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.
Astronauts at the International Space Station today depend on pre-packaged, freeze-dried food, plus some fresh produce thanks to regular resupply missions. This supply chain, however, will not be available on trips further out, such as the moon or Mars. So what are astronauts on long missions going to eat?
Going by the options available now, says Christel Paille, an engineer at the European Space Agency, a lunar expedition is likely to have only dehydrated foods. “So no more fresh product, and a limited amount of already hydrated product in cans.”
For the Mars mission, the situation is a bit more complex, she says. Prepackaged food could still constitute most of their food, “but combined with [on site] production of certain food products…to get them fresh.” A Mars mission isn’t right around the corner, but scientists are currently working on solutions for how to feed those astronauts. A number of boundary-pushing efforts are now underway.
The logistics of growing plants in space, of course, are very different from Earth. There is no gravity, sunlight, or atmosphere. High levels of ionizing radiation stunt plant growth. Plus, plants take up a lot of space, something that is, ironically, at a premium up there. These and special nutritional requirements of spacefarers have given scientists some specific and challenging problems.
To study fresh food production systems, NASA runs the Vegetable Production System (Veggie) on the ISS. Deployed in 2014, Veggie has been growing salad-type plants on “plant pillows” filled with growth media, including a special clay and controlled-release fertilizer, and a passive wicking watering system. They have had some success growing leafy greens and even flowers.
"Ideally, we would like a system which has zero waste and, therefore, needs zero input, zero additional resources."
A larger farming facility run by NASA on the ISS is the Advanced Plant Habitat to study how plants grow in space. This fully-automated, closed-loop system has an environmentally controlled growth chamber and is equipped with sensors that relay real-time information about temperature, oxygen content, and moisture levels back to the ground team at Kennedy Space Center in Florida. In December 2020, the ISS crew feasted on radishes grown in the APH.
“But salad doesn’t give you any calories,” says Erik Seedhouse, a researcher at the Applied Aviation Sciences Department at Embry-Riddle Aeronautical University in Florida. “It gives you some minerals, but it doesn’t give you a lot of carbohydrates.” Seedhouse also noted in his 2020 book Life Support Systems for Humans in Space: “Integrating the growing of plants into a life support system is a fiendishly difficult enterprise.” As a case point, he referred to the ESA’s Micro-Ecological Life Support System Alternative (MELiSSA) program that has been running since 1989 to integrate growing of plants in a closed life support system such as a spacecraft.
Paille, one of the scientists running MELiSSA, says that the system aims to recycle the metabolic waste produced by crew members back into the metabolic resources required by them: “The aim is…to come [up with] a closed, sustainable system which does not [need] any logistics resupply.” MELiSSA uses microorganisms to process human excretions in order to harvest carbon dioxide and nitrate to grow plants. “Ideally, we would like a system which has zero waste and, therefore, needs zero input, zero additional resources,” Paille adds.
Microorganisms play a big role as “fuel” in food production in extreme places, including in space. Last year, researchers discovered Methylobacterium strains on the ISS, including some never-seen-before species. Kasthuri Venkateswaran of NASA’s Jet Propulsion Laboratory, one of the researchers involved in the study, says, “[The] isolation of novel microbes that help to promote the plant growth under stressful conditions is very essential… Certain bacteria can decompose complex matter into a simple nutrient [that] the plants can absorb.” These microbes, which have already adapted to space conditions—such as the absence of gravity and increased radiation—boost various plant growth processes and help withstand the harsh physical environment.
MELiSSA, says Paille, has demonstrated that it is possible to grow plants in space. “This is important information because…we didn’t know whether the space environment was affecting the biological cycle of the plant…[and of] cyanobacteria.” With the scientific and engineering aspects of a closed, self-sustaining life support system becoming clearer, she says, the next stage is to find out if it works in space. They plan to run tests recycling human urine into useful components, including those that promote plant growth.
The MELiSSA pilot plant uses rats currently, and needs to be translated for human subjects for further studies. “Demonstrating the process and well-being of a rat in terms of providing water, sufficient oxygen, and recycling sufficient carbon dioxide, in a non-stressful manner, is one thing,” Paille says, “but then, having a human in the loop [means] you also need to integrate user interfaces from the operational point of view.”
Growing food in space comes with an additional caveat that underscores its high stakes. Barbara Demmig-Adams from the Department of Ecology and Evolutionary Biology at the University of Colorado Boulder explains, “There are conditions that actually will hurt your health more than just living here on earth. And so the need for nutritious food and micronutrients is even greater for an astronaut than for [you and] me.”
