- Email: [email protected]
The supportive academic environment: ingredients for success
Painter Festschrift
The Supportive Academic Environment: Ingredients for Success Nina F. Schor, MD, PhD Recent Gloom and Doom Editor’s Note PEDIATRIC NEUROLOGY is pleased to publish eight scientific papers presented at a Festschrift on January 3, 2002, in honor of Dr. Michael J. Painter. Each manuscript underwent the customary editorial board review process for publication. Despite the many dire pronouncements of the moribund status of the academic triple threat, this species is far from extinct. Maintenance and, indeed, expansion of this pool of individuals requires their identification and support early in their careers, and nurturing and mentoring throughout their careers. Increasing demands for clinical service and revenue generation make it all the more critical that institutions and their faculty and administrative personnel in leadership positions support these increasingly rare academicians and that the individuals themselves develop and maintain diligence, superlative organizational skills, the ability to prioritize and the flexibility to reprioritize, perseverance, and above all, a sense of humor. Early in career development, perhaps the most important element in this equation is the mentor. The present article is in large measure a tribute to the mentoring role played by Dr. Michael J. Painter in the careers of his residents, fellows, and faculty throughout more than two decades as Chief of the Division of Child Neurology at the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh. © 2003 by Elsevier Inc. All rights reserved.
In recent years, the medical literature has included several near-miss obituaries for the “triple-threat” in academic medicine [1,2]. As long ago as 1983, Robert Petersdorf [3] of the American Association of Medical Colleges asserted that the “triple-threat academician” was an extinct entity. All of these studies cite the increasing complexity of clinical and research medicine, increasing administrative demands, increasing emphasis on revenue generation, and decreasing reimbursement for clinical and teaching activities as reasons for the endangerment of this species. There can be no denying the increasing difficulty of maintaining as a single individual a credible presence in clinical medicine, research and teaching, and administrative service. Nor can one dispute the relative ease and perhaps equal effectiveness of the strategy of building a renaissance division or department, rather than mandating that each faculty member be a renaissance person. Nonetheless, there will always live among the Homo sapiens a few dinosaurs who refuse to say die. The following thoughts on the modern-day triple threat grow out of a talk I delivered at a Festschrift held in Pittsburgh, Pennsylvania, on January 3, 2002, on the occasion of the retirement of Dr. Michael J. Painter as Chief of the Division of Child Neurology at Children’s Hospital and the University of Pittsburgh, a post he held from 1978 through 2001. (Dr. Painter remains extraordinarily and characteristically active as Professor of Pediatrics and Neurology and Attending Physician of Child Neurology at Children’s Hospital and the University of Pittsburgh.)
Schor NF. The supportive academic environment: Ingredients for success. Pediatr Neurol 2003;29:370-373.
Burning Questions
From the Division of Child Neurology and Pediatric Center for Neuroscience, Departments of Pediatrics, Neurology, and Pharmacology, University and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
Communications should be addressed to: Dr. Schor; Division of Child Neurology; Children’s Hospital of Pittsburgh; 3705 Fifth Avenue; Pittsburgh, PA 15213. Received November 5, 2002; accepted February 6, 2003.
