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The short-chain fatty acid propionate is a potent inhibitor of molds that is widely used as a food preservative and endogenously produced by gut microbiota. Although generally recognized as safe by the U.S. Food and Drug Administration, the metabolic effects of propionate consumption in humans are unclear. Here, we report that propionate stimulates glycogenolysis and hyperglycemia in mice by increasing plasma concentrations of glucagon and fatty acid-binding protein 4 (FABP4). Fabp4-deficient mice and mice lacking liver glucagon receptor were protected from the effects of propionate. Although propionate did not directly promote glucagon or FABP4 secretion in ex vivo rodent pancreatic islets and adipose tissue models, respectively, it activated the sympathetic nervous system in mice, leading to secretion of these hormones in vivo. This effect could be blocked by the pharmacological inhibition of norepinephrine, which prevented propionate-induced hyperglycemia in mice. In a randomized, double-blind, placebo-controlled study in humans, consumption of a propionate-containing mixed meal resulted in a postprandial increase in plasma glucagon, FABP4, and norepinephrine, leading to insulin resistance and compensatory hyperinsulinemia. Chronic exposure of mice to a propionate dose equivalent to that used for food preservation resulted in gradual weight gain. In humans, plasma propionate decreased with weight loss in the Dietary Intervention Randomized Controlled Trial (DIRECT) and served as an independent predictor of improved insulin sensitivity. Thus, propionate may activate a catecholamine-mediated increase in insulin counter-regulatory signals, leading to insulin resistance and hyperinsulinemia, which, over time, may promote adiposity and metabolic abnormalities. Further evaluation of the metabolic consequences of propionate consumption is warranted.

The 2012 Lasker~Koshland Special Achievement Award in Medical Science recognizes Donald Brown (Carnegie Institute of Washington) and Thomas Maniatis (Columbia University) (Figure ​(Figure1),1), two scientists whose career-long contributions were seminal to our understanding of what genes are and our ability to study and manipulate them, and whose commitment to mentorship have had tremendous impact on a generation of scientists.

OBJECTIVE Genes responsible for monogenic forms of diabetes have proven very valuable for understanding key mechanisms involved in β-cell development and function. Genetic study of selected families is a powerful strategy to identify such genes. We studied a consanguineous family with two first cousins affected by neonatal diabetes; their four parents had a common ancestor, suggestive of a fully penetrant recessive mutation. RESEARCH DESIGN AND METHODS We performed genetic studies of the family, detailed clinical and biochemical investigations of the patients and the four parents, and biochemical and functional studies of the new mutation. RESULTS We found a novel mutation in the pancreatic and duodenal homeobox 1 gene (PDX1, IPF1) in the two patients, which segregated with diabetes in the homozygous state. The mutation resulted in an E178G substitution in the PDX1 homeodomain. In contrast to other reported PDX1 mutations leading to neonatal diabetes and pancreas agenesis, homozygosity for the E178G mutation was not associated with clinical signs of exocrine pancreas insufficiency. Further, the four heterozygous parents were not diabetic and displayed normal glucose tolerance. Biochemical studies, however, revealed subclinical exocrine pancreas insufficiency in the patients and slightly reduced insulin secretion in the heterozygous parents. The E178G mutation resulted in reduced Pdx1 transactivation despite normal nuclear localization, expression level, and chromatin occupancy. CONCLUSIONS This study broadens the clinical spectrum of PDX1 mutations and justifies screening of this gene in neonatal diabetic patients even in the absence of exocrine pancreas manifestations.

Type 1 diabetes results from autoimmune destruction of the insulin-producing beta cells of the pancreatic islets of Langerhans. Although developments in exogenous insulin therapy have greatly improved clinical outcomes in patients with diabetes, the ability of the pancreatic beta cell to exquisitely regulate the delivery of insulin and maintain normal levels of blood glucose is still far superior to what can be achieved by external delivery of insulin. As a result, the majority of patients with type 1 diabetes still experience the complications of chronic hyperglycemia or serious and potentially life-threatening hypoglycemia. The shortcomings of medical therapy have driven research toward more direct approaches of beta cell replacement. Indeed, the specificity of beta cell loss in type 1 diabetes makes this disease a particularly attractive candidate for cell-based therapies. In order for significant progress to be made, however, a thorough understanding of beta cell biology and more broadly islet biology is necessary. This review addresses recent advances in developmental biology that have expanded our understanding of islet cell differentiation, assesses the promise and limitations of islet transplantation, and discusses the future of alternative sources of beta cells, including directed differentiation of stem cells, replication of adult beta cells, and transdifferentiation of nonislet cells to a beta cell fate. =

Recent studies have shown that in addition to their traditionally recognized functions as building blocks, energy stores, or hazardous intermediates, lipids also have the ability to act as signaling molecules with potent effects on systemic metabolism and metabolic diseases. This Perspective highlights this somewhat less apparent biology of lipids, especially focusing on de novo lipogenesis as a process that gives rise to key messenger molecules mediating interorgan communication. Elucidating the mechanisms of lipid-dependent coordination of metabolism promises invaluable insights into the understanding of metabolic diseases and may contribute to the development of a new generation of preventative and therapeutic approaches.

