This company plans to transplant gene-edited pig hearts into babies next year

The baby baboon is wearing a mesh gown and appears to be sitting upright. “This little lady … looks pretty philosophical, I would say,” says Eli Katz, who is showing me the image over a Zoom call.

This baboon is the first to receive a heart transplant from a young gene-edited pig as part of a study that should pave the way for similar transplants in human babies, says Katz, chief medical officer at the biotech company eGenesis.

The company, based in Cambridge, Massachusetts, has developed a technique that uses the gene-editing tool CRISPR to make around 70 edits to a pig’s genome. These edits should allow the organs to be successfully transplanted into people, the team says. As soon as next year, eGenesis hopes to transplant pig hearts into babies with serious heart defects. The goal is to buy them more time to wait for a human heart. 

Before that happens, the team at eGenesis will practice on 12 infant baboons. Two such surgeries have been performed so far. Neither animal survived beyond a matter of days.

But the company is optimistic, as are others in the field. Many recipients of the first liver transplants didn’t survive either—but thousands of people have since benefited from such transplants, says Robert Montgomery, director of the NYU Langone Transplant Institute, who has worked with rival company United Therapeutics. Babies born with heart conditions represent “a great population to be focusing on,” he says, “because so many of them die.”

Editing risk

Over 100,000 people in the US alone are waiting for an organ transplant. Every day, around 17 of them die. Researchers are exploring multiple options, including the possibility of bioprinting organs or growing new ones inside people’s bodies. Transplanting animal organs is another potential alternative to help meet the need.

The idea of using organs and tissues from animals, known as xenotransplantation, is an old one—the first experiments were performed back in the 17th century. More recent attempts were made in the 1960s, and again in the 1990s. Many of these used organs from monkeys and baboons. But toward the start of the 1990s, a consensus emerged that pigs were the best donor candidates, says Montgomery. 

Primates are precious—they are intelligent animals that experience complex emotions. Only a small number can be used for human research, and at any rate, they reproduce slowly. They are also more likely to be able to pass on harmful viruses. On the other hand, people already know a lot about how to rear and farm pigs, and their organs are about the right size for humans.

But transferring organs between animals of different species isn’t straightforward. Even organs from another human can be rejected by a recipient’s immune system, and animal tissues have a lot more components that our immune systems will regard as “foreign.” This can cause the organ to be attacked by immune cells. There’s also the possibility of transferring a virus along with the organ, for example. Even if a donor animal isn’t infected, it will have “endogenous retroviruses”—genetic code for ancient viruses that have long since been incorporated into its DNA.

These viruses don’t cause problems for their animal hosts. But there’s a chance they could cause an infection in another species. “There’s a risk that viruses that are endemic to animals evolve in a human and become deadly,” says Chris Gyngell, a bioethicist at Murdoch Children’s Research Institute in Melbourne, Australia.

The team at eGenesis is using CRISPR to address this risk. “You can use CRISPR-Cas9 to inactivate the 50 to 70 copies of retrovirus in the genome,” says Mike Curtis, president and chief executive officer at eGenesis. The edits prevent retroviruses from being able to replicate, he says.

Scientists at the company perform other gene edits, too. Several serve to “knock out” pig genes whose protein products trigger harmful immune responses in humans. And the team members insert seven human genes, which they believe should reduce the likelihood that the organ will be rejected by a human recipient’s immune system. In all, “we’re producing [organ] donors with over 70 edits,” says Curtis.

The team performs these edits on pig fibroblasts—cells that are found in connective tissue. Then they take the DNA-containing nuclei of edited cells and put them into pig egg cells. Once an egg is fertilized with sperm, the resulting embryo is implanted into the uterus of an adult pig. Eventually, cloned piglets are delivered by C-section. “It’s the same technology that was used to clone Dolly back in the ’90s,” says Curtis, referring to the famous sheep that was the first animal cloned from an adult cell.

eGenesis has around 400 cloned pigs housed at a research facility in the Midwest (he is reluctant to reveal the exact location because facilities have been targeted by animal rights protesters). And early last year, the company set up a “clean” facility to produce organs fit for humans. Anyone who enters has to shower and don protective gear to avoid bringing in any bugs that might infect the pigs. The 200 pigs currently at this center live in groups of 15 to 25, says Curtis: “It’s basically like a very clean barn. We control all the feed that comes in, and we have waste control and airflow control.” There’s no mud.

