Body-on-a-chip, prime editing, and gut microbes all are poised to make a big impact in 2020.
1. Happening Now: Body-on-a-Chip Technology Is Enabling Safer Drug Trials and Better Cancer Research
Researchers have increasingly used the technology known as "lab-on-a-chip" or "organ-on-a-chip" to test the effects of pharmaceuticals, toxins, and chemicals on humans. Rather than testing on animals, which raises ethical concerns and can sometimes be inaccurate, and human-based clinical trials, which can be expensive and difficult to iterate, scientists turn to tiny, micro-engineered chips—about the size of a thumb drive.
It's possible that doctors could one day take individual cell samples and create personalized treatments, testing out any medications on the chip.
The chips are lined with living samples of human cells, which mimic the physiology and mechanical forces experienced by cells inside the human body, down to blood flow and breathing motions; the functions of organs ranging from kidneys and lungs to skin, eyes, and the blood-brain barrier.
A more recent—and potentially even more useful—development takes organ-on-a-chip technology to the next level by integrating several chips into a "body-on-a-chip." Since human organs don't work in isolation, seeing how they all react—and interact—once a foreign element has been introduced can be crucial to understanding how a certain treatment will or won't perform. Dr. Shyni Varghese, a MEDx investigator at the Duke University School of Medicine, is one of the researchers working with these systems in order to gain a more nuanced understanding of how multiple different organs react to the same stimuli.
Her lab is working on "tumor-on-a-chip" models, which can not only show the progression and treatment of cancer, but also model how other organs would react to immunotherapy and other drugs. "The effect of drugs on different organs can be tested to identify potential side effects," Varghese says. In addition, these models can help the researchers figure out how cancers grow and spread, as well as how to effectively encourage immune cells to move in and attack a tumor.
One body-on-a-chip used by Dr. Varghese's lab tracks the interactions of five organs—brain, heart, liver, muscle, and bone.
As their research progresses, Varghese and her team are looking for ways to maintain the long-term function of the engineered organs. In addition, she notes that this kind of research is not just useful for generalized testing; "organ-on-chip technologies allow patient-specific analyses, which can be used towards a fundamental understanding of disease progression," Varghese says. It's possible that doctors could one day take individual cell samples and create personalized treatments, testing out any medications on the chip for safety, efficacy, and potential side effects before writing a prescription.
2. Happening Soon: Prime Editing Will Have the Power to "Find and Replace" Disease-Causing Genes
Biochemist David Liu made industry-wide news last fall when he and his lab at MIT's Broad Institute, led by Andrew Anzalone, published a paper on prime editing: a new, more focused technology for editing genes. Prime editing is a descendant of the CRISPR-Cas9 system that researchers have been working with for years, and a cousin to Liu's previous innovation—base editing, which can make a limited number of changes to a single DNA letter at a time.
By contrast, prime editing has the potential to make much larger insertions and deletions; it also doesn't require the tweaked cells to divide in order to write the changes into the DNA, which could make it especially suitable for central nervous system diseases, like Parkinson's.
Crucially, the prime editing technique has a much higher efficiency rate than the older CRISPR system, and a much lower incidence of accidental insertions or deletions, which can make dangerous changes for a patient.
It also has a very broad potential range: according to Liu, 89% of the pathogenic mutations that have been collected in ClinVar (a public archive of human variations) could, in principle, be treated with prime editing—although he is careful to note that correcting a single genetic mutation may not be sufficient to fully treat a genetic disease.
Figuring out just how prime editing can be used most effectively and safely will be a long process, but it's already underway. The same day that Liu and his team posted their paper, they also made the basic prime editing constructs available for researchers around the world through Addgene, a plasmid repository, so that others in the scientific community can test out the technique for themselves. It might be years before human patients will see the results, and in the meantime, significant bioethical questions remain about the limits and sociological effects of such a powerful gene-editing tool. But in the long fight against genetic diseases, it's a huge step forward.
3. Happening When We Fund It: Focusing on Microbiome Health Could Help Us Tackle Social Inequality—And Vice Versa
The past decade has seen a growing awareness of the major role that the microbiome, the microbes present in our digestive tract, play in human health. Having a less-healthy microbiome is correlated with health risks like diabetes and depression, and interventions that target gut health, ranging from kombucha to fecal transplants, have cropped up with increasing frequency.
