It's All in the Translation

Translational medicine in rheumatology has benefitted from unsung but successful bridge-building efforts that facilitate mutually beneficial research relationships between basic scientists and clinicians working toward a common goal, and lately the fruits of such efforts have led to ground-breaking drug discoveries and therapeutic advances.

For rheumatology in particular, because the discipline encompasses multiple organ systems and diverse pathology, such translational research is critical for gaining an understanding of the complexities of the immune system and disease mechanisms and developing and testing treatment strategies, according to Dr. Iain McInnes, professor of experimental medicine and rheumatology at the University of Glasgow (Scotland). "It’s a simple concept, really. It’s the idea that we might understand more about the basic science pathways if we look at them operating in the real world. And it’s a two-way street. Basic science can in turn be informed by the clinical pathologic entity that people come to study."

Examples of "good translation stories," said Dr. McInnes, a clinician/scientist himself, include the tumor necrosis factor (TNF) blocking story and the interleukin-1 (IL-1) story. The development of the TNF blocking therapies, which have had a major impact on the treatment of rheumatoid arthritis and other inflammatory diseases, followed "a series of basic science and clinical medicine iterations, initially in the infectious diseases world and eventually in immunology and rheumatology," he said.

"The evolution of the IL-1 biology is an especially interesting translational story," Dr. McInnes acknowledged. Since it was first cloned in the 1980s, the cytokine family (IL-1a and IL-1b) was identified as a key player in regulating inflammatory processes. This led to the development of IL-1 inhibitors, which were tested primarily in rheumatoid arthritis, but with only modest success, he said. "But this helped investigators understand how IL-1 was synthesized and how its biology was regulated." Such insights eventually led to the development and testing of IL-1 directed agents such as anakinra and rilonacept in patients with hereditary autoinflammatory conditions and in nonhereditary inflammatory diseases associated with aberrant IL-1 signaling, including Mediterranean fever, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, and gout. In turn, the efficacy of IL-1 blockade in the treatment of many of these conditions "has changed the understanding of these disorders," he said, and has led to investigation IL-1’s role in other diseases, including adult-onset Still’s disease and systemic juvenile idiopathic arthritis.

The IL-1 story is "elegant science" with respect to the back and forth between the lap and clinical correlates, Dr. McInnes explained. "Although it ultimately did not lead to a good rheumatoid arthritis treatment, the continual cross talk allowed relevance to be maintained and clinical pathology to direct the lab focus over time."

Despite the successes, the bench-to-bedside lag is real and sometimes inevitable given the actual and perceived separation between basic science and clinical research. One of the fundamental reasons for the schism, according to Dr. McInnes, is that scientists and clinicians often don’t share the same philosophy. "We have to be careful about generalizations but, from an academic point of view, a basic scientist is driven by trying to answer a legitimate scientific question: Why is the sky blue? Why are daffodils yellow? How does this chemical activate this target cell?" he said. "So in our area of autoimmune research, a basic scientist’s approach to cytokine research would be, ‘I’m just going to keep chasing down this molecule and its biological effects until I get the answer.’ "

The clinical investigator, on the other hand, "is trying to understand the complex matrix of events that lead to the pathology or disease state, so he or she may well rely on a basic scientific pathway for a certain period of time, but if it turns out that the pathway is really not involved in the disease pathogenesis after a period of investigation, the clinician will part company with that scientist." So while the scientist presses ahead trying to answer the basic scientific question, the clinician investigators will be driven by where the disease takes them, he said.

The separation between basic science and clinical investigation is not deliberate as much as it is circumstantial, according to rheumatologist Dr. Bruce Cronstein, director of the Clinical and Translational Science Institute at New York University. "Many bench researchers are not aware of whom to contact among their clinical colleagues to best obtain relevant collaboration, and clinicians are also unaware of whom to contact among their bench research colleagues," he said. Further, in the United States, "rewards for collaboration have not aligned well with the clinic requirements. Increasing pressure to maximize income [both personal and institutional] by seeing more patients has diminished the time for clinicians to collaborate by gathering extensive data about patients or biosamples," he said.

