Delivering on the promise of precision medicine
No two tumors are alike. Different tumor cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. That explains why one cancer patient may respond positively to a drug treatment while another patient gets little or no benefit from it.

But the heterogeneity of tumor cells isn’t only found from one patient to another. It’s also true for cells within the same patient—and even within the same tumor. This makes diagnosis and treatment especially challenging. A needle biopsy might miss a tumor cell revealing a gene mutation, thereby compromising the effectiveness of treatment.

But what if a surgeon could acquire more complete and detailed molecular information about a tumor during surgery? What if a pathologist could directly visualize the molecular complexity on a biopsy? That information could provide immediate, reliable guidance about the most appropriate surgical and treatment options.

Prof. Ron Heeren of Maastricht University is utilizing mass spectrometry to make such “precision medicine” a reality—not only for cancers, but other diseases, as well. Co-founder of the Maastricht MultiModal Molecular Imaging Institute, Prof. Heeren is pioneering new techniques for visualizing and understanding the molecular structure of disease tissue.

On Friday, June 17, 2016, Waters welcomed Prof. Ron Heeren
and the Maastricht Multimodal Molecular Imaging Institute
into the Waters COI Program. Pictured (l to r) are:
Zoltan Takats, Imperial College, London;
Eric Fotheringham, Director - COI Program, Waters Corporation;
Liam McDonnell, Leiden University Medical Center, Netherlands;
Mike Morris, Waters; Markus Stoeckl, Novartis Institutes
for BioMedical Research, Switzerland; Steven Pringle, Waters;
Ron Heeren, Maastricht University/M4I, Netherlands;
Jim Langridge, Waters; Klaus Dreisewerd,
University of Münster, Germany;
Emanuelle Claude, Waters; Davy Petit, Waters;
Michel Nielen, Wageningen University, Netherlands.

Heeren sees his research working in two ways.

“On the one hand, we can make diagnostics more precise by revealing more local molecular players that define the actual biological mechanisms,” Heeren explained.  “And that we can do with spatial localization of molecules by ion mobility and high-resolution mass spectrometry. On the other hand, we can be more precise by giving doctors access to these technologies via intraoperative diagnostics—putting all the precise molecular information that we get with diagnostics at their fingertips to make their surgical procedures more precise.”

The value of imaging
Medical science is already using a form of precision medicine in the treatment of certain cancers. Patients with breast, lung, and colorectal cancers, as well as melanomas and leukemias, for instance, routinely undergo molecular testing as part of patient care, enabling physicians to select treatments that improve chances of survival and reduce exposure to adverse effects.

But Heeren is endeavoring to take it several steps further by using imaging mass spectrometry.

“If you think about most clinical diagnostics, they’re either blood-borne or urine-borne, which can dilute a lot of the very specific markers or molecular panels,” Heeren explained.  “So once we find a marker, we don’t really know where that is located or where the problem is. Now, with modern imaging techniques, we can

identify some morphological abnormalities. Just looking at the morphological abnormalities can tell you where the problem is, but it doesn’t reveal the chemistry. So, the trick is putting the two together.”

While pathologists can use biopsies to study the morphology of the tissue and gain some insights, this analysis does not reveal anything about the detailed biochemistry that occurs in the tissue.

“What we do takes it to a whole new level,” Heeren said. “We do the same thing a pathologist does, but now we add the chemistry and the molecular information that a mass spectrometer provides. We can look at individual molecules and put them within the context of a cell.  And we can do laser capture microdissection, extract a couple of cells, and then with cellular analysis we can put the cells in the context of tissue imaging mass spectrometry. And that’s really where the added bonus is, because you now can unravel the heterogeneity of such a complex tissue environment.”

Heeren and his team do a thorough analysis of the molecules within the tissue.

“We do a lot of work on primary metabolites, drugs and their metabolites,” he noted. “We have a strong program on lipid and lipid degradation, specifically in diseases that involve a lack of oxygen, either ischemia or hypoxia. We look at endogenous peptides in the brain -- so, signaling peptides. We look at proteins, either by looking at the intact proteins or by performing on-tissue tryptic digestion.”