In 1958, David J. Weatherall was a newly qualified physician preparing to enter the British Army for two years of compulsory service; terrified of flying and intimidated by the risks of violent combat and biting snakes, he hoped to serve his term in a hospital on UK soil. Two weeks later, though, he was on a ship bound for Sing­apore. Despite his trepidation, his experiences there launched not only a remarkable and distinguished research career, but also a new scientific field — molecular medicine. On September 21, Weatherall (Figure ​(Figure1)1) will receive the 2010 Lasker~Koshland Special Achievement Award in Medical Research, honoring his 50 years of dedication to the research and treatment of hereditary blood disorders. Figure 1 David Weatherall is the recipient of the 2010 Lasker~Koshland Special Achievement Award in Medical Research in recognition of his contributions to the molecular understanding and treatment of thalassemia.

Our understanding of the activation of the innate immune system, the body’s first line of defense against infection, is based largely on the contributions of Bruce Beutler and his research group. Among his many accomplishments, Beutler isolated TNF, discovered its inflammatory properties, and cloned the LPS receptor. In 2011 he shared the Nobel Prize in Physiology or Medicine with Ralph Steinman and Jules Hoffmann. Beutler’s work is further celebrated this year with the presentation of the 2013 ASCI/Stanley J. Korsmeyer Award. Beutler recently spoke to the JCI about his research career and scientific approach.

The San Raffaele del Monte Tabor Foundation in Milan, Italy, manages a multidisciplinary hospital and research institute, renowned as a center of excellence for biomedical research. Early in 2011, it was announced that the institute was in a precarious financial position, on the brink of bankruptcy. In October, a Milan government tribunal approved a restructuring plan that involves a financial takeover of the institute by the Vatican Bank and a private investor. The JCI recently spoke to Maria Grazia Roncarolo, the scientific director at San Raffaele, about this crisis and the institute’s future. JCI: What makes the San Raffaele Scientific Institute different from other European research centers? Roncarolo: We have a very large hospital and a research institute, which belong to the San Raffaele Foundation, and a private university, the San Raffaele Vita-Salute University, which is a separate legal entity. Research activities at the hospital, the research institute, and the university are well integrated. Most of our research programs move from the bench to the bedside and back. Our “brand” is translational research. These days translational research is very fashionable, but we’ve been doing it for many years. We currently have approximately 570 clinical trials ongoing, with about 10,500 patients involved. Of these trials, more than half are based on our own research. JCI: As the scientific director, what is your vision for the future of the institute? Roncarolo: We want to maintain our excellence in neuroscience, genetic diseases, and immunology-based diseases, and we want to expand our research in oncology and cardiovascular diseases, two disease areas for which the hospital projects its biggest growth. Further advancing our cutting-edge translational research will be another key priority. This is absolutely necessary to continue to deliver world-class personalized medicine in the future. We also want to keep a very strong focus on the training of physician-scientists, to provide them with a scientific infrastructure, which will allow them to develop and flourish. JCI: How did you find out about the financial crisis at the institute? Roncarolo: As long as I’ve been here, I’ve heard that we were in debt, but the scientific community of the institute was not aware of how serious the problem was. We knew that we were in debt because we had a lot of investments in new buildings, new technologies, new clinical departments, and in hiring new scientists, but we were not worried because we knew that our core business was financially healthy. The hospital has a positive balance, and research is financially on a good footing because of the quality of our scientists, who have substantial external funding granted. At the beginning of this year, we realized that the situation was much more serious than what we thought and that the institution didn’t have a sustainable financial future due to wrong investments in non-core business activities by the board. As scientists and physicians working here, we feel very bad about being in this crisis situation because it has nothing to do with our research and clinical activities which were — and remain — financially healthy. JCI: Have your scientists been able to work in the last few months? Roncarolo: It’s really impressive to realize that our scientific productivity, as of today, is still on the top of the curve. But in the last six months, we’ve worked under conditions that were very difficult. Because of the uncertain financial situation, suppliers didn’t want to deliver tools and reagents, funding agencies were questioning the continuation of research at San Raffaele, and talented potential new hires turned down job offers or could not be hired. Despite all this, we continued to work, but because of all the uncertainties, the daily conditions were difficult. Now that the tribunal has approved a restructuring plan, I’m hopeful that the worst is behind us and that we’ll be able to return to a certain degree of normalcy. JCI: What do you think about the possibility of a Vatican Bank bailout, and are you concerned about that organization having influence over the direction of the research? Roncarolo: I think that one of the biggest strengths of the institute is that we operate with the greatest degree of freedom in our research and clinical activities. That doesn’t mean a lack of governance. It means that we value our intellectual freedom. We strongly hope that this will be maintained with the present and future owners. Presently, the board consists of four people appointed by the Vatican. We are happy that they are here. They put on the table a concrete offer that allowed the tribunal to approve a restructuring plan. We really hope that the new board will keep the spirit of this place, which is scientific freedom and a high level of autonomy for innovative basic and clinical research. We hope that the merit-driven culture and the conviction that research provides the backbone of the institute will continue. We also hope that the new for-profit structure planned for San Raffaele’s core activities will not result in a separation of the basic and clinical research and teaching activities that, as a result of our hard work in the last years, are now fully and efficiently integrated. Such separation would make us lose our competitive edge in translational medicine. It is very clear that state-of-the-art clinical treatments are science driven and, if we would like to stay at the forefront of global developments in personalized medicine, basic and clinical research have to work side by side. The San Raffaele Scientific Institute is internationally a highly regarded center of excellence, based on its scientific productivity, the number of innovative clinical trials, the substantial external funding obtained through competitive grants, and the international standing of its scientists. This excellence is still there, and the financial crisis didn’t destroy it. We really hope that the new owners will realize the value of the institute and that they have the wisdom to enable us to further strengthen our international competitiveness and to support our scientific freedom.