The pigs that don’t end up having their organs used will be closely studied, says Curtis. The company needs to understand how the numerous gene edits they implement affect an animal over the course of its life. The team also wants to know if the human genes continue to be expressed over time. Some of the pigs are over four years old, says Curtis. “So far, it looks good,” he adds. 

EGENESIS

Complications

When it comes to organ transplants, size is important. Surgeons take care to match the size of a donor’s heart to that of the recipient. Baby baboons are small—only hearts taken from pigs aged one to two months old are suitable, says Curtis. Once they are transplanted, the hearts are expected to grow with the baboons.

The first baboon to get a pig heart, which was just under a year old, died within a day of surgery. “It was a surgical complication,” says Curtis. The intravenous tube providing essential fluids to the baboon became blocked, he says. “The animal had to be euthanized.”

A second baboon was operated on a few months later. The team encountered another surgical complication: this time, the surgeons couldn’t get the baboon’s blood vessels to stay attached to those in the pig’s organs. The baboon died nine days after the operation.

In both cases, “the heart itself was beating well,” says Curtis. “So far, the first two are very encouraging from cardiac performance … the hearts look good.” The surgeons who performed the operations are confident they’ll be able to avoid the surgical complications in the future, he says.

Tough decisions

Once the baboon trial is completed, the team at eGenesis wants to offer the pig hearts to babies under the age of two who were born with severe heart conditions. Such children have limited treatment options—human hearts of the right size are few and far between, and some of the devices used to treat heart conditions in adults aren’t suitable for little children with small hearts.

Curtis hopes the pig hearts could initially be used as a temporary measure for such children—essentially buying them more time to wait for a donated human heart. Once a potential recipient has been found, the company can seek approval for the surgery from the US Food and Drug Administration.

Ethicists will point out that babies won’t be able to give informed consent for surgery. That decision will come down to their caregiver, who will likely be in a dire situation, says Syd Johnson, a bioethicist at Upstate Medical University in Syracuse, New York. “These are parents who are desperate for anything that might save their child’s life,” she says.

But Gyngell thinks the focus should be on who has the most to gain from an experimental procedure like this. “The fact is that pediatric patients have a greater clinical need, because there are far fewer other options available to them,” he says.

Montgomery, who is himself the recipient of a donated human heart, agrees. He says he supports eGenesis’s goals. “These babies that have congenital heart disease … have a 50% mortality rate,” he says. “It’s a flip of a coin whether that kid is going to live or not.”

That reasoning doesn’t wash with Johnson. The procedure is risky, and a child whose immune system rejects the organ could suffer, she says: “One hundred percent of the patients who’ve been transplanted with an animal organ have died [soon after the procedure]—that’s just an inescapable fact.” David Bennett Sr., who was the first living person to receive a gene-edited pig heart, in 2022, died two months later. 

There are more risks when using organs from gene-edited animals, says Johnson. We still don’t know if these genetic modifications might affect human recipients, especially in the long term. “The desire to do something to save these babies [with heart conditions] is obviously very strong for everyone who is involved,” she says. “But we still need to be honest and transparent about what the risks are—and they are, to some extent, unknown.”

Montgomery himself has transplanted gene-edited pig organs into adults who have been declared brain dead. Those organs—which include kidneys and, in unpublished work, hearts—were from pigs bred by the rival company Revivicor, which was acquired by United Therapeutics. The experiments ran for just two or three days, but Montgomery plans to run a similar experiment in individuals who will be studied for a month after the transplant. So far, he says, “we’ve got very good results.”

He believes young children may be better candidates for pig organs than adults, because their immune systems are still developing and therefore might be less likely to reject the organ. “They may well have some level of tolerance,” he says.

A third baboon is due to receive a pig heart in August. The company plans to perform at least one such operation a month until 12 animals have been operated on. The team members hope they’ll be able to fix the surgical issues and enable the baboons to live longer. Some other non-human primates that have received kidneys from the gene-edited pigs have already survived over a year, says Curtis.

