Abstract
Dr. Crowley is professor of medicine at Harvard Medical School, chief of the Reproductive Endocrine Unit of the Department of Medicine at Massachusetts General Hospital (MGH), and director of the Harvard-wide Reproductive Endocrine Sciences Center at Harvard Medical School.
In addition, Dr. Crowley serves as the director of clinical research for the MGH and is a member of the MGH General Executive Committee, the Executive Committee on Research, and the Chiefs Council. In these roles, he has been working to focus the MGH's efforts on clinical research, to provide infrastructure for translational research, and to build an infrastructure for both clinical trials and outcomes/epidemiology/disease management research.
Dr. Crowley received his medical degree from Tufts University in Boston, Massachusetts in 1969 and received an honorary AM degree from Harvard University in 1992. He completed his residency in medicine at MGH and was general medical officer and lieutenant in the United States Navel Reserve, at the Naval Hospital in Newport, Rhode Island.
Dr. Crowley has contributed more than 200 articles, books, and chapters to scientific literature. He is a member of the editorial board for four leading journals. He is the founder of the Academic Health Center Clinical Research Forum. In addition, he served on the Clinical Research Roundtable, the Institute of Medicine, the National Academy of Sciences from 2000 to 2004, and on the board of advisors of the Center for Information and Study on Clinical Research Participation. He is also a past president of the Endocrine Society. Dr. Crowley was the first male to receive the Mentor of the Year by Women in Endocrinology in 2000 and will receive the Fred Conrad Koch Award, the Endocrine Society's highest scientific award, in 2005.
JIM: Your distinguished career as a physician and clinical investigator has spanned three decades. What led to your interest in reproductive endocrinology, and who were your mentors?
Dr. Crowley: At the time I was completing my endocrinology fellowship in 1975, this was the only specialty in medicine that required its fellows to spend a full year in research. This requirement actually led me to pursue that year in reproductive endocrinology. I was originally thinking of combining a career in endocrinology with nuclear medicine; however, in 1975, one could not obtain board certification as an endocrinologist without completing this research year. John Potts, MD, who was chief of our endocrine division at Massachusetts General Hospital (MGH) at that time, talked me into staying at the MGH rather than leaving for further training in nuclear medicine as there was an opportunity in reproductive endocrinology within our division. So he and I agreed that reproductive endocrinology would be an area that had many interesting, unsolved clinical problems.
Two other people who really piqued my interest in reproductive endocrinology were Daniel Federman, MD, with whom I spent an elective when I was a medical house officer at MGH, and Nan Forbes, MD, who had ties dating back to Fuller Albright's research group.
JIM: The overall goal of your laboratory over the past 25 years has been to improve the understanding and treatment of reproductive disorders affecting humans. You have focused on gaining insights into the neuroendocrine and genetic control of gonadotropin-releasing hormone (Gn-RH) secretion, its impact on gonadotropin secretion and gonadal physiology, and its regulation by higher neural regulation. What techniques and approaches do you use to understand and treat reproductive disorders? What do you consider the most significant discovery in identifying reproductive disorders over the past 25 years?
Dr. Crowley: The techniques I have used to understand reproductive disorders have changed dramatically during my career, and almost all of these skills were developed through timely collaborations with other disciplines. This is a key lesson for young investigators to understand because techniques will change over time, and it is critical for a clinical investigator to change with them.
For example, early on in my career, peptides and peptide chemistry were key things that a young investigator had to be interested in because Gn-RH was a decapeptide and a number of analogs of Gn-RH were being made that were both agonists and antagonists. Therefore, I had to learn a great deal about peptide chemistry, peptide analog design and selection, and bioassays in order to fully appreciate the value of these diagnostic and then therapeutic probes to reproductive endocrinology. At that time, I collaborated with Wiley Vale, PhD, and Jean Rivier, PhD, of the Salk Institute of San Diego, California, who were a physiologist and a peptide chemist, respectively. Both were part of the research team that were a part of the Nobel Prize-winning laboratory that developed Gn-RH analogs. In the middle of my career, it became necessary to understand molecular biology and the value it would play in elucidating some fundamental defects in gonadotropin biosynthesis. The development of some appreciation of the power of molecular biology was through a collaboration with Larry Jameson, MD, PhD, who was a molecular biologist at the MGH and Harvard Medical School and who is currently chairman of the Department of Medicine at Northwestern University. Most recently, the techniques we have been using are genetics learned through my collaborations with Jim Gusella, PhD, a geneticist at Harvard Medical School and director of the Center for Human Genetics at the MGH.
