- Email: [email protected]
The Challenge of “Tending the Bridge”
EDITORIALS
The Challenge of “Tending the Bridge” Ray C. J. Chiu, MD, PhD Division of Cardiothoracic Surgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
T
here is nothing new about the challenge faced by surgeons who wish to apply cutting edge science to benefit patients. Decades ago, Francis D. Moore stated: “A surgical investigator is a bridge tender, channeling knowledge from biological science to the patient’s bedside and back again. He traces his origin from both ends of the bridge. He is thus a bastard and is called this by everybody. Those at one end of the bridge say he is not a very good scientist, and those at the other say that he does not spend enough time in the operating room. If only he is willing to live with this abuse, he can continue to do his job effectively” [1]. Half a century later, the gulf is deeper and tending the bridge is much more challenging. The American Association for Thoracic Surgery is encouraging its members to alert the National Institutes of Health to the decline in For related article, see page 1151 research funding for cardiothoracic surgeons. However, as one who had served on the National Institutes of Health’s grant review committees for many years, I have often sensed the putative lack of cutting edge scientific sophistication in many of our proposals to be a major culprit. Likewise, a bridge tender who submits a translational research paper to a high-power basic science journal may be advised that the scientific concept or technology presented is not sufficiently novel, although such an article may be of interest to clinical-oriented journals. However, when it is submitted to a clinical journal, although the clinical importance may be readily recognized, the basic scientists invited to help review such a manuscript may demand use of more sophisticated basic science techniques to confirm the underlying science, because it is still considered controversial. Consequently, the proposed article was rejected by both journals, denying further development of the idea and preventing timely translation of a novel scientific concept to a possible groundbreaking therapeutic advance. Fortunately not all of our manuscripts end up with such a fate. The following case may be illustrative here, which was chosen for discussion as follows simply because the author happens to know the specific circumstances well, because they are from his own experience. Of course, there are many more worthy examples by other investigators. In 1994, we presented a new concept of inducing myocyte regeneration in an infarcted myocardium by cell Address correspondence to Dr Chiu, The Montreal General Hospital, MUHC, Suite C9-169, 1650 Cedar Ave, Montreal, Quebec, Canada H3G 1A4; e-mail: [email protected].
© 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
implantation (ie, in this case using “satellite cells,” which are progenitor skeletal myoblasts). We presented this at the annual meeting of The Society of Thoracic Surgeons, and our findings were subsequently published in The Annals of Thoracic Surgery under the title “Cellular Cardiomyoplasty” [2]. The end-points in this study were primarily indicated by histology, showing new muscle fibers growing in the middle of a homogenous scar created by cryo-injury. It lacked the use of methods used in modern molecular biology, and there was no study on functional outcome; therefore, rejection of this article could have been easily justified. Nevertheless, the clinical implication of this concept was evident so that shortly after its publication, the idea was quickly picked up by basic scientists. Numerous studies using advanced basic science technologies to explore this approach followed [3]. The term “Cellular Cardiomyoplasty” appeared in many articles, reflected by a recent Internet Google search of this term, which yielded 45,000 hits. The first clinical trial was reported within 5 years in the Lancet [4]. Thus in retrospect, our unsophisticated article in The Annals of Thoracic Surgery somehow served its mission well as translational research. This example and argument, however, runs the risk of appearing to defend scientific mediocrity in translational research. Of course we prefer manuscripts with clinically relevant innovative ideas supported by rigorous science. However, oftentimes many bridge tenders coming from the clinical side with valuable, novel ideas can not reach far into the latest basic science technologies, which are more easily and expertly carried out by specialized basic scientists. Let us face reality in that today, to be fully trained in a clinical specialty as well as a branch of basic science, by obtaining both board certification and perhaps a doctor of philosophy degree, requires more than a decade of post-medical school training. Even more challenging is to keep up with rapid advances both in the clinical and basic science fields year after year. You can also bet that this trend will not slow down. If we can not adapt, the bridge tenders will be an endangered species. An effective solution to this trend is for surgeons to join a collaborative team with competent basic scientists. Such multidisciplinary team effort is increasingly becoming essential to remain competitive in translational research. Unfortunately however, with increasing competition for research funding and diminishing clinical income used to be made available to support research efforts, the feasibility of maintaining such a team will be limited to fewer major centers. Furthermore we see in many occasions the surgeon’s contribution in such a team can be so limited as to simply supply fresh human tissues obtained during surgical procedures, such as Ann Thorac Surg 2008;85:1149 –50 • 0003-4975/08/$34.00 doi:10.1016/j.athoracsur.2008.01.073
