Lynn Julian Crisci, 40, is an actress, a singer-songwriter, and an ambassador for the U.S. Pain Foundation. She is also a Boston Marathon bombing survivor. Crisci has a genetic disorder called Ehlers-Danlos syndrome (EDS), which has magnified the impact of the traumatic brain injury she sustained as a result of the attack that occurred almost five years ago. Having EDS means that her brain tissue is weaker and more prone to injury.￼
"I would love to learn more about gene editing and the possibilities of using it to lessen the symptoms of EDS, or cure it completely."
"EDS is a genetic tissue disorder that forces the body to make defective collagen," Crisci told LeapsMag. Since collagen is the main component of connective tissue (bones, blood vessels, the gastrointestinal tract, skin, cartilage, etc.), and is the most abundant protein in mammals, EDS can affect virtually every part of the body. "This results in widespread joint pain, usually due to hypermobility, sometimes along with digestive issues such as inflammatory bowel disease, and prolapsed organs."
If life was difficult with Ehlers-Danlos syndrome alone, the addition of the brain injury has made Crisci's life feel unbearable at times. Amidst her week's back-to-back doctor's visits, Crisci said that she would "love to learn more about gene editing and the possibilities of using it to lessen the symptoms of Ehlers-Danlos syndrome, or cure it completely."
With all of the excitement these days around CRISPR, a precise and efficient way to edit DNA that has taken the world by storm, such treatments seem tantalizingly within reach. But is it fair to present the hope of such cures to those with life-limiting genetic disorders?
"From the experience that we've had from gene therapy — we're 20, almost 30 years past some of the initial gene therapy stuff — and there's still not a huge number of applications for it," said Scott Weissman, founder of Chicago Genetic Consultants, a company that provides genetic counseling services to patients. "Unfortunately, we have to wait and see if this is something that's truly viable, or if it's really just hype."
"I expect five years from now we'll look back and say, 'Wow, we were just scratching the surface.'"
Defining Our Terms
The terms "gene therapy" and "gene editing" are often used interchangeably, but not everyone agrees with this usage.
According to Editas Medicine, a leader in CRISPR technology, gene therapy involves the transfer of a new gene into a patient's cells to augment a defective gene, instead of using drugs or surgery to treat a condition. After a teenager's death in 1999 effectively shut down gene therapy research in the U.S., subsequent studies helped the field make a comeback, and the first such treatment for an inherited disease was approved by the FDA just a few weeks ago, for a rare form of vision loss. Called Luxturna, it is for treatment of patients with RPE65-mediated inherited retinal disease (IRD).
Since those with RPE65-mediated IRD typically become blind in childhood and have no pharmacologic treatment options, the FDA's approval of Luxturna is "a significant moment for patients," said Jeffrey Marrazzo, the chief executive officer of the company behind the product, Spark Therapeutics. Two other gene therapy treatments were also approved in the last five months, both for specific cancers.
Gene editing, on the other hand, refers to a group of technologies that enables scientists to precisely and directly change an organism's genes by adding, removing, or altering particular segments of DNA. Gene editing tools include Zinc Finger Nucleases (ZFNs), Transcription Activator-Like Effector Nucleases (TALENs), and CRISPR/Cas9. The first treatment using ZFNs happened in November in California, when a 44-year-old man with a metabolic ailment called Hunter syndrome was injected with gene editing tools. Results are not yet known.
Dr. David Valle, director of the Institute of Genetic Medicine at Johns Hopkins, said that gene therapy's "significant therapeutic misadventures" have actually been beneficial. They've helped us learn to "be rigorous in our thinking about what we can do and what we can't do with CRISPR" and other gene editing tools.
"It appears like we are really beginning to have, for the first time, some meaningful and good results from gene therapy — it's moving into the clinic now in a meaningful way," Valle said. "I expect five years from now we'll look back and say, 'Wow, we were just at this point in 2017 — we were just scratching the surface.'"
