Why Blindness Will Be the First Disorder Cured by Futuristic Treatments
A blind man with a cane goes for a walk at sunset. (© Prazis/Fotolia)
Stem cells and gene therapy were supposed to revolutionize biomedicine around the turn of the millennium and provide relief for desperate patients with incurable diseases. But for many, progress has been frustratingly slow. We still cannot, for example, regenerate damaged organs like a salamander regrows its tail, and genome engineering is more complicated than cutting and pasting letters in a word document.
"There are a number of things that make [the eye] ideal for new experimental therapies which are not true necessarily in other organs."
For blind people, however, the future of medicine is one step closer to reality. In December, the FDA approved the first gene therapy for an inherited disease—a mutation in the gene RPE65 that causes a rare form of blindness. Several clinical trials also show promise for treating various forms of retinal degeneration using stem cells.
"It's not surprising that the first gene therapy that was approved by the FDA was a therapy in the eye," says Bruce Conklin, a senior investigator at the San Francisco-based Gladstone Institutes, a nonprofit life science research organization, and a professor in the Medical Genetics and Molecular Pharmacology department at the University of California, San Francisco. "There are a number of things that make it ideal for new experimental therapies which are not true necessarily in other organs."
Physicians can easily see into the eye to check if a procedure worked or if it's causing problems. "The imaging technology within the eye is really unprecedented. You can't do this in someone's spinal cord or someone's brain cells or immune system," says Conklin, who is also deputy director of the Innovative Genomics Institute.
There's also a built-in control: researchers can test an intervention on one eye first. What's more, if something goes wrong, the risk of mortality is low, especially when compared to experimenting on the heart or brain. Most types of blindness are currently incurable, so the risk-to-reward ratio for patients is high. If a problem arises with the treatment their eyesight could get worse, but if they do nothing their vision will likely decline anyway. And if the treatment works, they may be able to see for the first time in years.
Gene Therapy
An additional appeal for testing gene therapy in the eye is the low risk for off-target effects, in which genome edits could result in unintended changes to other genes or in other cell types. There are a number of genes that are solely expressed in the eye and not in any other part of the body. Manipulating those genes will only affect cells in the eye, so concerns about the impact on other organs are minimal.
Ninety-three percent of patients who received the injection had improved vision just one month after treatment.
RPE65 is one such gene. It creates an enzyme that helps the eye convert light into an electrical signal that travels back to the brain. Patients with the mutation don't produce the enzyme, so visual signals are not processed. However, the retinal cells in the eye remain healthy for years; if you can restore the missing enzyme you can restore vision.
The newly approved therapy, developed by Spark Therapeutics, uses a modified virus to deliver RPE65 into the eye. A retinal surgeon injects the virus, which has been specially engineered to remove its disease-causing genes and instead carry the correct RPE65 gene, into the retina. There, it is sucked up by retinal pigment epithelial (RPE) cells. The RPE cells are a particularly good target for injection because their job is to eat up and recycle rogue particles. Once inside the cell, the virus slips into the nucleus and releases the DNA. The RPE65 gene then goes to work, using the cell's normal machinery to produce the needed enzyme.
In the most recent clinical trial, 93 percent of patients who received the injection—who range in age from 4 to 44—had improved vision just one month after treatment. So far, the benefits have lasted at least two years.
"It's an exciting time for this class of diseases, where these people have really not had treatments," says Spark president and co-founder, Katherine High. "[Gene therapy] affords the possibility of treatment for diseases that heretofore other classes of therapeutics really have not been able to help."
Stem Cells
Another benefit of the eye is its immune privilege. In order to let light in, the eye must remain transparent. As a result, its immune system is dampened so that it won't become inflamed if outside particles get in. This means the eye is much less likely to reject cell transplants, so patients do not need to take immunosuppressant drugs.
One study generating buzz is a clinical trial in Japan that is the first and, so far, only test of induced pluripotent stem cells in the eye.
Henry Klassen, an assistant professor at UC Irvine, is taking advantage of the eye's immune privilege to transplant retinal progenitor cells into the eye to treat retinitis pigmentosa, an inherited disease affecting about 1 in 4000 people that eventually causes the retina to degenerate. The disease can stem from dozens of different genetic mutations, but the result is the same: RPE cells die off over the course of a few decades, leaving the patient blind by middle age. It is currently incurable.