1150
EDITORIAL CHIU TENDING THE BRIDGE
pieces of atrial appendages or veins. He may be listed as a co-author, yet he is not a true “bridge tender,” who should be someone who can contribute new ideas and concepts. Another tactic is for a surgical department or division to hire basic scientists to produce manuscripts, even though the science they are pursuing may be barely relevant and understandable to the surgeons, and their manuscripts are published in unfamiliar journals. Regardless, they are listed in the Annual Report of the Division to claim its academic productivity, while the surgeons devote themselves to keep up with clinical practice and earnings. These are important issues we can not ignore if we wish to keep surgery from becoming just a trade. How might a professional journal deal with and encourage a risky but potentially clinically important idea without the danger of publishing scientifically mediocre or misleading manuscripts? Our experience described as follows reflects one ingenuous approach. In the year 2000, a manuscript in Nature Medicine reported that human bone marrow-derived mesenchymal stem cells (MSCs) injected into the near-term ovine fetus could survive and differentiate into various phenotypes without being immunologically rejected [5]. This was odd because the immune system of such a fetus had been shown to be capable of rejecting mismatched skin grafts. To us, the implication was that MSCs might be uniquely immune tolerant. The clinical implication was apparent because the immune tolerant cells could be used as universal donor cells. To test this hypothesis in fully grown mature animals, we injected mouse MSCs into the myocardium of immune competent adult rats and observed the successful formation of xenotransplant cardiac chimera. At that time, the mainline immunological dogma was not supportive for this observation, and this could have been the rationale for rejection by journals. The bridge could have been blocked. Our manuscript was eventually submitted to The Annals of Thoracic Surgery and the journal made an inspired compromise. It accepted the manuscript, but our study was published together with an invited commentary by Dr David Cooper, Director of the Xenotransplantation Biology Research Center at Harvard [6]. He correctly pointed out that “These results are certainly remarkable but, as with all experimental studies, leave many questions unanswered” Dr Cooper also listed a number of these unanswered questions. As can be expected, this “absurd” article met considerable skepticism, but it could have played a catalytic role. In the subsequent years, basic scientific studies were carried out by many immunologists and cell biologists on the mechanisms of im-
Ann Thorac Surg 2008;85:1149 –50
mune tolerance of MSCs and several other kinds of stem cells, and considerable advances have been made [7]. Clearly this bridge is a two-way street; new scientific discovery can be applied to improve patient care, while recognition of the potential for a major clinical impact can stimulate vigorous basic scientific research. Finally, let us return to the question of fostering research funding for cardiothoracic surgical investigators. The usual suggestion is to seek greater participation by cardiothoracic surgeons in the grant review processes. But this issue should not be perceived as a turf fight or as a compromise for the standard of excellence. Rather, we should recognize the bridge tenders are playing increasingly important roles in an era in which the gulf between clinical and basic science is getting deeper and wider. The funding criteria for a grant review committee entrusted to evaluate the applications of such translational projects should consider scientific rigorousness as well as the potential clinical impact. The reviewers should be qualified to judge not only the scientific merit, but also questions such as when and how to take bench findings to the bed side, thus to facilitate clinical application when appropriate. Grant reviews by another committee evaluating studies with the primary goal of expanding knowledge can be based on scientific merit alone, pursuing mechanistic investigations with cutting-edge research technologies. Funding agencies such as the National Institutes of Health may thus satisfy the aspiration of humanity to explore and learn more about nature while responding to the wishes of the taxpayers who support these agencies so that our patients may one day benefit from such efforts.
References 1. Moore FD. The university in American surgery. Surgery 1958;44:1–10. 2. Chiu RC-J, Zibaitis A, Kao RL. Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation. Ann Thorac Surg 1995;60:12– 8. 3. Taylor DA, Atkins BZ, Hungspreugs P, et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998;4:929 –33. 4. Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for myocardial infarction. Lancet 2001;357:279 – 80. 5. Liechty KW, MacKenzie TC, Shaaban AF, et al. Human mesenchymal stem cells engraft and demonstrate sitespecific differentiation after in utero transplantation in sheep. Nat Med 2000;11:1282– 6. 6. Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RCJ. Xenotransplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg 2002;74:19 –24. 7. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007;110:3499 –506.