Also, the mechanisms for sharing credit are poorly defined and there are few mechanisms available for scientists to share grants and funding with their clinical colleagues, according to Dr. Cronstein. "Does a clinician become an author of a high-profile science paper for supplying one patient’s samples? Two? Twenty?" And although the National Institutes of Health has recently defined the coinvestigator mechanism, "even that tends to slight the noncorresponding author." Although the importance of bringing clinical and scientific colleagues together is generally understood to be critical, "finding the appropriate venues to do so is very difficult to accomplish in practice," he said.

In an ideal world, the science/clinical collaboration would be more fluid than fixed, whereby the clinical investigator studying a pathologic state "would interact with several different scientists who offer their appropriate expertise to tease out different components and different pathways," said Dr. McInnes. "One of the difficulties is that we often don’t know where the starting point is in the pathological journey. We are informed by the circumstances of where we are looking." In rheumatoid arthritis, for example, "a lot of our thinking [behind recent developments] was provoked by what the joint looks like after 5-10 years of disease. Maybe the next advance will be provoked by what the joint looks like after just a couple of days of arthritis, if we could get to that window," he said. Out of circumstance, then, the divide between basic and clinical research is process driven because there are many different processes at work at different phases even in one disease."

Each discipline also has its own distinct obstacles that can preclude fluid cooperation. "At the moment, the challenges of successfully translating a bit of science into an understanding of pathogenesis are gargantuan. There’s the ethics of looking at human tissue, the willingness of patient populations to participate, and just the pragmatics of whereabouts in the patient you can look," said Dr. McInnes. "If the disease is a disease of the lymph node or bone marrow, before it becomes a disease of the joint, it’s not impossible but it is quite difficult to get bits of lymph node and bone marrow from human beings, although that’s some of the real interesting science that underpins what the disease may be." Unlike cancer, in which biopsies are part of routine care and as such can more readily be used for scientific investigation, "it’s not routine to biopsy joint tissue or synovial lining in rheumatoid arthritis patients, even if it’s something you would like to do, and it’s absolutely not routine practice to biopsy lymph nodes or bone marrow. The ethics are marginal."

Finally, there are simply not enough properly trained clinician scientists, in medicine in general and rheumatology specifically, Dr. McInnes said. "When they do exist, they are often hard-pressed to meet the demands of both the scientific and clinical communities." Efforts to chip away at this particular barrier are underway, thanks to innovative collaborations, within and between universities and medical schools, often supported by government and/or pharmaceutical company funding. The university-wide Clinical and Translational Science Institute at NYU, for example, in partnership with the New York City Health and Hospitals Corporation and with funding support from the NIH, is one of more than 45 such centers nationwide charged with the task of training clinician scientists and accelerating advances from the lab to the clinic.

Similarly, Dr. McInnes is deputy director of a novel translational medicine consortium comprising the Scottish universities of Aberdeen, Dundee, Edinburgh, and Glasgow, funded by the Wellcome Trust, a global charitable foundation, and Pfizer. Called the Scottish Translational Medicine and Therapeutics Initiative (STMTI), its mandate is to create a "new cadre" of academic clinicians with expertise in translational medicine and treatment by offering doctoral fellowship training programs for clinicians. "The goal is to meet the ongoing need for appropriately trained clinical investigators who have the basic science understanding who are backed by basic science training and expertise," he said. "Such individuals can act de facto as investigators, but also as catalysts. They can drive motivation within the basic science community and also engage the clinical community."

Importantly, however, translational activity cannot be forced, Dr. McInnes stressed. There are many ways to achieve collaboration, but, in my opinion, they all require one thing: curiosity," he said. "If a scientist and clinical investigator share an interest in getting an answer to questions that are either identical or sufficiently close to each other, that is a fruitful platform for a successful translational partnership." For example, if a scientist can demonstrate that a pathway is present in the disease state of interest to the clinician, both the scientist and the clinician will be curious to understand how it operates within that disease state and that will drive their work."

Additionally, translational research efforts are most likely to succeed using a team approach, Dr. McInnes said. "It is essential to recognize the different disciplines necessary to properly address the complex issues in human disease," he stressed. "The team requires people coming together and being prepared to work together and possibly change their own way of thinking a little bit."

