{"id":130437,"date":"2024-09-22T11:32:19","date_gmt":"2024-09-22T15:32:19","guid":{"rendered":"https:\/\/www.shortform.com\/blog\/?p=130437"},"modified":"2024-09-23T12:10:19","modified_gmt":"2024-09-23T16:10:19","slug":"what-is-crispr-and-how-does-it-work","status":"publish","type":"post","link":"https:\/\/www.shortform.com\/blog\/what-is-crispr-and-how-does-it-work\/","title":{"rendered":"What Is CRISPR, and How Does It Work? (The Code Breaker)"},"content":{"rendered":"\n<p>What is <a href=\"https:\/\/www.shortform.com\/blog\/crispr-gene-editing-technology\/\">CRISPR<\/a>, and how does it work? What if we could use nature&#8217;s defense mechanisms to revolutionize medicine?<\/p>\n\n\n\n<p>CRISPR, a natural biological feature found in some microorganisms, has become a powerful tool for genetic modification. Walter Isaacson&#8217;s book <em>The Code Breaker<\/em> explores its scientific background, discovery in nature, and how it functions as an antiviral defense mechanism in bacteria.<\/p>\n\n\n\n<p>Keep reading to learn what CRISPR is and how it works.<\/p>\n\n\n\n<!--more-->\n\n\n\n<h2 class=\"wp-block-heading\" id=\"h-the-biological-process-known-as-crispr\">The Biological Process Known as CRISPR<\/h2>\n\n\n\n<p>What is CRISPR, and how does it work? CRISPR is short for \u201cclustered regularly interspaced short palindromic repeats,\u201d which refers to a repetitive pattern inside the DNA of some types of micro-organisms. It\u2019s a natural biological feature that scientists discovered and used to facilitate gene editing. We\u2019ll give some scientific background that will help you understand CRISPR. Then, we\u2019ll explain how scientists discovered CRISPR in nature and figured out how it works.<\/p>\n\n\n\n<h3 class=\"wp-block-heading\" id=\"h-scientific-background\">Scientific Background<\/h3>\n\n\n\n<p>To help you understand CRISPR, Isaacson provides some scientific background information on three basic biological units: genes, DNA (deoxyribonucleic acid), and RNA (ribonucleic acid). Let\u2019s explore those now.<\/p>\n\n\n\n<h4 class=\"wp-block-heading\" id=\"h-genes\">Genes<\/h4>\n\n\n\n<p>Isaacson traces CRISPR\u2019s development back to the proto-genetic theories of scientists Charles Darwin and Gregor Mendel in the mid-1800s. Darwin, who proposed the theory of evolution, argued that certain traits were passed down through generations via a process called <a href=\"https:\/\/www.shortform.com\/blog\/natural-selection-in-evolution\/\">natural selection<\/a>. He thought reproduction occurred when tiny parts of both parents\u2019 bodies migrated into the egg and sperm and then blended in the offspring, but this wasn\u2019t quite correct. Mendel then showed that some<em> <\/em>traits are dominant (more likely to appear) and others are recessive (less likely to appear). These findings led other scientists to hypothesize about the existence of <strong><em>genes<\/em><\/strong><strong>\u2014molecular units containing inheritable traits<\/strong>.<\/p>\n\n\n\n<h4 class=\"wp-block-heading\" id=\"h-dna\">DNA<\/h4>\n\n\n\n<p>Later, scientists discovered that genes are segments of DNA (deoxyribonucleic acid), a molecule inside which inheritable traits are encoded. In the 1950s, scientists Rosalind Franklin, James Watson, and Francis Crick showed that DNA has a double helix structure that can be split in two and replicated\u2014this process is what enables genes to be inherited. Isaacson notes that Franklin\u2019s contributions to the discovery of DNA\u2019s structure were undervalued because of her gender (Watson and Crick were men and have received greater historical recognition).