The Challenge of “Tending the Bridge” Ray C. J. Chiu, MD, PhD Division of Cardiothoracic Surgery, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
T
here is nothing new about the challenge faced by surgeons who wish to apply cutting edge science to benefit patients. Decades ago, Francis D. Moore stated: “A surgical investigator is a bridge tender, channeling knowledge from biological science to the patient’s bedside and back again. He traces his origin from both ends of the bridge. He is thus a bastard and is called this by everybody. Those at one end of the bridge say he is not a very good scientist, and those at the other say that he does not spend enough time in the operating room. If only he is willing to live with this abuse, he can continue to do his job effectively” [1]. Half a century later, the gulf is deeper and tending the bridge is much more challenging. The American Association for Thoracic Surgery is encouraging its members to alert the National Institutes of Health to the decline in For related article, see page 1151 research funding for cardiothoracic surgeons. However, as one who had served on the National Institutes of Health’s grant review committees for many years, I have often sensed the putative lack of cutting edge scientific sophistication in many of our proposals to be a major culprit. Likewise, a bridge tender who submits a translational research paper to a high-power basic science journal may be advised that the scientific concept or technology presented is not sufficiently novel, although such an article may be of interest to clinical-oriented journals. However, when it is submitted to a clinical journal, although the clinical importance may be readily recognized, the basic scientists invited to help review such a manuscript may demand use of more sophisticated basic science techniques to confirm the underlying science, because it is still considered controversial. Consequently, the proposed article was rejected by both journals, denying further development of the idea and preventing timely translation of a novel scientific concept to a possible groundbreaking therapeutic advance. Fortunately not all of our manuscripts end up with such a fate. The following case may be illustrative here, which was chosen for discussion as follows simply because the author happens to know the specific circumstances well, because they are from his own experience. Of course, there are many more worthy examples by other investigators. In 1994, we presented a new concept of inducing myocyte regeneration in an infarcted myocardium by cell Address correspondence to Dr Chiu, The Montreal General Hospital, MUHC, Suite C9-169, 1650 Cedar Ave, Montreal, Quebec, Canada H3G 1A4; e-mail: [email protected].
© 2008 by The Society of Thoracic Surgeons Published by Elsevier Inc
implantation (ie, in this case using “satellite cells,” which are progenitor skeletal myoblasts). We presented this at the annual meeting of The Society of Thoracic Surgeons, and our findings were subsequently published in The Annals of Thoracic Surgery under the title “Cellular Cardiomyoplasty” [2]. The end-points in this study were primarily indicated by histology, showing new muscle fibers growing in the middle of a homogenous scar created by cryo-injury. It lacked the use of methods used in modern molecular biology, and there was no study on functional outcome; therefore, rejection of this article could have been easily justified. Nevertheless, the clinical implication of this concept was evident so that shortly after its publication, the idea was quickly picked up by basic scientists. Numerous studies using advanced basic science technologies to explore this approach followed [3]. The term “Cellular Cardiomyoplasty” appeared in many articles, reflected by a recent Internet Google search of this term, which yielded 45,000 hits. The first clinical trial was reported within 5 years in the Lancet [4]. Thus in retrospect, our unsophisticated article in The Annals of Thoracic Surgery somehow served its mission well as translational research. This example and argument, however, runs the risk of appearing to defend scientific mediocrity in translational research. Of course we prefer manuscripts with clinically relevant innovative ideas supported by rigorous science. However, oftentimes many bridge tenders coming from the clinical side with valuable, novel ideas can not reach far into the latest basic science technologies, which are more easily and expertly carried out by specialized basic scientists. Let us face reality in that today, to be fully trained in a clinical specialty as well as a branch of basic science, by obtaining both board certification and perhaps a doctor of philosophy degree, requires more than a decade of post-medical school training. Even more challenging is to keep up with rapid advances both in the clinical and basic science fields year after year. You can also bet that this trend will not slow down. If we can not adapt, the bridge tenders will be an endangered species. An effective solution to this trend is for surgeons to join a collaborative team with competent basic scientists. Such multidisciplinary team effort is increasingly becoming essential to remain competitive in translational research. Unfortunately however, with increasing competition for research funding and diminishing clinical income used to be made available to support research efforts, the feasibility of maintaining such a team will be limited to fewer major centers. Furthermore we see in many occasions the surgeon’s contribution in such a team can be so limited as to simply supply fresh human tissues obtained during surgical procedures, such as Ann Thorac Surg 2008;85:1149 –50 • 0003-4975/08/$34.00 doi:10.1016/j.athoracsur.2008.01.073