Thus, each of these skill sets has come to me through appropriate collaborations, by recognizing the need for utilizing new tools that are continually being generated by basic scientists, incorporating them into the human discovery process, and identifying the appropriate people for meaningful collaborations. Clinical investigators have to constantly patrol the border between basic science and clinical medicine, always seeking new tools to incorporate into their discovery process. This single feature is the key to success for a translational investigator.
From our laboratory, we have made three important contributions to reproductive disorders. The development of long-acting Gn-RH agonists that paradoxically blocked the reproductive system was pioneered in my laboratory. While these Gn-RH agonists were originally synthesized as long-acting stimulators of the pituitary gonadotropes, we discovered that prolonged exposure of the pituitary to Gn-RH agonists blocked rather than stimulated the reproductive axis at the level of the gonadotrope in a reversible fashion that was safe and very effective. We immediately saw that this phenomenon would apply broadly to four reproductive disorders: central precocious puberty, prostate cancer, endometriosis, and uterine fibroids. When considering which of these disorders to focus our research efforts upon, it seemed to me that three of the four already had alternative treatments. Prostate cancer could be treated by castration of the male, endometriosis by synthetic progestins, and uterine fibroids by surgery. The only one of these disorders that had no alternative treatment was precocious puberty, so we focused on this disorder and demonstrated the proof of principle for Gn-RH agonist use in these children, showing that Gn-RH agonists, after a 2-week period of stimulation, completely silenced the reproductive axis in these children. Although we first demonstrated the utility of the treatment in 1980, Gn-RH agonists remain the treatment of choice for all children with precocious puberty worldwide now some 25 years later. This treatment controls all of their symptoms, reverses their growth abnormalities, corrects their height deficits, and improves their adult stature, whereas before, this condition was the cause of dwarfism if its onset was early and severe enough.
The second significant discovery we applied to humans was that pulsatile Gn-RH administration was essential for normal gonadotrope function based upon some incisive primate studies performed by Professor Ernie Knobil, and we applied this to humans, demonstrating that pulsatile Gn-RH administration could reverse the entire family of reproductive dysfunctions that were hypothalamic in origin. Hypothalamic amenorrhea occurs in 3% of the female population, as well as in a rare group of males that have idiopathic hypogonadotropic hypogonadism and Kallmann syndrome. By modifying portable infusion pumps that worked in a continuous fashion, determining the frequency of the normal luteinizing hormone pulses, and then applying this normal frequency of Gn-RH, we developed a method for inducing ovulation in woman and puberty in men that still remains a viable treatment option for both reproductive disorders.
The third and most recent discovery from our group has been the use of genetic techniques to understand the genes that control Gn-RH secretion in humans. Given the high degree of species specificity to the genes that control reproduction, most of which operate via their effect on Gn-RH section, the pilot light of reproduction, we have always focused on humans. Using these techniques, we have unearthed a new pubertal gene, called GPR54, and its peptide ligand, metastin, which clearly are major gatekeepers of puberty. The physiology of this ligand/receptor pair is still unraveling with this discovery as it was just made within the last year.
JIM: Your laboratory has a remarkable record of training pre- and postdoctoral fellows for independent careers in academic medicine and biomedical research. What would you hope has been your greatest influence on your students?
Dr. Crowley: My hope would be that I have infused my students with a long-lasting spirit of curiosity, equipped them with the tools to answer important fundamental questions in humans, and demonstrated to them that this repertoire of tools must change over time as new and more powerful ones become available.
JIM: How has the Human Genome Project contributed to meeting the overall goals of your laboratory? What impact do you think genetic research has had on academic health centers and health care in general over the next several years?
