Until just decades ago, we had no way to rewrite DNA, the genetic code that programs life. That changed with the first forays into gene editing in the 1970s, but the process was the equivalent of programming the first room-sized mainframe computers. There were only a handful of labs with the required technical skills to edit DNA, and it often took years of trial and error to change a single gene.
And then, in 2012, came the invention that is to biology as Steve Jobs and Steve Wozniak’s Apple I was to computing: Researchers figured out how to use Crispr, a natural molecule, to dramatically cut the time and cost of gene editing.
With Crispr, suddenly any grad student in biology could successfully engineer organisms in weeks. It’s so accessible that, for $159, an Oakland company called The Odin will sell you a DIY Crispr kit with which you can, say, insert a jellyfish gene into yeast swabbed from your mouth, so it glows green. Here’s mine.
The affordability and ease that Crispr has brought to gene editing is triggering explosive innovation—and investment—in every industry that involves living things. It’s not only remaking the worlds of biological research and medicine, but also agriculture, pet care, and even the business of curing your hangover. It has transformed gene editing with a speed and thoroughness that’s quite rare, eating other gene-editing technologies in the same way smartphones ate point-and-shoot cameras, MP3 players, and GPS devices. And it’s going to change everything.
DATA POINT
Current price of Crispr on Addgene, the nonprofit DNA warehouse: $65, plus shipping
How Crispr works
Crispr is an acronym that stands for Clustered Regularly Interspaced Short Palindromic Repeats, but don’t worry about remembering that—even half the scientists working with Crispr are hard-pressed to come up with it. All you need to know is that Crispr is a natural molecule found in bacteria that can find a particular sequence of DNA in a cell and cut it with an enzyme called Cas9. Bacteria use Crispr to identify and slice up invading viruses. And in 2012, researchers figured out a way to repurpose Crispr to make precise changes to the DNA of virtually any living thing. Here’s how it works:
With Crispr, scientists can turn off a gene, jump-start a sleeping one, or make it behave differently. They can begin to program life.
Four industries that want to edit genes
Crispr is one of the greatest scientific breakthroughs of the last century, and that has understandably attracted a lot of attention from investors. Gene-editing companies, including those that work with Crispr, raised $3.8 billion in 2018. Most of them focus on one of four industries.
Biomedical research:We only know what a tiny fraction of genes do, but Crispr is quickly changing that by allowing scientists to easily turn off any gene they want, one by one, like flicking circuit breakers in the basement to see which lights go out.
Crispr is so cheap and easy to use that it is transforming research in every biological field, as can be seen in the number of papers citing Crispr that have been published each year:
As Crispr has risen, two slower and less flexible competing technologies, ZFNs and Talens, have flat-lined:
The agriculture industry: As we gain the ability to precisely control genes, we’re no longer limited to the designs nature has offered. Agriculture needn’t rely on traditional (and slow) breeding programs. We can tweak the exact trait we want. Crispr can be used to give crops better disease resistance or drought tolerance, improved nutritional content, superior flavor, and higher yields. Most recently, scientists have suggested using Crispr to make spicy tomatoes.
Biotech and human therapeutics: Most diseases that involve genes—which is pretty much all of them—will eventually be treated with gene-editing. Some, like beta thalassemia and sickle-cell anemia, already are. Instead of today’s drugs, which mostly treat the symptoms of disease, gene-editing allows us to fix the underlying problem—sometimes in a single treatment.
Industrial biology: Microorganisms can be powerful industrial workhorses. (Think about the yeast used to make wine and beer.) With gene editing, companies can tweak them to produce many valuable molecules, from biofuels and industrial chemicals to flavors and fragrances.
Crispr still ain’t perfect
Though venture capitalists and scientists agree that Crispr has vast potential, the technology itself still needs improvement before it should be used in people.
Crispr makes lots of mistakes, often editing genes that resemble the gene it was supposed to target—changes that can lead to cancer or other diseases. It’s also very difficult to deliver Crispr to millions of cells inside a body.
Most experts expect these problems to be solved eventually, leading to blockbuster medicines, but it’s good to remember that these approaches are brand new. Until a Crispr therapy actually succeeds in the marketplace, picking winners and losers is wildly speculative. The only three Crispr medical companies to go public have been on a roller-coaster ride, surging and plunging with every new report of Crispr’s successes and failures. Expect that to continue.
The major players
Gene therapy is Crispr’s most obvious application. Many human diseases are caused by a single faulty gene, including muscular dystrophy, Huntington’s disease, cystic fibrosis, sickle-cell anemia, and some cases of blindness. All are within Crispr’s sights.