Over 2300 gene therapy clinical trials are planned, ongoing, or have been completed so far. As for gene editing, no treatments are commercially available anywhere in the world. The expectation, however, is that many treatments that are "currently in or soon to enter clinical trials will come up for approval in coming years," according to a November 2016 report by the American Society of Gene & Cell Therapy.
CRISPR Therapeutics of Cambridge, Massachusetts will begin a European gene editing trial this year, with the hopes of creating a treatment for beta thalassemia, an inherited blood disorder. The company will also request approval from the FDA to begin a clinical trial using CRISPR for sickle-cell disease. And Stanford University School of Medicine researchers are planning a similar CRISPR clinical trial for sickle-cell disease. They hope to begin their trial in 2019.
Jim Burns, the president and chief executive officer of Casebia Therapeutics, told Leapsmag that the company will start animal research this year using CRISPR to treat autoimmune diseases, hemophilia A, and retinal diseases. They expect to begin clinical research in humans in 2019 or 2020. [Disclosure: Casebia Therapeutics is a novel joint venture between CRISPR Therapeutics and Leapsmag's founder, Leaps by Bayer, though Leapsmag is editorially independent of Bayer.]
Efforts are well underway to take genome-targeted treatments from the scientist's bench to the patient's bedside.
The Technology Isn't There Yet
Unlike germline gene editing — when egg and sperm cell DNA is edited in an embryo — somatic cell gene editing in adults is not very controversial, because the edits are not heritable. Since somatic cells contribute to the various tissues of the body but not to eggs or sperm cells, changes made to somatic cells are limited to the treated individual.
The number one reason that gene therapy and gene editing treatments are not yet widely available to the adult population is that the technology is not advanced enough. But it's getting there. Efforts are well underway to take genome-targeted treatments from the scientist's bench to the patient's bedside — especially in the case of monogenic diseases.
Roughly 10,000 genetic illnesses are monogenic, meaning that they result from a disease-causing variant in a single gene. Some monogenic diseases that have gene editing treatments currently in development for use in clinical trials include cystic fibrosis, Huntington's disease, Tay-Sachs disease, and sickle cell anemia.
Marrazzo of Spark Therapeutics told LeapsMag that his company is working on gene therapies for monogenic diseases that affect the eye, like the retinal disease that Luxturna targets, as well as neurodegenerative and liver diseases.
But most illnesses are polygenic, meaning that they result from multiple gene mutations that have a combined influence on disease progression. Polygenic diseases, like high blood pressure and diabetes, would therefore be more challenging to treat with genome-targeted interventions. As a result, most research is currently focused on monogenic diseases.
"We don't really know how to target the gene editing to a specific organ in the body once it's fully developed and matured."
A major hurdle of gene editing is the risk of off-target effects. Editing the genome "can have unpredictable effects on gene expression and unintended effects on neighboring genes," wrote Morgan Maeder and Charles Gersbach in a March 2016 article in Molecular Therapy. One such unintended effect is the development of leukemia when a new gene unintentionally activates a cancer gene.
And since there are roughly 37 trillion cells in the adult human body, getting the gene editing machinery to enough cells or target tissues to create a lasting and significant change is a daunting task.
"We don't really know how to target the gene editing to a specific organ in the body once it's fully developed and matured," said Weissman, the genetic counseling expert. If you take an adult patient with known BRCA1 or BRCA2 mutations, for example, how do you then "get the [gene editing] system in the breast so that it accurately cuts out the mutation in every single breast cell that could potentially turn into breast cancer, or in every single ovarian cell that could turn into ovarian cancer? We don't know how to target it like that, and I think that's the biggest reason you're not seeing it more somatically at this point in time."
Approval and Access
Debra Mathews, assistant director for science programs for the Johns Hopkins Berman Institute of Bioethics, told LeapsMag that pre-existing regulatory frameworks surrounding gene therapy have been sufficient for addressing ethical and regulatory concerns surrounding gene editing. A bigger concern, she said, centers around access to future genome-targeted treatments.
