Virchows Archiv https://doi.org/10.1007/s00428-018-2338-9
COMMENTARY
A brave new world Jose Costa 1,2 Received: 9 March 2018 / Accepted: 13 March 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018
Abstract Whereas up to 1950s the two major activities of academic Pathology—diagnostic and experimental—were both practiced by a single individual, thereafter, scientific, academic and economic factors created the conditions that favored monothematic practitioners. In this white paper, I argue that now, at the beginning of the 21st century, this separation is detrimental to the discipline, and I propose changes that would reunite the two strands. Keywords Academic pathology . Research in pathology . Diagnostic practice . Diagnostics . Postgraduate training
Pathology’s brave new world All of us perhaps have the feeling that as Physicians and Pathologists we are at the threshold of a new world, maybe even a brave new world. The Zeitgeist of the twenty-first century, in which we live, is that of rapid and disruptive change. For most people, this is a source of anxiety. A few thrive in instability and surf the waves of disruption but most cope the best we can. Pathology, like many other disciplines in Medicine, aims to understand the causes and effects of disease. It contributes to define the disease state and disease entities, it contributes to elucidate the etiology and mechanisms of disease and in so doing it devises diagnostic, prognostic and predictive methods to characterize the evolution of disease. It also provides the information necessary to imagine novel therapeutic avenues to be developed by others. Pathologists are well placed to work on the nature of disease because they are one step removed from the need to be personally invested in the direct effects of illness as experienced by the patient. Being a step removed from the individual suffering, they can more readily formulate a conceptual model or image of disease. Importantly, pathologists have ready access to human fluids and tissues that can be used for research. They are well placed to judge the use of this unique resource.
* Jose Costa
[email protected] 1
University of Lausanne, Lausanne, Switzerland
2
Yale School of Medicine, New Haven, CT, USA
This is the moment in time when we must find modern answers to the questions: What is the unique domain of Pathology? What is the essence of the Pathologist’s activities? How can we best conduct and support these activities in the near future?
A brief look through the rear-view mirror For hundreds of years, pathology was morbid anatomy practiced in the autopsy room and produced knowledge about the late phases of disease. Until the 1940’s Medicine had modest means to treat disease with drugs or surgery and influence the course of disease. Consequently, postmortem studies mostly shed light on the natural history of disease. In the 19th century, correlative studies were augmented by a new investigative approach: experimental pathology. Using animal models to study the etiology and physiopathology of disease in the laboratory, the schools of Claude Bernard and Rudolph Virchow gave life to this second strand of Pathology. Later, with progress in surgical technique and anesthesia, pathologists began to study the morphology of earlier phases of disease as seen in the surgical specimens excised from patients. Morphology became a major tool to define and classify disease and gross and microscopic findings were correlated to the effects of therapy. In the 1940’s core needle biopsy laid the foundation for the pathology of medical diseases and a few decades later, flexible endoscopes expanded the range of tissues routinely analyzed by pathologists. Once a diagnosis was established and increasingly powerful modern therapies modified the natural history of disease, the aim shifted from prognosis alone to include the prediction of the effects of therapies and evaluation of outcomes.
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Contemporaneously with the increase of clinical diagnostic activity seen in the second half of the 20th century, the study of preclinical models of disease in the experimental laboratory intensified and flourished. The Bceteris paribus^ possible in the laboratory but out of reach in the clinic, together with molecular biology and genetically modified organismal models, produced a series of impressive advances and insights into the mechanisms of disease at the molecular level. Towards the end of the 20th century, the rapid application of these insights to the clinical praxis gave rise to Translational Medicine, a modality already put in motion by Marie and Pierre Curie.
