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Getting ready for the bioinformatics shakeup

August 2002
Eric Skjei

Pathologists have long suspected, even feared, that bioinformatics would turn their world upside down.

It will. As test results and clinical patient data merge, and as the lines blur between anatomic and clinical pathology, no pathologist should expect her world to remain unshaken.

But if bioinformatics has thrown down the gauntlet, it has also opened the door to tremendous opportunity for laboratories and pa-thol-o-gists. The challenge for pathology is both "worse and more interesting than we originally thought," says Jonathan Braun, MD, professor and chair, Department of Pathology and Laboratory Medicine, Geffen School of Medicine, University of California, Los Angeles.

Recent advances in genetics research are yielding profound insights into disease identification and treatment, as well as suggesting new directions for how pathologists learn and practice their profession. Making use of these insights will require pathologists who understand molecular dynamics and can bridge the worlds of research and clinical care. It will also require pathologists who understand and can work comfortably with high-throughput technologies as well as the computational techniques and tools that make these insights accessible.

From the morphological to the molecular

But playing this role will cause deep changes in the profession. For example, predicts Bruce Friedman, MD, pathology will see a gradual shift from cell morphology to molecular structure and function of cells as an adjunct to the diagnostic process. In the future, says Dr. Friedman, pathologists "must be able to render a tissue diagnosis—most particularly for but not necessarily confined to tumors—that takes advantage of not only morphologic observations but also related genomic and proteomic testing." Ultimately, but "not tomorrow," Dr. Friedman says, morphology will dwindle in significance, becoming more of a diagnostic afterthought, referred to "on the way out the door, as a kind of final confirmation that you know what you’re doing and as a final check," as he puts it. Dr. Friedman is professor of pathology at the University of Michigan Medical School and Health System.

In many respects, this transition is already under way. He-mato-pa-thol-ogy and flow cytometry, to take just two instances, already take cell chemistry as well as morphology into account. Moreover, pathologists working in these fields tend to play a more active clinical role in shaping treatment decisions than do many other types of pathologists, a change Dr. Friedman believes pathology in general will be well advised to anticipate and seek in the future.

Another indication that this shift is under way is that "many or most of the new classification schemes for tumors have a genetic, not a morphologic, basis," Dr. Friedman says. As these new classification schemes develop, pathology is also learning more about the ways in which previous systems, largely or completely based on morphological characteristics, may have blurred functional distinctions with important clinical implications. "We’re finding that things we lumped together because they looked morphologically the same sometimes don’t really behave in the same way biologically," says Dr. Friedman. "We’re learning that they are genetically programmed to do different things, most importantly, to either remain in the same place or to metastasize."

In prostate research, for example, researchers armed with new genomics and proteomics insights are finding that certain smaller tumors, which might well have been regarded as innocuous in the past, are in fact aggressive and can metastasize in weeks, while other, larger tumors, which would previously have been viewed with concern, simply do not have the enzyme system and other cellular constituents required to implant elsewhere in the host, to metastasize. "Not all prostate tumors that look bad under the microscope need to be treated or treated aggressively," Dr. Friedman observes, "because they’re simply not all programmed to metastasize and become lethal."

Neither CP nor AP

Moving from the morphological to the molecular has blurred the traditional boundaries between anatomic and clinical pathology. In the future, Dr. Friedman suggests, pathologists are more likely to find that "what we will have to learn to do is talk about diagnosis and about the different ways to analyze the serum and tissue that’s sent to us, some of which are chemical, some of which are morphologic, but all of which are essentially part of the diagnostic domain."

UCLA’s Dr. Braun, who also sees deep changes ahead for pathology, tends to define this particular shift in terms of cell biology versus biochemistry. "In a way, AP has been focused on classic cell biology and on using that as a window for formulating questions and framing the pathologist’s diagnosis, prognosis, and treatment interpretations and options," Dr. Braun says. Laboratory medicine or clinical pathology, by contrast, has tended to focus more prominently on the biochemistry of disease.