“When you’re pioneering something new, there’s a steep learning curve,” Montgomery says.

More than 200 people have been treated with experimental CRISPR therapies

This article is from The Checkup, MIT Technology Review’s weekly biotech newsletter. To receive it in your inbox every Thursday, sign up here.

I’ve spent the last few days thinking about how, when, and if we should use gene-editing tools to change the human genome. These are huge questions, and very emotive ones—especially when it comes to editing embryos.

I watched scientists, ethicists, patient advocacy groups, and others wrestle with these topics at the Third International Summit on Human Genome Editing in London earlier this week.

There’s plenty to get excited about when it comes to gene editing. In the decade since scientists found they could use CRISPR to edit cell genomes, multiple clinical trials have sprung up to test the technology’s use for serious diseases. CRISPR has already been used to save some lives and transform others.

But it hasn’t all been smooth sailing. Not all of the trials have gone to plan, and some volunteers have died. Successful treatments are likely to be expensive, and thus limited to the wealthy few. And while these trials tend to involve changes to the genes in adult body cells, some are hoping to use CRISPR and other gene-editing tools in eggs, sperm, and embryos. The specter of designer babies continues to loom over the field.

It was at the last summit, held in Hong Kong in 2018, that He Jiankui, then based at the Southern University of Science and Technology in Shenzhen, China, announced that he had used CRISPR on human embryos. The news of the first “CRISPR babies,” as they became known, caused a massive ruckus, as you might imagine. “We’ll never forget the shock,” Victor Dzau, president of the US National Academy of Medicine, told us.

He Jiankui ended up in prison and was released only last year. And while heritable genome editing was already banned in China at the time—it has been outlawed since 2003—the country has since enacted a series of additional laws designed to prevent anything like that from happening again. Today, heritable genome editing is prohibited under criminal law, Yaojin Peng of the Beijing Institute of Stem Cell and Regenerative Medicine told the audience.

There was much less drama at this year’s summit. But there was plenty of emotion. In a session about how gene editing might be used to treat sickle-cell disease, Victoria Gray, a 37-year-old survivor of the disease, took to the stage. She told the audience about how her severe symptoms had disrupted her childhood and adolescence, and scuppered her dreams of training to be a doctor. She described episodes of severe pain that left her hospitalized for months at a time. Her children were worried she might die.

But then she underwent a treatment that involved editing the genes in cells from her bone marrow. Her new “super cells,” as she calls them, have transformed her life. Within minutes of receiving her transfusion of edited cells, she felt reborn and shed tears of joy, she told us. It took seven to eight months for her to feel better, but after that point, “I really began to enjoy the life that I once felt was just passing me by,” she said. I could see the typically stoic scientists around me wiping tears from their eyes.

Victoria is one of more than 200 people who have been treated with CRISPR-based therapies in clinical trials, said David Liu of the Broad Institute of MIT and Harvard, who has led the development of new and improved forms of CRISPR. Trials are also underway for a range of other diseases, including cancers, genetic vision loss, and amyloidosis.

Liu highlighted the case of Alyssa, a teenager in the UK who was diagnosed with a form of leukemia that affects a type of white blood cells called T cells. Chemotherapy didn’t work, and neither did a bone marrow transplant. So doctors at Great Ormond Street Hospital in London tried a CRISPR-based approach.

It involved taking healthy T cells from a donor and using CRISPR to modify them. The treated cells were altered so that they wouldn’t be rejected by Alyssa’s immune system, but they would be able to track down and attack Alyssa’s own cancerous T cells. These cells were then given to Alyssa as a treatment. It seems to have worked.

“As of now, approximately 10 months after treatment, her cancer remains undetectable,” Liu said.

It really is incredible that we are hearing such success stories already. But there are concerns.

The question of equity came up again and again at the summit. Gene-editing therapies are expected to cost a lot of money—likely millions of dollars. Who will be able to afford them? Probably not the people living in low- and middle-income countries, multiple attendees worried.

For now, CRISPR therapies are still considered experimental, and none have been approved, so the only way for people to access them is through clinical trials. The majority of these are being run in the rich world. Natacha Salomé Lima, a psychologist and bioethicist at the University of Buenos Aires in Argentina, pointed out that while 70% of global cancer cases are in low- and middle-income countries, two-thirds of gene-therapy cancer trials are taking place in wealthy countries.