Dr. Crowley: The unraveling of the human genome has empowered clinical investigators in general and our laboratory specifically in a most unusual way. The Human Genome Project has provided several phenomenally powerful tools with which to find genes and proteins that account for disorders that are critical in a particular disorder and define the critical role of these genes and proteins. There had been no way to get at that information until the tools of the human genome research were made available. Most importantly, these tools allow investigators to start with human conditions and work towards a fundamental answer using disease models. Thus, they have empowered clinical investigators to a greater degree than anything that has preceded them. So, they have fundamentally changed the investigative equation in academic health centers where these well-phenotyped disease models are cared for.
On the one hand, these are tremendously empowering tools; on the other, I am very concerned that most clinical investigators are not learning these techniques quickly enough nor embracing them with enough enthusiasm to understand their true potential to change their investigative lives. One of my greatest worries for clinical investigation is that there is a huge shortfall in the incorporation of genetic tools into the day-to-day lives of clinical investigators. I attribute this phenomenon to the great educational, temporal, and financial barriers that we impose to retool from a knowledge basis. In addition, initially, most investigators generating these tools are basic scientists, and there is an ongoing need for increased collaboration between basic scientists and clinical investigators. There has been an enormous pressure on clinical activities in virtually every academic center in this country that is pressuring clinical investigators to devote less and less time to research, and, in addition, most centers lack the infrastructure to build ongoing interfaces between the clinical operational missions of centers and their clinical research missions. These problems are global concerns that I have for academic health centers.
The impact of genetic research that began with investigations of patients with diseases such as Alzheimer's disease, Lou Gehrig's disease, and Huntington disease has been profound. The pathogenesis of each of these diseases was fundamentally enlightened by the study of families with these disorders that identified single genes. The findings emerging from these studies had a major impact in each of these areas. All of those discoveries came from clinical investigators working with geneticists to use up these tools. That said, I think this impact is minuscule compared to what is coming.
People are now talking about polygenic disorders because they are the diseases on which we spend most of our time, money, and effort on in patient care: hypertension, diabetes, schizophrenia, heart disease, stroke, and cancer. Thus, it is appropriate that we should be working on these illnesses, but the tools to look at polygenic disorders are not yet fully in place. For example, the haplotype map is a critical tool that is not yet worked out in the way that other tools are working, such as linkage. So, I think that while much of the promise for the future is clearly in polygenic disorders, there are lots of monogenic disorders that we see everyday that are capable of enlightening us in major ways that clinical investigators are not yet investigating. According to Francis Collins, MD, PhD, director of the National Human Genome Research Institute, of the monogenic diseases in the Online Mendelian Inheritance in Man database, in only 20% of these diseases has the defective gene yet been discovered. Therefore, 80% of these genes exist in families that are being seen everyday in various academic health centers. This has to be looked upon as the “low-hanging fruit” on the clinical investigative tree. All you need is a good family with a monogenic disorder to find these genes. As an example, we reported a single family with only six affected individuals in which we identified a gatekeeper gene for puberty, GPR54. Prior to our studies, there was no known phenotype of this gene and no known clinical association with anything. Thus, the power of genetics in elucidating monogenic traits in families is to unearth these diamonds in the rough that then generate huge amounts of research insights that are deep and profound. That is where the immediate potential is for academic health centers and for clinical investigators. Thus, the opportunity of the moment is monogenic traits, and, over the next several years, monogenic traits are the opportunity and then, over the longer term, polygenic traits. We will then experience a typical log order growth in the use of genetic tools in clinical medicine that will start with families and then expand rapidly to populations.
JIM: As a member of the Institute of Medicine's Clinical Research Roundtable, you and your colleagues described two translational blocks that impede scientific discovery from getting from the bench to the bedside: the translation from basic science to human studies and the translation of new knowledge into clinical practice and health decision making. How did you identify these blocks, and what must be done to surmount these translational blocks?