Efforts to foster such teams – particularly across public, private, and corporate sectors – can be hindered by administrative roadblocks, including concerns about obtaining consent from patients, intellectual property issues, and who stands to gain from knowledge obtained from any given study," Dr. Cronstein said. In addition, the "demonization" of the pharmaceutical industry in recent years "makes it difficult to collaborate with pharma without being penalized or at least having to run a major gauntlet of paperwork and review," he said. "Clearly, pharma will try to obtain a benefit for itself, but we can collaborate successfully to develop new drugs and new understanding of the diseases of the patients we care for."

At the end of the day, rheumatology is poised to gain much from such efforts. "The field of rheumatology stands to gain new understanding of the diseases that afflict our patients, new therapies for these diseases, and novel targets for development of drugs that can benefit our patients," said Dr. Cronstein. "The advantages of collaboration are overwhelming and the danger of fragmentation of efforts is critical."

The Translational Journey of JAKs

"Some of the most exciting translational research in rheumatology right now is the use of intracellular signal proteins as targets of small-molecule drugs," said Dr. McInnes. "There’s irony in this, because rheumatologists use small-molecule inhibitors all the time, including methotrexate and sulfasalazine. The difference is we’re now using new molecular entities that have been designed specifically to seek out some of the signal pathways that very elegant biology over the last 10-20 years has shown to have a role in inflammation."

The work by Dr. John O’Shea on cytokine signal transduction and the roles of janus kinases (JAKs) and signal transducer and activator of transcription (STAT) factors in immune cell development and differentiation are an excellent example, Dr. McInnes said. The research by Dr. O’Shea, scientific director of the intramural research program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health in Bethesda, Md., led to an NIH patent related to JAKs as a new class of immunosuppressive drug. Through a cooperative research agreement with Pfizer, a JAK3 compound (tofacitinib) is currently in phase III trials.

"These drugs are still not licensed, but the [translational] success story is that the proof of concept that JAKs are involved in the pathogenesis has been achieved," Dr. McInnes said. "When you block [the molecules], patients get better. That doesn’t mean you’ve got a drug, but it does tell you the biology pans out pretty well."

The research developments in this scenario were very much driven around the science of the JAKs initially, "then the investigators looked at people whose immune systems didn’t work very well to see if JAKs were deficient in them, which they were," Dr. McInnes explained. "The next step was to flip back to the lab to consider whether that information could be therapeutically useful, and eventually it found its way back to rheumatology practice.

"Although we still don’t know all that much about how these pathways work in rheumatoid tissue," Dr. McInnes said, "the translation journey [of JAKs] thus far "is one to be admired."

Dr. McInnes and Dr. Cronstein reported no relevant conflicts of interest.

Translational medicine in rheumatology has benefitted from unsung but successful bridge-building efforts that facilitate mutually beneficial research relationships between basic scientists and clinicians working toward a common goal, and lately the fruits of such efforts have led to ground-breaking drug discoveries and therapeutic advances.

For rheumatology in particular, because the discipline encompasses multiple organ systems and diverse pathology, such translational research is critical for gaining an understanding of the complexities of the immune system and disease mechanisms and developing and testing treatment strategies, according to Dr. Iain McInnes, professor of experimental medicine and rheumatology at the University of Glasgow (Scotland). "It’s a simple concept, really. It’s the idea that we might understand more about the basic science pathways if we look at them operating in the real world. And it’s a two-way street. Basic science can in turn be informed by the clinical pathologic entity that people come to study."

Examples of "good translation stories," said Dr. McInnes, a clinician/scientist himself, include the tumor necrosis factor (TNF) blocking story and the interleukin-1 (IL-1) story. The development of the TNF blocking therapies, which have had a major impact on the treatment of rheumatoid arthritis and other inflammatory diseases, followed "a series of basic science and clinical medicine iterations, initially in the infectious diseases world and eventually in immunology and rheumatology," he said.