I could tell that the summit’s organizers had made an effort to feature speakers from all over the world, and to include people who have the disorders being targeted by gene editing. But some attendees felt that some voices were still missing from the discussion. “What about the LGBTQ community?” Marc Dusseiller of ETH Zurich in Switzerland, who describes himself as a “workshopologist” interested in biohacking and bio art, asked me.

It’s also worth pointing out that not all CRISPR treatments have been a success. Multiple researchers noted that we still don’t fully understand how the treatment works. We know we can cut DNA, and swap either DNA bases or chunks of genetic code. But we can’t be sure about unintended effects elsewhere in the genome. It’s possible that you could accidentally trigger some genetic change elsewhere—one that might have harmful consequences.

Last year, 27-year-old Terry Horgan died while participating in a clinical trial of a CRISPR treatment designed to treat his Duchenne muscular dystrophy, a fatal disease that causes muscle degeneration. The cause of his death—and whether or not it might have been related to the treatment—has not been made clear.

And there’s always a risk that rogue scientists will set up companies offering unapproved procedures to desperate individuals who are willing to pay for them, said Robin Lovell-Badge, a stem-cell biologist at the Crick Institute, where the summit took place. They might even sell unauthorized procedures designed to enhance people rather than treat them.

On the first day of the summit, a couple of protesters stood at the entrance of the venue, holding a banner reading “Stop designer babies.” This sentiment is shared by a lot of scientists. They are particularly worried about future attempts to edit the genes of eggs, sperm, or embryos.

In theory, you could change the DNA of an embryo to prevent a baby from developing a heritable disease. But research into early embryos (scientists are generally allowed to study them for only 14 days before having to destroy them) suggests that they are even more likely to be affected by unintended, potentially harmful effects of gene editing. And these changes would be passed on to the next generation, too.

Most attendees focused on technical and ethical worries, but Dusseiller had another concern. The summit was too dry, he told me; the serious issues surrounding gene editing can be addressed with some degree of humor. “We need more weirdness,” he argued. “We need more jokes.”

Read more from Tech Review’s archive

There are more than 50 experimental studies underway that use gene editing in people to treat cancer, HIV, blood diseases, and more. Most of them involve CRISPR, my colleague Antonio Regalado reported earlier this week.

And last year, a volunteer in New Zealand became the first to receive an experimental CRISPR treatment to lower her cholesterol. One of the scientists behind the work thinks the approach could potentially benefit almost everyone.

CRISPR is also being explored for an inherited form of blindness. The first volunteer underwent the experimental treatment in 2020.

He Jiankui’s work was never published. It was rejected by the leading medical journals it was submitted to. But Antonio got hold of the manuscript, and showed it to four experts. Their verdicts were damning. He’s claims were not supported by his results, the babies’ parents may have been under pressure to agree to join the experiment, and the researchers went ahead without fully understanding what they were doing.

The summit was focused on human genome editing, but CRISPR is also being explored to make farmed animals bigger and stronger. One team of scientists has put an alligator gene into catfish in an attempt to make them more resistant to disease, for example.

From around the web

A microbiologist found a forgotten beef soup at the back of her fridge had turned bright blue. So she set out on a scientific quest to find out why. (Twitter)

Governments around the world are using algorithms to control access to various services. A system that flags people who might be committing benefits fraud in Rotterdam appears to discriminate on the basis of ethnicity and gender, according to an investigation. (Wired)

Last year, biotech company Retro Biosciences announced its launch with $180 million in funding. It turns out that all of that is from Sam Altman, the CEO of OpenAI. (MIT Technology Review)

Makena, a drug approved to prevent preterm birth, has been voluntarily pulled from the market by the company that makes it. Several studies have shown that the drug doesn’t work, and the US Food and Drug Administration recommended that it be withdrawn back in 2020. (The New York Times)

Forget designer babies. Here’s how CRISPR is really changing lives

Forget about He Jiankui, the Chinese scientist who created gene-edited babies. Instead, when you think about gene editing you should think of Victoria Gray, the African-American woman who says she’s been cured of her sickle-cell disease symptoms. 

