Fixing a Baby’s Abnormal Genes in the Womb May Soon Be Possible
By now you have probably heard something about CRISPR, the simple and relatively inexpensive method of precisely editing the genomes of plants, animals, and humans.
The treatment of disease in fetuses, the liminal category of life between embryos and humans, poses the next frontier.
Through CRISPR and other methods of gene editing, scientists have produced crops to be more nutritious, better able to resist pests, and tolerate droughts; engineered animals ranging from fruit flies to monkeys to make them better suited for scientific study; and experimentally treated the HIV virus, Hepatitis B, and leukemia in human patients.
There are also currently FDA-approved trials to treat blindness, cancer, and sickle cell disease in humans using gene editing, and there is consensus that CRISPR's therapeutic applications will grow significantly in the coming years.
While the treatment of human disease through use of gene editing is not without its medical and ethical concerns, the avoidance of disease in embryos is far more fraught. Nonetheless, Nature reported in November that He Jiankui, a scientist in China, had edited twin embryos to disable a gene called CCR5 in hopes of avoiding transmission of HIV from their HIV-positive father.
Though there are questions about the effectiveness and necessity of this therapy, He reported that sequencing has proven his embryonic gene edits were successful and the twins were "born normal and healthy," although his claims have not been independently verified.
More recently, Denis Rebrikov, a Russian scientist, announced his plans to disable the same gene in embryos to be implanted in HIV-positive women later this year. Futuristic as it may seem, prenatal gene editing is already here.
The treatment of disease in fetuses, the liminal category of life between embryos and humans, poses the next frontier. Numerous conditions—some minor, some resulting in a lifetime of medical treatment, some incompatible with life outside of the womb—can be diagnosed through use of prenatal diagnostic testing. There is promising research suggesting doctors will soon be able to treat or mitigate at least some of them through use of fetal gene editing.
This research could soon present women carrying genetically anomalous fetuses a third option aside from termination or birthing a child who will likely face a challenging and uncertain medical future: Whether to undergo a fetal genetic intervention.
However, genetic intervention will open the door to a host of ethical considerations, particularly with respect to the relationship between pregnant women and prenatal genetic counselors. Current counselors theoretically provide objective information and answer questions rather than advise their pregnant client whether to continue with her pregnancy, despite the risks, or to have an abortion.
In practice, though, prenatal genetic counseling is most often directive, and the nature of the counseling pregnant women receive can depend on numerous factors, including their religious and cultural beliefs, their perceived ability to handle a complicated pregnancy and subsequent birth, and their financial status. Introducing the possibility of a fetal genetic intervention will exacerbate counselor reliance upon these considerations and in some cases lead to counseling that is even more directive.
Some women in the near future will face the choice of whether to abort, keep, or treat a genetically anomalous fetus.
Future counselors will have to figure out under what circumstances it is even appropriate to broach the subject. Should they only discuss therapies that are FDA-approved, or should they mention experimental treatments? What about interventions that are available in Europe or Asia, but banned in the United States? Or even in the best case of scenario of an FDA-approved treatment, should a counselor make reference to it if she knows for a fact that her client cannot possibly afford it?
Beyond the basic question of what information to share, counselors will have to confront the fact that the very notion of fixing or "editing" offspring will be repugnant to many women, and inherent in the suggestion is the stigmatization of individuals with disabilities. Prenatal genetic counselors will be on the forefront of debates surrounding which fetuses should remain as they are and which ones should be altered.
Despite these concerns, some women in the near future will face the choice of whether to abort, keep, or treat a genetically anomalous fetus in utero. Take, for example, a woman who learns during prenatal testing that her fetus has Angelman syndrome, a genetic disorder characterized by intellectual disability, speech impairment, loss of muscle control, epilepsy, and a small head. There is currently no human treatment for Angelman syndrome, which is caused by a loss of function in a single gene, UBE3A.
But scientists at the University of North Carolina have been able to treat Angelman syndrome in fetal mice by reactivating UBE3A through use of a single injection. The therapy has also proven effective in cultured human brain cells. This suggests that a woman might soon have to consider injecting her fetus's brain with a CRISPR concoction custom-designed to target UBE3A, rather than terminate her pregnancy or bring her fetus to term unaltered.
Assuming she receives the adequate information to make an informed choice, she too will face an ethical conundrum. There will be the inherent risks of injecting anything into a developing fetus's brain, including the possibility of infection, brain damage, and miscarriage. But there are also risks specific to gene editing, such as so-called off-target effects, the possibility of impacting genes other than the intended one. Such effects are highly unpredictable and can be difficult to detect. So too is it impossible to predict how altering UBE3A might lead to other genetic and epigenetic changes once the baby is born.
There are no easy answers to the many questions that will arise in this space.
A woman deciding how to act in this scenario must balance these risks against the potential benefits of the therapy, layered on top of her belief system, resources, and personal ethics. The calculus will be different for every woman, and even the same woman might change her mind from one pregnancy to the next based on the severity of the condition diagnosed and other available medical options.
Her genetic counselor, meanwhile, must be sensitive to all of these concerns in helping her make her decision, keeping up to date on the possible new treatments, and carefully choosing which information to disclose in striving to be neutral. There are no easy answers to the many questions that will arise in this space, but better to start thinking about them now, before it is too late.
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.