"The evolution of the IL-1 biology is an especially interesting translational story," Dr. McInnes acknowledged. Since it was first cloned in the 1980s, the cytokine family (IL-1a and IL-1b) was identified as a key player in regulating inflammatory processes. This led to the development of IL-1 inhibitors, which were tested primarily in rheumatoid arthritis, but with only modest success, he said. "But this helped investigators understand how IL-1 was synthesized and how its biology was regulated." Such insights eventually led to the development and testing of IL-1 directed agents such as anakinra and rilonacept in patients with hereditary autoinflammatory conditions and in nonhereditary inflammatory diseases associated with aberrant IL-1 signaling, including Mediterranean fever, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, and gout. In turn, the efficacy of IL-1 blockade in the treatment of many of these conditions "has changed the understanding of these disorders," he said, and has led to investigation IL-1’s role in other diseases, including adult-onset Still’s disease and systemic juvenile idiopathic arthritis.

The IL-1 story is "elegant science" with respect to the back and forth between the lap and clinical correlates, Dr. McInnes explained. "Although it ultimately did not lead to a good rheumatoid arthritis treatment, the continual cross talk allowed relevance to be maintained and clinical pathology to direct the lab focus over time."

Despite the successes, the bench-to-bedside lag is real and sometimes inevitable given the actual and perceived separation between basic science and clinical research. One of the fundamental reasons for the schism, according to Dr. McInnes, is that scientists and clinicians often don’t share the same philosophy. "We have to be careful about generalizations but, from an academic point of view, a basic scientist is driven by trying to answer a legitimate scientific question: Why is the sky blue? Why are daffodils yellow? How does this chemical activate this target cell?" he said. "So in our area of autoimmune research, a basic scientist’s approach to cytokine research would be, ‘I’m just going to keep chasing down this molecule and its biological effects until I get the answer.’ "

The clinical investigator, on the other hand, "is trying to understand the complex matrix of events that lead to the pathology or disease state, so he or she may well rely on a basic scientific pathway for a certain period of time, but if it turns out that the pathway is really not involved in the disease pathogenesis after a period of investigation, the clinician will part company with that scientist." So while the scientist presses ahead trying to answer the basic scientific question, the clinician investigators will be driven by where the disease takes them, he said.

The separation between basic science and clinical investigation is not deliberate as much as it is circumstantial, according to rheumatologist Dr. Bruce Cronstein, director of the Clinical and Translational Science Institute at New York University. "Many bench researchers are not aware of whom to contact among their clinical colleagues to best obtain relevant collaboration, and clinicians are also unaware of whom to contact among their bench research colleagues," he said. Further, in the United States, "rewards for collaboration have not aligned well with the clinic requirements. Increasing pressure to maximize income [both personal and institutional] by seeing more patients has diminished the time for clinicians to collaborate by gathering extensive data about patients or biosamples," he said.

Also, the mechanisms for sharing credit are poorly defined and there are few mechanisms available for scientists to share grants and funding with their clinical colleagues, according to Dr. Cronstein. "Does a clinician become an author of a high-profile science paper for supplying one patient’s samples? Two? Twenty?" And although the National Institutes of Health has recently defined the coinvestigator mechanism, "even that tends to slight the noncorresponding author." Although the importance of bringing clinical and scientific colleagues together is generally understood to be critical, "finding the appropriate venues to do so is very difficult to accomplish in practice," he said.

In an ideal world, the science/clinical collaboration would be more fluid than fixed, whereby the clinical investigator studying a pathologic state "would interact with several different scientists who offer their appropriate expertise to tease out different components and different pathways," said Dr. McInnes. "One of the difficulties is that we often don’t know where the starting point is in the pathological journey. We are informed by the circumstances of where we are looking." In rheumatoid arthritis, for example, "a lot of our thinking [behind recent developments] was provoked by what the joint looks like after 5-10 years of disease. Maybe the next advance will be provoked by what the joint looks like after just a couple of days of arthritis, if we could get to that window," he said. Out of circumstance, then, the divide between basic and clinical research is process driven because there are many different processes at work at different phases even in one disease."