In January 2012, Laurie Glimcher (Figure ​(Figure1)1) will take a new position as the Dean of Weill Cornell Medical College in New York City. A celebrated immunologist who stresses the importance of interdisciplinary and collaborative science, Glimcher has contributed to the understanding of diverse fields from skeletal biology to metabolism. Glimcher recently spoke to the JCI about her science, her move, and her goals in the big city. Figure 1 Laurie Glimcher. JCI: You’ve spent most of your career in the Harvard system. Why is now the right time to move? Glimcher: It was the right job at the right time. If this had come up three or four years ago, I wouldn’t have even looked at it. But it struck me as an enormous opportunity. I could keep on doing exactly what I’m doing now, and I would still be very happy, but I felt that I should be thinking beyond my own lab at this point. I’m concerned about the future of academic medical centers in this country and the health of biomedical research, given the tremendous financial constraints that we’ve experienced in the last few years (and that I’m sure will continue) at the NIH. I wanted to play on a broader stage, really try to enable the science of others, and encourage the best translational research. I feel that requires bringing many different forces together — clinicians, basic scientists, philanthropists, pharma — anything that we can call on to facilitate the transfer of basic discoveries into the clinic. We should be able to do that, to use public-private partnerships to advance science and medicine, and I thought that given my background in biomedical science and my relationships to the private sector, I would be in a position to do that at Weill Cornell. JCI: Are you bringing your lab with you to New York? Glimcher: I am. It’s not going to be as big a lab as I have now, because I don’t think I can do everything, but I can’t imagine not continuing the research, because we have some really exciting projects at the moment. I’ll need to focus, to select the couple of areas I think are the most interesting. JCI: Your training was in immunology, but your research portfolio is quite diverse. How have your interests evolved during your career? Glimcher: I fell in love with immunology when I was a first year medical student at Harvard. I wanted to be a physician, but after internship and residency I went to the NIH, where I did a wonderful postdoc with Bill Paul. I’ve always sort of gone where the science has taken me, and a good example of that is the Xbp1 transcription factor that we cloned . . . following that pathway has led us into a lot of other systems, including lipid biology, diabetes, and now neurodegenerative disease. And then about six years ago, skeletal biology became a major interest in the lab. My dad is a skeletal biologist, so I guess I have the genes for it. We had dabbled in it before, but things really clicked when we knocked out a factor called Schnurri-3. We didn’t see the big blow-away immune phenotype when we deleted the gene that we expected. Then one day, the postdoc and the grad student working on the KO mouse came into my office, and I asked them what the bone marrow looked like. They said, “You know, we can’t really access it — for some reason the bone marrow seems filled in.” I suggested that they walk down to my father’s office at Children’s Hospital and take an X-ray of the mice. The mice had incredibly elevated bone density, and we then spent the next couple of years figuring out the mechanism by which that occurred. The work attracted a lot of interest from pharma, because osteoporosis is so common. We started a really wonderful collaboration with Merck, and I built a bone team that is now about half of my lab. The collaboration with Merck was more than just funding; our scientists worked with their scientists, and I think that could be a good model for that sort of partnership. JCI: Do you have a vision for what you’d like to create at Weill Cornell? Glimcher: Weill Cornell is in the perfect position for expansion because the current dean, Tony Gotto, and the board of overseers, chaired by Sandy Weill, have done such a wonderful job raising funds to build a new medical research building. That will allow us to recruit some really top-notch faculty to join the already excellent faculty there, and to forge ties with other institutions in New York City. Weill Cornell already has an outstanding clinical group, they have great medical students, and their biomedical research enterprise could very quickly become first rate. I hope to expand our clinical reach over the next few years to the medically under­served populations in New York. Also, medical education is very important to me. We need to figure out how to help medical students pay for medical school; I think too many of them end up in specialties that they wouldn’t necessarily have considered except that they have $200,000 in educational loans, so less lucrative specialties like primary care and pediatrics suffer. JCI: How does it feel to be the first female dean of Weill Cornell Medical School? Glimcher: It feels great. I’ve gotten so many e-mails from people offering their kind words. You know, I’m very interested in mentorship — I have been committed to it my entire career — and I admit that I have a special warm spot in my heart for women. I have worked very hard in my own group to make sure that the women have an equal playing field. I want to think a lot about that when I’m at Weill Cornell, about how we can emphasize diversity and really put our money where our mouth is to strengthen it.

