Microbes aren’t too smart—they don’t have brains or even nervous systems. But they’re good at what they do. Research suggests that about 30 trillion bacteria colonize a typical human body, living on the skin and in the gut. They even live inside tumors.
But what if bacteria could be made smarter? Tetsuhiro Harimoto, 32, a postdoc who goes by “Tetsu,” has spent the last few years trying to turn bacteria into “intelligent living medicines” that might be taught to automatically seek out and attack cancer.
“My vision is to create a new class of drug delivery technology made of engineered living microbes that can efficiently home to tumors, autonomously sense the environment, and produce drugs in a sustainable and controllable manner,” he says.
Using the tools of synthetic biology while getting his PhD at Columbia, he’s already demonstrated that it might be possible. To some bacteria, he added genes that let them detect when they’re inside a malignancy (low oxygen levels are common in tumors). To others, he gave the ability to pump out cancer-killing drugs.
His next project will be to bring these techniques together, creating bacteria that can sense cancer cells and, he hopes, kill them on the spot.
Tyler Allen, 31, developed a live imaging system that allows researchers to observe how tumor cells move through the body—which could pave the way to more effective cancer treatments.
Allen’s work tackles one of oncology’s major challenges: most serious cases of cancer occur after a tumor has spread, or metastasized. Yet that process, in which individual cells travel through the blood like cars on a highway, is poorly understood and hard to detect. Typically, doctors don’t know a cancer is spreading until they discover a second tumor. “By then, the prognosis is often severe,” Allen says.
Allen’s system, which he developed as a doctoral student at North Carolina State University, makes it possible to view this spread in real time. To build it, his team injected human cancer cells into a zebrafish, which they’d genetically modified to make its blood vessels glow. Using a high-powered laser microscope, they observed the cancer cells as they traveled through and exited the bloodstream, paying special attention to those traveling in clusters, which pose a higher risk of forming tumors.
Researchers had thought these clusters would need to break apart before leaving a blood vessel, but Allen’s team observed that some managed to exit intact. Those that did, moreover, were more likely to form a tumor in nearby tissue.
Allen continues to refine his technique as a postdoctoral fellow at the Duke Cancer Institute. The insights his approach makes possible could ultimately help researchers develop therapies that target cancer cells before they spread.
It doesn’t take much to tear a hole in an eardrum. Infections and injuries are common causes, but perforations can even be caused by the change in pressure scuba diving.
Fixing them isn’t always straightforward, as Nicole Black, 30, learned when she met two ear doctors while in graduate school for engineering sciences at Harvard. Eardrum repair procedures typically involve cutting a bit of tissue or cartilage from another part of the head and using it to patch up the hole. They aren’t always successful, and patients often require follow-up operations years later.
So she set out to develop a better treatment. Her goal was to 3D-print an all-new material that could be used in a patch—one that works like a healthy eardrum.
It wasn’t easy, because the eardrum has special properties that allow it to conduct sound waves. “Your eardrum vibrates like a soft material at low frequencies and like a stiff material at high frequencies,” says Black. The material needed to be able to support the growth of cells, including blood vessels. And it needed to be strong enough to withstand being handled by surgeons. But the human eardrum is only around 80 microns thick—around the width of a human hair. “It was a lot of trial and error,” she says.
Black began testing the devices on perforated eardrums in chinchillas—chosen for their huge ears. These animals have eardrums that are almost the same size as human ones. When she started getting promising results, she cofounded a company, Beacon Bio, to develop them further. That company was soon acquired by the 3D-printing firm Desktop Metal, where Black is currently vice president of biomaterials and innovation at the healthcare division, Desktop Health.
Black says her most significant breakthrough was being able to print a material with a structure that encourages cells to grow in specific patterns. This is essential for the eardrum, but it will also prove useful in 3D-printing medical devices for other organs and tissues, she says.
The latest version of her device, called the PhonoGraft, is shaped a bit like a flattened spool of thread, so it can be squeezed through a hole in an eardrum until half pops through to the other side.
The simplicity of its design means that you wouldn’t need an otologist to insert it—theoretically “any trained ear, nose and throat (ENT) specialist who can look in your ear with an endoscope can place one of these,” says Black, who hopes to start testing the device in humans toward the end of 2024.