This week in London, scientists are gathering for the Third International Summit on Human Genome Editing. It’s gene editing’s big event, where researchers get to awe the audience with their new ability to modify DNA—and ethicists get to worry about what it all means. 

The event got underway Monday with a look back at what organizers called the technology’s “misuse” in China to create designer babies in 2018. That was certainly an ethical dumpster fire and raised profound questions about whether we should meddle in evolution.

But the designer-baby debate is a distraction from the real story of how gene editing is changing people’s lives, through treatments used on adults with serious diseases. 

In fact, there are now more than 50 experimental studies underway that use gene editing in human volunteers to treat everything from cancer to HIV and blood diseases, according to a tally shared with MIT Technology Review by David Liu, a gene-editing specialist at Harvard University. 

Most of these studies—about 40 of them—involve CRISPR, the most versatile of the gene-editing methods, which was developed only 10 years ago. 

That is where Gray comes in. She was one of the first patients treated using a CRISPR procedure, in 2019, and when she addressed the group in London, her story left the room in tears. 

“I stand here before you today as proof miracles still happen,” Gray said of her battle with the disease, in which misshapen blood cells that don’t carry enough oxygen can cause severe pain and anemia.

But Gray’s case also shows the obstacles facing the first generation of CRISPR treatments, sometimes referred to as “CRISPR 1.0.” They will be hugely expensive and tricky to implement, and they could be quickly superseded by a next generation of improved editing drugs.

The company developing Gray’s treatment, Vertex Pharmaceuticals, says it’s treated more than 75 people in its studies of sickle cell, and a related disease, beta-thalassemia, and that the therapy could be approved for sale in the US within a year. It is widely expected to be the first treatment using CRISPR to go on sale. 

Vertex hasn’t said what it could cost, but you can expect a price tag in the millions.

A revelation

Researchers say the technique’s march forward to use in medicine has been remarkably fast. “I think CRISPR [has] outpaced every previous genomic therapy technology,” says Fyodor Urnov, a researcher at the University of California, Berkeley.

To scientists, CRISPR is a revelation because of how it can snip the genome at specific locations. It’s made up of a cutting protein paired with a short gene sequence that acts like GPS, zipping to a predetermined spot in a person’s chromosomes. 

What’s more, it’s trivially easy to change that GPS sequence, says Jennifer Doudna, the Berkeley biochemist who shared a Nobel for inventing the method. ​​“CRISPR is a technology that enables changes to DNA that are programmed,” she reminded the audience at the summit. 

Along with Vertex, a wave of biotech companies, like Intellia, Beam Therapeutics, and Editas Medicine, are hoping they can use this technology to develop successful treatments. Many of them are running the trials on Liu’s list. But not all of these trials will be successful.

For instance, in January the San Francisco biotech Graphite Bio had to stop its own tests of a gene-editing treatment for sickle-cell after its first patient’s blood cell counts dropped dangerously. The problem was caused by the treatment itself. Graphite’s stock has plunged more than 90%, and now the firm’s future is in question.

The trick facing all these efforts remains getting CRISPR where it needs to go in the body. That’s not easy. In Gray’s case, doctors removed bone marrow cells and edited them in the lab. But before they were put back in her body, she underwent punishing chemotherapy to kill off her remaining bone marrow in order to make room for the new cells.

LLUIS MONTOLIU

In essence, the Vertex treatment requires a bone marrow transplant. That is an ordeal in itself, and not every patient will be ready for it. Vertex thinks the treatment will be suitable for “severe” cases, a market it estimates includes 32,000 people in Europe and the US.

Even then, patients won’t get the treatments if insurers and governments balk at paying. It’s a real risk. For instance, a different gene therapy for beta-thalassemia, developed by Bluebird Bio, was pulled out of the European market after governments there refused to pay the $1.8 million price.  

CRISPR 2.0

The first generation of CRISPR treatments are also limited in another way. Most use the tool to damage DNA, essentially shutting off genes—a process famously described as “genome vandalism” by Harvard biologist George Church.

Treatments that attempt to break genes include one designed to try to zap HIV. Another is the one Gray got. By breaking a specific bit of DNA, her treatment unlocks a second version of the hemoglobin gene that people normally use only as babies. Since hemoglobin is the errant protein in sickle-cell, booting up another copy solves the problem.