Whether enzymatic or structural, the three-dimensional shape into which a protein folds is a critical determinant of all aspects of its function. Proteins fold from an initial chain of amino acids into complex helices and beta-pleated sheets based on intramolecular interactions that favor exposed hydrophilic residues and buried greasy hydrophobic side chains. The 2011 Albert Lasker Basic Medical Research Award recognizes the work of two scientists, Franz-Ulrich Hartl (Max Planck Institute of Biochemistry) and Arthur L. Horwich (Yale University) (Figure ​(Figure1),1), whose collaborative and independent work led to a new understanding of how cells can control this complex process. Their findings not only reveal secrets of basic protein chemistry, but could also have a dramatic impact on the treatment of the many diseases in which protein folding goes awry. Figure 1 Franz-Ulrich Hartl (left) and Arthur Horwich (right) are the recipients of the 2011 Albert Lasker Basic Medical Research Award. Insight into the mystery of how protein folding occurs was in part revealed in the early 1960s, when Christian Anfinsen, working at the NIH, demonstrated that a denatured protein called ribonuclease could spontaneously refold in a test tube. In doing so, he showed that the amino acid sequence of a protein provided the necessary information to allow it to fold properly, dictating its three-dimensional shape and thus its activity (1–3). Following the establishment of this “Anfinsen dogma,” most biologists assumed that all proteins folded spontaneously as they were synthesized on the ribosome. As Hartl recalled in a recent interview with the JCI, “For many years, cell biologists just were not interested in protein folding; it was the domain of biophysicists and biochemists who studied the spontaneous reactions in the test tube.”