Black also plans to create devices for other health needs. Her next goal is to create vascular grafts, which help repair damage to blood vessels—for example, after bypass surgery.
mRNA vaccines—and the scientists behind them—were among the heroes of the covid-19 pandemic. These drugs work by delivering a bit of genetic code that allows our bodies to essentially make our own medicines. Today, over 360 million doses of mRNA vaccines for covid have been administered in the US alone. Other such vaccines are being developed for flu and HIV, and as cancer therapies.
But there’s plenty of room for improvement. Anna Blakney, 33, a bioengineer at the University of British Columbia in Vancouver, Canada, is among those leading the hunt for better RNA vaccines—drugs that are more effective, offer longer-lasting protection, and can be delivered at lower doses with fewer side effects than existing versions.
Common side effects of existing mRNA vaccines include fever and chills, but some people have experienced cardiovascular problems, such as blood clots. “One of the biggest challenges in the field right now is safety and the side effects that we see with our new vaccines,” says Blakney. “Going forward, we really need to think about ways to minimize the dose of RNA that we need to use.”
To do that, Blakney has focused on self-amplifying RNA—a form of mRNA that can make copies of itself once it gets inside cells. In theory, you’d need to use less of it in a vaccine or therapy than you would standard mRNA: “You could use about a hundred times lower dose,” says Blakney. And while mRNA typically codes for proteins for around three to five days, saRNA does it for around 30 to 60 days, she says. That means it should work for longer in the body than existing vaccines, so booster doses might not have to be as frequent.
Blakney has also been working on ways to add new features to mRNA. As part of a recent project she led, she incorporated code for new proteins that help the mRNA dodge an attack by a person’s immune system. As a result, the mRNA can work for longer, making more proteins. “It works better as a vaccine,” says Blakney, who has tested the drug in rabbits.
Julia Joung, 32, arrived at the Broad Institute, in Cambridge, Massachusetts, and the lab of gene-editing expert Feng Zhang in the early days of the excitement over the gene-editing tool CRISPR. There, Joung dove into “genome-scale screening,” or using tools such as CRISPR to alter each of the 20,000 genes in the human genome—and then watching to see what happens.
Such genetic screening, often carried out on stem cells, is a top priority for data-driven labs seeking to explore biology’s logic from a wide angle.
In theory, stem cells can be coaxed to develop into any type of cell. In practice, though, many types are hard—even impossible—to generate in the lab.
Proteins called transcription factors can determine what cells decide to become. But which ones? There are more than 1,500 factors in our bodies.
Initially, Joung found a single factor that would turn stem cells into nervous system cells. But her research evolved into a larger project. Why not add every single transcription factor to stem cells and measure the effect each factor had on how those cells behaved?
The result of her survey, published in January, is an “atlas” of how individual transcription factors affect the identity of stem cells. The ultimate goal, she says, “is to be able to make any cell type, and in a very controlled way.”
Supplies of specific cells could be useful for testing drugs or new types of therapies. Other scientists studying transcription factors hope to find combinations that will form human eggs in the lab or even provide the key to rejuvenation treatments. “We aren’t just generating lists when we screen. It’s a list with a purpose,” says Joung. “There’s always that end goal.”
Christina Kim, 33, developed a technique to identify the nerve cells involved in different animal behaviors—which could lead to better treatments for neuropsychiatric conditions like depression, anxiety, and drug and alcohol addiction.
In both human and animal brains, nerve cells—also called neurons—encompass hundreds of cell types. It’s long been difficult to detect which types are activated in response to a particular stimulus, like a loud noise, strong smell, or drug injection. Past methods of recording different types of neural activity in mice, whose brains have many similarities to humans’, were limited to specific brain areas, or they inhibited the behaviors researchers hoped to study.
Kim’s method, which she developed as a postdoctoral researcher at Stanford, works by identifying cells with elevated levels of calcium, which rushes into neurons when they fire. Her team injected mice with genetically modified proteins, exposed their brains to a beam of blue light, and recorded their response to a nicotine injection and other external stimuli. In neurons where calcium level was high, this light then drove transcription of an additional protein, this one fluorescent—a “tag” that they could later detect under a microscope. Her team then used RNA sequencing to uncover the specific genes present in the tagged neurons—effectively determining their type.
