Understanding what is taking place inside the human body is at the heart of medicine. For centuries, scientists have looked for better ways to detect problems, conditions, and diseases ranging from high blood pressure to cancer.
An array of sensing devices—from thermometers and blood pressure cuffs to blood oximeters—have made it easier to monitor vital signs and detect potential problems. Now, researchers are taking sensing to the molecular level using nanotechnology and synthetic biology: they are developing biosensors that boldly go where medicine has not gone before.
"It's becoming possible to design sensors that deliver a specific piece of information. Biomedical diagnostics is expanding into many applications. Researchers are discovering ways to detect biomarkers even at a single-cell level," says Gabe Kwong, an associate professor in the Department of Biomedical Engineering at the Georgia Institute of Technology (Georgia Tech).
These emerging systems will spot infections, detect cancerous tumors, and identify the presence of other chronic diseases, which should translate into earlier interventions and better treatments that save lives. "Living biosensors are a promising way to improve our diagnostics abilities," says Robert Cooper, a staff research associate in the Biocircuits Institute at the University of California, San Diego (UCSD).
A New View
Using biomarkers to diagnose and treat conditions is not new. At a basic level, blood and urine tests offer insights into events taking place inside the human body. Yet, for all the progress that has taken place in medicine over the last century, there is still a long way to go regarding the diagnosis and treatment of many conditions.
Part of the problem is that detecting the presence of specific molecules or cells can be extraordinarily difficult. For example, a standard 10-milliliter blood draw may contain only a handful of cancer molecules, which could evade detection during a test. "It's difficult to find the signal among the noise—particularly when the cancer is embedded in a complex organ like a liver or a lung," Kwong says.
This has implications for early detection, as well as monitoring treatment. For instance, immune checkpoint blockade (ICB) inhibitors now are used to treat an array of cancers. Although they are far more effective at treating malignancies than conventional treatments, only about 25% of patients benefit from the drugs, which work by blocking proteins that prevent the immune system from attacking cancer cells. Worse: many of the gains are only temporary.
Consequently, researchers are focusing on developing a new class of biosensors and related treatment methods that function at a far more sophisticated level, using probiotics, synthetic biology, and specific gene editing tools such as CRISPR to design both organic and inorganic biomarkers. "It's possible to engineer agents, such as bacteria, to accomplish specific tasks," Cooper explains.
"Biosensors can detect subtle chemical reactions and produce readouts, whether it's blood glucose level or a malignancy," says Kwong. "The body sheds cells in blood and urine that can indicate the presence of cancer cells or other conditions. The goal is to detect these biomarkers using various instruments."
Kwong is at the forefront of this revolution. He and a team of researchers at Georgia Tech have developed synthetic biosensors that detect whether ICB therapy is working through non-invasive urinalysis. The technique sidesteps the need for a painful biopsy or a computed tomography (CT) scan, which can produce inconclusive or misleading results. Instead, it relies on detecting a high presence of proteins that T cells emit after taking an ICB drug.
The nanotechnology utilizes biosensors that attach to the ICB drug. After an injection, they travel through the body to the tumor site, where proteases from both T cells and tumor cells trigger a signaling agent that is released into the urine. The resulting reading—in some cases aided by artificial intelligence and machine learning techniques that can spot patterns that evade humans—determines whether or not a patient is responding to the therapy.
"Synthetic biology allows us to custom-design sensors for highly specific needs," Kwong says. What is more, it is possible to manipulate the size, shape, color, and other characteristics of materials to achieve different results—or measure different things. "As you shrink different materials, say to 10 or 100 nanometers, you see different emergent properties." This may lead to changes in color or other characteristics that an analysis can identify.
Scientists at UCSD and in Australia also are pushing the boundaries of biosensing. They use a gene-swapping technique they have dubbed CATCH to identify the presence of colon cancers in live organisms.
"The prototype biosensors turn on antibiotic resistance as an output, which is fairly easy to detect," Cooper says. "You spread a sample on a petri dish with the antibiotic and you count how many cells grow." However, before clinical use, they plan to replace antibiotic resistance with a safer output signal, such as a fluorescent molecule detectable in urine.
So far, the group has tested the technique successfully on mice, and they hope to expand it to humans within a few years. "It also opens the possibility of more highly targeted treatment methods," Cooper says.
Meanwhile, a group at Cornell University has developed silica-hybrid nanoparticles ('C-dots') that deliver both positron emission tomography (PET) and optical imaging contrast in the same platform using florescent materials. A group at Columbia University has engineered probiotic bacteria that colonize tumors, thus making them more easily detectable. The team designs gene circuits that control the behavior of living cells to sense and respond to their environments in real time.
The future of biosensing looks bright, though Kwong, Cooper, and others say that it will take several years for the technology to play out and become practical for humans. "There are a number of important problems to solve before these technologies can be tested on humans. It's essential to know that these technologies work and that they are safe outside a controlled environment," Cooper says.
Eventually, Kwong says, next-generation nanosensors and biosensing could be used to detect and treat a wide range of conditions and diseases. "The technology could transform early detection and preventative medicine," he says. In addition, biosensing could revolutionize areas outside of medicine, including environmental tracking, agriculture, and food safety.
"We are approaching an era where it's possible to engineer cells as sensors that deliver early information about various conditions and diseases," Kwong concludes. "The result will be more informed decision making and healthier lives."
Samuel Greengard is an author and journalist based in West Linn, OR, USA.
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