Each discipline also has its own distinct obstacles that can preclude fluid cooperation. "At the moment, the challenges of successfully translating a bit of science into an understanding of pathogenesis are gargantuan. There’s the ethics of looking at human tissue, the willingness of patient populations to participate, and just the pragmatics of whereabouts in the patient you can look," said Dr. McInnes. "If the disease is a disease of the lymph node or bone marrow, before it becomes a disease of the joint, it’s not impossible but it is quite difficult to get bits of lymph node and bone marrow from human beings, although that’s some of the real interesting science that underpins what the disease may be." Unlike cancer, in which biopsies are part of routine care and as such can more readily be used for scientific investigation, "it’s not routine to biopsy joint tissue or synovial lining in rheumatoid arthritis patients, even if it’s something you would like to do, and it’s absolutely not routine practice to biopsy lymph nodes or bone marrow. The ethics are marginal."

Finally, there are simply not enough properly trained clinician scientists, in medicine in general and rheumatology specifically, Dr. McInnes said. "When they do exist, they are often hard-pressed to meet the demands of both the scientific and clinical communities." Efforts to chip away at this particular barrier are underway, thanks to innovative collaborations, within and between universities and medical schools, often supported by government and/or pharmaceutical company funding. The university-wide Clinical and Translational Science Institute at NYU, for example, in partnership with the New York City Health and Hospitals Corporation and with funding support from the NIH, is one of more than 45 such centers nationwide charged with the task of training clinician scientists and accelerating advances from the lab to the clinic.

Similarly, Dr. McInnes is deputy director of a novel translational medicine consortium comprising the Scottish universities of Aberdeen, Dundee, Edinburgh, and Glasgow, funded by the Wellcome Trust, a global charitable foundation, and Pfizer. Called the Scottish Translational Medicine and Therapeutics Initiative (STMTI), its mandate is to create a "new cadre" of academic clinicians with expertise in translational medicine and treatment by offering doctoral fellowship training programs for clinicians. "The goal is to meet the ongoing need for appropriately trained clinical investigators who have the basic science understanding who are backed by basic science training and expertise," he said. "Such individuals can act de facto as investigators, but also as catalysts. They can drive motivation within the basic science community and also engage the clinical community."

Importantly, however, translational activity cannot be forced, Dr. McInnes stressed. There are many ways to achieve collaboration, but, in my opinion, they all require one thing: curiosity," he said. "If a scientist and clinical investigator share an interest in getting an answer to questions that are either identical or sufficiently close to each other, that is a fruitful platform for a successful translational partnership." For example, if a scientist can demonstrate that a pathway is present in the disease state of interest to the clinician, both the scientist and the clinician will be curious to understand how it operates within that disease state and that will drive their work."

Additionally, translational research efforts are most likely to succeed using a team approach, Dr. McInnes said. "It is essential to recognize the different disciplines necessary to properly address the complex issues in human disease," he stressed. "The team requires people coming together and being prepared to work together and possibly change their own way of thinking a little bit."

Efforts to foster such teams – particularly across public, private, and corporate sectors – can be hindered by administrative roadblocks, including concerns about obtaining consent from patients, intellectual property issues, and who stands to gain from knowledge obtained from any given study," Dr. Cronstein said. In addition, the "demonization" of the pharmaceutical industry in recent years "makes it difficult to collaborate with pharma without being penalized or at least having to run a major gauntlet of paperwork and review," he said. "Clearly, pharma will try to obtain a benefit for itself, but we can collaborate successfully to develop new drugs and new understanding of the diseases of the patients we care for."

At the end of the day, rheumatology is poised to gain much from such efforts. "The field of rheumatology stands to gain new understanding of the diseases that afflict our patients, new therapies for these diseases, and novel targets for development of drugs that can benefit our patients," said Dr. Cronstein. "The advantages of collaboration are overwhelming and the danger of fragmentation of efforts is critical."

The Translational Journey of JAKs

"Some of the most exciting translational research in rheumatology right now is the use of intracellular signal proteins as targets of small-molecule drugs," said Dr. McInnes. "There’s irony in this, because rheumatologists use small-molecule inhibitors all the time, including methotrexate and sulfasalazine. The difference is we’re now using new molecular entities that have been designed specifically to seek out some of the signal pathways that very elegant biology over the last 10-20 years has shown to have a role in inflammation."