370
PEDIATRIC NEUROLOGY
Vol. 29 No. 5
My career mentoring interactions with high school, undergraduate, graduate, and medical students are always
© 2003 by Elsevier Inc. All rights reserved. doi:10.1016/S0887-8994(03)00308-4 ● 0887-8994/03/$—see front matter
dominated by the same three questions. At all levels, students ask, “What do you do?”, “How do you do it (all)?”, and “What do you really do?” I assume they mean to ask me, respectively, what my career and personal identities are, how I manage to fit science, students, patients, family, and community into a singular identity and, indeed, into a 24-hour day, and what the specifics of the questions I seek to ask in my professional life are. The narrative that follows answers each of these questions in turn. It is meant as a personal but highly generalizable story, as well as a tribute to Dr. Painter as colleague, facilitator, and mentor. What Do You Do? An academic physician-scientist is asked to build a dossier that includes varying proportions of clinical service, research, teaching and mentoring, and administrative service. The last of these often includes components inside and outside the institution with which the physician is affiliated. How Do You Do It? There are three critical ingredients for a successful career in academic medicine: one needs, to coin a paraphrase, a (wo)man, a plan, and a fan. The man or woman pursuing the career is perhaps the most important of these components. He or she must have a passion for the pursuit of excellence, an insatiable hunger for knowledge, and the fortitude and humility to admit when he or she does not know something. A hefty sense of humor helps a great deal, as well. There needs to evolve early in the educational and career-building process an overall plan. This plan forces one to be goal-directed, to set priorities, and to make critical and tough choices. It is, however, important that the plan not be cast in stone. Resources, political, academic, and economic climate, personal preferences, and institutional and community needs change, and one must be able to adapt and thrive in the face of these changes. Interestingly, the Department of Pediatrics of the University of Pittsburgh School of Medicine recently mandated the formation of a “career mentoring committee” for each fellow and junior faculty member. These committees consist of two or three individuals in addition to the Division Chief or research mentor of the fellow or faculty member. They meet at least twice yearly to help formulate and perpetually reevaluate the plan for the person being mentored in light of his or her short- and long-term career goals. The fan in this equation often is a facilitator, a mentor, a champion of the success of the junior academician. Most often, this individual is the chairman or chief of the department or division with which the junior academician is associated, but this need not be the case. For me, having joined the Division of Child Neurology of the University
and Children’s Hospital of Pittsburgh right out of residency, that fan turned out to be Dr. Michael J. Painter. When I arrived in Pittsburgh in July 1986, I had been hired to add a “research presence” to and build a research program in the division. The division consisted of five academic clinicians, three of whom had ongoing clinical research programs directly related to their clinical service activities. There was no basic or translational research associated with the division. As such, there was no one in the division to whom I could turn for scientific advice. Fortunately, the University of Pittsburgh is one of the most nonhierarchical, boundary-free, collegial intellectual environments I have encountered. There was no shortage of collaborators and mentors in the Departments of Biochemistry, Pharmacology, and Neurobiology. What I needed was someone who would advocate for the importance and time- and resource-worthiness of a research program in a clinical department. Dr. Painter was exactly this kind of person for me. He was called upon many times during the two years before I garnered extramural support for my salary to defend the value of basic research against the concerns of the other members of the Division of Child Neurology, the chairman of the Department of Pediatrics, and the medical director of the hospital. My contribution to this rather awkward transition period was to participate in virtually every clinical conference run by the division and department and to present my research at such conferences so that it would be relevant to my clinical colleagues. Dr. Painter has always had a way of being available and accessible when he is needed, and making himself scarce when he would otherwise have been in the way. This habit gave me an advocate, a confidant, and a mentor when I needed one and the independence I needed to build my own reputation when I could handle things on my own.
How Do You Do It (All)? Five watchwords serve to summarize the characteristics that allow one, throughout one’s career, not only to do it all but also to make that “all” into a single, unified whole that makes sense as an academic entity. They are as follows: ● ● ● ● ●
Organization Hard work Consolidation Flexibility and prioritization Communication
It is critical that anyone embarking upon a career in academic medicine be organized. No one is born organized. However, some acquire and integrate this skill more easily than others. For most, this approach begins with list making in internship. However it is acquired, it is organization that allows one to take stock of what needs to be
Schor: Supportive Academic Environments 371
completed and accomplish it in the most expedient fashion. There is no substitute for hard work in anything that is worth doing. The willingness to continue working although the clock may suggest otherwise is borne solely of the love for what one does. It is not possible to devote most of one’s life to any enterprise that is not rewarding, interesting, and, yes, fun. When there are a dozen tasks that need to be accomplished in the limited number of hours encompassed in daily work, one does best to see if one action can accomplish two or more of the tasks. For example, “quality time” with one’s children may include explaining to them at whatever level possible what one is doing while one constructs PowerPoint slides on a laptop computer at home for a lecture to be given. Not only is it not a bad thing that work is brought home, but also it is a good thing to share with one’s family such an important part of one’s life. It has become increasingly difficult throughout the years for me to separate the “me” who is at home from the “me” who is at work. My spouse and children are intensely proud of the latter and excited that it is part of the former. If there is one skill that has enabled most of us in academic medicine to spend effective fractions of our time in each of several disparate activities, it is that of prioritization. It is absolutely crucial not only that one determine the immediacy and precision with which each task must be accomplished but also that one remain flexible enough to reprioritize each time during a given day or week or month that a new task is added to one’s agenda. One of the most exciting things about clinical work, research, teaching, and administrative work alike is that one never knows at the beginning of a new day what is going to cross the threshold of one’s office or laboratory. Priorities cannot be set in stone if they are to be made current as new information and new prerogatives arise. Finally, one’s body of work cannot be called a career unless one shares this body of work with others in a way that is meaningful and important to them. For those of us in academic medicine, this sharing means the translation of clinical observations into questions to be answered or responses to questions raised in the laboratory and, conversely, the translation of answers or questions generated through laboratory experimentation into respective questions or answers for the clinical arena. It is this dialogue that unifies the “triply threatening” individual’s career and the many individuals who make up a division or department. From a practical standpoint, this method means never sequestering oneself in the laboratory or clinic. Venues, such as case conferences and research seminars, in which such dialogues are facilitated are critical components of any career development program. To be effective, they must include the tacit and enforced expectation that researchers and clinicians alike frame their contributions to the discussions in a language common to and understood by all.