On June 26, 2011, in San Diego, the Merrifield Award of the American Peptide Society was given to Richard DiMarchi of Indiana University. A day later, again in San Diego, the Outstanding Scientific Achievement Award of the American Diabetes Association was given to Matthias Tschop of the University of Cincinnati. Those attending both lectures might have witnessed many similarities; the Tschop and DiMarchi laboratories had been working as a single integrated unit across two universities for the last seven years, designing and optimizing new therapeutics for the treatment of diabetes and obesity (Figure ​(Figure1). 1). Figure 1 Richard DiMarchi (left) and Matthias Tschop. JCI: How did the two of you start collaborating? Tschop: We met at the Eli Lilly Research Laboratories, where Richard led drug discovery as a group vice president, while I was a postdoctoral fellow. Years later, when I had moved back to the US from Germany and Richard had left Lilly to be a chair of chemistry at Indiana University, we reconnected — our labs suddenly were just a two-hour drive apart. JCI: What avenue of research do you think has the greatest potential to improve the outlook for the obesity epidemic? Tschop: It seems increasingly clear that more than one neuroendocrine signal may have to be modulated at the same time in order to achieve beneficial metabolic effects with curative potential. Richard and I have been working on a series of approaches in which we are combining two or three gastrointestinal hormones into a single molecule. JCI: So are you both optimistic that we’ll find a drug-based cure for metabolic syndrome? DiMarchi: I am a perpetual optimist, supported by three decades of personal experiences. This kind of work requires steady progress made through contributions from many laboratories establishing a foundation for the discovery of transformative medicines. We believe that our work is contributing to the identification of a novel formula that might define a successful prescription for treatment. Tschop: More skeptical colleagues frequently point out to me that evolutionary pressures drove the development of redundant systems to efficiently ingest and store calories. My answer is always that reproduction is a pretty important requirement for the survival of the species too, but endocrinologists figured out how to interrupt it by tricking the brain into believing that there was already an ongoing pregnancy. We need to figure out how to trick the brain into believing that the stomach has been bypassed without actually cutting patients open. JCI: Your work at Lilly and now at Indiana University is largely based on macromolecules and, in particular, peptides — in spite of the limitation that peptide-based drugs almost always require injection. What are the advantages? DiMarchi: In many ways the peptides and proteins that have emerged as drugs are nature’s medicines. They have a high specificity of action with minimal off-target toxicity and natural routes of metabolic clearance. While injection is a limitation, the huge benefit is performance. However, it is important not to frame the question of drug discovery as an either/or option of conventional small molecules versus macromolecules. The combination of the two can deliver unprecedented efficacy with fewer adverse effects. JCI: Given that you moved from pharma to academe, you’re perhaps well positioned to answer the question of whether scientists will be successful in drug discovery outside of the pharmaceutical industry. DiMarchi: Large organizations may be required for cost-efficient drug development and production and marketing of drugs. However, it is individual scientists who deliver breakthrough discoveries. A laboratory composed of broadly trained chemists and pharmacologists can make a huge difference, if properly funded and appropriately nurtured. I am quite certain that Bruce Merrifield, the father of solid-phase chemical synthesis, could not have invented the concept if employed in a less supportive environment than an academic center like The Rockefeller University. JCI: You’re moving back to Germany this year. Will that be a challenge for your collaboration? Tschop: My wife and I are both from Munich, so when the Munich Hemholtz Centre together with the Technical University and the Ludwig Maximilians University Munich invited us to help build a new German Diabetes Center, it turned out to be an offer we couldn’t refuse. With our history of intense collaboration, Richard and I are both confident that the most fun is still ahead of us. And, Richard has a standing invitation for a sabbatical in the Bavarian Alps! JCI: How important have these collaborations been to shaping your science? Tschop: The most important lesson I have learned is that interdisciplinary and translational teamwork is — at least for us — key to every single breakthrough. It was painful at times, since we all speak different languages (literally and figuratively!) — but it always paid off.

In the US, the battle over whether to devote government funding to ES cell research has waged since the Dickey-Wicker amendment passed in 1996, banning federal funding of work that involved the destruction of human embryos. In the ensuing years, it has been unclear whether that law applies to research performed on human ES cell lines derived with private funding, and the conflicting policies of the Bush and Obama administrations have left researchers in the field on uncertain ground. Recently, the argument landed in the court system, and in late April of this year, the Federal Court of Appeals for the District of Columbia issued a decision that effectively allows NIH-supported researchers to use established ES cell lines, regardless of their source. The JCI recently spoke to David Scadden (Figure ​(Figure1),1), cofounder and codirector of the Harvard Stem Cell Institute (HSCI), about how these shifting policies have shaped stem cell research as well as his visions for the future of the field. Figure 1 David Scadden. JCI: How do you think that the federal limitations on ES cell research funding affected where we are in stem cell biology today? Scadden: This area is one that has been very hotly contested since its inception, and there’s no doubt that has affected research progress. The issues are very important and have continued to be problematic. The current appeals court ruling is basically just an interpretation of the Dickey-Wicker amendment, which allows federal funding of human ES cell research, but prohibits the destruction of embryos to create human ES cell lines. I think that the instability and uncertainty of funding has had an immeasurable impact on the progress of the science because it’s discouraged junior investigators from devoting their careers to this kind of research. We’ve really lost an entire generation of scientists who could have been working on these questions; we can’t know what they might have discovered, or how long it will take us to catch up. JCI: Do you think a Supreme Court decision is necessary to really settle the legal questions surrounding ES cell research? Scadden: It’s not settled now, that’s for sure. The case has gone back to the courts, and it’s not clear what the final decision will be; that leaves everyone who works on stem cells uncertain. Even for us at HSCI, where we’re fortunate enough to be able to raise funds to do the work, we have graduate students whose stipend funding is in question. I think what it will really take to settle the question is legislative action . . . though given the current political climate, that’s unlikely to be forthcoming in the near future. JCI: Do you think the recent advances in induced pluripotency might have lagged if there had been greater federal support for human ES research projects in the last 15 years? Scadden: I really don’t believe that. The advances in pluripotency were built on John Gurdon’s early nuclear transfer experiments, which were the first insight into nuclear reprogramming, performed well before anyone was working on human ES cells. It’s important to keep in mind that ES cells and induced pluripotent stem (iPS) cells are of course very different entities; we’re learning that they have different expression patterns and different potentials. Of course the study of ES cells is necessary to define our standard, our understanding of what a pluripotent cell looks like, but I don’t think that the advances in iPS cell research happened because people turned away from working on ES cells. The work of Yamanaka, for example, was a great leap forward in pluripotent cell biology, but that work had its own, solid foundation. JCI: Most of your work is on hematopoietic stem cells. How would federal funding for human ES cell projects affect your current research or your future research plans? Scadden: I think it doesn’t matter whether you work on pluripotent stem cells or multipotent stem cells, adult stem cells or ES cells; the work on each informs the other. When we’re talking about understanding how cells are programmed and might be reprogrammed, they’re not different sciences, they’re like limbs on the same body. So whether or not I use ES cells in my lab, my science will be advanced by research on ES cells. JCI: Where do you think stem cell research is headed? What do you think will be the next big breakthrough? Scadden: ES cells as a source for cell therapy was, for a long time, the dominant concept driving the field: ES cells providing a tool to rebuild parts of the body. That is now recognized as a far too narrow lens through which to view the potential for stem cell–based medicine. First, most adult tissues are now recognized to harbor endogenous stem cells. What was a curious aspect of the blood now appears to be the rule for many tissue types, which suggests that by understanding how those cells are regulated, we might be able to enhance their regenerative activity in the setting of injury or disease. Turning on the body’s intrinsic repair capability is the basic idea, and studying stem cells in their niche is how to get there, in my view. Second, cell reprogramming is a revolutionary technology that allows us to generate primary human cells that represent the cell type affected by a disease — and we can generate them from the very patient affected. That can become the ultimate personalized medicine tool kit: a stem cell–based tool kit to study what goes wrong, determine what drug candidates might affect it, and possibly even supply the cells to replenish those lost in the disease. So we have a range of options now for thinking about how stem cell biology can become stem cell–based therapies — each of them offers new types of therapies. These are much-needed new arrows in the quiver of future physician-scientists.