Proteomics and bioinformatics may offer something of a third choice, a bridge of sorts, one that touches on both of its traditional predecessors, Dr. Braun says. "So, for example, if you collect some tissue, prepare an expression array, 1 analyze the levels of the proteins and the other specific things that define a disease state, and look at that over time to understand whether the disease state is remaining or going away and how your treatment recommendations are working, you’re starting with cells, but the approach you’re taking is really a biochemical one," Dr. Braun says. "The process is in some sense right in the middle between the anatomic pathologist and the lab medicine pathologist, and connected in significant ways to the work both of them do."

More reporting

As bioinformatics becomes a more central and significant driving force in pathology, it is likely to transform even the most basic day-to-day functions and priorities of the pathologist. Results reporting, for example, is likely to steadily demand a far greater proportion of the pathologist’s time and attention in the future. "In the past, we spent 90 percent of our time actually doing the test and 10 percent providing the result," says Michael Becich, MD, PhD. This will change dramatically, he predicts.

"The amount of time spent actually doing the test will decrease, and the amount of time spent integrating test data and patient data—the analytical dimension of patho-bioinformatics, if you will—will consume the major part of the pathologist’s workload," he says. Dr. Becich is director of the Center for Pathology Informatics and director for the Benedum Oncology Informatics Center at the University of Pittsburgh Medical School.

Parenthetically, Dr. Becich sees this change as yet another way in which the practice of pathology will necessarily blur the traditional distinction between anatomic and clinical domains. "In the past, if you had a clinical pathology test, you shot out a page of numbers," Dr. Becich says. "If you had an anatomic pathology test, you shot out a page of text, and never the twain would meet." In the future, by contrast, neither one of these modes is likely to prove sufficient. "Integrating and interpreting both numeric and textual data into one integrated report is going to be the good work of future pathologists."

Closely related to these changes is the need and opportunity for pathologists in the future to assume a more active role in clinical decision-making. Pathologists in the past had a tendency to remain somewhat detached from care delivery, Dr. Becich says. "Until now, we’ve had a tendency to sit behind a curtain, spew out our reports, and let the physicians figure them out," he says. "It was a little like the Wizard of Oz, sitting behind the curtain and uttering oracular pronouncements."

Back in the days when the testing options were relatively simple—"when we had an SMA 20 and a handful of AP tests," as Dr. Becich puts it—that posture may have been appropriate, he adds. But it isn’t likely to work in the future. "If we want the insights that are now becoming available from patho-bioinformatics to really have an impact on patient care, pathologists will no longer be able to just toss the diagnosis over the transom, as it were, but will instead find that we need to get out from behind the curtain and take on the job of integrating and interpreting reports for our clinical colleagues," he says. "That is the ’sweet spot’ for our profession, actively participating in shaping the process of delivering care."

What is a "disease"?

At the same time that the world of bioinformatics is promising to overturn the pathologist’s world, it is also raising difficult questions about the very object of that work, the very nature of disease.

"The concept behind bioinformatics is to look for significant patterns in large datasets, not at individual biological entities," says UCLA’s Dr. Braun. "This has been profoundly annoying to basic biologists." In other words, he explains, people who have worked hard to understand the behavior of individual proteins and how they are regulated are now being told to let go of that perspective. "Suddenly a group of rash informatics people is telling them that that is not the big, the important question," Dr. Braun says. "The important question, they’re being told, is finding ways to collect very large datasets and identify patterns or signatures of biologic states."

Even then, the bioformatics challenge continues. Knowing when the patterns found in those large datasets relate to a traditional disease state—or, for that matter, a known biologic condition—is not always simple. "One of the questions we are still trying hard to answer is, How do you set up an approach where after a period of time you can determine that one signature or pattern does relate to a specific biologic state?" Dr. Braun says. "And even if we can answer that question, we aren’t sure whether those biologic states will be ones we’ve formulated before or are entirely new and different."