372
PEDIATRIC NEUROLOGY
Vol. 29 No. 5
What Do You Really Do? Although one tries in academic medicine to split oneself into at least three pieces, at the end of the day, one needs to decide who and what one wants to be and of what fabric one wants to fashion one’s national and international persona. For myself, I design and test in preclinical models targeted therapies for neural crest tumors and use the information gained in the process of so doing to understand basic mechanisms of regulation of cell number, be it by cell death, proliferation, or static persistence [4,5]. For example, one of the most interesting stories to emerge from my laboratory is the story of a candidate chemotherapeutic compound that paradoxically works better in the presence of the antiapoptotic protein, Bcl-2 [6]. Bcl-2 has relatively recently been characterized as a molecule that regulates cell number by interfering with the machinery that would otherwise set in motion the program leading to cell death. All conventional chemotherapeutic agents that induce cell death through the apoptosis pathway are less effective the more Bcl-2 a cancer cell produces. Cancer cells are by no means stupid, and so many have evolved ways of overexpressing Bcl-2 and its relatives. How, then, does this experimental drug, neocarzinostatin, work better as an apoptosis-inducing agent the more Bcl-2 that a cell makes? It turns out that, through a mechanism that requires the enzyme caspase 3, neocarzinostatin induces the cleavage of Bcl-2 to a proapoptotic fragment missing the Nterminal 3 kDa of the molecule [7,8]. It is not entirely clear how neocarzinostatin induces the cleavage, but it is known that neocarzinostatin does not simply directly activate caspase 3. In any case, apoptosis is potentiated by this fragment of Bcl-2, and neocarzinostatin works better the more this fragment is produced. Cisplatin and vincristine, agents the effectiveness of which is thwarted by Bcl-2, do not induce cleavage of Bcl-2 to its proapoptotic fragment. Furthermore, chemically and specifically inhibiting caspase 3 prevents cleavage of Bcl-2 and Bcl-2-induced potentiation of the apoptosis-inducing effects of neocarzinostatin. Finally, subcutaneous tumors from xenografted Bcl-2-replete cells are two to three times as sensitive to ablation by neocarzinostatin as Bcl-2-deficient cell tumors. This story, others like it, and the grant support and articles that underlie them are in the largest sense what make my national and international reputation. But the confluence of this work with my clinical efforts, divisionbuilding, mentoring, and parenting activities is what makes me who I am. I have no doubt at all that this confluence makes my research and my life infinitely different (richer, I believe) than they otherwise would be. In fact, one might say that the more difficult it is to separate one’s clinical work from one’s research from one’s teaching activities, the more successful one has been at building a unified, manageable career. It is perhaps less difficult to achieve this level of synthesis as a “bedside” clinician-scientist or clinical researcher. It is possible in
this arena, for example, to render clinical care to patients afflicted with the disease one wishes to study or to have the potential to offer experimental therapies to those patients in one’s clinic who have not improved with more conventional measures. The involvement of medical students, residents, and fellows in this enterprise makes it the perfect “triple threat as unified whole.” In the recent past, the difficulty with this strategy has been related to the difficulty of obtaining funding for clinical trials and epidemiologic or descriptive studies and being awarded promotion and tenure for clinical activity. Both of these difficulties are being addressed to some extent in the current academic health care environment. New initial review groups, programs, and dedicated monies are being allocated specifically for clinical trials and research at the national level; faculty members involved in clinical research are eligible for debt forgiveness programs vis-a`-vis their medical school tuition loans and such; and many schools, including the University of Pittsburgh School of Medicine, have developed criteria and tracks for promotion in either the tenure or nontenure stream on the basis of innovative, scholarly clinical pursuits. Conclusion There are three take-home messages that arise from all of this: (1) you are what you produce; (2) you produce best and most what you enjoy; and (3) it helps to feel supported, appreciated, and in delightful company. As a member of the Division of Child Neurology at Children’s Hospital, I have had the outstanding good
fortune to love what I do and whom I am with, and to have had the support, appreciation, and wonderful company of Dr. Michael J. Painter.