In March 2010, Judge Robert Sweet of the Southern District of New York issued a ruling against Myriad Genetics, holder of exclusive patents on the breast cancer genes BRCA1 and BRCA2, indicating that genes should not be eligible for patent protection. In October, the Justice Department surprised policy watchers by filing an amicus brief in support of the ruling. James Evans (Figure ​(Figure1),1), who chaired a task force on gene patents and licensing practices for the Department of Health and Human Services (HHS), recently spoke to the JCI about gene patents and the likely impact of this ruling. Figure 1 James Evans, MD, PhD, is a medical geneticist at the University of North Carolina School of Medicine. JCI: About 20% of human genes are currently under patent protection. How does that affect researchers who want to work on those genes and gene products? Evans: From a clinical standpoint, it is very restrictive. The genes under patent and exclusive license, like BRCA1/2, can only be analyzed by a single laboratory. For basic research, in practice, most holders of gene patents have not vigorously enforced their claim, even though in principle they could certainly keep anyone from doing research on a gene that they own a patent on. It’s often been cited by proponents of gene patents that there has been little patent-related restriction of basic research. But the reason for that is that patent holders have often chosen not to enforce their rights, and that researchers have generally ignored patents, which is hardly a ringing endorsement of the system. JCI: How did this most recent ruling affect those who currently hold gene patents? Evans: In tangible, practical terms, the ruling by Judge Sweet doesn’t do anything, because it only pertains to the southern district of New York. However, there are more intangible effects. It was the first time that a federal judge had ruled on this issue, and his ruling that genes are not eligible for patent protection sent shock waves through the intellectual property community. Just having done that, regardless of the fact that it only holds in his district, is significant. This decision is being appealed, so the impact could be profound if it is upheld by either the Court of Appeals or the Supreme Court. JCI: The Department of Justice filed an amicus brief asserting that isolated DNA is a product of nature and should not be patentable, but it supports the right of corporations to patent manipulated genes. Do you see a difference between isolated DNA and manipulated DNA in terms of patentability? Evans: The DOJ brief drew a very bright and logical line, saying that a natural gene, which evolved over millions of years, is hardly patent eligible. It’s ineligible for patent for the same reason that gold, or sunshine, or a beetle that you find under a rock would be ineligible. It’s not an invention, no matter how hard or how useful it was to isolate. They drew a line between that and a manipulated DNA sequence. I think that’s interesting, and a useful starting place, but I think that Judge Sweet actually got closer to the truth when he made the distinction in his ruling about what the gene does being the important factor. A gene in the cell transmits information, and if the information that it transmits in vivo is the same as the information that it transmits in the test tube, then in isolating it you really haven’t done anything that should be eligible for patenting. JCI: Do you think cell lines — including human stem cell lines or induced pluripotent stem cells — should be patentable? Evans: Claiming a patent on a manipulated cell line is very different from claiming a patent on a gene. I’m not a lawyer, but I would think that an induced pluripotent stem cell line that was created by people — engineered with genes that impart information for the cell to do something new — would be very reasonable to patent. JCI: If an actual gene sequence shouldn’t be patentable, should a genetic test? Evans: I feel strongly that claiming patent protection of a genetic test that relies on analysis of a naturally occurring gene makes no sense. Not only that, but it’s demonstrably harmful to patients, researchers, and, for that matter, the market. To be tested for cystic fibrosis or Huntington disease — genes that are not under patent — you can go to any of about 60 laboratories to have that testing done. Those laboratories vie for your business by trying to develop innovative methods for testing, better quality, or better service. On the other hand, there is just a single laboratory you can go to for BRCA1/2 testing. That laboratory is under no pressure to improve its service, because there’s no competition. JCI: Are you concerned that disallowing gene patents would decrease investment in the research and development of gene products and genetic testing? Evans: Patent protection is a tricky business — if you do it too far upstream, you squelch creativity; if you do it too far downstream, it does no good. I think patents at the level of the gene are clearly too far upstream. The pro-patent people have a stronger argument in the realm of therapeutics, since they may need incentives to promote research and development. My counter to that is that therapeutics rely upon a welter of patentable facets, and it’s hard to imagine that therapeutics would rely upon patenting of the gene itself. By not patenting the gene, you encourage more investigators to work on therapeutics, which would then be patented because of the truly inventive things they came up with. The patent system exists for a single purpose: to promote the progress of science and the useful arts. It is designed to promote progress, to promote activity, to open up investigations. The idea of restricting research with patents is profoundly antithetical to the very purpose of the patent system. Therefore, I feel that patents that either restrict or potentially restrict research are harmful. One of the recommendations that our task force made to the Secretary of HHS was that there be a broad research use exemption from infringements regarding gene patents. What we advocate is that researchers should be free to use genes in their research, without fear of infringement. If they’re allowed to do that, everyone wins.