Crispr Therapeutics was the first gene therapy company out of the gate, beginning European clinical trials of its Crispr-based treatment for the blood disorders beta thalassemia and sickle-cell anemia in November 2018, with US clinical trials to follow in 2019 and a potential market date of 2022.
Hot on Crispr Therapeutics’s heels is Editas Medicine, cofounded by Crispr pioneers Feng Zhang, George Church, and Jennifer Doudna (though Doudna soon left to focus on her own company, Caribou Biosciences), which also received approval from the Food and Drug Administration (FDA) in late 2018 to begin clinical trials of its Crispr drug to treat a previously untreatable form of genetic blindness. The trial will be the first to inject Crispr inside human subjects. Editas has additional ocular therapies in the pipeline, as well as a partnership with Juno Therapeutics to develop Crispr-based cancer therapies, and a treatment for sickle-cell anemia and beta thalassemia that will be injected into the body, unlike Crispr Therapeutics’ approach (which involves removing the blood cells, Crispr-ing them, and then returning them to the body).
The third major Crispr company, Intellia Therapeutics, is a year behind its competitors in the race to clinical trials, but it has powerful partners for its liver disease treatments in Novartis and Regeneron.
Three names to know
One thing you notice when you survey the Crispr state of play is that the same three names keep coming up: Jennifer Doudna of the University of California-Berkeley, Feng Zhang of the Broad Institute of MIT and Harvard, and George Church of Harvard Medical School. Doudna and her colleague Emmanuelle Charpentier invented the basic method for turning Crispr into a gene-editing tool; Zhang invented the method for using it in mammalian cells; and Church has invented multiple ways to make it work better and faster. Zhang and Church also work at two elite institutions—the Broad Institute (insider tip: say brode) and the Wyss Institute for Biologically Inspired Engineering (say vees) that pioneered the process of fast-tracking the commercialization of scientific discoveries, and Berkeley is quickly catching up, so it’s no surprise so many Crispr ventures lead back to them. Doudna, Zhang, and Church and their grad students constantly turn their research into new startups, and it probably won’t be long before the three are sharing the stage in Stockholm for the awarding of the Nobel Prize.
Cancer is the ultimate genetic disease
Most of the diseases being tackled with Crispr in these early days are low-hanging fruit—fairly rare diseases with no known cures and relatively simple genetic fixes. The real blockbuster would be a successful cancer treatment—and early signs are good.
In 2017, the FDA approved a revolutionary new type of cancer treatment for leukemia and lymphoma known as CAR-T. Many cancers are able to proliferate unchecked by the body’s own immune system due to mutations that prevent T cells—the immune system’s policemen—from recognizing them. In CAR-T therapy, a patient’s own T cells are removed and a gene is inserted that allows those cells, once added back into the body, to recognize and eliminate the cancer cells. Many critically ill patients have achieved complete remission with CAR-T, but the treatment is currently done with a clunky, pre-Crispr form of gene-editing that takes weeks to prepare, costs hundreds of thousands of dollars, and has to rely on the already hobbled T cells from weakened patients.
A new Crispr CAR-T should solve these problems. It can use engineered T cells from any healthy donor, so instead of having to extract and modify cells from the patient, Crispr T cells would be off-the-shelf and much cheaper. Editas has teamed with Juno Therapeutics (later acquired by Celgene) to develop a Crispr CAR-T treatment for multiple myeloma and solid tumors. Intellia and Novartis are also working on Crispr CAR-T. Meanwhile, Crispr Therapeutics has several therapies in the pipeline targeting lymphoma, multiple myeloma, and other cancers, and will begin clinical trials in 2019. We could see a dozen Crispr CAR-T drugs hit the market in the next five years.
Ag is the easy money
The path to profitability with Crispr gets a whole lot easier once you take humans out of the picture. The first Crispr crop, a type of corn in development by DuPont, for use as a starchy thickener, which will have improved yields over its predecessors, should hit the market in 2020. Within a few years, Crispr and other gene-editing techniques will completely replace GMOs, which were always a mixed bag: Though genetically modified crops like Roundup Ready corn and soybeans were embraced enthusiastically by farmers, they were distrusted by some consumers and highly regulated by the USDA. But the USDA has ruled that crops edited with Crispr or other gene-editing techniques, as long as they don’t introduce any foreign genes, are not considered GMOs and don’t require any additional regulation or labeling. Bonanza!