Many thanks to Dr. Patricia K. Crumrine, Ms Holly R. Schaupp, and Ms Mary E. Dulgeroff for doing the lion’s share of the work required to make the Michael J. Painter Festschrift a success. The basic science presented in this article was supported by grants from the National Institutes of Health (R01-NS38569 and R01-CA74289) and by the Carol Ann Craumer Endowment Fund for Pediatric Research, Children’s Hospital of Pittsburgh.
References [1] Herbert RS, Elasy TA, Canter JA. The Oslerian triple-threat: An endangered species? A survey of Department of Medicine chairs. Am J Med 2000;109:346-9. [2] Centor RM. Erstwhile triple threat. J Gen Intern Med 2002;17: 572-3. [3] Petersdorf RG. Is the establishment defensible? N Engl J Med 1983;309:1053-7. [4] Schor NF. Neuroblastoma as a neurobiological disease. J NeuroOncol 1999;41:159-66. [5] Schor NF. Whimpers and bangs: Of death and dying in the nervous system. J Child Neurol 1998;13:307-12. [6] Cortazzo M, Schor NF. Potentiation of enediyne-induced apoptosis and differentiation by Bcl-2. Cancer Res 1996;56:1199-203. [7] Liang Y, Nylander KD, Schor NF. Role of caspase 3-dependent Bcl-2 cleavage in potentiation of apoptosis by Bcl-2. Mol Pharmacol 2002;61:142-9. [8] Liang Y, Yan C, Nylander KD, et al. Proximal events in Bcl-2-mediated potentiation of neocarzinostatin-induced apoptosis. Soc Neurosci Abstr 2002;28:702-1.
Schor: Supportive Academic Environments 373
The Supportive Academic Environment: Ingredients for Success Nina F. Schor, MD, PhD Recent Gloom and Doom Editor’s Note PEDIATRIC NEUROLOGY is pleased to publish eight scientific papers presented at a Festschrift on January 3, 2002, in honor of Dr. Michael J. Painter. Each manuscript underwent the customary editorial board review process for publication. Despite the many dire pronouncements of the moribund status of the academic triple threat, this species is far from extinct. Maintenance and, indeed, expansion of this pool of individuals requires their identification and support early in their careers, and nurturing and mentoring throughout their careers. Increasing demands for clinical service and revenue generation make it all the more critical that institutions and their faculty and administrative personnel in leadership positions support these increasingly rare academicians and that the individuals themselves develop and maintain diligence, superlative organizational skills, the ability to prioritize and the flexibility to reprioritize, perseverance, and above all, a sense of humor. Early in career development, perhaps the most important element in this equation is the mentor. The present article is in large measure a tribute to the mentoring role played by Dr. Michael J. Painter in the careers of his residents, fellows, and faculty throughout more than two decades as Chief of the Division of Child Neurology at the University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh. © 2003 by Elsevier Inc. All rights reserved.
In recent years, the medical literature has included several near-miss obituaries for the “triple-threat” in academic medicine [1,2]. As long ago as 1983, Robert Petersdorf [3] of the American Association of Medical Colleges asserted that the “triple-threat academician” was an extinct entity. All of these studies cite the increasing complexity of clinical and research medicine, increasing administrative demands, increasing emphasis on revenue generation, and decreasing reimbursement for clinical and teaching activities as reasons for the endangerment of this species. There can be no denying the increasing difficulty of maintaining as a single individual a credible presence in clinical medicine, research and teaching, and administrative service. Nor can one dispute the relative ease and perhaps equal effectiveness of the strategy of building a renaissance division or department, rather than mandating that each faculty member be a renaissance person. Nonetheless, there will always live among the Homo sapiens a few dinosaurs who refuse to say die. The following thoughts on the modern-day triple threat grow out of a talk I delivered at a Festschrift held in Pittsburgh, Pennsylvania, on January 3, 2002, on the occasion of the retirement of Dr. Michael J. Painter as Chief of the Division of Child Neurology at Children’s Hospital and the University of Pittsburgh, a post he held from 1978 through 2001. (Dr. Painter remains extraordinarily and characteristically active as Professor of Pediatrics and Neurology and Attending Physician of Child Neurology at Children’s Hospital and the University of Pittsburgh.)
