Biotechnology

Our immune systems are vastly complex networks involving hundreds of proteins that send signals to dozens of cells. Ang Cui, 34, uses machine learning to engineer tools that can make sense of such huge amounts of data. She developed her first machine learning model—an algorithm to study childhood arthritis—as an undergraduate studying computer engineering.

Cui has now applied her computational skills to understand why men’s and women’s immune systems appear to work differently, especially in old age. “Older men are more vulnerable to infections and cancer, whereas older women and women in general are more susceptible to autoimmune diseases,” she says.

Cui developed a tool to analyze genetic mutations in B cells—a type of immune cell that makes antibodies—from healthy volunteers. She analyzed just over 985,000 mutations, a large-scale approach that helped her identify a key molecular pathway important for the development of antibodies and one that seems to differ in older men and women. 

Cui, now at Harvard University, has spent 10 years working out the best way to use big data to understand the immune system. Take, for example, cytokines: proteins that direct other immune cells. There are over a hundred of them, each influencing around 18 types of immune cell. Getting a clear picture of all the various possible interactions was generally considered impossible. “Nobody ever really tried to do it,” says Cui.

Cui set out to change that by injecting 86 cytokines into mice and measuring the responses of 17 cell types. She built a computational tool to analyze her data and began compiling information about how each cytokine influences each type of cell. The result is the Immune Dictionary, which Cui describes as being “like a periodic table” for the immune system.

Although it was compiled using data collected from mice, the Immune Dictionary can give researchers insight into how the human immune system works. Cui and her colleagues have created free online software to allow scientists to make use of it. Within days of its launch in December, the web portal “completely crashed” because it was so popular, says Cui—since then, the dictionary has been accessed over 181,000 times.

When Alejandro Aguilera Castrejón, 32, was growing up in the Ecatepec, a low-income suburb of Mexico City, he dreamed of a better place. “I didn’t even know you could be a scientist,” says Castrejón. “But I liked animals, and in university I got interested in molecular biology, and then stem cells.” 

He landed at a cutting-edge lab in Israel studying embryology, or how animals develop. In 2021, Castrejón proved he could grow mouse embryos ex utero, that is, outside the uterus, inside a rotating bottle under just the right gas pressure and bathed in human blood. The mouse embryos survived about a third of their 19-day gestation period, long enough to develop brains and fast-beating hearts. 

No mammal had ever developed so extensively outside of its mother, excluding oddballs like the platypus, which lays eggs. 

The New York Times hailed the team’s feat as a “mechanical womb.” And, this year, Castrejón opened his own lab at the top-flight Janelia Research Campus in Loudoun County, Virginia, to take the system even further. “My dream, or aim, is to see if a mouse can be born this way,” he says. Collaborators, meanwhile, are clamoring for his help to nurture and grow human tissues as well, such as brain organoids, or ovaries that could be used to treat infertility. 

Long-term, there is the unnerving prospect of growing a human baby outside the body. But that’s “like 100 years away,” says Castrejón. For now, he says, the mechanical womb offers a new way to observe fetal animals as they grow and change. “I think we are creating a general system that could work for many species,” he says. “For scientists, it’s a window to perform experiments in a really easy way.” 

DNA’s double-helical structure is so well-recognized that the image has become synonymous with the idea of science. But this structure can be coiled, squished, and folded to create all sorts of shapes. By creating synthetic DNA, scientists can twist and fold the structures like origami.

Leopold Green, 34, is specifically interested in creating tubes, which have the benefit of allowing things to pass through them. Put these tubes into cells, and proteins or other chemicals could get in or out, potentially changing the way the cells work.

Green, a synthetic biologist at Purdue University, has developed a way to create DNA nanotubes using microscopic tiles of DNA. These tiles can join together to form tubes, and can grow or shrink. “It’s a beautiful balance of art and science and engineering,” he says.

Green wants to use this approach to tackle chronic diseases, many of which are linked to atypical immune responses. What if we could harness “good” microbes that happily reside inside us to dampen those responses? Green’s lab developed a strain of E. coli Nissle, a microbe that has been used as a probiotic, that can secrete a protein that influences the way our immune cells work. If microbes like these can be developed to sense signals of disease and respond to them—through nanotubes embedded in their membranes—they could “help push the system in the right direction,” says Green.

For a condition like eczema, researchers might focus on skin microbes. But Green is also studying microbes found in the vaginal tract. And microbes could be altered to target a range of other body cells—including those in the brain. In theory, researchers could take a microbe from a person’s body, modify it, and then reintroduce it as a probiotic-like therapy. “That’s my long-term vision,” says Green.

Mireille Kamariza, 35, created a new test for Mycobacterium tuberculosis that is cheap, can check for drug resistance, and is far faster than the most widely used alternatives, cutting the time it takes to get diagnostic results. 