Want a mushroom or an apple that doesn’t discolor after slicing? Just turn off its browning gene. Crispr has been used to make more flavorful tomatoes and strawberries, naturally decaffeinated coffee beans, non-allergenic wheat, and disease-resistant pigs, grapes, bananas, and cacao. Researchers have supersized sweet potatoes and ground cherries—delicious wild fruits that were always too small and low-yielding for commercial cultivation. Calyxt, the Minnesota-based giant of crop gene-editing (using both Crispr and other techniques), has more than a dozen products in the pipeline, from healthier soybeans and potatoes to low-gluten wheat.
An even bigger gene-edited agricultural innovation isn’t something you eat at all. It’s a microbe called Proven that farmers apply in their furrows with their corn seed. The microbe, which grows symbiotically on the corn roots, has been engineered to pull nitrogen from the atmosphere and feed it to the corn, reducing the need to apply chemical fertilizer, which is a massive source of global warming and water pollution. The microbe was invented by Pivot Bio, a Berkeley startup that raised $70 million in Series B funding in 2018 and announced a partnership with Bayer to create nitrogen-fixing microbes for soybeans. After performing well in thousands of test plots in 2017 and 2018, Proven is on the market in select states in 2019.
Pets are people with less regulation
That’s the idea behind Rejuvenate Bio, a stealth startup cofounded by Harvard’s George Church in 2018. Dozens of gene therapies—many Crispr-based—have effectively extended the lifespans of lab animals by either turning off genes that become dangerous with age or restarting genes that tend to falter with age. Bringing any of those treatments to market for people is a very lengthy and expensive process because of FDA regulations. But doing it for dogs and other pets involves far less regulation or expensive clinical trials—and dogs are a huge market in themselves. Rejuvenate Bio believes it can reverse aging in many dogs through gene therapies, building a thriving business in the process, and then eventually bring those therapies to humans. It has begun by treating a common heart defect in Cavalier King Charles Spaniels for free.
Beyond slice and dice
Perhaps the craziest thing of all about Crispr is that, as revolutionary as it is, the technology is still only a small start of a much bigger revolution: The ability to read and write genetic code.
The first application of Crispr was a customized version of what it does in nature: Look for a specific sequence of DNA and cut it with an enzyme called Cas9. But the more we play around with Crispr, and the more different enzymes we discover that we can attach to it, the more new applications we invent.
The original Crispr could become obsolete
Since the original discovery of Crispr-Cas9, dozens of other Crispr versions have been discovered and invented. One can silence a gene without cutting it. Another version called Crispr-Cas13 edits RNA (which is temporary and reversible) instead of DNA. Another type of Crispr, invented by Feng Zhang and David Liu of the Broad Institute, can change a single letter of DNA or RNA without making any cuts at all. This could solve Crispr’s issues with off-target cuts and faulty repairs. And while changing one letter of DNA doesn’t sound like much, many diseases, including sickle-cell anemia and cystic fibrosis, are caused by just such a single-letter mutation. That technology is being commercialized by Beam Therapeutics, an Editas spinoff that launched in 2018 with $87 million of Series A funding.
Remember that it is very early in the Crispr story. If Crispr Therapeutics is MySpace, Beam might just be Facebook.
Crispr is a nanotechnology
At heart, Crispr is a molecule-sized, programmable nanobot. That insight led Feng Zhang and two of his students at the Broad Institute to invent Sherlock (Specific High-sensitivity Enzymatic Reporter unLOCKing), a Crispr system that triggers a visible signal when it detects a particular genetic sequence. This causes a line to form on a paper strip dipped in the sample, just like a pregnancy test. Whereas previously detecting the presence of a virus like dengue or Zika required refrigerating a sample and bringing it to a centralized lab, Sherlock can be used in an hour at ambient temperature. This could revolutionize field work, especially in the developing world, and transform the $40 billion global diagnostics market.
Sherlock can also be used to identify particular strains of cancer, environmental pathogens, or any other living substance. In addition to healthcare, it could be used by farmers to detect crop pathogens, or the food services industry to detect the presence of pathogens that cause food-borne illness.
Sherlock already has competition from Mammoth Biosciences, a Berkeley startup cofounded by Jennifer Doudna, which is developing a version called Detectr that works with a credit-card-sized device that instantly uploads sample results to a smartphone.
It’s not just editing: reading and writing new DNA is also getting easier
The Human Genome Project, launched in 1990, needed 13 years and $3 billion to sequence the first human genome. Now you can get your complete genetic code delivered to your cell phone in eight weeks for $999, and experts say the $100 genome is nigh. Tens of thousands of organisms have been sequenced. And the more code we look at, the more we can begin to understand it—and learn to write our own.