The work by Dr. John O’Shea on cytokine signal transduction and the roles of janus kinases (JAKs) and signal transducer and activator of transcription (STAT) factors in immune cell development and differentiation are an excellent example, Dr. McInnes said. The research by Dr. O’Shea, scientific director of the intramural research program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health in Bethesda, Md., led to an NIH patent related to JAKs as a new class of immunosuppressive drug. Through a cooperative research agreement with Pfizer, a JAK3 compound (tofacitinib) is currently in phase III trials.

"These drugs are still not licensed, but the [translational] success story is that the proof of concept that JAKs are involved in the pathogenesis has been achieved," Dr. McInnes said. "When you block [the molecules], patients get better. That doesn’t mean you’ve got a drug, but it does tell you the biology pans out pretty well."

The research developments in this scenario were very much driven around the science of the JAKs initially, "then the investigators looked at people whose immune systems didn’t work very well to see if JAKs were deficient in them, which they were," Dr. McInnes explained. "The next step was to flip back to the lab to consider whether that information could be therapeutically useful, and eventually it found its way back to rheumatology practice.

"Although we still don’t know all that much about how these pathways work in rheumatoid tissue," Dr. McInnes said, "the translation journey [of JAKs] thus far "is one to be admired."

Dr. McInnes and Dr. Cronstein reported no relevant conflicts of interest.

Translational medicine in rheumatology has benefitted from unsung but successful bridge-building efforts that facilitate mutually beneficial research relationships between basic scientists and clinicians working toward a common goal, and lately the fruits of such efforts have led to ground-breaking drug discoveries and therapeutic advances.

For rheumatology in particular, because the discipline encompasses multiple organ systems and diverse pathology, such translational research is critical for gaining an understanding of the complexities of the immune system and disease mechanisms and developing and testing treatment strategies, according to Dr. Iain McInnes, professor of experimental medicine and rheumatology at the University of Glasgow (Scotland). "It’s a simple concept, really. It’s the idea that we might understand more about the basic science pathways if we look at them operating in the real world. And it’s a two-way street. Basic science can in turn be informed by the clinical pathologic entity that people come to study."

Examples of "good translation stories," said Dr. McInnes, a clinician/scientist himself, include the tumor necrosis factor (TNF) blocking story and the interleukin-1 (IL-1) story. The development of the TNF blocking therapies, which have had a major impact on the treatment of rheumatoid arthritis and other inflammatory diseases, followed "a series of basic science and clinical medicine iterations, initially in the infectious diseases world and eventually in immunology and rheumatology," he said.

"The evolution of the IL-1 biology is an especially interesting translational story," Dr. McInnes acknowledged. Since it was first cloned in the 1980s, the cytokine family (IL-1a and IL-1b) was identified as a key player in regulating inflammatory processes. This led to the development of IL-1 inhibitors, which were tested primarily in rheumatoid arthritis, but with only modest success, he said. "But this helped investigators understand how IL-1 was synthesized and how its biology was regulated." Such insights eventually led to the development and testing of IL-1 directed agents such as anakinra and rilonacept in patients with hereditary autoinflammatory conditions and in nonhereditary inflammatory diseases associated with aberrant IL-1 signaling, including Mediterranean fever, Muckle-Wells syndrome, neonatal onset multisystem inflammatory disease, and gout. In turn, the efficacy of IL-1 blockade in the treatment of many of these conditions "has changed the understanding of these disorders," he said, and has led to investigation IL-1’s role in other diseases, including adult-onset Still’s disease and systemic juvenile idiopathic arthritis.

The IL-1 story is "elegant science" with respect to the back and forth between the lap and clinical correlates, Dr. McInnes explained. "Although it ultimately did not lead to a good rheumatoid arthritis treatment, the continual cross talk allowed relevance to be maintained and clinical pathology to direct the lab focus over time."