<\/p>\n\n\n\n<p>(Shortform note: All living organisms have DNA. DNA is made of substances called <a href=\"https:\/\/www.genome.gov\/about-genomics\/fact-sheets\/Deoxyribonucleic-Acid-Fact-Sheet\" target=\"_blank\" rel=\"noreferrer noopener\"><em>nucleotides<\/em><\/a>, and each nucleotide is composed of phosphate, sugar, and a nitrogenous base. There are four types of nitrogenous bases; different combinations of these result in different instructions for the composition of an organism. For example, your nucleotides are arranged differently than a bird\u2019s, which is why you\u2019re so different from birds. In fact, your nucleotides are arranged differently than anyone else\u2019s\u2014<a href=\"https:\/\/www.mcgill.ca\/oss\/article\/general-science\/identical-twins-are-not-identical\" target=\"_blank\" rel=\"noreferrer noopener\">even if you have an identical twin<\/a>\u2014which is why you\u2019re not exactly like <em>anybody<\/em>.)<\/p>\n\n\n\n<p>According to Isaacson, experts long believed that they could begin to solve inheritable medical problems by studying DNA and identifying problematic genes. This led to the formation of the <a href=\"https:\/\/www.shortform.com\/blog\/what-was-the-human-genome-project\/\">Human Genome Project<\/a> (an international effort to catalog human DNA) in the 1990s. But Isaacson explains that this approach was lacking\u2014<strong>DNA only tells you which genes are present in a cell, <\/strong><strong><em>not <\/em><\/strong><strong>how to alter them.<\/strong><\/p>\n\n\n\n<p>(Shortform note: The Human Genome Project was devoted to <a href=\"https:\/\/www.nature.com\/scitable\/topicpage\/the-order-of-nucleotides-in-a-gene-6525806\/\" target=\"_blank\" rel=\"noreferrer noopener\"><em>DNA sequencing<\/em><\/a><em>\u2014<\/em>the process of determining the order of nucleotides in a strand of DNA. While the Human Genome Project didn\u2019t teach scientists how to alter problematic genes, it <em>did <\/em>help scientists <a href=\"https:\/\/www.britannica.com\/event\/Human-Genome-Project\/Advances-based-on-the-HGP\" target=\"_blank\" rel=\"noreferrer noopener\">establish links between certain genes and certain diseases and disease immunities<\/a>. With those genes identified, it\u2019ll be easier for scientists in the future to create <a href=\"https:\/\/www.genengnews.com\/insights\/gene-therapy-adopts-new-tools-to-guarantee-quality\/\" target=\"_blank\" rel=\"noreferrer noopener\">precisely targeted gene therapies<\/a>.)<\/p>\n\n\n\n<h4 class=\"wp-block-heading\" id=\"h-rna\">RNA<\/h4>\n\n\n\n<p>Alongside DNA, cells contain a molecule called RNA (ribonucleic acid). Until the 1980s, scientists only knew about one type of RNA: <em>messenger RNA <\/em>(<em>mRNA), <\/em>which copies and transmits genetic information. Then, scientists discovered another type of RNA called <em>ribozymes<\/em>, which act like enzymes (a kind of protein that catalyzes chemical reactions). They also found out that ribozymes could help RNA molecules <em>splice <\/em>themselves\u2014that is, the molecules could make copies of themselves that automatically cut out certain unnecessary sections. Isaacson explains that this discovery opened the door for scientists like <a href=\"https:\/\/www.shortform.com\/blog\/who-is-jennifer-doudna\/\">Jennifer Doudna<\/a> to research how <strong>RNA could be used to alter genes.<\/strong><\/p>\n\n\n\n<p>(Shortform note: mRNA was <a href=\"https:\/\/www.pasteur.fr\/en\/home\/research-journal\/news\/discovery-messenger-rna-1961\" target=\"_blank\" rel=\"noreferrer noopener\">discovered by two French scientists<\/a>\u2014Fran\u00e7ois Gros and Fran\u00e7ois Jacob\u2014at the same time (1961). The <a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/12440996\/#:~:text=In%201982%20we%20reported%20the,of%20the%20Tetrahymena%20pre%2DrRNA.\" target=\"_blank\" rel=\"noreferrer noopener\">1982 discovery<\/a> of self-splicing RNA (which is <a href=\"https:\/\/pdb101.rcsb.org\/motm\/65\" target=\"_blank\" rel=\"noreferrer noopener\">more common than previously believed<\/a>) led researchers to study RNA\u2019s potential for gene editing, but note that self-splicing RNA and ribozymes are <em>not <\/em>involved in traditional CRISPR gene editing technology. However, scientists have recently begun exploring ribozymes\u2019 potential applications with regard to CRISPR. For example, <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC8925089\/#:~:text=Ribozyme%2Dmediated%20CRISPR%2FCas9%20systems,RNA%20polymerase%20II%2Ddependent%20promoter.