New research from the University of Maine's Dr. Suzanne Ishaq takes an even broader view, arguing that low-income and disadvantaged populations are less likely to have healthy, diverse gut bacteria, and that increasing access to beneficial microorganisms is an important juncture of social justice and public health.
"Basically, allowing people to lead healthy lives allows them to access and recruit microbes."
"Typically, having a more diverse bacterial community is associated with health, and having fewer different species is associated with illness and may leave you open to infection from bacteria that are good at exploiting opportunities," Ishaq says.
Having a healthy biome doesn't mean meeting one fixed ratio of gut bacteria, since different combinations of microbes can generate roughly similar results when they work in concert. Generally, "good" microbes are the ones that break down fiber and create the byproducts that we use for energy, or ones like lactic acid bacteria that work to make microbials and keep other bacteria in check. The microbial universe in your gut is chaotic, Ishaq says. "Microbes in your gut interact with each other, with you, with your food, or maybe they don't interact at all and pass right through you." Overall, it's tricky to name specific microbial communities that will make or break someone's health.
There are important corollaries between environment and biome health, though, which Ishaq points out: Living in urban environments reduces microbial exposure, and losing the microorganisms that humans typically source from soil and plants can reduce our adaptive immunity and ability to fight off conditions like allergies and asthma. Access to green space within cities can counteract those effects, but in the U.S. that access varies along income, education, and racial lines. Likewise, lower-income communities are more likely to live in food deserts or areas where the cheapest, most convenient food options are monotonous and low in fiber, further reducing microbial diversity.
Ishaq also suggests other areas that would benefit from further study, like the correlation between paid family leave, breastfeeding, and gut microbiota. There are technical and ethical challenges to direct experimentation with human populations—but that's not what Ishaq sees as the main impediment to future research.
"The biggest roadblock is money, and the solution is also money," she says. "Basically, allowing people to lead healthy lives allows them to access and recruit microbes."
That means investment in things we already understand to improve public health, like better education and healthcare, green space, and nutritious food. It also means funding ambitious, interdisciplinary research that will investigate the connections between urban infrastructure, housing policy, social equity, and the millions of microbes keeping us company day in and day out.
In Ethiopia, Samuna’s three donkeys help her transport produce to market and to collect the water essential to her family, neighbours and livestock. Donkeys are more endangered than people realize, experts say.
“That's the reason why some breeds begin to disappear because humans were not really interested in having that specific breed anymore,” Gambini says. Nonetheless, in Africa, India and Latin America millions of rural families still rely on these hardy creatures for agriculture and transportation. And the only two wild donkey species—Equus africanus in Africa and Equus hemionus in Asia—are also dwindling, due to losing their habitats to human activities, diseases and slow reproduction rates. Gambini’s team wanted to create a way to preserve the animals for the future. “Donkeys are more endangered than people realize,” he says.
There’s much more to donkeys' trouble though. For the past 20 or so years, they have been facing a huge existential threat due to their hide gelatin, a compound derived from their skins by soaking and stewing. In Chinese traditional medicine, the compound, called ejiao, is believed to have a medicinal value, so it’s used in skin creams, added to food and taken in capsules. Centuries ago, ejiao was a very expensive luxury product available only for the emperor and his household. That changed in the 1990s when the Chinese economy boomed, and many people were suddenly able to afford it. “It went from a very elite product to a very popular product,” says Janneke Merkx, a campaign manager at The Donkey Sanctuary, a United Kingdom-based nonprofit organization that keeps tabs on the animals’ welfare worldwide. “It is a status symbol for gift giving.”
Having evolved in the harsh and arid mountainous terrains where food and water were scarce, donkeys are extremely adaptable and hardy. But the Donkey Sanctuary documented cases in which an entire village had their animals disappear overnight, finding them killed and skinned outside their settlement.
The Chinese donkey population was quickly decimated. Unlike many other farm animals, donkeys are finicky breeders. When stressed and unhappy, they don’t procreate, so growing them in large industrial settings isn’t possible. “Donkeys are notoriously slow breeders and really very difficult to farm,” says Merkx. “They are not the same as other livestock like sheep and pigs and cattle.” Within years the, the donkey numbers in China dropped precipitously. “China used to have the largest donkey population in the world in the 1990s. They had 11 million donkeys, and it's now down to less than 3 million, and they just can't keep up with the demand.”
