Is this the next breakthrough in medicine?

MRIs and PET scans once occupied the domain of science fiction. Today, these methods are commonplace in the health care industry.

Yet science constantly moves forward.

Groups of researchers are taking a giant leap in the diagnosis and treatment of disease. They are applying an established technology ― Raman spectroscopy ― to biomedical research.

Raman spectroscopy is a non-destructive chemical analysis technique yielding detailed information about a material’s chemical structure. The basis of Raman spectroscopy is the interaction of light with the chemical bonds within a material.

Rapid advances in light microscopy have transformed the capacity to study biological systems at the microscopic level. It is helping to unravel biological processes that are complex, localized in space, and changing with time.

Researchers are using Raman microscopy for biomedical imaging in some basic research labs today. But one New York team of scientists have found a novel way of applying the technology.

Wei Min, Ph.D., is a Harvard-educated Professor of Chemistry at the Kavli Institute for Brain Science at Columbia University. He is also at the forefront of this research. His goal is to invent optical methods for biomedical imaging ― ones that address fundamental biological questions.

Those answers, he expects will translate into applications for hospitals in diagnosis and treatment, and for pharmaceutical companies, in the making of better drugs.

In plain terms, Min is finding ways to identify the processes and factors that cause disease, using Raman spectroscopy ― by visualizing and understanding dynamic behaviors of bio-molecules and its interactions in living cells and organisms.

“Raman spectroscopy is extremely powerful, but its role in biomedical applications has not yet been fully explored,” he said.

Min’s research covers two areas. One is in addressing biomedical problems. The other is evolutionary. It focuses on developing a novel technique to enhance ways of characterizing diseased tissue. Both use Raman spectroscopy.

Min says metabolism plays a primary role in many diseases.

“A lot of medical diseases are in general metabolic diseases,” Min said. “So basically, the organisms have something wrong with their metabolism. There are many examples, like cancer, obesity, diabetes, heart disease, and even some local neurodegenerative diseases. It’s many of those so-called chronic diseases.”

These diseases have as its foundation misregulated metabolism. If scientists can understand how the metabolism went awry, practitioners can diagnose the disease earlier. Or they can use that as a way to treat the disease or screen for better drugs.

 “I think in a way that many of the chronic diseases are tightly linked to metabolic disorders,” Min said.

He uses Raman imaging with chemical probes to identify metabolic processes in the tissue. His unique probes permit him to visualize the chemical activity in cells.

“We will be able to image and visualize metabolism in cells and tissues,” he said.

Understanding the metabolic processes is one step towards the diagnosis and treatment of various diseases, according to Min.

Scientists consider Raman as a label-free technique. That means researchers do not need probes. The operator simply mounts the sample and measures it. Min’s approach, using multiple probes, is a paradigm shift. Researchers usually synthesize these molecules in the lab in a way that allows specific measurements.

Min uses a technique called stimulated Raman scattering (SRS) to make his measurements. It yields vastly increased sensitivity and accuracy.

He refers to multiplexing measurements as the ability to monitor and measure large number of features with markers simultaneously. This is critical for a system level understanding of complex systems.

He and his team of post-doctoral students have developed a technique called supermultiplexed optical imaging. It uses multiple Raman probes, or dyes whose sharp non-overlapping Raman bands allow simultaneous imaging of a vast number of molecular species inside cells and tissues. It is something no other current imaging techniques can achieve. 

Supermultiplexed optical imaging tracks a large number of markers inside of tissue to characterize that tissue. Multiplexing imaging is the development of this array of Raman probes.

Instead of a small number of probes, or molecules to manipulate a biological system, Min uses between 50 and 100 at a time.

There are practical applications. For example, the large number of distinct types of neurons that interconnect at different places in the brain constrains research in neuroscience. Min’s supermultiplexed technique lets his team image different receptors so that they can identify different types of neurons at different locations in the brain.

“We design new Raman probes in a way that each one has a sharp and distinguished characteristic frequency, using chemicals to make them,” he said. “It’s like a palate with a large number of probes. We target the markers with the Raman probes and use sensitive microscopy methods to visualize it in the cells and make measurements.”

The Raman probes, through Raman spectroscopy, indicates what is happening inside the cell. Both his study on metabolism and supermultiplexed optical imaging rely on probes. Studying metabolism depends on a small number of Raman probes. Supermultiplexed optical imaging depends on a large number of probes applied during a single observation.

“By increasing the number of markers you measure, by increasing the multiplexing capability, you're exponentially increasing the information content in a complex tissue.”

Besides the neuroscience example above, supermultiplexed optical imaging can distinguish various cancer markers. Cancers occur in sub-typing that show what kind of cancer is present. Practitioners categorize each cancer at a hospital by measuring a panel of markers. Often, practitioners can only make a small number of repeated measurements. Because there are dozens of different subtypes of cancers, a diagnostician needs multiplexing measurements to be able to get down to that kind of fine detail in a shorter amount of time and with greater accuracy than other methods.

Min uses specialized equipment for multiplexing, including special lasers and microscopes.

“But that's really not critical,” he said. “I think the most specialized things are the probes we use.”

So far, Min’s studies have focused on mice. He has published several papers on the subject. Min compared the tissue of healthy mice with sick ones, and could distinguish them using the supermultiplexing technique. Min also studied human tissue under the technique. His results are forthcoming.

“We’ve established proof of principle in animals and in labs,” he said. “From the biology aspect, we’ve shown we have the capability. But as far as it being applied to hospitals and medical practices, we're not there yet.”

He thinks pharmaceutical applications will be the first to commercialize this technology. Only time and further research will tell what the future holds.

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