Demmig-Adams, who has worked on increasing the nutritional quality of plants for long-duration spaceflight missions, also adds that there is no need to reinvent the wheel. Her work has focused on duckweed, a rather unappealingly named aquatic plant. “It is 100 percent edible, grows very fast, it’s very small, and like some other floating aquatic plants, also produces a lot of protein,” she says. “And here on Earth, studies have shown that the amount of protein you get from the same area of these floating aquatic plants is 20 times higher compared to soybeans.”
Aquatic plants also tend to grow well in microgravity: “Plants that float on water, they don’t respond to gravity, they just hug the water film… They don’t need to know what’s up and what’s down.” On top of that, she adds, “They also produce higher concentrations of really important micronutrients, antioxidants that humans need, especially under space radiation.” In fact, duckweed, when subjected to high amounts of radiation, makes nutrients called carotenoids that are crucial for fighting radiation damage. “We’ve looked at dozens and dozens of plants, and the duckweed makes more of this radiation fighter…than anything I’ve seen before.”
Despite all the scientific advances and promising leads, no one really knows what the conditions so far out in space will be and what new challenges they will bring. As Paille says, “There are known unknowns and unknown unknowns.”
One definite “known” for astronauts is that growing their food is the ideal scenario for space travel in the long term since “[taking] all your food along with you, for best part of two years, that’s a lot of space and a lot of weight,” as Seedhouse says. That said, once they land on Mars, they’d have to think about what to eat all over again. “Then you probably want to start building a greenhouse and growing food there [as well],” he adds.
And that is a whole different challenge altogether.
We are sticking our heads into the sand of reality on Omicron, and the results may be catastrophic.
Omicron is over 4 times more infectious than Delta. The Pfizer two-shot vaccine offers only 33% protection from infection. A Pfizer booster vaccine does raises protection to about 75%, but wanes to around 30-40 percent 10 weeks after the booster.
That’s because the much faster disease transmission and vaccine escape undercut the less severe overall nature of Omicron. That’s why hospitals have a large probability of being overwhelmed, as the Center for Disease Control warned, in this major Omicron wave.
Yet despite this very serious threat, we see the lack of real action. The federal government tightened international travel guidelines and is promoting boosters. Certainly, it’s crucial to get as many people to get their booster – and initial vaccine doses – as soon as possible. But the government is not taking the steps that would be the real game-changers.
Pfizer’s anti-viral drug Paxlovid decreases the risk of hospitalization and death from COVID by 89%. Due to this effectiveness, the FDA approved Pfizer ending the trial early, because it would be unethical to withhold the drug from people in the control group. Yet the FDA chose not to hasten the approval process along with the emergence of Omicron in late November, only getting around to emergency authorization in late December once Omicron took over. That delay meant the lack of Paxlovid for the height of the Omicron wave, since it takes many weeks to ramp up production, resulting in an unknown number of unnecessary deaths.
We humans are prone to falling for dangerous judgment errors called cognitive biases.
Widely available at-home testing would enable people to test themselves quickly, so that those with mild symptoms can quarantine instead of infecting others. Yet the federal government did not make tests available to patients when Omicron emerged in late November. That’s despite the obviousness of the coming wave based on the precedent of South Africa, UK, and Denmark and despite the fact that the government made vaccines freely available. Its best effort was to mandate that insurance cover reimbursements for these kits, which is way too much of a barrier for most people. By the time Omicron took over, the federal government recognized its mistake and ordered 500 million tests to be made available in January. However, that’s far too late. And the FDA also played a harmful role here, with its excessive focus on accuracy going back to mid-2020, blocking the widespread availability of cheap at-home tests. By contrast, Europe has a much better supply of tests, due to its approval of quick and slightly less accurate tests.
Neither do we see meaningful leadership at the level of employers. Some are bringing out the tired old “delay the office reopening” play. For example, Google, Uber, and Ford, along with many others, have delayed the return to the office for several months. Those that already returned are calling for stricter pandemic measures, such as more masks and social distancing, but not changing their work arrangements or adding sufficient ventilation to address the spread of COVID.
Despite plenty of warnings from risk management and cognitive bias experts, leaders are repeating the same mistakes we fell into with Delta. And so are regular people. For example, surveys show that Omicron has had very little impact on the willingness of unvaccinated Americans to get a first vaccine dose, or of vaccinated Americans to get a booster. That’s despite Omicron having taken over from Delta in late December.
What explains this puzzling behavior on both the individual and society level? We humans are prone to falling for dangerous judgment errors called cognitive biases. Rooted in wishful thinking and gut reactions, these mental blindspots lead to poor strategic and financial decisions when evaluating choices.