Bridging the divide between research and clinical settings

In the true spirit of precision medicine, Heeren’s work at the MultiModal Molecular Imaging Institute is being done in close partnership with physicians at

Academic Hospital Maastricht, the main hospital in the city of Maastricht, which is associated with Maastricht University.

“Right now, we are engaged in a number of projects funded by the hospital in which researchers from both the mass-spec imaging side as well as the surgical side jointly pursue certain problems,” Heeren said. “We have one where we’re looking at the molecular signatures of cholangiocarcinoma and putting them in context. We have one where we look at osteoarthritis—the degradation of cartilage and what molecular signals give it a certain state of cartilage degeneration and how certain drugs change those molecular signatures and change the patient outcome. We have a study where we’re looking at colorectal-cancer patients trying to run large cohorts to come up with specific markers to stage these patients and predict what therapy would serve them best.”

Key to Heeren’s research is the Institute’s multimodal approach, which uses an array of imaging modalities—from Secondary Ion Mass Spectrometry (SIMS) to dual polarity MALDI with ion mobility to 3D microscope mode MS imaging using innovative detectors—to gain different insights.

Heeren identified three technological advances that have accelerated his work by adding analytical information and speeding results: ion-mobility-based imaging, high-resolution mass spectrometry, and improvements in imaging mass spectrometry.

“Three years ago, everybody was doing imaging mass spectrometry and the speed at which the analytical instrument acquired the data to generate the image was one pixel per second. Now with the DESI and the Xevo TQ-S micro, we’ve speeded that up twentyfold.”

A diverse scientific background

Straddling multiple disciplines is nothing new to Prof. Heeren, who jokes, “I was trained as a physicist, became a professor of chemistry, and now am a professor of molecular imaging working in a biomedical environment.”
That wide-ranging interest began in childhood.

“I spent my childhood in the South of the Netherlands, and I always had a huge interest in science and technology,” he recalled. “When I was a young kid, I got the chemistry sets and the electronics sets, and I was building my own radios and trying to tinker with technology out of an intrinsic curiosity in how the world around me worked.”

Heeren went on to earn a degree in physics at The Hague University of Applied Sciences, then moved on to the University of Amsterdam, where he earned his doctorate.

“When I was doing my PhD in physics, it was actually nuclear-fusion science,” he noted. “I already was exposed to mass spectrometry, and then immediately realized -- this was in the early ’90s -- that there is so much to be gained by applying these technologies in other fields. Wouldn’t it be wonderful if you could apply them to intact bio molecules and look how they behave? I decided that it was way too exciting and I had to switch fields.”

Heeren furthered his research at the Fundamental Research on Matter (FOM) Institute AMOLF, which is part of the Dutch Organization for Scientific Research in Amsterdam. In late 2014, he moved to Maastricht to found the MultiModal Molecular Imaging Institute and accept an appointment as university professor and Limburg Chair in the field of molecular imaging in late 2014. A team of 20 FOM researchers accompanied him. The laboratories were built and largely operational by January of 2016.

While setting up the Institute has kept Heeren busy, he still finds time for athletic pursuits.

“I’m a licensed volleyball trainer,” he noted. “I still play at the highest regional league here close to Amsterdam.  But I also trained, up until last year, the first ladies team of the club that I played with.”

He and his wife and two children also enjoy getting out into nature--biking, sailing on the Adriatic, fishing, and hiking. But the lure of the laboratory remains strong.

“Every day that I come in, I get to think about where this world is going, and work with a whole bunch of young scientists I see make that happen,” Heeren said.  “And even though sometimes you only make a very minute contribution, that still drives me forward. Just the fun of working in such a high-tech environment and making a difference to the patients and working with the clinicians. If you had asked me 10 years ago, ‘Do you see yourself ever in an operating theater?,’ I would have said, ‘Are you crazy?’  But there I am—working with the surgeons I collaborate with.”