRISPR, a type of genetic guide. The Cas9 enzyme is derived from bacteria. When viruses attack bacteria, this enzyme can cut the microbe's DNA, rendering it harmless.

cellThe smallest structural and functional unit of the organization. Usually too small to be seen with the naked eye, it consists of a watery fluid surrounded by a membrane or wall. Animals consist of thousands to trillions of cells, depending on their size. Some organisms, such as yeasts, molds, bacteria and some algae, consist of a single cell.

chemical substanceA substance made up of two or more atoms that combine (join together) in a fixed ratio and structure. For example, water is a chemical substance consisting of two hydrogen atoms bonded to one oxygen atom. Its chemical symbol is H2O.

CRISPRAbbreviation - pronounced crispier - for "grouped regularly punctuated short recursive repetitions". These are parts of RNA, a molecule that carries information. They are copied from the genetic material of viruses that infect bacteria. When a bacterium encounters a virus it has previously been exposed to, it produces a copy of the CRISPR RNA that contains the genetic information of that virus. The RNA then instructs an enzyme, called Cas9, to cut the virus and render it harmless. Scientists are now making their own versions of CRISPR RNA. These laboratory RNAs instruct an enzyme to interrupt specific genes in other organisms. Scientists use them, like genetic scissors, to edit - or change - specific genes so they can then study how the gene works, repair damage to broken genes, insert new genes or turn off harmful ones. .

developmental(in biology) An adjective that refers to the changes an organism goes through from conception to adulthood. These changes often involve chemistry, size, and sometimes even shape.

DNA(short for deoxyribonucleic acid) A long, double-stranded, coiled molecule inside most living cells that carries genetic instructions. It is built on the backbone of phosphorus, oxygen and carbon atoms. In all living things, from plants and animals to microbes, these instructions tell cells what molecules to make.

engineeringA field of study that uses mathematics and science to solve practical problems.

fieldField of study, such as: Her field of research was biology. Also a term to describe the actual environment in which some research is conducted, such as at sea, in a forest, on top of a mountain, or on a city street. This is the opposite of an artificial environment, such as a research laboratory.

fluorescentnaAble to absorb and re-emit light. This emitted light is known as fluorescence.

gen(adj. genetic) A segment of DNA that codes or contains instructions for making proteins. Offspring inherit genes from parents. Genes influence the appearance and behavior of an organism.

byThe complete set of genes or genetic material in a cell or organism. The study of this genetic inheritance within cells is known as genomics.

armA type of tissue used to produce movement by contracting its cells, known as muscle fibers. Muscle is rich in protein, which is why predatory species look for prey that contains a lot of this tissue.

mutation(v. to mutate) Some change that occurs in a gene in the DNA of an organism. Some mutations occur naturally. Others may be caused by external factors, such as pollution, radiation, drugs, or something in the diet. A gene with this change is called mutated.

coreThe plural is core. (in biology) A dense structure present in many cells. Usually a rounded structure enclosed within a membrane, the nucleus contains genetic information.

organ(in biology) Various parts of an organism that perform one or more specific functions. For example, the ovary is the organ that produces eggs, the brain is the organ that interprets nerve signals, and the roots of a plant are the organ that receives nutrients and moisture.

go back(adj. reflexive) A word, name, or phrase that has the same letter order when read forwards or backwards. For example,Tataimamaboth are palindromes.

proteinA compound consisting of one or more long chains of amino acids. Proteins are an essential part of all living organisms. They are the basis of living cells, muscles and tissues. they also do work inside the cells. Hemoglobin in the blood and the antibodies that try to fight infections are among the most well-known, autonomous proteins. Medicines often work by binding to proteins.

RNAA molecule that helps "read" the genetic information contained in DNA. The cell's molecular machinery reads DNA to make RNA, and then reads the RNA to make proteins.

to mark(in biology) To attach a tight band or bundle of organs to an animal. Sometimes a tag is used to give each person a unique identification number. Once attached to a creature's leg, ear, or other body part, it can effectively become the animal's "name." In some cases, the tag can also collect information from the environment around the animal. This helps scientists understand the environment and the role of animals in it.

Reference

The newspaper:Q. Wang i sir.A two-color RNA aptamer-based CRISPR tagging system.Scientific reports. Vol. 6, May 27, 2016, p. 26857. doi:10.1038/srep26857.

The newspaper:ONE. C. Komor i sur.Programmable target base editing in genomic DNA without DNA double-strand breaks.Nature. Vol. 533, 19 May 2016, published online 20 April 2016, p. 420. doi:10.1038/nature17946.

The newspaper:And D.A. Nelles et al.Programmable tracking of RNA in living cells with CRISPR/Cas9.Cell. Vol. 165, April 7, 2016, p. 488. doi: 10.1016/j.cell.2016.02.054.

Explanation: How CRISPR works (1)

Tina Hesman Saey is a columnist and reports on molecular biology atScience news. He has a Ph.D. in molecular genetics from the University of Washington in St. Louis and a master's degree in science journalism from Boston University.

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