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.
On the morning of April 12, 1955, newsrooms across the United States inked headlines onto newsprint: the Salk Polio vaccine was "safe, effective, and potent." This was long-awaited news. Americans had limped through decades of fear, unaware of what caused polio or how to cure it, faced with the disease's terrifying, visible power to paralyze and kill, particularly children.
The announcement of the polio vaccine was celebrated with noisy jubilation: church bells rang, factory whistles sounded, people wept in the streets. Within weeks, mass inoculation began as the nation put its faith in a vaccine that would end polio.
Today, most of us are blissfully ignorant of child polio deaths, making it easier to believe that we have not personally benefited from the development of vaccines. According to Dr. Steven Pinker, cognitive psychologist and author of the bestselling book Enlightenment Now, we've become blasé to the gifts of science. "The default expectation is not that disease is part of life and science is a godsend, but that health is the default, and any disease is some outrage," he says.
The Rise and Fall of Public Trust<p>When the polio vaccine was released in 1955, "we were nearing an all-time high point in public trust," says Matt Baum, Harvard Kennedy School professor and lead author of <a href="http://www.kateto.net/covid19/COVID19%20CONSORTIUM%20REPORT%2013%20TRUST%20SEP%202020.pdf" target="_blank" rel="noopener noreferrer"><u>several</u></a> <a href="https://shorensteincenter.org/wp-content/uploads/2020/09/COVID19-CONSORTIUM-REPORT-14-MISINFO-SEP-2020.pdf" target="_blank" rel="noopener noreferrer"><u>reports</u></a> measuring public trust and vaccine confidence. Baum explains that the U.S. was experiencing a post-war boom following the Allied triumph in WWII, a popular Roosevelt presidency, and the rapid innovation that elevated the country to an international superpower.</p><p> The 1950s witnessed the emergence of nuclear technology, a space program, and unprecedented medical breakthroughs, adds Emily Brunson, Texas State University anthropologist and co-chair of the Working Group on Readying Populations for COVID-19 Vaccine. "Antibiotics were a game changer," she states. While before, people got sick with pneumonia for a month, suddenly they had access to pills that accelerated recovery. </p><p>During this period, science seemed to hold all the answers; people embraced the idea that we could "come to know the world with an absolute truth," Brunson explains. Doctors were portrayed as unquestioned gods, so Americans were primed to trust experts who told them the polio vaccine was safe. </p>
The Shift in How We Consume Information<p>In the 1950s, the media created an informational consensus. The fundamental ideas the public consumed about the state of the world were unified. "People argued about the best solutions, but didn't fundamentally disagree on the factual baseline," says Baum. Indeed, the messaging around the polio vaccine was centralized and consistent, led by President Roosevelt's successful <a href="https://files.eric.ed.gov/fulltext/EJ978264.pdf" target="_blank" rel="noopener noreferrer"><u>March of Dimes crusade</u></a>. People of lower socioeconomic status with limited access to this information were <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1551508/?page=3" target="_blank" rel="noopener noreferrer"><u>less likely to have confidence</u></a> in the vaccine, but most people consumed <a href="https://www.c-span.org/video/?506891-1/a-special-report-polio" target="_blank" rel="noopener noreferrer"><u>media that assured them</u></a> of the vaccine's safety and <a href="https://www.cbsnews.com/news/the-salk-polio-vaccine-greatest-public-health-experiment-in-history/" target="_blank" rel="noopener noreferrer"><u>mobilized them</u></a> to receive it. </p><p>Today, the information we consume is no longer centralized—in fact, just the opposite. "When you take that away, it's hard for people to know what to trust and what not to trust," Baum explains. We've witnessed an increase in polarization and the technology that makes it easier to give people what they want to hear, reinforcing the human tendencies to vilify the other side and reinforce our preexisting ideas. When information is engineered to further an agenda, each choice and risk calculation made while navigating the COVID-19 pandemic <a href="https://www.nytimes.com/2020/12/19/opinion/sunday/coronavirus-science.html?referringSource=articleShare" target="_blank" rel="noopener noreferrer"><u>is deeply politicized</u></a>. </p><p>This polarization maps onto a rise in socioeconomic inequality and economic uncertainty. These factors, associated with a sense of lost control, prime people to embrace misinformation, explains