\" target=\"_blank\" rel=\"noreferrer noopener\">one 2022 study<\/a> showed how ribozymes could make CRISPR target specific genes in a more specific way than previous methods.)<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table><tbody><tr><td><strong>The (Often Winding) Road Toward Recognition for Genetic Scientists<\/strong><br><br>A central theme in <em>The Code Breaker <\/em>is recognition\u2014which scientists are acclaimed for their discoveries and why? Let\u2019s discuss discrepancies in science historians\u2019 recognition of early genetic scientists.<br><br>Isaacson says Darwin and Mendel should receive partial credit for the discovery of genes<em>. <\/em>In <a href=\"https:\/\/shortform.com\/app\/book\/the-gene\/1-page-summary\" target=\"_blank\" rel=\"noreferrer noopener\"><em>The Gene<\/em><\/a><em>, <\/em>Siddhartha Mukherjee explains how Mendel improved upon Darwin\u2019s understanding of heredity: Darwin mistakenly believed that traits were passed down <a href=\"https:\/\/shortform.com\/app\/book\/the-gene\/1-page-summary#darwins-theory-of-evolution\" target=\"_blank\" rel=\"noreferrer noopener\">in blendable particles called <em>gemmules<\/em><\/a>. Mendel disproved this theory by showing that some traits (like the color of flowers) are passed down completely intact, which meant that single traits must be individually packaged in <a href=\"https:\/\/shortform.com\/app\/book\/the-gene\/1-page-summary#mendels-unit-of-heredity\" target=\"_blank\" rel=\"noreferrer noopener\">encasements he called \u201cfactors.\u201d<\/a> (We now call these <a href=\"https:\/\/shortform.com\/app\/book\/the-gene\/1-page-summary#part-2-chromosomes-and-dna\" target=\"_blank\" rel=\"noreferrer noopener\"><em>chromosomes<\/em><\/a>.) While <a href=\"http:\/\/www.dnaftb.org\/4\/bio.html\" target=\"_blank\" rel=\"noreferrer noopener\">Mendel didn\u2019t receive any recognition<\/a> for his proto-genetic research until the 20th century, Darwin\u2019s work was <a href=\"https:\/\/www.genome.gov\/25520157\/online-education-kit-1859-darwin-published-on-the-origin-of-species-proposing-continual-evolution-of-species\" target=\"_blank\" rel=\"noreferrer noopener\">widely recognized as impactful<\/a> as soon as he published <a href=\"https:\/\/shortform.com\/app\/book\/on-the-origin-of-species\/1-page-summary\" target=\"_blank\" rel=\"noreferrer noopener\"><em>On the Origin of Species<\/em><\/a><em>.<\/em><br><br>Another drama played out in the 1950s. Isaacson explains that Franklin\u2019s role in the discovery of DNA\u2019s structure is often underplayed because she was a woman, while Watson and Crick (both men) remain in the limelight. In 2023, Watson and Crick\u2019s biographers revealed just how much Franklin has been undervalued: Many believe that Franklin was the first to discover DNA\u2019s structure but didn\u2019t understand its significance, and that <a href=\"https:\/\/www.city-journal.org\/article\/the-myth-of-the-wronged-heroine#\" target=\"_blank\" rel=\"noreferrer noopener\">Watson and Crick deserve <em>more <\/em>credit than she did<\/a> because they made important inferences based on her discovery (albeit, without her permission). However, primary documents reveal that Franklin <em>did <\/em>understand the significance of her discovery and <a href=\"https:\/\/www.nature.com\/articles\/d41586-023-01313-5\" target=\"_blank\" rel=\"noreferrer noopener\">should get equal recognition<\/a>.