The cost of manufacturing DNA has fallen nearly as fast as the cost of sequencing it. Ten years ago, it cost $10,000 to synthesize a gene. Now it can be done for the price of a tuna wrap.
For comparison, this beats Moore’s Law, which means that the power of programming with DNA is rising even faster than the power of computers. In other words, what happened to computers in a generation (room-sized mainframes to globally connected smartphones) is now happening to biology.
As the price of DNA continues to plunge, eventually we’ll be able to create new organisms without using Crispr at all.If Crispr is like being able to take scissors to the pages of an existing manuscript and cut and paste words where you want them, DNA synthesis is like writing a new document on your laptop and printing it out. Got an idea for a new animal? Just print its genome.
The current leader in DNA synthesis is Twist Bioscience, a Bay Area startup that has raised $259 million in funding since it opened its doors in 2013, including $70 million in its 2018 IPO. It has a new generation of startups nipping at its heels, including Evonetix, Synthomics, and DNA Script.
The dark side of Crispr
Biology is potentially the most formidable technology the planet has ever seen, can easily be put into the hands of millions of people, and is still not well understood. Unsurprisingly, this keeps many experts up at night. They tend to worry about three things: bioweapons, gene drives, and designer babies.
Engineered plagues
Bioweapons sound like the scariest of the three, but they are probably of the least concern. The idea of somebody engineering a virus like Ebola or even the flu to be more lethal or virulent, and then unleashing it upon the world, sounds like the worst of all nightmares. But experts think it isn’t very likely. Mother Nature is constantly tinkering away on things like virulence in her evolutionary workshops; if a killer virus was within easy reach, she’d have already found it. The level of knowledge required to design significantly deadlier bioweapons is still years beyond us.
Gene drives
Because Crispr is made from natural biological molecules, it can be built right into a gene and passed down to offspring. A gene drive is a Crispr system built into an organism that guarantees inheritance of a particular gene by all generations of its offspring. When offspring inherit a Crispr gene drive from one parent, it cuts the opposite gene (inherited from the other parent) and copies itself in place, so that individual has two copies of the gene drive and is guaranteed to pass one down to all offspring, where the same thing happens.
Agricultural enterprises would love to destroy entire populations of weeds and pests by building a toxic gene drive into a few individuals and releasing them into the wild. Kevin Esvelt, the MIT scientist who first saw how Crispr could be used to build a gene drive, has proposed using one to make all the white-footed mice in the Northeast US immune to Lyme disease, breaking the cycle of transmission. In the UK, Target Malaria (with funding from the Gates Foundation) has already built a gene drive into Anopheles gambiae, one species of the mosquito that carries malaria. The drive kills all female offspring. The males keep passing the female-killing gene down through the generations, until there are no females left and the population collapses, in theory taking malaria with it. Right now it’s working well in the lab.
Many people worry about the ethics of using gene drives to intentionally force a species, even a troublesome one, to extinction, and about the unintended consequences of releasing a gene drive into the natural world. Esvelt recently proposed that gene drives be allowed only for noncommercial purposes. Expect corporate interests to feign disinterest while the technology matures, but keep your eye on them.
DATA POINT
Number of labs using Crispr around the world: 100,000
Look Honey, I edited the kids
The third of the three big fears, designer babies, is of course here now. In November, a rogue Chinese scientist announced that he’d used the gene-editing tool Crispr to alter the genomes of twin girls in an effort to make them immune to the HIV virus.
Crispr’s biggest challenge—how to deliver it into the trillions of existing cells in an adult body—disappears when you edit an embryo in a dish. The modified genome in that first cell becomes the template for all the rest as the organism grows—and gets passed down to future generations.
We’ve done that with lots of organisms, from dogs to pigs, but nearly everyone agreed that it would be unethical to try it in people right now. Crispr makes too many mistakes that could introduce new genetic diseases. And once we start customizing our kids’ genes, will we know when to stop? Will we just use Crispr to eliminate heritable diseases, or will we be tempted to make our kids more talented or better looking? Do the rich not only get richer, but healthier, smarter, and better looking too?
That’s why the scientific world freaked out when He Jiankui, the Chinese doctor, announced the birth of his Crispr twins. It felt too soon. Most countries will probably agree to a moratorium on human germline editing for now. But with the capabilities well within the reach of any sophisticated fertility clinic, and the temptation for a spot in the history books so strong, we will probably see more He Jiankuis in the coming years.