Tuberculosis kills around 1.3 million people a year, making it more deadly than any other infectious disease, with the recent exception of covid-19. But the standard test used in the developing world—in which a doctor looks at a sputum sample (also known as phlegm) under a microscope to search for the bacteria—hasn’t changed much in over 100 years, and it can take weeks to return results that are not always accurate.

Kamariza’s test is based on a special dye she invented that fluoresces when it’s incorporated into the cell walls of living M. tuberculosis. By attaching her dye to trehalose, a sugar the bacteria use for fuel, Kamariza ensures the dye ends up in a living sample. In other words, feed the dyed trehalose to the bacterium from a sputum sample, and in as little as a few minutes it will glow under fluorescent light. Then, if you give a patient an antibiotic, within a few hours you’ll see if a new sample still lights up.

Kamariza’s breakthrough is based on fundamental chemical and biological concepts that have existed for decades. “The tricky thing was recognizing that this kind of chemistry could be applied in a diagnostic landscape,” she says. “I think no one had really considered it. It was a long shot.” 

To move her technology from the lab to the field, Kamariza co-founded a company structured to benefit the public rather than focus on profits. Now, while pursuing clinical trials, her team has shown that the same dye works on blood samples, which could make testing in the field safer and more broadly available.

“This dye can attach to a different sugar that targets a different bacteria, or virus, or parasite, or even the host,” Kamariza says. “Potentially even a cancer cell.”

Josie Kishi, 31, co-developed Light-Seq, a technology that lets researchers look at cells under a microscope before sequencing them to analyze their genetic code. Previously those two techniques could not be done together. The technology will be a major boost to disease research, drug discovery, and treatment plans for cancer and other pathologies.   

“If you look at the standard methods, you’re faced with an impossible choice,” says Kishi. “You either use microscopy to measure cells—where cells are, how they are interacting with one another—or you use genetic RNA sequencing to understand what those cells are doing.”

Preparing a sample for one method tends to ruin it for the other. This is a significant loss, considering that they both provide unique insights. Combining the two would offer even more.

Kishi unraveled the problem by borrowing an idea from the computer industry, mimicking the lithography process used to print silicon chips. First, a sample is bathed in a solution containing tiny bits of barcode-like segments of DNA that only attach to specific regions of interest in the intact sample when intense light is focused on those regions. Then, after the samples are analyzed optically, the tissue can be sequenced using regular machines.

What’s more, the barcode labeling process can be done multiple times in a row, using different DNA barcodes—like underlining text in contrasting colors of ink to indicate different types of words—to label specific structures, cell types, or areas. In this way, multiple structures from the same sample can be matched to their unique genetic sequences and function.

Inspired by how quickly companies like BioNTech and Moderna produced vaccines during the covid-19 pandemic, Kishi co-founded Digital Biology. The company will use Light-Seq to investigate how disease forms, which could someday help scientists to identify which drugs are most likely to prevent cancer relapse, or treat specific conditions, in people with a given set of markers.

Changyang Linghu, 33, is inspired by the concept of emergence: the idea that complex systems can take on properties that cannot be explained by their component parts alone. Understanding how this works in the human brain, which has 86 billion neurons, would entail recording cellular activity at a massive scale. Existing ways of measuring neural activity through electrical or light signals could never work with the brain as a whole, whereas brain-wide imaging tools like CT scans or fMRI lack single-cell precision.

Linghu devised a new approach. Instead of measuring cellular activity with an external interface, he sought to “trick” neurons into recording their activity themselves. To do so, he genetically engineered a set of two proteins that work like a ticker tape. When genes encoding them are delivered to a cell, the cell produces one of the proteins in a continually growing chain and the other only during cellular events, such as activities known to drive memory formation. Later, researchers can view that protein ticker tape under a microscope to get a timeline of the cell’s activity, similar to the way scientists study the rings of a tree.

Linghu has tested this method with both neurons cultured in a lab and in the brains of mice.  He and colleagues at the University of Michigan Neuroscience Institute, where he’s a professor of cell and developmental biology, have begun using AI to look for patterns in this data.  

Linghu hopes his technique could unpack one of the scientific world’s great mysteries: how the brain achieves high-level functions such as learning, memory, and consciousness.

Early on as a PhD student at Harvard, Aditya Raguram, 27, helped develop two groundbreaking tools based on the genetic engineering technique CRISPR that both have the potential to treat a wide range of genetic disorders. But these tools—made of large proteins that can erase and rewrite segments of DNA—are hard to deliver safely into cells of the body. Modified viruses, a common delivery mechanism for vaccines and other therapeutics, aren’t great couriers of proteins. And packaging these tools as DNA or mRNA, which would then synthesize the proteins once inside the cells, comes with risks that edits could be made in undesired places.

Prior to completing his PhD, Raguram devised a fix. Working with Samagya Banskota (one our 35 Innovators in 2022), he developed a new type of engineered virus-like particles that not only managed to handle bulky protein cargo, but could release it at just the right moment when in contact with a target cell. The team used these particles to deliver gene-editing therapies to mice, including one that corrected a mutation causing blindness; it was able to partially restore vision.