Kim, now a professor of neuroscience at the University of California, Davis, is refining the technique—known as fast light and calcium-regulated expression—to better understand how brain signaling works at the molecular level. Ultimately, it could help drive the development of more targeted and effective therapeutics.
Jiawen Li, 34, engineered a tiny device to help cardiologists with a common problem: how to tell which patients may be at greatest risk of heart attack.
Li’s innovation, an ultrathin 3D-printed endoscope, is designed to probe inside a blood vessel and generate high-quality images of the plaques that build up over a lifetime. Most of these plaques pose little danger, but certain types risk blocking arteries and causing them to rupture. None of the probes used by physicians today are good enough to reliably predict which plaques are likely to cause trouble. This often leads to costly overtreatment or—worse—sudden death.
Li, a biomedical engineer at the University of Adelaide in Australia, set out to build a “camera” that would give clinicians the image quality they need—while still being small enough to fit inside an artery. Her approach combines two light-based imaging techniques into a single lens no bigger than a grain of salt; together, they provide a high-resolution snapshot of a plaque’s structure, as well as molecular clues about the likelihood of rupture. Working with researchers in Germany, she developed a way to print the lens onto a fiber-optic cable as thin as a human hair, which can be fed through the arteries and toward the heart.
Li and her colleagues have successfully tested the device in pigs and are working toward clinical trials in humans. In addition to improving diagnosis of heart disease, they think it could eventually help physicians detect cancer in hard-to-image areas, including the bile duct (which carries bile from the gallbladder to the small intestine to aid digestion) and the lungs.
Can the bacteria responsible for a highly contagious respiratory infection also be the key to engineering lifelike soft tissue? Danielle Mai, 34, thinks so. Her Stanford University lab is using proteins from pertussis, or whooping cough, to bioengineer new material that functions like human skin and muscle.
During an internship with the Rogers Corporation, a maker of engineered materials, Mai began working with protein-based polymers, which are large chain-like molecules that serve as building blocks for many types of organisms. That work quickly became her passion.
By identifying naturally occurring proteins and then reproducing them within her lab, Mai can engineer biopolymers that mimic the properties and functions of human muscles, especially their ability to stretch and contract—attributes that have been difficult to harness in engineered tissue thus far. Bacteria like pertussis, she says, are a perfect model because they have highly repetitive protein sequences, which are easy to mimic.
“Naturally occurring proteins have amazing functionality along with these beautiful, built-in molecular sequences that have allowed them to survive in harsh environments for billions of years” says Mai. “We can take that functionality and build it into engineered materials.”
Mai envisions multiple applications for these new biopolymers, including soft robotics, regenerative medicine, and sustainably produced animal-free meat.
Courtney Young, 32, was a senior in high school when her two-year-old nephew, Christopher, was diagnosed with Duchenne muscular dystrophy, a fatal genetic disorder. The diagnosis rocked Young’s family and sent her on a journey to find a cure. Her recent work with gene editing offers one of the most promising advances in decades.
Muscular dystrophy results from a mutation that prevents the body from producing proteins needed to create and sustain healthy muscle. Using CRISPR-Cas9, Young and her team at MyoGene Bio can change a patient’s DNA, restoring the ability to create the necessary proteins.
Young and her team can target a commonly mutated portion of a gene and remove it, after which the DNA can repair itself naturally. Although CRISPR-Cas9 has been used to address genetic mutations for a decade, Young’s research has pushed the boundaries, proving that far larger deletions are possible than previously thought.
“Current approved therapies for Duchenne muscular dystrophy address downstream side effects or offer only modest benefits,” says Young. “Our approach targets the underlying cause of the disease.”
Young envisions packaging CRISPR in a harmless virus that can be injected into the bloodstream. The virus could then infiltrate the muscle cells, allowing the editing technology to do its work on the patient’s DNA. Young thinks clinical trials could be as near as two years away.
“The clock is ticking,” she says. “Once approved, this therapy could help up to 10,000 new Duchenne patients every year.”