In September, Dario Altieri (Figure ​(Figure1),1), former chair of the Department of Cancer Biology at the University of Massachusetts Medical School, took on a new challenge when he was named the director of the Wistar Institute Cancer Center and chief scientific officer of the Wistar Institute in Philadelphia. Altieri has led a successful research career that includes the cloning of the gene Survivin, a member of the family of inhibitors of apoptosis proteins (IAPs). Altieri recently spoke to the JCI about his research and this most recent career transition. Figure 1 Dario Altieri is the new director of the Wistar Institute Cancer Center. JCI: Can you tell us a little about IAPs and Survivin? Altieri: Survivin is a gene that we cloned in our laboratory in 1997. It’s a member of the IAP family, but it does a lot more than inhibit apoptosis. It’s required for cell division, for the proper segregation of chromosomes during mitosis. And importantly, it seems to be upregulated in almost every human cancer, so it obviously holds a lot of potential as a therapeutic target. Attempts to decrease Survivin levels in tumors or inhibit its function have led to . . . I don’t know how many patents. JCI: How will being chief scientific officer and director of the Wistar Institute Cancer Center be different from your position (chair of Cancer Biology) at UMass? Altieri: I think the scopes are broader and the impact is greater. I was the founding chair of the Cancer Biology department at UMass — and that was a great challenge. When I arrived, I had 24,000 square feet of empty lab space to fill. In just a few years, we were the number three cancer research program in the country. I learned a lot. This move to Philadelphia was an opportunity to take advantage of what I had learned and apply it in a new place. Wistar is undergoing the largest expansion in 40 years — we’re building a new research tower — it’s a $100 million project. It’s also in a unique location. We sit right in the middle of the University of Pennsylvania campus. Close to the Children’s Hospital of Philadelphia. And there’s Jefferson University and Drexel and Temple. My goal is to establish and foster long-term collaborations with those institutions. JCI: What does a chief scientific officer do? Altieri: That’s a good question, I still need to figure this out. I think the mandate is to be an advocate, to promote growth and expansion of the entire research and training portfolio at the Institute, not just in the Cancer Center. JCI: Did you bring your research group with you to Wistar? Altieri: I did. I was lucky enough to bring 5 members with me — two of them senior. That should help us to . . . if not hit the ground running, at least ease the transition, and allow us not to lose too much time in our work. JCI: You did your medical training at University of Milan School of Medicine. Do you still do any clinical work? Altieri: I don’t. The demands of providing high-quality clinical care and doing high-quality research are enormous. Being able to do both is very challenging and requires a special person and a special situation. JCI: Do you think your medical training influenced your research interests? Altieri: Enormously. My work has always been focused on elucidating mechanisms with a backdrop of disease relevance. We always work to keep that bigger picture in mind, about how basic discoveries will be translated to help patients. I think my medical training fueled that tremendously. JCI: Do you have a vision for Wistar, for the changes you’d like to see in the next decade? Altieri: I do have a vision. There is one — in my opinion — remarkable asset to a non-profit research institution like Wistar. It obviously has this amazing history and longstanding tradition of being a place where many discoveries were made that eventually were translated into real clinical treatments. But the most remarkable asset is that it has a very clear, targeted vision: advancing science. So everyone working there can be dedicated to working toward making scientific advancement. It’s that laser-focused vision that will allow us to make great scientific impact, to recruit new top faculty. I want Wistar to become a destination program, to create an environment that fosters the highest quality research and attracts the highest quality scientists. JCI: So now that you’re here, will you root for the Red Sox or the Phillies? Altieri: This is an embarrassment. I’ve been in this country for 25 years, and I still don’t know if the guy with the bat plays for or against the guy with the glove. Soccer I know . . . you know, we got a lot of advice when we were making the transition, but probably the best advice I got was from the auto insurance person when we were changing our policy. She asked where we were moving from, and when I told her she paused and then said, “Do NOT bring any Patriots paraphernalia with you.”