The present predicament Whereas In the late 19th and early 20th centuries pathologists that were active in the clinic, carried out significant experimental programs, from the 1950’s on, the intellectual climate and culture in Departments of Pathology, responding to a variety of factors discussed below, created a split between the pathologist researcher and the pathologist active in diagnostics. This split has only increased with time and has resulted in an almost complete polarization. Today, in many if not most academic pathology departments, clinically engaged pathologists find themselves with little time and few resources to engage in investigative endeavors and are increasingly distant from experimental pathologists. Conversely, the highly specialized demands of patient care forbid entry of the investigative pathologist to the clinical arena. Three great forces have shaped and maintained this polarization: the sources of funding for each respective kind of activity, the massive growth of knowledge and information and the technological revolution. Economic factors and business models providing financial support are powerful determinants of the culture for each of the Btwo Pathologies^. The experimental investigative activity carried out in academic institutions is funded by peer review mechanisms, the funds obtained supporting not only direct research but also the infrastructure of institutions. In contrast, the academic diagnostic activities carried out in university hospitals are supported by CMS through a mixed professional and technical billing mechanism. The difference in the nature of the source of support has favored a separation of the two major kinds of activity, research and service, isolating them from each other. Perhaps more importantly, the nature of the research is molded by the source of support. Experimentalists competing with investigators in basic departments (cell biology, biochemistry, physiology and pharmacology) tend to drift away from the biology of disease, whereas the clinical diagnostic pathologist is limited to correlative studies or serves as a collaborator that provides data for translational studies. Absorbed by the need to be efficient in order to lower the cost of health care, by the explosion of knowledge and by rapidly changing technologies, the diagnostician is seldom
driven by a truly original question and personal intellectual agenda. Furthermore, the emphasis of diagnostic pathology as a BService^ encourages the view of the discipline as a subordinate and purely transactional activity rather than a full equal partner in innovating health care. The explosion of information is a second force and an obvious source of stress for the clinically active pathologist. It is also an agent of further fragmentation for the clinician: the era of the generalist is past. Keeping up competence in a specialty or even subspecialty demands time, effort and engagement with peers, patients and funding agencies. Medicine has reached a level of complexity inside each domain that just keeping up consumes the effort of a single intellect and may inhibit creativity. The result is increasing specialization and sub-specialization in the clinical practice that demands competency-based training which emphasizes Bknowing the answer^ rather than Basking the right question^. The expansion of knowledge in the basic sciences has not been so much of an issue for the experimentalist, who focuses on the understanding of the basis of disease that underpins the clinical practice, rather than adding descriptive knowledge that does not necessarily provide insights into the nature of disease. The third force, rapidly evolving technology is undoubtedly one of the most powerful agents impacting both the investigative and clinical care domains. The challenge is aggravated by the pervasiveness of the technological revolution, which is occurring quasi simultaneously across most scientific disciplines. Mastering even one of these new technologies requires a high level of personal investment and sharp focus. There was a time when investigators devised techniques to solve the questions they were asking. At present, innovation in technology is so fast paced and complex that very few investigators can muster the creative energy to devise the technique necessary to solve a burning biological question or to open a field that had remained beyond reach. Complex technology platforms are now manned by technical teams and organized and maintained as Bshared resources^ that serve a variety of research programs. Specialized vocabularies emerge that further isolate each domain and as a consequence, the chasm between research and clinical care widens. The capability to easily generate entire profiles of molecules present in a tissue or fluid, generates, large data sets that require sophisticated computational tools to extract the useful information from the noise. Omics technologies make possible detailed and objective descriptions of clinical observations and enable the recording of the effects of therapy in the clinic or of experimental perturbations in the laboratory. Together with mathematical and in silico modeling, these large data sets enable integration of concepts across scales of organization, linking molecular alterations (mutations) to phenotypic changes at the organismal level (metastases, emergence of resistance). Artificial intelligence (AI) being able to learn but unable to teach the route to access the knowledge, will accelerate discovery.
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Looking forward If we subscribe to the notion that the separation of diagnostic and experimental pathology is detrimental to the mission of the discipline, inasmuch as it divorces intimate clinical knowledge and experience from the understanding of disease and basic biological mechanisms, what is it that we have to do to go back to the time when it was not unusual for a pathologist to contribute to both clinical diagnosis and fundamental knowledge about disease? First, we have to recognize that the central focus of the discipline is disease. A telling test of the pertinence of a research program in Pathology is whether that program can be easily transferred to a basic science department or division. If the answer is Bno^ it is likely to mean that the research is conceptually rooted in physiopathology of disease and intimately linked to the clinic. If the answer is Byes^ one should question whether the program belongs in a Pathology department. The investigative activity can take place both in the experimental laboratory and in the clinic, where advantage can be taken of diverse patient populations and the perturbations introduced by therapy to advance knowledge. Many of the questions resolved by experimentation, will originate from observations in the clinic and will address mechanistic aspects of the disease or create novel tests or instrumentation to improve diagnostics. The research conducted by pathologists is intrinsically of translational nature. Some argue that the most productive translational investigators think clearly but are confused as to whether they are in the laboratory or in the clinic.