"We know more about the genetics of Caucasian populations than other populations," Mathews explained, due to how genomic data is gathered. This "could lead to problems not just of financial but of biological access to new therapies." In other words, she said, "if you're of European ancestry, there may be a greater chance that there's a relevant genetically-targeted therapy for you than if you're of non-European ancestry."
Ensuring that genome-targeted treatments are accessible to all will require increased cooperation and data-sharing among key stakeholders around the world, as well as increased public engagement that is inclusive of a wide range of voices.
"It's important to be realistic in our predictions to the public."
The Coming Wave of Gene Editing Treatments
Ehlers-Danlos syndrome alone has 13 monogenic subtypes, each with its own genetic basis and set of clinical criteria. Though several of the gene mutations causing EDS subtypes have been identified, the genetic basis for the most common subtype that Lynn Julian Crisci has — hypermobile EDS — remains unknown. What this means, according to Valle, the doctor from Johns Hopkins, is that a gene therapy or gene editing approach "really cannot be contemplated because we don't know what we're trying to fix" yet. This is the case for many genetic illnesses.
Efforts are ongoing in gene discovery by organizations such as the Baylor-Hopkins Center for Mendelian Genomics, of which Valle is the principal investigator. "Our objective," he said, "is to identify the genes and variants responsible" in monogenic disorders.
While Valle is optimistic about the coming wave of commercially available gene therapy and gene editing treatments, he also thinks that "it's important to be realistic in our predictions to the public." As eager as physicians are to offer cures to their patients, "we have to make sure that we're rigorous in our thinking and our ideas are well-buttressed with results."
Estimates vary for how long Crisci and others with genetic illnesses will have to wait for genome-targeted treatment options. Depending on the illness, viable gene editing treatments could hit the market within the next ten years. Though patients have already waited a long while, the revolutionary technology allowing us to fix nature's mistakes could make up for lost time and lost hope.
You are driving along the highway and see an electronic sign that reads: “3,238 traffic deaths this year.” Do you think this reminder of roadside mortality would change how you drive? According to a recent, peer-reviewed study in Science, seeing that sign would make you more likely to crash. That’s ironic, given that the sign’s creators assumed it would make you safer.
The study, led by a pair of economists at the University of Toronto and University of Minnesota, examined seven years of traffic accident data from 880 electric highway sign locations in Texas, which experienced 4,480 fatalities in 2021. For one week of each month, the Texas Department of Transportation posts the latest fatality messages on signs along select traffic corridors as part of a safety campaign. Their logic is simple: Tell people to drive with care by reminding them of the dangers on the road.
But when the researchers looked at the data, they found that the number of crashes increased by 1.52 percent within three miles of these signs when compared with the same locations during the same month in previous years when signs did not show fatality information. That impact is similar to raising the speed limit by four miles or decreasing the number of highway troopers by 10 percent.
The scientists calculated that these messages contributed to 2,600 additional crashes and 16 deaths annually. They also found a social cost, meaning the financial expense borne by society as a whole due to these crashes, of $377 million per year, in Texas alone.
The cause, they argue, is distracted driving. Much like incoming texts or phone calls, these “in-your-face” messages grab your attention and undermine your focus on the road. The signs are particularly distracting and dangerous because, in communicating that many people died doing exactly what you are doing, they cause anxiety. Supporting this hypothesis, the scientists discovered that crashes increase when the signs report higher numbers of deaths. Thus, later in the year, as that total mortality figure goes up, so do the percentage of crashes.
Boomerang effects happen when those with authority, in government or business, fail to pay attention to the science. These leaders rely on armchair psychology and gut intuitions on what should work, rather than measuring what does work.
That change over time is not simply a function of changing weather, the study’s authors observed. They also found that the increase in car crashes is greatest in more complex road segments, which require greater focus to navigate.