Retinal progenitor cells are baby retinal cells that develop naturally from stem cells and will turn into one of several types of adult retinal cells. When transplanted into a patient's eye, the progenitor cells don't replace the lost retinal cells, but they do secrete proteins and enzymes essential for eye health.
"At the stage we get the retinal tissue it's immature," says Klassen. "They still have some flexibility in terms of which mature cells they can turn into. It's that inherent flexibility that gives them a lot of power when they're put in the context of a diseased retina."
Klassen's spin-off company, jCyte, sponsored the clinical trial with support from the California Institute for Regenerative Medicine. The results from the initial study haven't been published yet, but Klassen says he considers it a success. JCyte is now embarking on a phase two trial to assess improvements in vision after the treatment, which will wrap up in 2021.
Another study generating buzz is a clinical trial in Japan that is the first and, so far, only test of induced pluripotent stem cells (iPSC) in the eye. iPSC are created by reprogramming a patient's own skin cells into stem cells, circumventing any controversy around embryonic stem cell sources. In the trial, led by Masayo Takahashi at RIKEN, the scientists transplant retinal pigment epithelial cells created from iPSC into the retinas of patients with age-related macular degeneration. The first woman to receive the treatment is doing well, and her vision is stable. However, the second patient suffered a swollen retina as a result of the surgery. Despite this recent setback, Takahashi said last week that the trial would continue.
Botched Jobs
Although recent studies have provided patients with renewed hope, the field has not been without mishap. Most notably, an article in the New England Journal of Medicine last March described three patients who experienced severe side effects after receiving stem cell injections from a Florida clinic to treat age-related macular degeneration. Following the initial article, other reports came out about similar botched treatments. Lawsuits have been filed against US Stem Cell, the clinic that conducted the procedure, and the FDA sent them a warning letter with a long list of infractions.
"One red flag is that the clinics charge patients to take part in the treatment—something extremely unusual for legitimate clinical trials."
Ajay Kuriyan, an ophthalmologist and retinal specialist at the University of Rochester who wrote the paper, says that because details about the Florida trial are scarce, it's hard to say why the treatment caused the adverse reaction. His guess is that the stem cells were poorly prepared and not up to clinical standards.
Klassen agrees that small clinics like US Stem Cell do not offer the same caliber of therapy as larger clinical trials. "It's not the same cells and it's not the same technique and it's not the same supervision and it's not under FDA auspices. It's just not the same thing," he says. "Unfortunately, to the patient it might sound the same, and that's the tragedy for me."
For patients who are interested in joining a trial, Kuriyan listed a few things to watch out for. "One red flag is that the clinics charge patients to take part in the treatment—something extremely unusual for legitimate clinical trials," he says. "Another big red flag is doing the procedure in both eyes" at the same time. Third, if the only treatment offered is cell therapy. "These clinics tend to be sort of stand-alone clinics, and that's not very common for an actual big research study of this scale."
Despite the recent scandal, Klassen hopes that the success of his trial and others will continue to push the field forward. "It just takes so many decades to move this stuff along, even when you're trying to simplify it as much as possible," he says. "With all the heavy lifting that's been done, I hope the world's got the patience to get this through."
The upcoming vaccine is changing the way we look at treating one of the country’s deadliest cancers.
Last week, researchers at the University of Oxford announced that they have received funding to create a brand new way of preventing ovarian cancer: A vaccine. The vaccine, known as OvarianVax, will teach the immune system to recognize and destroy mutated cells—one of the earliest indicators of ovarian cancer.
Understanding Ovarian Cancer
Despite advancements in medical research and treatment protocols over the last few decades, ovarian cancer still poses a significant threat to women’s health. In the United States alone, more than 12,0000 women die of ovarian cancer each year, and only about half of women diagnosed with ovarian cancer survive five or more years past diagnosis. Unlike cervical cancer, there is no routine screening for ovarian cancer, so it often goes undetected until it has reached advanced stages. Additionally, the primary symptoms of ovarian cancer—frequent urination, bloating, loss of appetite, and abdominal pain—can often be mistaken for other non-cancerous conditions, delaying treatment.