Dr. Crowley: As soon as any group of people who are dealing with clinical investigation in the broadest sense get together, these two things leap out at you. The Journal of Investigative Medicine would be seen as typically focusing on the first translational block, the bench to bedside block, which is where translational investigators work. On the other hand, when you begin to look at the whole health care system, you begin to see that there are numerous drugs that we have proven to be effective in large-scale clinical trials that are not being applied to our patient populations, and that is the second translational block. This problem initially pops up on pharmaceutical company screens when they project a market size for a drug based upon the prevalence of that disease within the population. Then there is often a shortfall in sales that surprises the drug marketers when a drug is not being sold in the numbers anticipated. That is the pharmaceutical industry's version of the second translational block. Our version within the academic centers is that if drugs such as aspirin, β-blockers, and angiotensin-converting enzyme (ACE) inhibitors work in people who have had myocardial infarctions, how come the majority of our patients with this disorder are not taking them? This is by far the largest gap in public health.
The components of the first translational block relate to human studies, Institutional Review Board (IRB) regulations, General Clinical Research Centers, interfaces between basic and clinical investigators, infrastructure, and human experimentation. The components of the second translational block, on the other hand, are intimately tied up with the practice of medicine, the reimbursement system, billing and payment contracts, and time spent with patients. It is the ever-increasing demands for throughput of our current health systems that will gradually self-destruct if we don't do something to change these current dynamics. We are facing a major health care crisis at the same time that costs are spinning out of control at 12 to 15% increments per year. Relatively speaking, in terms of public health, the second block dwarfs the first block in term of its economic implications, yet for long-term importance for getting more treatments in man, the first block is key. So the first translational block really relates to innovation, whereas the second block is intimately tied to implementation. Both blocks are critical to progress of our nation's health, each with its own context of differing obstacles.
JIM: How have your experiences in clinical practice influenced your work as a clinical investigator?
Dr. Crowley: This is a critical issue for clinical investigators in general because when I am seeing my patients, I am always thinking of the basic research principles that I am investigating in the lab and how they may apply to those patients to enable me to understand them from a pathophysiologic point of view and to provide therapies that are based on that pathophysiology. Conversely, when I am back in the lab, I am always thinking of how the patients I've just seen don't fit my current construct of a disease. So the patients continually inform me by being exceptions to the rules that I set down, and, therefore, they are desperately trying to teach me what I don't know. In addition, like any physician, when you see the patients suffering from a disease, it fuels the engines of my motivation. Therefore, patients are important in two ways. First, they are dropping scientific clues right and left that I should be using, and, second, they are great motivators.
JIM: MGH was the first to build a functioning clinical research infrastructure within an academic medical center. Has this been used as a model elsewhere in the United States?
Dr. Crowley: MGH was the first to build a functioning clinical research infrastructure, but history will have to determine whether or not MGH is a model used around the country. There is a slogan that goes, “If you've seen one academic health center, you've seen one academic health center.” All of these places are so unique in the way things are constructed, are funded, function, and interdigitate that solutions for one center do not always work for another center. That said, there are clearly some generics that do work. When putting together a research enterprise, whether it is basic or clinical, three things are constant needs: people, space, and core laboratories. Basic science needs more laboratory space than clinical investigators. Clinical investigators need things such as education, support structures in terms of study coordinators, biostatistical consultations, mentorship, grant support for infrastructure, and budgets—all of which are common across all academic health centers, and the MGH Clinical Research Program has put in place most of these for our clinical investigative community. They also need consultation in new scientific areas like genetics and genomics, a functioning information technology (IT) infrastructure, and a coherent way to interface with disease and disease management. At MGH, we have five units within the Clinical Research Program: the education unit, the genetic and genomics unit, the IT infrastructure unit, the clinical research support office, and the disease management unit. The common element is that they are all service functions and they are set up to succeed only if the clinical investigator succeeds. Their only rationale is to support other people, and there is no individual aggrandizement of their research programs, only that which comes through the success of others. Therefore, the Clinical Research Program is a support infrastructure fuctioning on a service model, and these will likely be common elements required for success across academic health centers. Currently, academic medical centers are dividing themselves into those that are building infrastructure for clinical research and those that are not. I would go so far as to say that those that are building this type of infrastructure will be the survivor because a few tectonic plates have shifted within the medical research community. The National Institutes of Health (NIH) has become more disease, therapy, and public health oriented than its traditional curiosity-driven status. That means the linkage of basic research to patient care has to be real and palpable. The second shift is in the post-Health Insurance Portability and Accountability Act (HIPAA) era that we are currently in; it is clear that research centers and groups can exchange information in a way that is now not encumbered by the confidentiality issues. What we have seen as somewhat of an obstacle to research, ie, HIPAA, is really enabling to the future of communications of large patient populations within and across health centers. This issue is critical in the genome era, when polygenic traits become the main issues where large numbers of patients are required to find genes, as opposed to monogenic disorders, where the functioning unit is a family. Studying polygenic disorders requires thousands of patients, and the post-HIPAA era will enable that in a way that will be important. The third tectonic shift is that IT professionals in the academic health centers are gradually beginning to understand that for a marginal additional investment in their clinical operations, they can actually get very useful information for clinical research. These three shifts are creating a wonderful opportunity for clinical investigators—sort of the “best of times” scenario. The “worst of times” element is the flattening of the NIH budget, the regulatory environment in the IRBs that is becoming almost a stranglehold for young investigators, and the clinical operations of these centers that threaten to wipe out any time for clinical research.