Despite the successes, the bench-to-bedside lag is real and sometimes inevitable given the actual and perceived separation between basic science and clinical research. One of the fundamental reasons for the schism, according to Dr. McInnes, is that scientists and clinicians often don’t share the same philosophy. "We have to be careful about generalizations but, from an academic point of view, a basic scientist is driven by trying to answer a legitimate scientific question: Why is the sky blue? Why are daffodils yellow? How does this chemical activate this target cell?" he said. "So in our area of autoimmune research, a basic scientist’s approach to cytokine research would be, ‘I’m just going to keep chasing down this molecule and its biological effects until I get the answer.’ "

The clinical investigator, on the other hand, "is trying to understand the complex matrix of events that lead to the pathology or disease state, so he or she may well rely on a basic scientific pathway for a certain period of time, but if it turns out that the pathway is really not involved in the disease pathogenesis after a period of investigation, the clinician will part company with that scientist." So while the scientist presses ahead trying to answer the basic scientific question, the clinician investigators will be driven by where the disease takes them, he said.

The separation between basic science and clinical investigation is not deliberate as much as it is circumstantial, according to rheumatologist Dr. Bruce Cronstein, director of the Clinical and Translational Science Institute at New York University. "Many bench researchers are not aware of whom to contact among their clinical colleagues to best obtain relevant collaboration, and clinicians are also unaware of whom to contact among their bench research colleagues," he said. Further, in the United States, "rewards for collaboration have not aligned well with the clinic requirements. Increasing pressure to maximize income [both personal and institutional] by seeing more patients has diminished the time for clinicians to collaborate by gathering extensive data about patients or biosamples," he said.

Also, the mechanisms for sharing credit are poorly defined and there are few mechanisms available for scientists to share grants and funding with their clinical colleagues, according to Dr. Cronstein. "Does a clinician become an author of a high-profile science paper for supplying one patient’s samples? Two? Twenty?" And although the National Institutes of Health has recently defined the coinvestigator mechanism, "even that tends to slight the noncorresponding author." Although the importance of bringing clinical and scientific colleagues together is generally understood to be critical, "finding the appropriate venues to do so is very difficult to accomplish in practice," he said.

In an ideal world, the science/clinical collaboration would be more fluid than fixed, whereby the clinical investigator studying a pathologic state "would interact with several different scientists who offer their appropriate expertise to tease out different components and different pathways," said Dr. McInnes. "One of the difficulties is that we often don’t know where the starting point is in the pathological journey. We are informed by the circumstances of where we are looking." In rheumatoid arthritis, for example, "a lot of our thinking [behind recent developments] was provoked by what the joint looks like after 5-10 years of disease. Maybe the next advance will be provoked by what the joint looks like after just a couple of days of arthritis, if we could get to that window," he said. Out of circumstance, then, the divide between basic and clinical research is process driven because there are many different processes at work at different phases even in one disease."

Each discipline also has its own distinct obstacles that can preclude fluid cooperation. "At the moment, the challenges of successfully translating a bit of science into an understanding of pathogenesis are gargantuan. There’s the ethics of looking at human tissue, the willingness of patient populations to participate, and just the pragmatics of whereabouts in the patient you can look," said Dr. McInnes. "If the disease is a disease of the lymph node or bone marrow, before it becomes a disease of the joint, it’s not impossible but it is quite difficult to get bits of lymph node and bone marrow from human beings, although that’s some of the real interesting science that underpins what the disease may be." Unlike cancer, in which biopsies are part of routine care and as such can more readily be used for scientific investigation, "it’s not routine to biopsy joint tissue or synovial lining in rheumatoid arthritis patients, even if it’s something you would like to do, and it’s absolutely not routine practice to biopsy lymph nodes or bone marrow. The ethics are marginal."

Finally, there are simply not enough properly trained clinician scientists, in medicine in general and rheumatology specifically, Dr. McInnes said. "When they do exist, they are often hard-pressed to meet the demands of both the scientific and clinical communities." Efforts to chip away at this particular barrier are underway, thanks to innovative collaborations, within and between universities and medical schools, often supported by government and/or pharmaceutical company funding. The university-wide Clinical and Translational Science Institute at NYU, for example, in partnership with the New York City Health and Hospitals Corporation and with funding support from the NIH, is one of more than 45 such centers nationwide charged with the task of training clinician scientists and accelerating advances from the lab to the clinic.