Second, we have to conceive a mode of research that accommodates the integration of diagnostics and clinical practice with experimental work. A possible model that accommodates closing the gap between these two domains of activity is shown in the Fig. 1. Both investigational and clinical activities are organized around a specific disease or group of diseases rather than based on a discipline or a departmental structure. The loop is envisioned as a constant flow of information, ideas and information, being contributed by members of a diverse multidisciplinary team and initiated at any of the activities enumerated in the boxes anchoring corners of the loop. The of this constant process of collaboration is to refine the understanding of a disease by identifying new preclinical models, improve its predictive and personalized diagnosis and point the way to new therapies. It also evaluates therapeutic modalities and outcomes. All kinds of specialists can be accommodated, and transiently coopted, as long as they are focused on a disease question. A large proportion of members must be clinically engaged and be capable of interacting with experts in technology and basic science. The participation of basic scientists primarily animated by curiosity of finding how Nature works is facilitated by scientistscoordinators trained in the BScience of Team Science^. The platforms needed for tissue services (grossing and histology, digitized histology, including IHC, FISH,) can efficiently be managed by physician assistants and technical personnel supervised by a small cadre of professionals. Experiments and clinical tests based on complex technologies, such as Cy-tof, proteomics, NGS etc. can be provided by a combination of internal or
Fig. 1 A schematic view of possible multidisciplinary interactions that close the gap between the two poles, research and practice, and support translational research. At its center is a question about disease. Modified with permission from [1]
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external technical resources. Sweden has successfully implemented a free-standing Life Sciences Center for four of its Universities to do just that. In the clinic, results of diagnostic tests can then be available at digital stations where the gross and microscopic images and data would be available and ready to be integrated by the consultative pathologist. It is easy to see how quantitative image data and AI could be seamlessly integrated in the workflow. As new diagnostic platforms emerge, specialists embedded in clinical disease oriented teams would be well placed to test them, evaluate their efficacy and incorporate them in the workup of patients. The flow in the loop process will facilitate identifying the outstanding questions whose answers would improve disease management. Most of the team members will have mixed clinical and experimental activities in different proportions. Each disease-focused unit has well defined objectives and milestones. Its funding and productivity are periodically peer reviewed. To put this modality into practice, ad-hoc and specific local solutions need to be found and will most likely be articulated around the disease focused units already existing in many clinics. We will only learn how to launch more complex activities that are truly integrative by actually building such programs and improving them as we go. Third, in order to participate in innovation, academic pathologists have to have time away from illness in order to devote creative energies to disease, in other words be relieved of the intense mission of immediate clinical care. This research time has to be of a significant duration and continuity to allow a productive engagement. Pathologists should be among the drivers of innovation rather than reacting to, and sometimes resisting, conceptual and technical advances. Why is it, that whereas radiologists are constantly on the leading edge of technology, diagnostic pathologists have been woefully slow in embracing efficiencies, so natural to the discipline, such as digital working stations, being tissue-type agnostic in favor of the identification of therapeutic targets, or using AI to screen digital slides for morphological abnormalities? Nowadays, most diagnostic pathologists are simply so consumed by the demands of the clinical service that they do not have time to innovate. Fourth, we need to imagine how the health care system will support the kind of integrated research argued for here. The transition of the business of health system from procedurebased to value-based care provides an opportunity to create a business model that favors the re-integration of diagnostic and experimental Pathology. For the last hundred years little has fundamentally changed concerning the general organization of Medical Schools or Academic Departments of Pathology. The latter have maintained the two independent streams of economical revenue: grant funding and clinical. This duality of funding sources has worked well in the past but it selects against integration (see Bpresent predicament^ above). When medical groups are forced to
negotiate the value of Pathology’s contribution to the care and outcome of each and every patient, the diagnostic act needs to be seen from a broader perspective. It is not each act or the tools used but the experience in combining diagnostic modalities and ultimately the degree of constant improvement through innovation that will count. How precise and how predictive is the diagnosis? Constant improvement in these capacities can only come through integrated research and innovation. This is the most rational and principled way to show and hence determine the value of pathology’s contribution to the outcome of care at the population level. The integration of innovation and care argues strongly for the disease-focused units, rather than in the traditional Departments, being the source of economic support for the activity and faculty members. Although this may sound radical, one has to remember that at the dawn of surgical pathology as a sub-specialty, pathologists were recruited and paid by Surgery Departments and that only later they were co-opted by Pathology Departments.
Closing remarks Based on my experience I have offered some considerations to use as starting points for debate, debate that should hopefully lead to clarity. Clarity is needed to organize or re-organize departments and more importantly, to shape postgraduate training programs. Should the divorce between diagnostic and experimental pathology remain and each activity be maximized? or should we implement the change that will reanneal both strands? Some will argue that going back to Virchow is not possible, that the model is not sustainable, that it is naïve, overambitious and impracticable in the present health care system. We will hear that demands for efficient clinical care will not tolerate the burdens of investigational activity. But I submit that it is also possible to argue that some variation of the models here discussed will move us to a rapidly evolving, efficient precision personalized medicine. Should not we strive for the capacity to forecast and monitor an individual’s trajectory of healthy aging and to correct minimal deviations before they become catastrophic? In closing it is clear that it behooves pathologists to influence the socio-medical-industrial environment in such a way that the forces of selection that are at work on the discipline and shape institutional policies will maximize the best Pathology has to offer.
References Costa J (2008) Systems medicine in oncology. Nat Clin Pract Oncol 5(3): 117. https://doi.org/10.1038/ncponc1070