April 2008
Feature Story

Anne Ford

If the emerging field of morphoproteomics had an ad campaign, its tagline might be: “Outsmarting Chemoresistant Tumors Since 2003.” And if that campaign had a manager, it would likely be Robert E. Brown, MD, who five years ago founded a consultative proteomics analysis service at Geisinger Medical Center, Danville, Pa., and who has been so instrumental in the field’s development that he has trademarked the very term “consultative proteomics.” How did it all begin?

“I was interested in signal transduction pathways and their impact on tumor genesis,” he says, “and the role that the pathologist might play in trying to identify them. I thought pathology was really poised to contribute in that regard because we can look at the tissues and gain a perspective of what there is in terms of the tumor—its heterogeneity and its association with other structures like blood vessels. I got the appropriate probes to look at signal transduction pathways, and that’s how it developed.” Dr. Brown is now professor and Harvey S. Rosenberg chair of pathology and laboratory medicine at the University of Texas Medical School, Houston, where he has continued his consultative proteomics practice. As far as he knows, his is the first such service to rely heavily on morphoproteomics.

His explanation of morphoproteomics’ genesis sounds almost too simple for this multifaceted field, which combines the disciplines of morphology, molecular biology, biochemistry, and clinical medicine. Having a background in endocrine pathology and cytokine research doesn’t hurt, either. As Dr. Brown says, this is not an area of study for the easily intimidated: “You have to be able and willing to understand all of those disciplines and be able to integrate them into your practice of pathology.” But its rewards are many. Not only does consultative proteomics offer hope to patients whose tumors have not responded to treatment, it also allows pathologists to become “collaborators in the decision about therapies for an individual patient,” he says. “We have a tremendous potential to be able to contribute not only to the categorization of a patient’s disease, but also to its management.”

In his talk at the second annual CAP Foundation Future­scape of Pathology Conference June 6–8 in Rosemont, Ill., Dr. Brown will discuss his work in the consultative proteomics service at UT and his vision of how morphoproteomics can make it possible for anatomic pathology to play a role in personalized medicine. It will be just one of many opportunities for conference attendees to learn about ongoing transformations in health care—transformations that, says planning committee chair and CAP Foundation program chair Harry Zemel, MD, are “going to lead to innovative changes in the way medicine is practiced.” He adds, “We think pathologists need to watch that curve very carefully and decide how and when they want to jump on.”

Indeed, part of the aim of Dr. Brown’s talk is to introduce the new field of morphoproteomics to young physicians who may decide to specialize in it. Specifically, he plans to take his audience through the processes he uses to create consultative proteomics reports for his clinical colleagues. A quick preview:

First, consider that if you interrupt one of a tumor’s pathways of convergence, the tumor of course “can adapt and develop alternative pathways or use other upstream signaling molecules,” he says. Therefore, in morphoproteomics, “we have elected to look at the pathways of convergence in the signal transduction model. And we know that most tyrosine kinases converge on those pathways. So if we can use morphoproteomics to identify which pathways are constitutively activated, then we know what major pathways are operative in the tumor. We use phosphospecific probes directed against putative sites of activation on signal transduction molecules, and by using those phosphospecific probes, we are able to determine whether or not the protein analyte in question is phosphorylated.

“We can also assess the compartmentalization of that activated molecule,” he continues. “In other words, we can look at the tumor cell and say: ‘Is this molecule expressed in the cytoplasm? Is it expressed on the cell membrane? Is it expressed in the nucleus?’ For example, p-ERK 1/2 is a molecule that needs to be translocated to the nucleus. If it’s retained on the cell membrane, or it’s retained in the cytoplasm, we are less confident that it is activated and operative in this signal transduction pathway. Similarly, if protein kinase C[PKC]-alpha is translocated to the cell membrane, we know that that’s activated.