An American woman has roughly a one percent chance of developing ovarian cancer throughout her lifetime. However, these odds increase significantly if she has inherited mutations in the BRCA1 or BRCA2 genes. Women who carry these mutations face a 46% lifetime risk for ovarian and breast cancers.
An Unlikely Solution
To address this escalating health concern, the organization Cancer Research UK has invested £600,000 over the next three years in research aimed at creating a vaccine, which would destroy cancerous cells before they have a chance to develop any further.
Researchers at the University of Oxford are at the forefront of this initiative. With funding from Cancer Research UK, scientists will use tissue samples from the ovaries and fallopian tubes of patients currently battling ovarian cancer. Using these samples, University of Oxford scientists will create a vaccine to recognize certain proteins on the surface of ovarian cancer cells known as tumor-associated antigens. The vaccine will then train that person’s immune system to recognize the cancer markers and destroy them.
The next step
Once developed, the vaccine will first be tested in patients with the disease, to see if their ovarian tumors will shrink or disappear. Then, the vaccine will be tested in women with the BRCA1 or BRCA2 mutations as well as women in the general population without genetic mutations, to see whether the vaccine can prevent the cancer altogether.
While the vaccine still has “a long way to go,” according to Professor Ahmed Ahmed, Director of Oxford University’s ovarian cancer cell laboratory, he is “optimistic” about the results.
“We need better strategies to prevent ovarian cancer,” said Ahmed in a press release from the University of Oxford. “Currently, women with BRCA1/2 mutations are offered surgery which prevents cancer but robs them of the chance to have children afterward.
Teaching the immune system to recognize the very early signs of cancer is a tough challenge. But we now have highly sophisticated tools which give us real insights into how the immune system recognizes ovarian cancer. OvarianVax could offer the solution.”
How sharing, hearing, and remembering positive stories can help shape our brains for the better
Across cultures and through millennia, human beings have always told stories. Whether it’s a group of boy scouts around a campfire sharing ghost stories or the paleolithic Cro-Magnons etching pictures of bison on cave walls, researchers believe that storytelling has been universal to human beings since the development of language.
But storytelling was more than just a way for our ancestors to pass the time. Researchers believe that storytelling served an important evolutionary purpose, helping humans learn empathy, share important information (such as where predators were or what berries were safe to eat), as well as strengthen social bonds. Quite literally, storytelling has made it possible for the human race to survive.
Today, neuroscientists are discovering that storytelling is just as important now as it was millions of years ago. Particularly in sharing positive stories, humans can more easily form relational bonds, develop a more flexible perspective, and actually grow new brain circuitry that helps us survive. Here’s how.
How sharing stories positively impacts the brain
When human beings share stories, it increases the levels of certain neurochemicals in the brain, neuroscientists have found. In a 2021 study published in Proceedings of the National Academy of Sciences (PNAS), Swedish researchers found that simply hearing a story could make hospitalized children feel better, compared to other hospitalized children who played a riddle game for the same amount of time. In their research, children in the intensive care unit who heard stories for just 30 minutes had higher levels of oxytocin, a hormone that promotes positive feelings and is linked to relaxation, trust, social connectedness, and overall psychological stability. Furthermore, the same children showed lower levels of cortisol, a hormone associated with stress. Afterward, the group of children who heard stories tended to describe their hospital experiences more positively, and even reported lower levels of pain.
Annie Brewster, MD, knows the positive effect of storytelling from personal experience. An assistant professor at Harvard Medical School and the author of The Healing Power of Storytelling: Using Personal Narrative to Navigate Illness, Trauma, and Loss, Brewster started sharing her personal experience with chronic illness after being diagnosed with multiple sclerosis in 2001. In doing so, Brewster says it has enabled her to accept her diagnosis and integrate it into her identity. Brewster believes so much in the power of hearing and sharing stories that in 2013 she founded Health Story Collaborative, a forum for others to share their mental and physical health challenges.“I wanted to hear stories of people who had found ways to move forward in positive ways, in spite of health challenges,” Brewster said. In doing so, Brewster believes people with chronic conditions can “move closer to self-acceptance and self-love.”