Schor NF. The supportive academic environment: Ingredients for success. Pediatr Neurol 2003;29:370-373.
Burning Questions
From the Division of Child Neurology and Pediatric Center for Neuroscience, Departments of Pediatrics, Neurology, and Pharmacology, University and Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
Communications should be addressed to: Dr. Schor; Division of Child Neurology; Children’s Hospital of Pittsburgh; 3705 Fifth Avenue; Pittsburgh, PA 15213. Received November 5, 2002; accepted February 6, 2003.
370
PEDIATRIC NEUROLOGY
Vol. 29 No. 5
My career mentoring interactions with high school, undergraduate, graduate, and medical students are always
© 2003 by Elsevier Inc. All rights reserved. doi:10.1016/S0887-8994(03)00308-4 ● 0887-8994/03/$—see front matter
dominated by the same three questions. At all levels, students ask, “What do you do?”, “How do you do it (all)?”, and “What do you really do?” I assume they mean to ask me, respectively, what my career and personal identities are, how I manage to fit science, students, patients, family, and community into a singular identity and, indeed, into a 24-hour day, and what the specifics of the questions I seek to ask in my professional life are. The narrative that follows answers each of these questions in turn. It is meant as a personal but highly generalizable story, as well as a tribute to Dr. Painter as colleague, facilitator, and mentor. What Do You Do? An academic physician-scientist is asked to build a dossier that includes varying proportions of clinical service, research, teaching and mentoring, and administrative service. The last of these often includes components inside and outside the institution with which the physician is affiliated. How Do You Do It? There are three critical ingredients for a successful career in academic medicine: one needs, to coin a paraphrase, a (wo)man, a plan, and a fan. The man or woman pursuing the career is perhaps the most important of these components. He or she must have a passion for the pursuit of excellence, an insatiable hunger for knowledge, and the fortitude and humility to admit when he or she does not know something. A hefty sense of humor helps a great deal, as well. There needs to evolve early in the educational and career-building process an overall plan. This plan forces one to be goal-directed, to set priorities, and to make critical and tough choices. It is, however, important that the plan not be cast in stone. Resources, political, academic, and economic climate, personal preferences, and institutional and community needs change, and one must be able to adapt and thrive in the face of these changes. Interestingly, the Department of Pediatrics of the University of Pittsburgh School of Medicine recently mandated the formation of a “career mentoring committee” for each fellow and junior faculty member. These committees consist of two or three individuals in addition to the Division Chief or research mentor of the fellow or faculty member. They meet at least twice yearly to help formulate and perpetually reevaluate the plan for the person being mentored in light of his or her short- and long-term career goals. The fan in this equation often is a facilitator, a mentor, a champion of the success of the junior academician. Most often, this individual is the chairman or chief of the department or division with which the junior academician is associated, but this need not be the case. For me, having joined the Division of Child Neurology of the University
and Children’s Hospital of Pittsburgh right out of residency, that fan turned out to be Dr. Michael J. Painter. When I arrived in Pittsburgh in July 1986, I had been hired to add a “research presence” to and build a research program in the division. The division consisted of five academic clinicians, three of whom had ongoing clinical research programs directly related to their clinical service activities. There was no basic or translational research associated with the division. As such, there was no one in the division to whom I could turn for scientific advice. Fortunately, the University of Pittsburgh is one of the most nonhierarchical, boundary-free, collegial intellectual environments I have encountered. There was no shortage of collaborators and mentors in the Departments of Biochemistry, Pharmacology, and Neurobiology. What I needed was someone who would advocate for the importance and time- and resource-worthiness of a research program in a clinical department. Dr. Painter was exactly this kind of person for me. He was called upon many times during the two years before I garnered extramural support for my salary to defend the value of basic research against the concerns of the other members of the Division of Child Neurology, the chairman of the Department of Pediatrics, and the medical director of the hospital. My contribution to this rather awkward transition period was to participate in virtually every clinical conference run by the division and department and to present my research at such conferences so that it would be relevant to my clinical colleagues. Dr. Painter has always had a way of being available and accessible when he is needed, and making himself scarce when he would otherwise have been in the way. This habit gave me an advocate, a confidant, and a mentor when I needed one and the independence I needed to build my own reputation when I could handle things on my own.