The overall findings represent what behavioral scientists like myself call a “boomerang effect,” meaning an intervention that produces consequences opposite to those intended. Unfortunately, these effects are all too common. Between 1998 and 2004, Congress funded the $1 billion National Youth Anti-Drug Media Campaign, which famously boomeranged. Using professional advertising and public relations firms, the campaign bombarded kids aged 9 to 18 with anti-drug messaging, focused on marijuana, on TV, radio, magazines, and websites. A 2008 study funded by the National Institutes of Health found that children and teens saw these ads two to three times per week. However, more exposure to this advertising increased the likelihood that youth used marijuana. Why? Surveys and interviews suggested that young people who saw the ads got the impression that many of their peers used marijuana. As a result, they became more likely to use the drug themselves.
Boomerang effects happen when those with authority, in government or business, fail to pay attention to the science. These leaders rely on armchair psychology and gut intuitions on what should work, rather than measuring what does work.
To be clear, message campaigns—whether on electronic signs or through advertisements—can have a substantial effect on behavior. Extensive research reveals that people can be influenced by “nudges,” which shape the environment to influence their behavior in a predictable manner. For example, a successful campaign to reduce car accidents involved sending smartphone notifications that helped drivers evaluate their performance after each trip. These messages informed drivers of their personal average and best performance, as measured by accelerometers and gyroscopes. The campaign, which ran over 21 months, significantly reduced accident frequency.
Nudges work best when rigorously tested with small-scale experiments that evaluate their impact. Because behavioral scientists are infrequently consulted in creating these policies, some studies suggest that only 62 percent have a statistically significant effect. Other research reveals that up to 15 percent of desired interventions may backfire.
In the case of roadside mortality signage, the data are damning. The new research based on the Texas signs aligns with several past studies. For instance, research has shown that increasing people’s anxiety causes them to drive worse. Another, a Virginia Tech study in a laboratory setting, found that showing drivers fatality messages increased what psychologists call “cognitive load,” or the amount of information your brain is processing, with emotionally-salient information being especially burdensome and preoccupying, thus causing more distraction.
Nonetheless, Texas, along with at least 28 other states, has pursued mortality messaging campaigns since 2012, without testing them effectively. Behavioral science is critical here: when road signs are tested by people without expertise in how minds work, the results are often counterproductive. For example, the Virginia Tech research looked at road signs that used humor, popular culture, sports, and other nontraditional themes with the goal of provoking an emotional response. When they measured how participants responded to these signs, they noticed greater cognitive activation and attention in the brain. Thus, the researchers decided, the signs worked. But a behavioral scientist would note that increased attention likely contributes to the signs’ failure. As the just-published study in Science makes clear, distracting, emotionally-loaded signs are dangerous to drivers.
But there is good news. First, in most cases, it’s very doable to run an effective small-scale study testing an intervention. States could set up a safety campaign with a few electric signs in a diversity of settings and evaluate the impact over three months on driver crashes after seeing the signs. Policymakers could ask researchers to track the data as they run ads for a few months in a variety of nationally representative markets for a few months and assess their effectiveness. They could also ask behavioral scientists whether their proposals are well designed, whether similar policies have been tried previously in other places, and how these policies have worked in practice.
Everyday citizens can write to and call their elected officials to ask them to make this kind of research a priority before embracing an untested safety campaign. More broadly, you can encourage them to avoid relying on armchair psychology and to test their intuitions before deploying initiatives that might place the public under threat.
I walked through the Dong Makkhai forest-products market, just outside of Vientiane, the laid-back capital of the Lao Peoples Democratic Republic or Lao PDR. Piled on rough display tables were varieties of six-legged wildlife–grasshoppers, small white crickets, house crickets, mole crickets, wasps, wasp eggs and larvae, dragonflies, and dung beetles. Some were roasted or fried, but in a few cases, still alive and scrabbling at the bottom of deep plastic bowls. I crunched on some fried crickets and larvae.