These cognitive biases stem from the more primitive, emotional, and intuitive part of our brains that ensured survival in our ancestral environment. This quick, automatic reaction of our emotions represents the autopilot system of thinking, one of the two systems of thinking in our brains. It makes good decisions most of the time but also regularly makes certain systematic thinking errors, since it’s optimized to help us survive. In modern society, our survival is much less at risk, and our gut is more likely to compel us to focus on the wrong information to make decisions.
One of the biggest challenges relevant to Omicron is the cognitive bias known as the ostrich effect. Named after the myth that ostriches stick their heads into the sand when they fear danger, the ostrich effect refers to people denying negative reality. Delta illustrated the high likelihood of additional dangerous variants, yet we failed to pay attention to and prepare for such a threat.
We want the future to be normal. We’re tired of the pandemic and just want to get back to pre-pandemic times. Thus, we greatly underestimate the probability and impact of major disruptors, like new COVID variants. That cognitive bias is called the normalcy bias.
When we learn one way of functioning in any area, we tend to stick to that way of functioning. You might have heard of this as the hammer-nail syndrome: when you have a hammer, everything looks like a nail. That syndrome is called functional fixedness. This cognitive bias causes those used to their old ways of action to reject any alternatives, including to prepare for a new variant.
Our minds naturally prioritize the present. We want what we want now, and downplay the long-term consequences of our current desires. That fallacious mental pattern is called hyperbolic discounting, where we excessively discount the benefits of orienting toward the future and focus on the present. A clear example is focusing on the short-term perceived gains of trying to return to normal over managing the risks of future variants.
The way forward into the future is to defeat cognitive biases and avoid denying reality by rethinking our approach to the future.
The FDA requires a serious overhaul. It’s designed for a non-pandemic environment, where the goal is to have a highly conservative, slow-going, and risk-averse approach so that the public feels confident trusting whatever it approved. That’s simply unacceptable in a fast-moving pandemic, and we are bound to face future pandemics in the future.
The federal government needs to have cognitive bias experts weigh in on federal policy. Putting all of its eggs in one basket – vaccinations – is not a wise move when we face the risks of a vaccine-escaping variant. Its focus should also be on expediting and prioritizing anti-virals, scaling up cheap rapid testing, and subsidizing high-filtration masks.
For employers, instead of dictating a top-down approach to how employees collaborate, companies need to adopt a decentralized team-led approach. Each individual team leader of a rank-and-file employee team should determine what works best for their team. After all, team leaders tend to know much more of what their teams need, after all. Moreover, they can respond to local emergencies like COVID surges.
At the same time, team leaders need to be trained to integrate best practices for hybrid and remote team leadership. Companies transitioned to telework abruptly as part of the March 2020 lockdowns. They fell into the cognitive bias of functional fixedness and transposed their pre-existing, in-office methods of collaboration on remote work. Zoom happy hours are a clear example: The large majority of employees dislike them, and research shows they are disconnecting, rather than connecting.
Yet supervisors continue to use them, despite the existence of much better methods of facilitating colalboration, which have been shown to work, such as virtual water cooler discussions, virtual coworking, and virtual mentoring. Leaders also need to facilitate innovation in hybrid and remote teams through techniques such as virtual asynchronous brainstorming. Finally, team leaders need to adjust performance evaluation to adapt to the needs of hybrid and remote teams.
On an individual level, people built up certain expectations during the first two years of the pandemic, and they don't apply with Omicron. For example, most people still think that a cloth mask is a fine source of protection. In reality, you really need an N-95 mask, since Omicron is so much more infectious. Another example is that many people don’t realize that symptom onset is much quicker with Omicron, and they aren’t prepared for the consequences.
Remember that we have a huge number of people who are asymptomatic, often without knowing it, due to the much higher mildness of Omicron. About 8% of people admitted to hospitals for other reasons in San Francisco test positive for COVID without symptoms, which we can assume translates for other cities. That means many may think they're fine and they're actually infectious. The result is a much higher chance of someone getting many other people sick.
During this time of record-breaking cases, you need to be mindful about your internalized assumptions and adjust your risk calculus accordingly. So if you can delay higher-risk activities, January and February might be the time to do it. Prepare for waves of disruptions to continue over time, at least through the end of February.
Of course, you might also choose to not worry about getting infected. If you are vaccinated and boosted, and do not have any additional health risks, you are very unlikely to have a serious illness due to Omicron. You can just take the small risk of a serious illness – which can happen – and go about your daily life. If doing so, watch out for those you care about who do have health concerns, since if you infect them, they might not have a mild case even with Omicron.
In short, instead of trying to turn back the clock to the lost world of January 2020, consider how we might create a competitive advantage in our new future. COVID will never go away: we need to learn to live with it. That means reacting appropriately and thoughtfully to new variants and being intentional about our trade-offs.