<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<h3 class=\"wp-block-heading\" id=\"h-crispr-in-nature\">CRISPR in Nature<\/h3>\n\n\n\n<p>Now that you know the fundamental science underlying CRISPR, let\u2019s talk about what CRISPR is and how it works. As a reminder, the label \u201cCRISPR\u201d refers to a repetitive pattern inside DNA. Isaacson explains that scientists in the 1980s noticed that this phenomenon occurred in some bacterial cells, but they weren\u2019t sure what it was or why it mattered. A researcher solved that mystery a few years later\u2014in the bacteria he studied, cells with CRISPR were immune to viral infection, while cells without CRISPR were susceptible to viral infection. Therefore, he dubbed CRISPR a natural antiviral defense mechanism.<\/p>\n\n\n\n<p>Once CRISPR was discovered, scientists set out to decipher how it worked. First, they noticed that the pattern was usually accompanied by enzymes known as <em>Cas enzymes<\/em>. They theorized that when a virus attacks a bacterial cell, the bacterial cell\u2019s Cas enzymes cut segments of the virus\u2019s genetic material (either DNA or RNA, depending on the virus). Then, the cell copies those segments into the bacteria\u2019s DNA, which results in the DNA pattern known as CRISPR. The next time the virus attacks, the cell \u201crecognizes\u201d the virus because its genes are now encoded in the cell\u2019s DNA\u2014which enables the cell to better defend itself against that specific virus. Isaacson explains that this understanding of how CRISPR and Cas work is correct, but not complete.<\/p>\n\n\n\n<p>Isaacson says in 2012, American biochemist Jennifer Doudna teamed up with French scientist Emmannuelle Charpentier to fully explain how<strong> CRISPR-Cas systems defend bacterial cells against invading viruses<\/strong>. They published a paper on how three essential molecules\u2014a Cas enzyme called Cas9 and two kinds of RNA called crRNA (CRISPR RNA) and tracrRNA (trans-activating CRISPR RNA)\u2014work together to facilitate the process. First, tracrRNA creates crRNA, and these molecules combine to produce \u201cguide RNA\u201d (gRNA) and then bind to Cas9. Then, using its matching code as a guide, the gRNA finds the right spot to slice the virus\u2019s DNA. Finally, Cas9 makes a cut in the DNA where the gRNA attached, disabling the virus.&nbsp;<\/p>\n\n\n\n<p>Importantly, in this paper, Doudna and Charpentier also suggested that in the future, scientists could potentially use the CRISPR-Cas9 system to edit human genes.<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table><tbody><tr><td><strong>CRISPR Antiviral Defense Happens in Three Steps<\/strong><br><br>Isaacson explains that, in bacteria, CRISPR serves as a kind of immune system that uses RNA to identify and destroy invading viruses. Now, we\u2019ll discuss how CRISPR works in finer detail.&nbsp;<br><br>Bacteria use CRISPR to defend against viruses <a href=\"https:\/\/innovativegenomics.org\/crisprpedia\/crispr-in-nature\/\" target=\"_blank\" rel=\"noreferrer noopener\">by carrying out three steps<\/a>. Isaacson says that in the first step, the bacterial cell cuts a segment of genetic material from an attacking virus\u2019s DNA or RNA. Then, the segment is incorporated into the bacterial cell\u2019s own DNA. Experts refer to this step as the <em>spacer acquisition step<\/em> (since the segment of viral DNA or RNA is called a \u201cspacer\u201d) and explain that it results in a cellular \u201cmemory\u201d of the virus.<br><br>Isaacson says that once the virus\u2019s genes have been encoded in a bacterial cell\u2019s DNA, the cell is able to recognize and defend itself against the virus when it attacks again in the future. But the cell doesn\u2019t compare invading viruses against its own DNA\u2014in a step scientists call <em>CRISPR RNA biogenesis<\/em>, the cell copies the parts of bacterial DNA that contain viral genes onto crRNA molecules.&nbsp;<br><br>These crRNA copies become important in the final step of the CRISPR immune response, which is called <em>interference. <\/em>The crRNA molecules partner with Cas proteins to form what\u2019s called a <em>surveillance complex<\/em>, which patrols the cell for invading genetic material (when a virus attacks a bacterial cell, it injects its DNA or RNA into the cell). When the surveillance complex detects invading material, it inspects the material for any genetic sequences that match the crRNA copies the cell made beforehand. If there\u2019s a match, the surveillance complex destroys the invading material by cutting it into small pieces, effectively dismembering the virus.