Cancer is one slippery SOB. It can appear mysteriously, then hang out, thrive, and grow for ages without being spotted. When it is detected, cancer is often unpredictable: It can be fatal, it can be harmless. When under attack, it doesn’t easily fall. Radiation, chemotherapy, and other drugs might curb its spread or substantially shrink it, but they rarely wipe it out. Even under the swift and steady surgeon’s knife, bits of cancer manage to escape.
Take breast cancer. Nearly 700,000 women are diagnosed with it every year in the United States and Europe. About half undergo breast conserving surgery, in which surgeons attempt to excise the tumor while preserving as much healthy tissue as possible. The procedure is tougher than it sounds. Surgeons rely on images of the tumor to guide their cuts, but often have trouble determining its precise borders while the patient is on the table. If they’re not sure whether a piece of tissue is cancerous, they can snip it out and send it to a nearby laboratory for analysis. Then they wait, anywhere from 20 minutes to an hour, all while the patient is still under anesthesia, to get the results. It’s no wonder that even the best surgeons can miss part of the tumor; an estimated 20 percent of women who go through the surgery end up repeating it.
Those numbers may improve thanks to a new surgical tool called the iKnife (i for intelligent). As described in today’s issue of Science Translational Medicine, the tool does sophisticated chemical fingerprinting to help surgeons identify — in real time, right there in the operating room — whether tissue is cancerous or healthy.
“With our technology, identification takes a second — actually, 0.7 seconds,” says Zoltán Takáts, an analytical chemist at Imperial College London who invented the new tool. “One can sample thousands of points during a surgical intervention and it still wouldn’t increase the length of the surgery.”
Takáts’s story begins more than a decade ago, when as a postdoctoral fellow at Purdue University he came up with an important innovation in mass spectrometry. Mass spec, as it’s often called, is a common method for determining the chemical make-up of a substance. Mass spec can measure traces of illicit drugs in an athlete’s blood, for example, or the type of pesticide residue covering an apple, or the amount of caffeine in a cup of coffee. Before going through mass spec, samples have to be converted from atoms or molecules into ions — a process that used to require vacuum chambers and tedious preparations. But in 2004, Takáts’s team published in Science a way to ionize samples by simply putting them under a gas jet.
Takáts was immediately interested in applying the new technique to the identification of biological tissues during surgery. The method turned out not to work for this purpose, but while he was figuring that out, he generated a lot of excitement from the surgical community. “They were chasing us,” he says, laughing. “They were saying, ‘OK, we understand that you can’t use this method, but can’t you come up with something else which would work?’”
The idea for the iKnife came from the realization that there’s no need to create a tool that ionizes tissue — surgeons already have one that’s used all the time. Its technical name is an “electrosurgical device”; a more descriptive one is “flesh vaporizer”. Since 1925, doctors have been using these small electric wands for cauterizing wounds and performing dissections. “Pretty much in every surgical theater all over the planet you can find it being used on an everyday basis,” Takáts says.
The worst part about these devices is the smoke they produce. “This is really a smoke of burnt flesh. It’s as nasty as it sounds,” Takáts says. But that smelly smoke contains ionized tissue that’s perfect for mass spec analysis.
Over the past several years, Takáts and his colleagues have conducted a series of rodent experiments testing the new tool, which is essentially an electrosurgical wand hooked up to a rolling mass spec machine (see top photo). They found that smoke produced from burning one type of tissue has a different mass-spec signature than does smoke coming from another kind of tissue. More importantly, they found that cancerous tissue leaves a different chemical trace than healthy tissue does.
That makes sense. Most of the chemicals sensed with this method are phospholipids, fat molecules that line the membrane of each cell. Cancer cells are constantly dividing into new cells, which means they’re constantly synthesizing phospholipids. “So the membrane lipid composition of tumor cells will be quite different from healthy cells. This is what allows us to differentiate them,” Takáts says.
In the new study, the researchers apply the technology to human tissues for the first time. They first created a database of chemical signatures gleaned from doing mass spec on thousands of stored tumor samples. The researchers then put all of that data through a complicated statistical analysis to find patterns that reliably distinguished one tissue type from another. Finally, they tested whether those algorithms could correctly identify cancerous tissue as it was being removed, right in the operating room. It worked: The iKnife was used in 91 surgeries, and in every single one, the tissue identification it made in the operating room matched the one made by traditional laboratory methods after the surgery.
The paper is “a tour de force,” says Nick Winograd, a professor of chemistry at Penn State who was not involved in the research. Winograd is an expert in using mass spec to identify biological samples.
Over the years there have been many attempts to get this technology into a clinical setting, Winograd notes. “But so far there hasn’t really been anything that you can really raise your flag about.” Part of the problem, he says, is that these chemical signatures are only subtly different from one another. They’re all made of the same molecules, just in slightly different combinations. “So you really have to be clever in your data analysis if you’re going to find [patterns] that differ in a systematic way from tissue type to tissue type,” he says.
The iKnife is just one example of a bigger trend of metabolic profiling in medical science. Just as geneticists have done oodles of association studies pairing specific genetic variants to this or that disease, researchers hope to find links between chemical signatures and disease. Proponents say that metabolic studies will give even more information than their genomic counterparts, because they are influenced by both genetic and environmental factors. The foods, medications, and chemical exposures we take in every day don’t change our DNA code, but they do leave a chemical imprint in our tissues. “Understanding that interface of genes and environment is absolutely critical for the future,” says Jeremy Nicholson, a chemist who leads the department of surgery and cancer at Imperial, where the iKnife work took place.
Just last month, Imperial launched a multi-million dollar “Phenome Centre” aimed at conducting chemical studies at many levels — on the scale of the individual patient, like the iKnife work, but also at a population scale, comparing chemicals from the blood, urine, and even microbial communities of groups of people over time.
The Centre has 19 high-tech spectroscopy machines, giving it the capacity to perform more than a million discrete assays a year, Nicholson says. The machines are hand-me-downs from the 2012 Olympic Games, held in London. The U.K. spent around $30 million for equipment to screen the thousands of Olympians for illicit drug use, Nicholson says. “They only found 12 people who were cheating.”