Why Blindness Will Be the First Disorder Cured by Futuristic Treatments
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."
Autonomous, indoor farming gives a boost to crops
The glass-encased cabinet looks like a display meant to hold reasonably priced watches, or drugstore beauty creams shipped from France. But instead of this stagnant merchandise, each of its five shelves is overgrown with leaves — moss-soft pea sprouts, spikes of Lolla rosa lettuces, pale bok choy, dark kale, purple basil or red-veined sorrel or green wisps of dill. The glass structure isn’t a cabinet, but rather a “micro farm.”
The gadget is on display at the Richmond, Virginia headquarters of Babylon Micro-Farms, a company that aims to make indoor farming in the U.S. more accessible and sustainable. Babylon’s soilless hydroponic growing system, which feeds plants via nutrient-enriched water, allows chefs on cruise ships, cafeterias and elsewhere to provide home-grown produce to patrons, just seconds after it’s harvested. Currently, there are over 200 functioning systems, either sold or leased to customers, and more of them are on the way.
The chef-farmers choose from among 45 types of herb and leafy-greens seeds, plop them into grow trays, and a few weeks later they pick and serve. While success is predicated on at least a small amount of these humans’ care, the systems are autonomously surveilled round-the-clock from Babylon’s base of operations. And artificial intelligence is helping to run the show.
Babylon piloted the use of specialized cameras that take pictures in different spectrums to gather some less-obvious visual data about plants’ wellbeing and alert people if something seems off.
Imagine consistently perfect greens and tomatoes and strawberries, grown hyper-locally, using less water, without chemicals or environmental contaminants. This is the hefty promise of controlled environment agriculture (CEA) — basically, indoor farms that can be hydroponic, aeroponic (plant roots are suspended and fed through misting), or aquaponic (where fish play a role in fertilizing vegetables). But whether they grow 4,160 leafy-green servings per year, like one Babylon farm, or millions of servings, like some of the large, centralized facilities starting to supply supermarkets across the U.S., they seek to minimize failure as much as possible.
Babylon’s soilless hydroponic growing system
Courtesy Babylon Micro-Farms
Here, AI is starting to play a pivotal role. CEA growers use it to help “make sense of what’s happening” to the plants in their care, says Scott Lowman, vice president of applied research at the Institute for Advanced Learning and Research (IALR) in Virginia, a state that’s investing heavily in CEA companies. And although these companies say they’re not aiming for a future with zero human employees, AI is certainly poised to take a lot of human farming intervention out of the equation — for better and worse.
Most of these companies are compiling their own data sets to identify anything that might block the success of their systems. Babylon had already integrated sensor data into its farms to measure heat and humidity, the nutrient content of water, and the amount of light plants receive. Last year, they got a National Science Foundation grant that allowed them to pilot the use of specialized cameras that take pictures in different spectrums to gather some less-obvious visual data about plants’ wellbeing and alert people if something seems off. “Will this plant be healthy tomorrow? Are there things…that the human eye can't see that the plant starts expressing?” says Amandeep Ratte, the company’s head of data science. “If our system can say, Hey, this plant is unhealthy, we can reach out to [users] preemptively about what they’re doing wrong, or is there a disease at the farm?” Ratte says. The earlier the better, to avoid crop failures.
Natural light accounts for 70 percent of Greenswell Growers’ energy use on a sunny day.
Courtesy Greenswell Growers
IALR’s Lowman says that other CEA companies are developing their AI systems to account for the different crops they grow — lettuces come in all shapes and sizes, after all, and each has different growing needs than, for example, tomatoes. The ways they run their operations differs also. Babylon is unusual in its decentralized structure. But centralized growing systems with one main location have variabilities, too. AeroFarms, which recently declared bankruptcy but will continue to run its 140,000-square foot vertical operation in Danville, Virginia, is entirely enclosed and reliant on the intense violet glow of grow lights to produce microgreens.
Different companies have different data needs. What data is essential to AeroFarms isn’t quite the same as for Greenswell Growers located in Goochland County, Virginia. Raising four kinds of lettuce in a 77,000-square-foot automated hydroponic greenhouse, the vagaries of naturally available light, which accounts for 70 percent of Greenswell’s energy use on a sunny day, affect operations. Their tech needs to account for “outside weather impacts,” says president Carl Gupton. “What adjustments do we have to make inside of the greenhouse to offset what's going on outside environmentally, to give that plant optimal conditions? When it's 85 percent humidity outside, the system needs to do X, Y and Z to get the conditions that we want inside.”
AI will help identify diseases, as well as when a plant is thirsty or overly hydrated, when it needs more or less calcium, phosphorous, nitrogen.
Nevertheless, every CEA system has the same core needs — consistent yield of high quality crops to keep up year-round supply to customers. Additionally, “Everybody’s got the same set of problems,” Gupton says. Pests may come into a facility with seeds. A disease called pythium, one of the most common in CEA, can damage plant roots. “Then you have root disease pressures that can also come internally — a change in [growing] substrate can change the way the plant performs,” Gupton says.
AI will help identify diseases, as well as when a plant is thirsty or overly hydrated, when it needs more or less calcium, phosphorous, nitrogen. So, while companies amass their own hyper-specific data sets, Lowman foresees a time within the next decade “when there will be some type of [open-source] database that has the most common types of plant stress identified” that growers will be able to tap into. Such databases will “create a community and move the science forward,” says Lowman.
In fact, IALR is working on assembling images for just such a database now. On so-called “smart tables” inside an Institute lab, a team is growing greens and subjects them to various stressors. Then, they’re administering treatments while taking images of every plant every 15 minutes, says Lowman. Some experiments generate 80,000 images; the challenge lies in analyzing and annotating the vast trove of them, marking each one to reflect outcome—for example increasing the phosphate delivery and the plant’s response to it. Eventually, they’ll be fed into AI systems to help them learn.