<br><br>How does tracrRNA, which Doudna and Charpentier identified as a key component of the CRISPR immune response, fit into all of this? Scientists have discovered that there are <a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC7508700\/#b0090\" target=\"_blank\" rel=\"noreferrer noopener\"><em>three <\/em>major classes of CRISPR-Cas systems<\/a>, each requiring a different combination of molecules. In the class Doudna and Charpentier studied (a Type II system known as CRISPR-Cas9), tracrRNA was needed for crRNA to do its job. In contrast, <a href=\"https:\/\/ann-clinmicrob.biomedcentral.com\/articles\/10.1186\/s12941-019-0317-x\" target=\"_blank\" rel=\"noreferrer noopener\">tracrRNA isn\u2019t required in Type I or Type III systems<\/a>, which use different Cas proteins (as opposed to the Cas9 protein involved in Type II systems) to defend against viruses. Depending on the type of CRISPR system a cell employs, it might perform each of the three steps we\u2019ve covered slightly differently.<\/td><\/tr><\/tbody><\/table><\/figure>\n","protected":false},"excerpt":{"rendered":"<p>What is CRISPR, and how does it work? What if we could use nature&#8217;s defense mechanisms to revolutionize medicine? CRISPR, a natural biological feature found in some microorganisms, has become a powerful tool for genetic modification. Walter Isaacson&#8217;s book The Code Breaker explores its scientific background, discovery in nature, and how it functions as an antiviral defense mechanism in bacteria. Keep reading to learn what CRISPR is and how it works.<\/p>\n","protected":false},"author":9,"featured_media":130445,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[160],"tags":[1595],"class_list":["post-130437","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-science","tag-the-code-breaker","","tg-column-two"],"yoast_head":"<!-- This site is optimized with the Yoast SEO Premium plugin v24.3 (Yoast SEO v24.3) - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>What Is CRISPR, and How Does It Work? (The Code Breaker) - Shortform Books<\/title>\n<meta name=\"description\" content=\"CRISPR, a natural biological feature found in some microorganisms, is now a tool for genetic modification. 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Learn what it is and how it works.\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.shortform.com\/blog\/what-is-crispr-and-how-does-it-work\/\" \/>\n<meta property=\"og:site_name\" content=\"Shortform Books\" \/>\n<meta property=\"article:published_time\" content=\"2024-09-22T15:32:19+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-09-23T16:10:19+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/s3.amazonaws.com\/wordpress.shortform.com\/blog\/wp-content\/uploads\/2024\/09\/bacterial-cells.webp\" \/>\n\t<meta property=\"og:image:width\" content=\"1344\" \/>\n\t<meta property=\"og:image:height\" content=\"768\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/webp\" \/>\n<meta name=\"author\" content=\"Elizabeth Whitworth\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"Elizabeth Whitworth\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"9 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\/\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\/\/www.shortform.com\/blog\/what-is-crispr-and-how-does-it-work\/#article\",\"isPartOf\":{\"@id\":\"https:\/\/www.shortform.com\/blog\/what-is-crispr-and-how-does-it-work\/\"},\"author\":{\"name\":\"Elizabeth Whitworth\",\"@id\":\"https:\/\/www.shortform.com\/blog\/#\/schema\/person\/d2928cf6c11a69ced1491d6a5b74fb13\"},\"headline\":\"What Is CRISPR, and How Does It Work? 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