JIM: As a member of the board of advisors of the Center for Information and Study on Clinical Research Participation, how can you best educate, inform, and empower patients about clinical research participation and what it means to be an active participant in the process?
Dr. Crowley: In general, there is a huge need to inform the public about clinical trials and clinical research in the way that industries have traditionally marketed their products. There is a huge benefit to participating in clinical research, both individually and for society. Society is varied in its opinion from one segment that considers itself guinea pigs to another segment that considers itself fortunate to get into clinical research trials. We must espouse the view that clinical trials are the window to the future, and we must communicate to society how these trials have led to the 80 to 90% cure rates of leukemia and a variety of other illnesses. I think this center is trying to accomplish that objective by marketing the benefits of clinical research, and we need to support this mission.
JIM: What do you feel are the greatest challenges facing reproductive endocrinology and growth disorders today?
Dr. Crowley: On the one hand, in vitro fertilization (IVF) centers have really been a wonderful therapy for infertile couples, yet, on the other hand, they have stifled the development of young clinical investigators in obstetrics and gynecology (OB-GYN). Because of the amount of money, cache, and power of the therapy, IVF has seduced an entire generation of OB-GYN professionals away from clinical and basic research at a time when they are critically needed. I don't see that going away because of the financial power of IVF. Within medicine, I think the greatest challenge is the increasing regulatory burden that exists within academic centers. The emphasis on regulatory restrictions has overwhelmed the transactional cost of doing things. IRBs must understand that efficiency is not the enemy of safety. IRBs and safety are the absolute number one job of everyone involved in clinical research, but that doesn't mean that all this paperwork is contributing anything to safety. In fact, I don't think it is; I think it is extinguishing young people's careers as they see the paperwork as insurmountable. I think the third challenge is the flattening of the NIH budget related to the political funding climate in which NIH funding is being discussed. Embryonic stem cell research and its regulation are currently hampering reproductive endocrinology.
JIM: The Reproductive Endocrine Unit at MGH is supported by 1 of 15 NIH-funded National Centers for Excellence in Reproductive Endocrinology. What do you attribute to your success in earning this distinction?
Dr. Crowley: We have focused constantly on the first translational block in reproductive endocrinology at the human basic science interface in a way that has distinguished our center over the years. The niche for which I have targeted our center over the past 15 years is for our young investigators to oscillate back and forth between the human disease models and basic science. I think that we are relatively unique in this regard.
JIM: You have been a forceful proponent for clinical research for decades. What do you see as the greatest challenges facing clinical research? What changes need to be implemented, and how do you think the needed changes can be implemented?
Dr. Crowley: The flattening of the NIH budget, strangulating regulations, and lack of infrastructure support for young clinical investigators. The goal of our clinical research program has been twofold: to attract, train, and retain the brightest young physicians and PhDs into the field of human investigation and to create a nurturing environment in which they can continue to maintain long-term career stability.