For all the enthusiasm surrounding this technology, it’s not without downsides. Training just one AI system can emit over 250,000 pounds of carbon dioxide, according to MIT Technology Review. AI could also be used “to enhance environmental benefit for CEA and optimize [its] energy consumption,” says Rozita Dara, a computer science professor at the University of Guelph in Canada, specializing in AI and data governance, “but we first need to collect data to measure [it].”
The chef-farmers can choose from 45 types of herb and leafy-greens seeds.
Courtesy Babylon Micro-Farms
Any system connected to the Internet of Things is also vulnerable to hacking; if CEA grows to the point where “there are many of these similar farms, and you're depending on feeding a population based on those, it would be quite scary,” Dara says. And there are privacy concerns, too, in systems where imaging is happening constantly. It’s partly for this reason, says Babylon’s Ratte, that the company’s in-farm cameras all “face down into the trays, so the only thing [visible] is pictures of plants.”
Tweaks to improve AI for CEA are happening all the time. Greenswell made its first harvest in 2022 and now has annual data points they can use to start making more intelligent choices about how to feed, water, and supply light to plants, says Gupton. Ratte says he’s confident Babylon’s system can already “get our customers reliable harvests. But in terms of how far we have to go, it's a different problem,” he says. For example, if AI could detect whether the farm is mostly empty—meaning the farm’s user hasn’t planted a new crop of greens—it can alert Babylon to check “what's going on with engagement with this user?” Ratte says. “Do they need more training? Did the main person responsible for the farm quit?”
Lowman says more automation is coming, offering greater ability for systems to identify problems and mitigate them on the spot. “We still have to develop datasets that are specific, so you can have a very clear control plan, [because] artificial intelligence is only as smart as what we tell it, and in plant science, there's so much variation,” he says. He believes AI’s next level will be “looking at those first early days of plant growth: when the seed germinates, how fast it germinates, what it looks like when it germinates.” Imaging all that and pairing it with AI, “can be a really powerful tool, for sure.”
Scientists make progress with growing organs for transplants
Story by Big Think
For over a century, scientists have dreamed of growing human organs sans humans. This technology could put an end to the scarcity of organs for transplants. But that’s just the tip of the iceberg. The capability to grow fully functional organs would revolutionize research. For example, scientists could observe mysterious biological processes, such as how human cells and organs develop a disease and respond (or fail to respond) to medication without involving human subjects.
Recently, a team of researchers from the University of Cambridge has laid the foundations not just for growing functional organs but functional synthetic embryos capable of developing a beating heart, gut, and brain. Their report was published in Nature.
The organoid revolution
In 1981, scientists discovered how to keep stem cells alive. This was a significant breakthrough, as stem cells have notoriously rigorous demands. Nevertheless, stem cells remained a relatively niche research area, mainly because scientists didn’t know how to convince the cells to turn into other cells.
Then, in 1987, scientists embedded isolated stem cells in a gelatinous protein mixture called Matrigel, which simulated the three-dimensional environment of animal tissue. The cells thrived, but they also did something remarkable: they created breast tissue capable of producing milk proteins. This was the first organoid — a clump of cells that behave and function like a real organ. The organoid revolution had begun, and it all started with a boob in Jello.
For the next 20 years, it was rare to find a scientist who identified as an “organoid researcher,” but there were many “stem cell researchers” who wanted to figure out how to turn stem cells into other cells. Eventually, they discovered the signals (called growth factors) that stem cells require to differentiate into other types of cells.
For a human embryo (and its organs) to develop successfully, there needs to be a “dialogue” between these three types of stem cells.
By the end of the 2000s, researchers began combining stem cells, Matrigel, and the newly characterized growth factors to create dozens of organoids, from liver organoids capable of producing the bile salts necessary for digesting fat to brain organoids with components that resemble eyes, the spinal cord, and arguably, the beginnings of sentience.
Synthetic embryos
Organoids possess an intrinsic flaw: they are organ-like. They share some characteristics with real organs, making them powerful tools for research. However, no one has found a way to create an organoid with all the characteristics and functions of a real organ. But Magdalena Żernicka-Goetz, a developmental biologist, might have set the foundation for that discovery.
Żernicka-Goetz hypothesized that organoids fail to develop into fully functional organs because organs develop as a collective. Organoid research often uses embryonic stem cells, which are the cells from which the developing organism is created. However, there are two other types of stem cells in an early embryo: stem cells that become the placenta and those that become the yolk sac (where the embryo grows and gets its nutrients in early development). For a human embryo (and its organs) to develop successfully, there needs to be a “dialogue” between these three types of stem cells. In other words, Żernicka-Goetz suspected the best way to grow a functional organoid was to produce a synthetic embryoid.
As described in the aforementioned Nature paper, Żernicka-Goetz and her team mimicked the embryonic environment by mixing these three types of stem cells from mice. Amazingly, the stem cells self-organized into structures and progressed through the successive developmental stages until they had beating hearts and the foundations of the brain.
“Our mouse embryo model not only develops a brain, but also a beating heart [and] all the components that go on to make up the body,” said Żernicka-Goetz. “It’s just unbelievable that we’ve got this far. This has been the dream of our community for years and major focus of our work for a decade and finally we’ve done it.”
If the methods developed by Żernicka-Goetz’s team are successful with human stem cells, scientists someday could use them to guide the development of synthetic organs for patients awaiting transplants. It also opens the door to studying how embryos develop during pregnancy.