How Do You Do It (All)? Five watchwords serve to summarize the characteristics that allow one, throughout one’s career, not only to do it all but also to make that “all” into a single, unified whole that makes sense as an academic entity. They are as follows: ● ● ● ● ●
Organization Hard work Consolidation Flexibility and prioritization Communication
It is critical that anyone embarking upon a career in academic medicine be organized. No one is born organized. However, some acquire and integrate this skill more easily than others. For most, this approach begins with list making in internship. However it is acquired, it is organization that allows one to take stock of what needs to be
Schor: Supportive Academic Environments 371
completed and accomplish it in the most expedient fashion. There is no substitute for hard work in anything that is worth doing. The willingness to continue working although the clock may suggest otherwise is borne solely of the love for what one does. It is not possible to devote most of one’s life to any enterprise that is not rewarding, interesting, and, yes, fun. When there are a dozen tasks that need to be accomplished in the limited number of hours encompassed in daily work, one does best to see if one action can accomplish two or more of the tasks. For example, “quality time” with one’s children may include explaining to them at whatever level possible what one is doing while one constructs PowerPoint slides on a laptop computer at home for a lecture to be given. Not only is it not a bad thing that work is brought home, but also it is a good thing to share with one’s family such an important part of one’s life. It has become increasingly difficult throughout the years for me to separate the “me” who is at home from the “me” who is at work. My spouse and children are intensely proud of the latter and excited that it is part of the former. If there is one skill that has enabled most of us in academic medicine to spend effective fractions of our time in each of several disparate activities, it is that of prioritization. It is absolutely crucial not only that one determine the immediacy and precision with which each task must be accomplished but also that one remain flexible enough to reprioritize each time during a given day or week or month that a new task is added to one’s agenda. One of the most exciting things about clinical work, research, teaching, and administrative work alike is that one never knows at the beginning of a new day what is going to cross the threshold of one’s office or laboratory. Priorities cannot be set in stone if they are to be made current as new information and new prerogatives arise. Finally, one’s body of work cannot be called a career unless one shares this body of work with others in a way that is meaningful and important to them. For those of us in academic medicine, this sharing means the translation of clinical observations into questions to be answered or responses to questions raised in the laboratory and, conversely, the translation of answers or questions generated through laboratory experimentation into respective questions or answers for the clinical arena. It is this dialogue that unifies the “triply threatening” individual’s career and the many individuals who make up a division or department. From a practical standpoint, this method means never sequestering oneself in the laboratory or clinic. Venues, such as case conferences and research seminars, in which such dialogues are facilitated are critical components of any career development program. To be effective, they must include the tacit and enforced expectation that researchers and clinicians alike frame their contributions to the discussions in a language common to and understood by all.
372
PEDIATRIC NEUROLOGY
Vol. 29 No. 5
What Do You Really Do? Although one tries in academic medicine to split oneself into at least three pieces, at the end of the day, one needs to decide who and what one wants to be and of what fabric one wants to fashion one’s national and international persona. For myself, I design and test in preclinical models targeted therapies for neural crest tumors and use the information gained in the process of so doing to understand basic mechanisms of regulation of cell number, be it by cell death, proliferation, or static persistence [4,5]. For example, one of the most interesting stories to emerge from my laboratory is the story of a candidate chemotherapeutic compound that paradoxically works better in the presence of the antiapoptotic protein, Bcl-2 [6]. Bcl-2 has relatively recently been characterized as a molecule that regulates cell number by interfering with the machinery that would otherwise set in motion the program leading to cell death. All conventional chemotherapeutic agents that induce cell death through the apoptosis pathway are less effective the more Bcl-2 a cancer cell produces. Cancer cells are by no means stupid, and so many have evolved ways of overexpressing Bcl-2 and its