According to Liu’s analysis, two-thirds of current studies aim at “disrupting” genes in this way.

Liu’s lab is working on next-generation gene-editing approaches. These tools also employ the CRISPR protein, but it’s engineered not to cut the DNA helix, but instead to deftly swap individual genetic letters or make larger edits. These are known as “base editors.”

According to Lluís Montoliu, a gene scientist at Spain’s National Center for Biotechnology, these new versions of CRISPR have “lower risk and better performance,” although delivering them “to the right target cell in the body” remains difficult. 

At his lab, Montoliu is using base editors to cure mice of albinism, in some cases from birth. It’s a step, he says, toward a treatment newborn humans could receive, although not to change their skin color. Instead, he dreams of putting Liu’s molecules in their eyes to correct severe vision problems that albinism can cause. 

So far, though, the albinism project is not a commercial venture. And that points to one of the biggest limits on CRISPR’s impact now and in the foreseeable future. Nearly all CRISPR trials underway aim at either cancer or sickle-cell disease, with multiple companies chasing the exact same problems.

According to Urnov, this means thousands of other inherited diseases that could be treated with CRISPR are just being ignored. “This is near-entirely due to the fact that most of them are too rare to be a viable commercial opportunity,” he says.  

At the London meeting, however, Urnov will be presenting his ideas on how treatments could be tested even for ultra-rare diseases, including some genetic conditions so unusual they affect just one person. 

That’s not a commercial opportunity, but because of how CRISPR can be programmed to go anywhere in the genome, it’s scientifically possible. Now that gene editing has had its first successes, Urnov says, there’s an “urgent need” to open a “path to the clinic for all.”

How CRISPR could help save crops from devastation caused by pests

Central California grape-grower Steve McIntyre was familiar with Pierce’s Disease. But that did not prepare him for what he saw when he visited his brother’s Southern California citrus and avocado farm in 1998. The disease, which causes vines to wither and grapes to deflate like old balloons, had long existed in California. But the infection he saw on a farm adjacent to his brother’s property seemed different. 

“It was devastation,” says McIntyre. Blocks of grapes looked as though their irrigation had been entirely cut. On his flight home, McIntyre contemplated calling a realtor to offload his land. His own vines, he thought, were doomed. 

Less than a decade after it was first identified in California, an invasive insect called the glassy-winged sharpshooter had turned the bacterium that causes Pierce’s from a nuisance to a nightmare. The oblong bug, with wings like red-tinged stained glass, is quicker and flies further afield than sharpshooters native to the state, and it can feed on tougher grapevines. Its arrival, which the state suspects was in the late ‘80s, supercharged the spread of the disease. 

RODRIGO KRUGNER/USDA-ARS

Through inspections and targeted pesticide spraying, the state has largely been able to confine the invasive sharpshooter to Southern California. But the disease still has no cure, and it’s at risk of getting worse and harder to combat due to climate change. 

Researchers are now looking to add cutting-edge technology to California’s anti-Pierce’s arsenal, by changing the genome of the glassy-winged sharpshooter so that it can no longer spread the bacterium.  

Such a solution is possible thanks to CRISPR gene-editing technology, which has made modifying the genes of any organism increasingly simple. The technique has been used in experiments in cancer immunotherapy, apple breeding, and—controversially—human embryos. Now a growing number of researchers are applying it to agricultural pests, aiming to control a range of insects that together destroy about 40% of global crop production each year. If successful, these efforts could reduce reliance on insecticides and provide an alternative to genetic modifications to crops.

For now, these gene-edited insects are shut away in labs across the globe, but that is poised to change. This year, a US company expects to start greenhouse tests in conjunction with the US Department of Agriculture (USDA) of fruit-damaging insects made sterile using CRISPR. At the same time, scientists at government and private institutions are beginning to learn more about pest genetics and to make edits in more species.

The use of gene-edited organisms remains controversial, and edited agricultural pests haven’t  been approved for widespread release in the US yet. A potentially lengthy and still-evolving regulatory process awaits. But scientists say CRISPR has ushered in a critical moment for the use of gene edits in insects that impact agriculture, with more discoveries on the horizon. 