While hearing and sharing positive stories has been shown to increase oxytocin and other “feel good” chemicals, simply remembering a positive story has an effect on our brains as well. Mark Hoelterhoff, PhD, a lecturer in clinical psychology at the University of Edinburgh, recalling and “savoring” a positive story, thought, or feedback “begins to create new brain circuitry—a new neural network that’s geared toward looking for the positive,” he says. Over time, other research shows, savoring positive stories or thoughts can literally change the shape of your brain, hard-wiring someone to see things in a more positive light.How stories can change your behavior
In 2009, Paul Zak, PhD, a neuroscientist and professor at Claremont Graduate University, set out to measure how storytelling can actually change human behavior for the better. In his study, Zak wanted to measure the behavioral effects of oxytocin, and did this by showing test subjects two short video clips designed to elicit an emotional response.
In the first video they showed the study participants, a father spoke to the camera about his two-year-old son, Ben, who had been diagnosed with terminal brain cancer. The father told the audience that he struggled to connect with and enjoy Ben, as Ben had only a few months left to live. In the end, the father finds the strength to stay emotionally connected to his son until he dies.
The second video clip, however, was much less emotional. In that clip, the same father and son are shown spending the day at the zoo. Ben is only suggested to have cancer (he is bald from chemotherapy and referred to as a ‘miracle’, but the cancer isn’t mentioned directly). The second story lacked the dramatic narrative arc of the first video.
Zak’s team took blood before and after the participants watched one of the two videos and found that the first story increased the viewers’ cortisol and oxytocin, suggesting that they felt distress over the boy’s diagnosis and empathy toward the boy and his father. The second narrative, however, didn’t increase oxytocin or cortisol at all.
But Zak took the experiment a step further. After the movie clips, his team gave the study participants a chance to share money with a stranger in the lab. The participants who had an increase in cortisol and oxytocin were more likely to donate money generously. The participants who had increased cortisol and oxytocin were also more likely to donate money to a charity that works with children who are ill. Zak also found that the amount of oxytocin that was released was correlated with how much money people felt comfortable giving—in other words, the more oxytocin that was released, the more generous they felt, and the more money they donated.
How storytelling strengthens our bond with others
Sharing, hearing, and remembering stories can be a powerful tool for social change–not only in the way it changes our brain and our behavior, but also because it can positively affect our relationships with other people
Emotional stimulation from telling stories, writes Zak, is the foundation for empathy, and empathy strengthens our relationships with other people. “By knowing someone’s story—where they come from, what they do, and who you might know in common—relationships with strangers are formed.”
But why are these relationships important for humanity? Because human beings can use storytelling to build empathy and form relationships, it enables them to “engage in the kinds of large-scale cooperation that builds massive bridges and sends humans into space,” says Zak.
Storytelling, Zak found, and the oxytocin release that follows, also makes people more sensitive to social cues. This sensitivity not only motivates us to form relationships, but also to engage with other people and offer help, particularly if the other person seems to need help.
But as Zak found in his experiments, the type of storytelling matters when it comes to affecting relationships. Where Zak found that storytelling with a dramatic arc helps release oxytocin and cortisol, enabling people to feel more empathic and generous, other researchers have found that sharing happy stories allows for greater closeness between individuals and speakers. A group of Chinese researchers found that, compared to emotionally-neutral stories, happy stories were more “emotionally contagious.” Test subjects who heard happy stories had greater activation in certain areas of their brains, experienced more significant, positive changes in their mood, and felt a greater sense of closeness between themselves and the speaker.
“This finding suggests that when individuals are happy, they become less self-focused and then feel more intimate with others,” the authors of the study wrote. “Therefore, sharing happiness could strengthen interpersonal bonding.” The researchers went on to say that this could lead to developing better social networks, receiving more social support, and leading more successful social lives.
Since the start of the COVID pandemic, social isolation, loneliness, and resulting mental health issues have only gotten worse. In light of this, it’s safe to say that hearing, sharing, and remembering stories isn’t just something we can do for entertainment. Storytelling has always been central to the human experience, and now more than ever it’s become something crucial for our survival.
Want to know how you can reap the benefits of hearing happy stories? Keep an eye out for Upworthy’s first book, GOOD PEOPLE: Stories from the Best of Humanity, published by National Geographic/Disney, available on September 3, 2024. GOOD PEOPLE is a much-needed trove of life-affirming stories told straight from the heart. Handpicked from Upworthy’s community, these 101 stories speak to the breadth, depth, and beauty of the human experience, reminding us we have a lot more in common than we realize.