One stall offered Giant Asian hornets, both babies and adults. I suppressed my inner squirm and, in the interests of world food security and equity, accepted an offer of the soft, velvety larva; they were smooth on the tongue and of a pleasantly cool, buttery-custard consistency. Because the seller had already given me a free sample, I felt obliged to buy a chunk of the nest with larvae and some dead adults, which the seller mixed with kaffir lime leaves.
The year was 2016 and I was in Lao PDR because Veterinarians without Borders/Vétérinaires sans Frontières-Canada had initiated a project on small-scale cricket farming. The intent was to organize and encourage rural women to grow crickets as a source of supplementary protein and sell them at the market for cash. As a veterinary epidemiologist, I had been trained to exterminate disease spreading insects—Lyme disease-carrying ticks, kissing bugs that carry American Sleeping Sickness and mosquitoes carrying malaria, West Nile and Zika. Now, as part of a global wave promoting insects as a sustainable food source, I was being asked to view arthropods as micro-livestock, and devise management methods to keep them alive and healthy. It was a bit of a mind-bender.
The 21st century wave of entomophagy, or insect eating, first surged in the early 2010s, promoted by a research centre in Wageningen, a university in the Netherlands, conferences organized by the Food and Agriculture Organization of the United Nations, and enthusiastic endorsements by culinary adventurers and celebrities from Europeanized cultures. Headlines announced that two billion people around the world already ate insects, and that if everyone adopted entomophagy we could reduce greenhouse gases, mitigate climate change, and reign in profligate land and water use associated with industrial livestock production.
Furthermore, eating insects was better for human health than eating beef. If we were going to feed the estimated nine billion people with whom we will share the earth in 2050, we would need to make some radical changes in our agriculture and food systems. As one author proclaimed, entomophagy presented us with a last great chance to save the planet.
In 2010, in Kunming, a friend had served me deep-fried bamboo worms. I ate them to be polite. They tasted like French fries, but with heads.
The more recent data suggests that the number of people who eat insects in various forms, though sizeable, may be closer to several hundreds of millions. I knew that from several decades of international veterinary work. Sometimes, for me, insect eating has been simply a way of acknowledging cultural diversity. In 2010, in Kunming, a friend had served me deep-fried bamboo worms. I ate them to be polite. They tasted like French fries, but with heads. My friend said he preferred them chewier. I never thought about them much after that. I certainly had not thought about them as ingredients for human health.
Is consuming insects good for human health? Researchers over the past decade have begun to tease that apart. Some think it might not be useful to use the all-encompassing term insect at all; we don’t lump cows, pigs, chickens into one culinary category. Which insects are we talking about? What are they fed? Were they farmed or foraged? Which stages of the insects are we eating? Do we eat them directly or roasted and ground up?
The overall research indicates that, in general, the usual farmed insects (crickets, locusts, mealworms, soldier fly larvae) have high levels of protein and other important nutrients. If insects are foraged by small groups in Laos, they provide excellent food supplements. Large scale foraging in response to global markets can be incredibly destructive, but soldier fly larvae fed on food waste and used as a substitute for ground up anchovies for farmed fish (as Enterra Feed in Canada does) improves ecological sustainability.
Entomophagy alone might not save the planet, but it does give us an unprecedented opportunity to rethink how we produce and harvest protein.
The author enjoys insects from the Dong Makkhai forest-products market, just outside of Vientiane, the capital of the Lao Peoples Democratic Republic.
Between 1961 and 2018, world chicken production increased from 4 billion to 20 billion, pork from 200 million to over 100 billion pigs, human populations doubled from 3.5 billion to more than 7 billion, and life expectancy (on average) from 52 to 72 years. These dramatic increases in food production are the result of narrowly focused scientific studies, identifying specific nutrients, antibiotics, vaccines and genetics. What has been missing is any sort of peripheral vision: what are the unintended consequences of our narrowly defined success?