“Until CRISPR, the technology simply wasn’t there,” says Peter Atkinson, an entomologist at the University of California, Riverside, who is working on modifying the sharpshooter. “We’re entering this new age where genetic control can be realistically contemplated.” 

Know your enemy

Scientists didn’t know much about the genetics of the glassy-winged sharpshooter until recently. The first draft of its genome was mapped out in 2016, by a group at the USDA and Baylor College of Medicine, in Texas. But the map had gaps. In 2021, researchers at UC Riverside, including Atkinson, filled in many of them to produce a more complete version. 

As scientists set out to gene edit more pest species, a better understanding of their biology and genetics will be important, says Linda Walling, a plant geneticist at UC Riverside who is working on the sharpshooter research. “There’s going to have to be a very big investment in understanding biology,” she says. “All we’ve previously wanted to do is just kill them.”

That understanding goes beyond DNA sequencing. Before making edits, researchers have to figure out what could stop an insect from harming a plant and then determine which edits could make that happen. In the case of the sharpshooter, there was a good candidate in hand: previous research from University of California, Berkeley, has shown that a carbohydrate in the sharpshooter’s mouth makes it easier for Pierce’s-causing bacteria to stick, and pointed to certain molecules scientists could modify to change that. 

ALAMY

Now, a group at UC Riverside, including Atkinson and Walling, is trying to make those changes. 

Part of the challenge is simply finding a way to deliver gene editing machinery to minuscule and fast-developing bug embryos. 

“Delivery is the secret of everything,” says Wayne Hunter, a research entomologist with the USDA who worked on the 2016 draft of the sharpshooter genome.  

Glassy-winged sharpshooter embryos are about 3 mm long. The Riverside team developed a novel way to inject them with CRISPR/Cas9 machinery without removing them from the leaf where they’re laid. The technique, according to a paper published last year, was “simple to perform, as a mass with 20 eggs can be injected within ten minutes by a novice operator.” 

After injection, the team showed that CRISPR technology could cut and change the sharpshooter genome (as a proof of principle, the researchers used the technology to knock out genes that control sharpshooter eye color). Now, the group is working to insert genes in the sharpshooter’s genome that they hope will transform the tissue in the bug’s mouth so that it acts like Teflon, causing Pierce’s-causing bacteria to slide right off. 

The team has received funding from the USDA as well as a board of wine industry representatives specifically convened by California’s government to combat Pierce’s. 

The board, of which McIntyre is a member, supports a range of potential approaches to defeating the disease, including gene editing of grapevines as well as biopesticides, which are usually derived from natural materials. Pierce’s is a “uniquely terrible” problem for grape growers, says Kristin Lowe, the board’s research coordinator. “With most plant pathogens that are [spread] by an insect, you have to exploit any and all weaknesses you can find—in the biology, in the environment, in the ecology of that disease—to get long-term control.” 

Operation fruit fly

Another California-hatched CRISPR technology has already begun the lengthy process toward commercialization for use in an agricultural pest. 

Omar Akbari began using CRISPR as a postdoc in biological engineering at Caltech, soon after the release of a seminal paper on the technology. A decade later, his lab at the University of California, San Diego, uses CRISPR in nearly a dozen insect species. 

One of its subjects is Drosophila suzukii, or spotted wing drosophila, a species of fruit fly that cuts holes in soft, ripe fruit like cherries and plums to lay its eggs. The flies, which spoil about $500 million in US fruit crops every year, have already grown resistant to some pesticides. 

Akbari’s lab has used CRISPR to modify genes in order to create sterile males and kill females. Were those male flies to be released, they’d mingle with normal flies, and their inability to reproduce could depress the overall population. 

Agragene, a company that licensed Akbari’s technology, has raised $5.2 million to commercialize this sterilization method in crop pests. The company is testing the product this year at greenhouses in Oregon. 

The possible strategies for controlling pest populations and the diseases they transmit using CRISPR are numerous. “Your experiment is only limited by your ingenuity, to some degree,” says Nikolay Kandul, who works with Akbari at UC San Diego. 

But researchers must also contend with biology, and the implications of their choices. For certain systems, like Akbari’s fruit fly edits, a change shouldn’t remain in the population unless gene-edited insects continue to be released. “It’s safe, it’s effective, it’s confinable, it’s not going to persist in the environment,” says Akbari. 