1150
EDITORIAL CHIU TENDING THE BRIDGE
pieces of atrial appendages or veins. He may be listed as a co-author, yet he is not a true “bridge tender,” who should be someone who can contribute new ideas and concepts. Another tactic is for a surgical department or division to hire basic scientists to produce manuscripts, even though the science they are pursuing may be barely relevant and understandable to the surgeons, and their manuscripts are published in unfamiliar journals. Regardless, they are listed in the Annual Report of the Division to claim its academic productivity, while the surgeons devote themselves to keep up with clinical practice and earnings. These are important issues we can not ignore if we wish to keep surgery from becoming just a trade. How might a professional journal deal with and encourage a risky but potentially clinically important idea without the danger of publishing scientifically mediocre or misleading manuscripts? Our experience described as follows reflects one ingenuous approach. In the year 2000, a manuscript in Nature Medicine reported that human bone marrow-derived mesenchymal stem cells (MSCs) injected into the near-term ovine fetus could survive and differentiate into various phenotypes without being immunologically rejected [5]. This was odd because the immune system of such a fetus had been shown to be capable of rejecting mismatched skin grafts. To us, the implication was that MSCs might be uniquely immune tolerant. The clinical implication was apparent because the immune tolerant cells could be used as universal donor cells. To test this hypothesis in fully grown mature animals, we injected mouse MSCs into the myocardium of immune competent adult rats and observed the successful formation of xenotransplant cardiac chimera. At that time, the mainline immunological dogma was not supportive for this observation, and this could have been the rationale for rejection by journals. The bridge could have been blocked. Our manuscript was eventually submitted to The Annals of Thoracic Surgery and the journal made an inspired compromise. It accepted the manuscript, but our study was published together with an invited commentary by Dr David Cooper, Director of the Xenotransplantation Biology Research Center at Harvard [6]. He correctly pointed out that “These results are certainly remarkable but, as with all experimental studies, leave many questions unanswered” Dr Cooper also listed a number of these unanswered questions. As can be expected, this “absurd” article met considerable skepticism, but it could have played a catalytic role. In the subsequent years, basic scientific studies were carried out by many immunologists and cell biologists on the mechanisms of im-
Ann Thorac Surg 2008;85:1149 –50
mune tolerance of MSCs and several other kinds of stem cells, and considerable advances have been made [7]. Clearly this bridge is a two-way street; new scientific discovery can be applied to improve patient care, while recognition of the potential for a major clinical impact can stimulate vigorous basic scientific research. Finally, let us return to the question of fostering research funding for cardiothoracic surgical investigators. The usual suggestion is to seek greater participation by cardiothoracic surgeons in the grant review processes. But this issue should not be perceived as a turf fight or as a compromise for the standard of excellence. Rather, we should recognize the bridge tenders are playing increasingly important roles in an era in which the gulf between clinical and basic science is getting deeper and wider. The funding criteria for a grant review committee entrusted to evaluate the applications of such translational projects should consider scientific rigorousness as well as the potential clinical impact. The reviewers should be qualified to judge not only the scientific merit, but also questions such as when and how to take bench findings to the bed side, thus to facilitate clinical application when appropriate. Grant reviews by another committee evaluating studies with the primary goal of expanding knowledge can be based on scientific merit alone, pursuing mechanistic investigations with cutting-edge research technologies. Funding agencies such as the National Institutes of Health may thus satisfy the aspiration of humanity to explore and learn more about nature while responding to the wishes of the taxpayers who support these agencies so that our patients may one day benefit from such efforts.
References 1. Moore FD. The university in American surgery. Surgery 1958;44:1–10. 2. Chiu RC-J, Zibaitis A, Kao RL. Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation. Ann Thorac Surg 1995;60:12– 8. 3. Taylor DA, Atkins BZ, Hungspreugs P, et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998;4:929 –33. 4. Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for myocardial infarction. Lancet 2001;357:279 – 80. 5. Liechty KW, MacKenzie TC, Shaaban AF, et al. Human mesenchymal stem cells engraft and demonstrate sitespecific differentiation after in utero transplantation in sheep. Nat Med 2000;11:1282– 6. 6. Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RCJ. Xenotransplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg 2002;74:19 –24. 7. Nauta AJ, Fibbe WE. Immunomodulatory properties of mesenchymal stromal cells. Blood 2007;110:3499 –506.