relatives. How, then, does this experimental drug, neocarzinostatin, work better as an apoptosis-inducing agent the more Bcl-2 that a cell makes? It turns out that, through a mechanism that requires the enzyme caspase 3, neocarzinostatin induces the cleavage of Bcl-2 to a proapoptotic fragment missing the Nterminal 3 kDa of the molecule [7,8]. It is not entirely clear how neocarzinostatin induces the cleavage, but it is known that neocarzinostatin does not simply directly activate caspase 3. In any case, apoptosis is potentiated by this fragment of Bcl-2, and neocarzinostatin works better the more this fragment is produced. Cisplatin and vincristine, agents the effectiveness of which is thwarted by Bcl-2, do not induce cleavage of Bcl-2 to its proapoptotic fragment. Furthermore, chemically and specifically inhibiting caspase 3 prevents cleavage of Bcl-2 and Bcl-2-induced potentiation of the apoptosis-inducing effects of neocarzinostatin. Finally, subcutaneous tumors from xenografted Bcl-2-replete cells are two to three times as sensitive to ablation by neocarzinostatin as Bcl-2-deficient cell tumors. This story, others like it, and the grant support and articles that underlie them are in the largest sense what make my national and international reputation. But the confluence of this work with my clinical efforts, divisionbuilding, mentoring, and parenting activities is what makes me who I am. I have no doubt at all that this confluence makes my research and my life infinitely different (richer, I believe) than they otherwise would be. In fact, one might say that the more difficult it is to separate one’s clinical work from one’s research from one’s teaching activities, the more successful one has been at building a unified, manageable career. It is perhaps less difficult to achieve this level of synthesis as a “bedside” clinician-scientist or clinical researcher. It is possible in
this arena, for example, to render clinical care to patients afflicted with the disease one wishes to study or to have the potential to offer experimental therapies to those patients in one’s clinic who have not improved with more conventional measures. The involvement of medical students, residents, and fellows in this enterprise makes it the perfect “triple threat as unified whole.” In the recent past, the difficulty with this strategy has been related to the difficulty of obtaining funding for clinical trials and epidemiologic or descriptive studies and being awarded promotion and tenure for clinical activity. Both of these difficulties are being addressed to some extent in the current academic health care environment. New initial review groups, programs, and dedicated monies are being allocated specifically for clinical trials and research at the national level; faculty members involved in clinical research are eligible for debt forgiveness programs vis-a`-vis their medical school tuition loans and such; and many schools, including the University of Pittsburgh School of Medicine, have developed criteria and tracks for promotion in either the tenure or nontenure stream on the basis of innovative, scholarly clinical pursuits. Conclusion There are three take-home messages that arise from all of this: (1) you are what you produce; (2) you produce best and most what you enjoy; and (3) it helps to feel supported, appreciated, and in delightful company. As a member of the Division of Child Neurology at Children’s Hospital, I have had the outstanding good
fortune to love what I do and whom I am with, and to have had the support, appreciation, and wonderful company of Dr. Michael J. Painter.
Many thanks to Dr. Patricia K. Crumrine, Ms Holly R. Schaupp, and Ms Mary E. Dulgeroff for doing the lion’s share of the work required to make the Michael J. Painter Festschrift a success. The basic science presented in this article was supported by grants from the National Institutes of Health (R01-NS38569 and R01-CA74289) and by the Carol Ann Craumer Endowment Fund for Pediatric Research, Children’s Hospital of Pittsburgh.
References [1] Herbert RS, Elasy TA, Canter JA. The Oslerian triple-threat: An endangered species? A survey of Department of Medicine chairs. Am J Med 2000;109:346-9. [2] Centor RM. Erstwhile triple threat. J Gen Intern Med 2002;17: 572-3. [3] Petersdorf RG. Is the establishment defensible? N Engl J Med 1983;309:1053-7. [4] Schor NF. Neuroblastoma as a neurobiological disease. J NeuroOncol 1999;41:159-66. [5] Schor NF. Whimpers and bangs: Of death and dying in the nervous system. J Child Neurol 1998;13:307-12. [6] Cortazzo M, Schor NF. Potentiation of enediyne-induced apoptosis and differentiation by Bcl-2. Cancer Res 1996;56:1199-203. [7] Liang Y, Nylander KD, Schor NF. Role of caspase 3-dependent Bcl-2 cleavage in potentiation of apoptosis by Bcl-2. Mol Pharmacol 2002;61:142-9. [8] Liang Y, Yan C, Nylander KD, et al. Proximal events in Bcl-2-mediated potentiation of neocarzinostatin-induced apoptosis. Soc Neurosci Abstr 2002;28:702-1.
Schor: Supportive Academic Environments 373