“Then we look downstream from those pathways, and we say, ‘Okay, they’re activated, but so what? What are they doing?’ So we look at the cell cycle. By using probes, we know whether the cell is cycling. And if it’s not, then all of the che­mo­­therapy that’s directed against a phase of the cell cycle is just being wasted. We look downstream also at the pathways of chemoresistance to see if they are constitutively activated, and also if there is correlative expression of other molecules that are associated with the activation state of the pathway.”

Finally, “we convey that in a report to our clinical colleagues, and we discuss it with them, and once again the clinicians call us and say, ‘Okay, we want to consider this alternative therapy now. How does it relate to what you found in your morphoproteomic analysis?’” Thus there is the potential to not only dramatically affect patient care, but also to “raise the status of the pathologist from being able to classify—which is a very important role; I’m not demeaning that role—to one of a collaborator in the decision about therapies for an individual patient.”

If that prospect feels unfamiliar, well, you may want to get used to the sensation, considering how Dr. Zemel characterizes the conference’s goal: “We’re trying to convince the audience that ‘pathology as usual’ is not the case,” he says. “We’re trying to show them [attendees] that there’s a lot ­going on, and the world is changing. We’re not talking about something that their kids will worry about; we’re talking about something that will impact their ability to treat and diagnose patients in their lifetime.”

That theme of rapid change also underlies the message of the conference’s keynote speak­er, Jason Hwang, MBA, MD, executive director of health care at Innosight Institute, a social-sector think tank based in Watertown, Mass. Dr. Hwang, coauthor of a forthcoming book on disruptive innovation in medicine, will give a talk titled “Diagnosing the Disease: An Examination of the Future of Health Care Through the Lenses of Disruptive Innovation.”

“Disruptive innovation basically says that in an industry that used to rely on costly expertise, complex activities eventually get transferred into simpler, rules-based work that less-skilled individuals can perform at lower cost,” Dr. Hwang says. “We’ve seen this in every industry we’ve studied. The expectation is that it should be occurring in health care, and yet it does not occur at the same pace we would expect.”

If it were occurring, he says, “there would be far less dependence on complex, expensive systems, things like specialty physicians and hospitals that do a very good job of treating the most complex medical problems, but whose business models are not well equipped to deal with some of the simpler problems,” such as earaches. “It’s even simpler for things like a flu shot. We’re already seeing pharmacies and grocery stores popping up to fill that need, because nobody wants to seek that sort of care from the health care system.” For such basic medical needs, retail clinics are a much more efficient and financially sound model, he says.

That’s because of something he calls “precision medicine.” Instead of relying on physicians’ intuition and complex diagnostic equipment, “precision medicine says that you are able to diagnose precisely the nature and root cause of disease, and it allows us to give a predictably effective therapy once that diagnosis is made.” Disruptive business models such as retail clinics “are very effective because they only treat the diseases that are rules-based,” he says. “We’re not expecting these business models to care for very complex cancers or heart disease. That’s still in the realm of intuitive medicine. But we need to recognize that we need to hand off some of these simpler diseases to these business models, because they’re much more suited to deal with those sorts of conditions.”

Why should pathologists care? Because they are “perhaps best positioned to play a role in this precision medicine world” in that “they drive a lot of disease diagnosis in getting it down to the molecular level,” Dr. Hwang says. “And really, that’s what is enabling a lot of these business models to happen.” Think of a nurse administering a strep test in a retail clinic. “You couldn’t have that test developed if you didn’t understand the molecular pathology that underlies strep,” he points out.

Thanks to a lineup of these and other timely, stimulating topics—biomarkers, medical imaging workstations, infusion centers, computer-assisted IHC image analysis, and more—Dr. Zemel expects a full house at Futurescape. “I think by showing people what’s out there, they can see how this may impact them and their practice, how they want to pursue the career of pathology, and how they want to help in this transformational process,” he says. “We believe that trying to nudge pathologists to begin to look down the road and see what’s around the bend is important, because we want them to become more cognizant of the fact that they have the knowledge, skills, and data to enhance their roles as physicians.” By adding and integrating the new tech­nologies and tools, he says, patholo­gists can help improve patient care in diagnosis and therapy.