Baum, especially when the situation is difficult to comprehend. "The beauty of conspiratorial thinking is that it provides answers to all these questions," he says. Today's insidious fragmentation of news media accelerates the circulation of mis- and disinformation, reaching more people faster, regardless of veracity or motivation. In the case of vaccines, skepticism around their origin, safety, and motivation is intensified. </p><p>Alongside the rise in polarization, Pinker says "the emotional tone of the news has gone downward since the 1940s, and journalists consider it a professional responsibility to cover the negative." Relentless focus on everything that goes wrong further erodes public trust and paints a picture of the world getting worse. "Life saved is not a news story," says Pinker, but perhaps it should be, he continues. "If people were more aware of how much better life was generally, they might be more receptive to improvements that will continue to make life better. These improvements don't happen by themselves."</p>
The Future Depends on Vaccine Confidence<p>So far, the U.S. has been unable to mitigate the catastrophic effects of the pandemic through social distancing, testing, and contact tracing. President Trump has <a href="https://www.washingtonpost.com/politics/bob-woodward-rage-book-trump/2020/09/09/0368fe3c-efd2-11ea-b4bc-3a2098fc73d4_story.html" target="_blank" rel="noopener noreferrer"><u>downplayed the effects and threat of the virus</u></a>, <a href="https://www.washingtonpost.com/outlook/2020/07/14/cdc-directors-trump-politics/" target="_blank" rel="noopener noreferrer"><u>censored experts and scientists</u></a>, <a href="https://www.theatlantic.com/science/archive/2020/06/america-giving-up-on-pandemic/612796/" target="_blank" rel="noopener noreferrer"><u>given up on containing the spread</u></a>, and <a href="https://www.nytimes.com/2020/09/16/world/covid-coronavirus.html" target="_blank" rel="noopener noreferrer"><u>mobilized his base to protest masks</u></a>. The Trump Administration failed to devise a national plan, so our national plan has defaulted to hoping for the <a href="https://www.politico.com/news/2020/08/26/nation-of-miracles-pence-coronavirus-vaccine-rnc-402949" target="_blank" rel="noopener noreferrer"><u>"miracle" of a vaccine</u></a>. And they are "something of a miracle," Pinker says, describing vaccines as "the most benevolent invention in the history of our species." In record-breaking time, three vaccines have arrived. But their impact will be weakened unless we achieve mass vaccination. As Brunson notes, "The technology isn't the fix; it's people taking the technology."</p><p> Significant challenges remain, including facilitating widespread access and supporting on-the-ground efforts to allay concerns and build trust with <a href="https://www.newyorker.com/news/daily-comment/african-american-resistance-to-the-covid-19-vaccine-reflects-a-broader-problem" target="_blank" rel="noopener noreferrer"><u>specific populations with historic reasons for distrust</u></a>, says Brunson. Baum predicts continuing delays as well as deaths from other causes that will be linked to the vaccine. </p><p> Still, there's every reason for hope. The new administration "has its eyes wide open to these challenges. These are the kind of problems that are amenable to policy solutions if we have the will," Baum says. He forecasts widespread vaccination by late summer and a bounce back from the economic damage, a "Good News Story" that will bolster vaccine acceptance in the future. And Pinker reminds us that science, medicine, and public health have greatly extended our lives in the last few decades, a trend that can only continue if we're willing to roll up our sleeves. </p>
Imagine this scenario: you get an annoying cough and a bit of a fever. When you wake up the next morning you lose your sense of taste and smell. That sounds familiar, so you head to a doctor's office for a Covid test, which comes back positive.
Your next step? An anti-Covid nasal spray of course, a "trickster drug" that will clear the once-dangerous and deadly virus out of the body. The drug works by tricking the coronavirus with decoy receptors that appear to be just like those on the surface of our own cells. The virus latches onto the drug's molecules "thinking" it is breaking into human cells, but instead it flushes out of your system before it can cause any serious damage.
This may sounds like science fiction, but several research groups are already working on such trickster coronavirus drugs, with some candidates close to clinical trials and possibly even becoming available late this year. The teams began working on them when the pandemic arrived, and continued in lockdown.
Biochemist David Baker, pictured in his lab at the University of Washington.