Similarly, Dr. McInnes is deputy director of a novel translational medicine consortium comprising the Scottish universities of Aberdeen, Dundee, Edinburgh, and Glasgow, funded by the Wellcome Trust, a global charitable foundation, and Pfizer. Called the Scottish Translational Medicine and Therapeutics Initiative (STMTI), its mandate is to create a "new cadre" of academic clinicians with expertise in translational medicine and treatment by offering doctoral fellowship training programs for clinicians. "The goal is to meet the ongoing need for appropriately trained clinical investigators who have the basic science understanding who are backed by basic science training and expertise," he said. "Such individuals can act de facto as investigators, but also as catalysts. They can drive motivation within the basic science community and also engage the clinical community."

Importantly, however, translational activity cannot be forced, Dr. McInnes stressed. There are many ways to achieve collaboration, but, in my opinion, they all require one thing: curiosity," he said. "If a scientist and clinical investigator share an interest in getting an answer to questions that are either identical or sufficiently close to each other, that is a fruitful platform for a successful translational partnership." For example, if a scientist can demonstrate that a pathway is present in the disease state of interest to the clinician, both the scientist and the clinician will be curious to understand how it operates within that disease state and that will drive their work."

Additionally, translational research efforts are most likely to succeed using a team approach, Dr. McInnes said. "It is essential to recognize the different disciplines necessary to properly address the complex issues in human disease," he stressed. "The team requires people coming together and being prepared to work together and possibly change their own way of thinking a little bit."

Efforts to foster such teams – particularly across public, private, and corporate sectors – can be hindered by administrative roadblocks, including concerns about obtaining consent from patients, intellectual property issues, and who stands to gain from knowledge obtained from any given study," Dr. Cronstein said. In addition, the "demonization" of the pharmaceutical industry in recent years "makes it difficult to collaborate with pharma without being penalized or at least having to run a major gauntlet of paperwork and review," he said. "Clearly, pharma will try to obtain a benefit for itself, but we can collaborate successfully to develop new drugs and new understanding of the diseases of the patients we care for."

At the end of the day, rheumatology is poised to gain much from such efforts. "The field of rheumatology stands to gain new understanding of the diseases that afflict our patients, new therapies for these diseases, and novel targets for development of drugs that can benefit our patients," said Dr. Cronstein. "The advantages of collaboration are overwhelming and the danger of fragmentation of efforts is critical."

The Translational Journey of JAKs

"Some of the most exciting translational research in rheumatology right now is the use of intracellular signal proteins as targets of small-molecule drugs," said Dr. McInnes. "There’s irony in this, because rheumatologists use small-molecule inhibitors all the time, including methotrexate and sulfasalazine. The difference is we’re now using new molecular entities that have been designed specifically to seek out some of the signal pathways that very elegant biology over the last 10-20 years has shown to have a role in inflammation."

The work by Dr. John O’Shea on cytokine signal transduction and the roles of janus kinases (JAKs) and signal transducer and activator of transcription (STAT) factors in immune cell development and differentiation are an excellent example, Dr. McInnes said. The research by Dr. O’Shea, scientific director of the intramural research program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health in Bethesda, Md., led to an NIH patent related to JAKs as a new class of immunosuppressive drug. Through a cooperative research agreement with Pfizer, a JAK3 compound (tofacitinib) is currently in phase III trials.

"These drugs are still not licensed, but the [translational] success story is that the proof of concept that JAKs are involved in the pathogenesis has been achieved," Dr. McInnes said. "When you block [the molecules], patients get better. That doesn’t mean you’ve got a drug, but it does tell you the biology pans out pretty well."

The research developments in this scenario were very much driven around the science of the JAKs initially, "then the investigators looked at people whose immune systems didn’t work very well to see if JAKs were deficient in them, which they were," Dr. McInnes explained. "The next step was to flip back to the lab to consider whether that information could be therapeutically useful, and eventually it found its way back to rheumatology practice.

"Although we still don’t know all that much about how these pathways work in rheumatoid tissue," Dr. McInnes said, "the translation journey [of JAKs] thus far "is one to be admired."

Dr. McInnes and Dr. Cronstein reported no relevant conflicts of interest.