Today, practitioners are beginning to use CRISPR-based techniques to treat disorders in humans by editing stem cells in a lab and then transplanting them back into the body. Raguram’s innovation marks a major step toward using gene editing to make fixes to the body directly—perhaps with a single injection.

The “Firefly” glowing petunia is one of the first biotech house plants you can buy—and the only one that glows in the dark. It’s sold in the US by a startup, Light Bio, but was created in Russia by a team co-led by Karen Sarkisyan, 34, a Moscow native now running a synthetic biology lab at MRC Laboratory of Medical Sciences, in London.

A few organisms luminesce naturally, but not plants. Wouldn’t it be nice if they did? Like in the movie Avatar, you could imagine moon gardens full of softly glowing creatures. “I wanted to make glowing plants,” says Sarkisyan, “but realized there was no technology to do it.”

That changed when a team at the Russian Academy of Sciences worked out how tropical fungi glow in the dark. Sarkisyan then dipped into these organisms’ genomes to identify the genes they need to pull it off. The result? A package of just five genes that Sarkisyan and his colleagues showed can be transferred to any plant to make it light up. The result, he says, is “genetically encoded transferrable bioluminescence.”

A glowing plant is pretty cool. But it’s serious science, too. Sarkisyan has found that the property can be used to watch, in real time, as a plant produces a hormone or responds to an attack by pests. “The next step for us is to use the system to view plant physiology,” he says. “It makes it easy to image a plant.”

The business of glowing plants looks promising, too. Light Bio sold out of its $29 light-up petunias in a few months. Sarkisyan, who is the startup’s chief scientist, says he’s now trying to double the petunia’s brightness (from a faint shine, like moonlight). “It has been more successful than we could have hoped,” he says of the startup. “And it’s a monopoly.” A patent he and colleagues are seeking could mean only Light Bio can legally produce this unique produc

Christina Tringides, 31, built a new type of electrocorticogram—a thin gadget that sits directly on the brain during an invasive procedure, like the removal of a tumor or tissue responsible for epilepsy, and records its electrical activity. These devices help surgeons determine what to remove and what to keep: If they are too aggressive with a tumor, for example, they might extract brain tissue that’s responsible for movement or speech.

Today’s versions consist of metal electrodes attached to a sheath of plastic. They are stiff, but the brain is soft; Tringides likens them to a spatula placed on top of tofu. “It doesn’t conform to the contours of the brain the way surgeons would like it to,” she says. That mismatch reduces the device’s accuracy and can damage underlying neurons.

To improve the devices, Tringides turned to hydrogels, a class of polymers that, like the brain, exhibit properties of both liquids and solids. By tinkering with a hydrogel derived from alginate, a substance that naturally occurs in seaweed, she created a film that closely matches the brain’s mechanical properties and could thus adhere to its geometry in ways that current devices cannot. She then embedded spaghetti-like electrodes made from carbon nanotubes and flakes of graphene, a conductive form of carbon that can easily bend and flex, into the gadget. Her prototype has been used to record and map signals emitted by the brains of rats—including the hard-to-reach auditory cortex, responsible for hearing, which required it to bend more than 180 degrees.

Every year, millions of tons of pesticides are used in agriculture, globally. These chemicals, which cost tens of billions of dollars to produce, protect plants, but they also cause pollution and harm biodiversity. And they don’t offer full protection: “[Growers] still expect to lose 20% to 40% of their crops to pests and disease,” says Andee Wallace, 33. She’s developing an alternative: engineered microbes that can provide tailored crop protection without the downsides of chemical pesticides.

While earning a PhD at MIT, Wallace worked to understand how tiny marine creatures called diatoms create miniature glass structures. She also began growing vegetables and nurturing plants at her apartment. She became fascinated by their microscopic ecosystems; microbes cover every leaf, root, and petal, and they help plants process nutrients and protect them from disease. What if these microbes could be engineered to provide all the benefits of chemical pesticides, she thought, but without the drawbacks?

Wallace cofounded her company, Robigo, to pursue this idea. Robigo’s first target was a bacterium that causes disease in tomato plants. To tackle it, Wallace’s team started with a microbe commonly found on plants. They developed a CRISPR system that cuts a key region of DNA in the harmful bacteria, effectively killing them, then engineered the system into the microbes, which can then be applied to tomato plants. Because microbes commonly share DNA with their neighbors, the engineered ones should be able to pass the CRISPR system to harmful bacteria, triggering their destruction.

In an early, unpublished test on tomato plants treated with the engineered microbes, the plants grew 15% to 20% taller than untreated ones and showed a 90% reduction in symptoms of disease. An early field trial was less promising, failing to show any benefit, but Wallace is undeterred. “I think the fact that we were able to get our microbes into a field and run a trial is really a huge milestone for the company … and for the field of synthetic biology,” she says.