If we look more broadly, we can see that this narrowly defined success led to industrial farming, which caused wealth, health and labor inequities; polluted the environment; and created grounds for disease outbreaks. Recent generations of Europeanized people inherited the ideas of eating cows, pigs and chickens, along with their products, so we were focused only on growing them as efficiently as possible. With insects, we have an exciting chance to start from scratch. Because, for Europeanized people, insect eating is so strange, we are given the chance to reimagine our whole food system in consultation with local experts in Asia and Africa (many of them villagers), and to bring together the best of both locally adapted food production and global distribution.
For this to happen, we will need to change the dietary habits of the big meat eaters. How can we get accustomed to eating bugs? There’s no one answer, but there are a few ways. In many cases, insects are ground up and added as protein supplements to foods like crackers or bars. In certain restaurants, the chefs want you to get used to seeing the bugs as you eat them. At Le Feston Nu in Paris, the Arlo Guthrie look-alike bartender poured me a beer and brought out five small plates, each featuring a different insect in a nest of figs, sun-dried tomatoes, raisins, and chopped dried tropical fruits: buffalo worms, crickets, large grasshoppers (all just crunchy and no strong flavour, maybe a little nutty), small black ants (sour bite), and fat grubs with a beak, which I later identified as palm weevil larvae, tasting a bit like dried figs.
Some entomophagy advertising has used esthetically pleasing presentations in classy restaurants. In London, at the Archipelago restaurant, I dined on Summer Nights (pan fried chermoula crickets, quinoa, spinach and dried fruit), Love-Bug Salad (baby greens with an accompanying dish of zingy, crunchy mealworms fried in olive oil, chilis, lemon grass, and garlic), Bushman’s Cavi-Err (caramel mealworms, bilinis, coconut cream and vodka jelly), and Medieaval Hive (brown butter ice cream, honey and butter caramel sauce and a baby bee drone).
The Archipelago restaurant in London serves up a Love-Bug Salad: baby greens with an accompanying dish of zingy, crunchy mealworms fried in olive oil, chilis, lemon grass, and garlic.
Some chefs, like Tokyo-based Shoichi Uchiyama, try to entice people with sidewalk cooking lessons. Uchiyama's menu included hornet larvae, silkworm pupae, and silkworms. The silkworm pupae were white and pink and yellow. We snipped off the ends and the larvae dropped out. My friend Zen Kawabata roasted them in a small pan over a camp stove in the street to get the "chaff" off. We made tea from the feces of worms that had fed on cherry blossoms—the tea smelled of the blossoms. One of Uchiyama-san’s assistants made noodles from buckwheat dough that included powdered whole bees.
At a book reading in a Tokyo bookstore, someone handed me a copy of the Japanese celebrity scandal magazine Friday, opened to an article celebrating the “charms of insect eating.” In a photo, scantily-clad girls were drinking vodka and nibbling giant water bugs dubbed as toe-biters, along with pickled and fried locusts and butterfly larvae. If celebrities embraced bug-eating, others might follow. When asked to prepare an article on entomophagy for the high fashion Sorbet Magazine, I started by describing a clip of Nicole Kidman delicately snacking on insects.
Taking a page from the success story of MacDonald’s, we might consider targeting children and school lunches. Kids don’t lug around the same dietary baggage as the grownups, and they can carry forward new eating habits for the long term. When I offered roasted crickets to my grandchildren, they scarfed them down. I asked my five-year-old granddaughter what she thought: she preferred the mealworms to the crickets – they didn’t have legs that caught in her teeth.
Entomo Farms in Ontario, the province where I live, was described in 2015 by Canadian Business magazine as North America’s largest supplier of edible insects for human consumption. When visiting, I popped some of their roasted crickets into my mouth. They were crunchy, a little nutty. Nothing to get squeamish over. Perhaps the human consumption is indeed growing—my wife, at least, has joined me in my entomophagy adventures. When we celebrated our wedding anniversary at the Public Bar and Restaurant in Brisbane, Australia, the “Kang Kong Worms” and “Salmon, Manuka Honey, and Black Ants” seemed almost normal. Of course, the champagne helped.