Akbari has also worked on another approach that could be more permanent: gene drives. This technique cheats the rules of genetics, increasing an organism’s chance of inheriting certain genes and spreading them through the population. The technology’s potential has drawn excitement as well as concern (there are efforts underway to examine the use of gene drives in mosquitoes to disrupt malaria transmission, but many scientists have pointed out potential risks and urged caution). 

“Chemicals can only travel so far before they degrade in the environment,” says Jason Delborne, a professor of science, policy, and society at North Carolina State University. “If you introduce a gene-edited organism that can move through the environment, you have the potential to change or transform environments across a huge spatial and temporal scale.”

Kandul puts it more bluntly. Gene drives, he says, can be “sloppy.” 

Agragene considered deploying them in fruit flies, but Akbari says executives decided it would be difficult to attract investors and gain regulatory approval. Instead, the company went with the sterilization technology. After completing lab cage tests last year, Agragene is starting greenhouse tests in collaboration with the USDA, ones it hopes will ultimately pave the way for widespread release.

“You’re gathering enough data to show that your sterile insect is, in this case, safe,” says Agragene CEO Bryan Witherbee, who previously worked at Monsanto and other biotech companies. 

The tests Agragene completed last year gave the company confidence that its sterile bugs could survive and function like nonedited bugs, says Witherbee, and the company also worked on techniques to manufacture sterile insects at scale. But Agragene is still determining what data it will need to submit to the US Environmental Protection Agency to get approval to release the bugs, a process that could take years. 

In the US, the regulatory environment around CRISPR-modified insects is currently “evolving,” according to an EPA spokesperson. Government guidance released in 2017 outlined a coordinated approach that suggested the USDA will largely have authority over genetically engineered animals related to agriculture. But jurisdiction may vary depending on whether an edited organism is intended to reduce the population of an insect or disrupt disease transmission. Thus far, the US government has allowed the release of genetically modified mosquitoes, but tests of crop pests, like diamondback moths and pink bollworms, have been limited. 

UC Riverside’s Walling and Atkinson expect that it will take years to refine genetically altered agricultural pests and get approval for their release. Agragene hopes the timeline could be faster: the company, which has already been in communication with the EPA, is targeting 2024 to submit an application for regulatory approval for commercial use of its fruit flies and expects the process to take up to two years. 

Beyond editing

Gene editing insects may be a powerful tactic, but some experts in plant and insect biology see promise in other techniques as well.

For more than a decade, Hunter, the USDA entomologist, has worked on various efforts to map the genome of a pest that causes billions of dollars in damage across six continents each year: the Asian citrus psyllid, which spreads a disease that kills citrus trees, but not before leaving behind yellowed leaves and green, bitter fruit. 

“You really don’t have much to sell even if the tree is alive,” he says.

He’s now part of a large, grant-funded team working on a variety of potential methods to protect trees from citrus greening disease. In the next few years, the group hopes to focus on several products or solutions that can then be commercialized for use in the field.

PEGGY GREB/USDA-ARS; ALAMY

This year, Hunter will start using CRISPR to tweak genes that may neutralize the psyllid as a vector for spreading citrus greening disease. But he says plants modified to resist bacteria are still the most likely solution to deal with the disease. “That’s where the real answer is going to come from,” he says. Targeting insects could leave the disease circulating, albeit in a smaller number of bugs, but plant immunity would blunt the disease’s impact. 

Still, modifying plants has its limitations as a general solution to the agricultural pest problem. Bugs like the spotted wing drosophila impact so many different fruits that producing resistant plant varieties would be exceedingly cumbersome, says Anthony Shelton, professor emeritus at Cornell University’s Department of Entomology who has worked on producing sterile diamondback moths.

When it comes to the age-old struggle between farmers and pests, Shelton says, it’s important to embrace a variety of new tools.   

“I think we’ve all learned enough to know that there’s no silver bullet in agriculture or in medical entomology to try and control pests,” he says. “We’ve all become smarter, hopefully.”

Emma Foehringer Merchant is a journalist who often covers climate change, energy, and the environment. She is based in California.