To keep the ejiao conveyor going, some producers turned to the illegal wildlife trade. Poachers began to steal and slaughter donkeys from rural villages in Africa. The Donkey Sanctuary documented cases in which an entire village had their animals disappear overnight, finding them killed and skinned outside their settlement. Exactly how many creatures were lost to the skin trade to-date isn’t possible to calculate, says Faith Burden, the Donkey Sanctuary’s director of equine operations. Traditionally a poor people’s beast of burden, donkey counts are hard to keep track of. “When an animal doesn't produce meat, milk or eggs or whatever edible product, they're often less likely to be acknowledged in a government population census,” Burden says. “So reliable statistics are hard to come by.” The nonprofit estimates that about 4.8 million are slaughtered annually.
During their six to seven thousand years of domestication, donkeys rarely got the full appreciation for their services. They are often compared to horses, which doesn’t do them justice. They’re entirely different animals, Burden says. Built for speed, horses respond to predators and other dangers by running as fast as they can. Donkeys, which originate from the rocky, mountainous regions of Africa where running is dangerous, react to threats by freezing and assessing the situation for the best response. “Those so-called stubborn donkeys that won’t move as you want, they are actually thinking ‘what’s the best approach,’” Burden says. They may even choose to fight the predators rather than flee, she adds. “In some parts of the world, people use them as guard animals against things like coyotes and wolves.”
Scientists believe that domestic donkeys take their origin from Equus africanus or African wild ass, originally roaming where Kenya, Ethiopia and Eritrea are today. Having evolved in the harsh and arid mountainous terrains where food and water were scarce, they are extremely adaptable and hardy. Research finds that they can go without water for 72 hours and then drink their fill without any negative consequences. Their big jaws let them chew tough desert shrubs, which horses can’t exist on. Their large ears help dissipate heat. Their little upright hooves are a perfect fit for the uneven rocky or other dangerous grounds. Accustomed to the mountain desert climate with hot days and cold nights, they don’t mind temperature flux.
“The donkey is the most supremely adapted animal to deal with hostile conditions,” Burden says. “They can survive on much lower nutritional quality food than a cow, sheep or horse. That’s why communities living in some of the most inhospitable places will often have donkeys with them.” And that’s why losing a donkey to an illegal skin trade can devastate a family in places like Eritrea. Suddenly everything from water to firewood to produce must be carried by family members—and often women.
Workers unloading donkeys at the Shinyanga slaughterhouse in Tanzania. Fearing a future in which donkeys go extinct, scientists have found ways to cryopreserve a donkey embryo in liquid nitrogen.
TAHUCHA
One can imagine a time when worldwide donkey populations may dwindle to the point that they would need to be restored. That includes their genetic variability too. That’s where the frozen embryos may come in handy. We may be able to use them to increase the genetic variability of donkeys, which will be especially important if they get closer to extinction, Gambini says. His team had already created frozen embryos for horses and zebras, an idea similar to a seed bank. “We call this concept the Frozen Zoo.”
Creating donkey embryos proved much harder than those of zebras and horses. To improve chances of fertilization, Gambini used the intracytoplasmic sperm injection or ICSI, in which he employed a tiny needle called a micropipette to inject a donkey sperm into an egg. That was a step above the traditional IVF method, in which the egg and a sperm are left floating in a test tube together. The injection took, but during the incubating week, one after the other, the embryos stopped dividing. Finally, on day seven, Gambini finally spotted the exact sight he was hoping to see. One of the embryos developed into a burgeoning ball of cells.
“That stage is called a blastocyst,” Gambini says. The clump of cells had a lot of fluids mixed within them, which indicated that they were finally developing into a viable embryo. “When we see a blastocyst, we know we can transfer that into a female.” He was so excited he immediately called all his collaborators to tell them the good news, which they later published in the journal of Theriogenology.
The one and only embryo to reach that stage, the blastocyst was cryopreserved in liquid nitrogen. The team is waiting for the next breeding season to see if a female donkey may carry it to term and give birth to a healthy foal. Gambini’s team is hoping to polish the process and create more embryos. “It’s our weapon in the conservation ass-enal,” he says.