Answers to these questions are not likely to be quickly or easily forthcoming. "Talk to anyone who is doing bioinformatics in a basic research lab and they will tell you that while it probably will take only a few days to collect the data, it may take months to analyze it, and even more months to understand how what is found relates to what we already think we know about, say, breast cancer—if it does at all," Dr. Braun says. "We may look at data from, say, 100 or 1,000 people, and we may find 10 major patterns or signatures, but they won’t necessarily relate to previously defined diagnostic disease states." We now face this very challenge, he adds, in current research on lymphoma and breast cancer. "None of this new work is interesting unless it helps define and guide prognosis and treatment," he says.

The critical biorepository

Pathology also must understand its stewardship of a resource that is likely to become more critical to bioinformatics research: the tissue or biorepository. Says Dr. Becich, "Every tissue that comes across our surgical benches and every blood sample that comes into our clinical pathology laboratories has to be highly managed and refined to allow controlled genomic and therapeutic investigation to occur."

Comprehensive and well-organized biorepositories with a sophisticated "infostructure" are critical to bioinformatics advances, and the importance of this resource is likely to grow. "There is a lot to be gained by managing tissue and serum samples and creating refined products for very well-classified disease states, so we know, for example, what a true normal is, for comparative analysis," Dr. Becich says. For example, having a prostate cancer sample that has never been treated with radiation, never been treated with any kind of endocrine therapy, and that comes from a patient without a family history of prostate cancer means it can serve as a standard for comparative analysis. Or, a repository might be able to provide equally important longitudinal information, by obtaining samples ranging from needle biopsy samples from a patient in, say, 1994, then from that patient’s prostatectomy in 1996, metastatic disease in 1999, and at his death in 2001. "If you have samples from each of these stages, you have the entire life cycle of an individual tumor," Dr. Becich says. "That is the most valuable information of all, but obtaining it takes a very coordinated effort."

What you gain from such effort is a rich clinical biorepository, a resource that "will be as strategic to pathology in the future as running a control panel of electrolytes on cardiac enzymes is today," says Dr. Becich. So strategic, he notes, that several commercial start-ups, one of which he himself participates in, offer for-profit services in this space. "If pathology doesn’t rally and take the lead in this aspect of the bioinformatics initiative, other groups—departments of medicine, structural biology departments—will."

Getting from here to there

What is the role for pathology in this postgenomics era? "Pa-thol-ogy is as well poised as any discipline to be able to drive these innovations," Dr. Braun says. "On the lab medicine side we have the expertise in biochemistry and in handling large datasets, and on the AP side we have the perspective of understanding cell biology, which is what a lot of this is about."

If there is a danger, it is that the challenge may appear too risky. "We may find ourselves saying, ’We’ll do it when it’s ready,’" Dr. Braun says. "But if we take that position, pathology as a whole may miss the opportunity to be the innovator here." Identifying and deploying new bioinformatics insights will undoubtedly proceed, but it could bypass pathology. "We have to have individuals who can jump into the breach and develop both a deep understanding of these new dimensions of biology while also working effectively with the computational systems that are necessary to handle and analyze the data," he says. "That’s the test ahead."

The solution involves a primary focus on training the next generation of pathologists to be pathology bioinformaticians. Dr. Friedman is proposing changes at the University of Michigan that would incorporate more exposure to genomics and proteomics for medical students and pathology residents. He is also urging his colleagues to see the value of "abundant training in advanced pathology bioinformatics such that the trainees understand the computational tools necessary to manage sophisticated data and digital images and will feel comfortable in future careers in pathology where a large portion of their professional responsibility will involve the manipulation and query of complex datasets using computers."

Pathologists need to focus on training pathologists as well as graduate students and other trainees in bioinformatics, Dr. Becich agrees. "In the same way that we moved pathology informatics forward by taking an aggressive stance on the importance of training young docs and graduate students in this area, we need to do the same thing now with bioinformatics."

References

1.  See Arraying the data: Bringing order to tissue microarray technology," CAP TODAY, March 2001, pp. 60-64.

Eric Skjei is a writer in Stinson Beach, Calif.