Type 2 diabetes mellitus (T2DM) results from pancreatic beta cell failure in the setting of insulin resistance. Heterozygous mutations in the gene encoding the beta cell transcription factor pancreatic duodenal homeobox 1 (Pdx1) are associated with both T2DM and maturity onset diabetes of the young (MODY4), and low levels of Pdx1 accompany beta cell dysfunction in experimental models of glucotoxicity and diabetes. Here, we find that Pdx1 is required for compensatory beta cell mass expansion in response to diet-induced insulin resistance through its roles in promoting beta cell survival and compensatory hypertrophy. Pdx1-deficient beta cells show evidence of endoplasmic reticulum (ER) stress both in the complex metabolic milieu of high-fat feeding as well as in the setting of acutely reduced Pdx1 expression in the Min6 mouse insulinoma cell line. Further, Pdx1 deficiency enhances beta cell susceptibility to ER stress-associated apoptosis. The results of high throughput expression microarray and chromatin occupancy analyses reveal that Pdx1 regulates a broad array of genes involved in diverse functions of the ER, including proper disulfide bond formation, protein folding, and the unfolded protein response. These findings suggest that Pdx1 deficiency leads to a failure of beta cell compensation for insulin resistance at least in part by impairing critical functions of the ER.

The homeodomain transcription factor pancreatic duodenal homeobox 1 (Pdx1) is a major mediator of insulin transcription and a key regulator of the β cell phenotype. Heterozygous mutations in PDX1 are associated with the development of diabetes in humans. Understanding how Pdx1 expression levels are controlled is therefore of intense interest in the study and treatment of diabetes. Pdx1 C terminus-interacting factor-1 (Pcif1, also known as SPOP) is a nuclear protein that inhibits Pdx1 transactivation. Here, we show that Pcif1 targets Pdx1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increased Pdx1 protein levels in cultured mouse β cells, and Pcif1 heterozygosity normalized Pdx1 protein levels in Pdx1(+/-) mouse islets, thereby increasing expression of key Pdx1 transcriptional targets. Remarkably, Pcif1 heterozygosity improved glucose homeostasis and β cell function and normalized β cell mass in Pdx1(+/-) mice by modulating β cell survival. These findings indicate that in adult mouse β cells, Pcif1 limits Pdx1 protein accumulation and thus the expression of insulin and other gene targets important in the maintenance of β cell mass and function. They also provide evidence that targeting the turnover of a pancreatic transcription factor in vivo can improve glucose homeostasis.

Background Prader-Willi and Angelman syndrome (PWS and AS) patients typically have an ~5 Mb deletion of human chromosome 15q11-q13, of opposite parental origin. A mouse model of PWS and AS has a transgenic insertion-deletion (TgPWS/TgAS) of chromosome 7B/C subsequent to paternal or maternal inheritance, respectively. In this study, we define the deletion endpoints and examine the impact on expression of flanking genes. Results Using molecular and cytological methods we demonstrate that 13 imprinted and 11 non-imprinted genes are included in the TgPWS/TgAS deletion. Normal expression levels were found in TgPWS brain for genes extending 9.1- or 5.6-Mb centromeric or telomeric of the deletion, respectively. Our molecular cytological studies map the proximal deletion breakpoint between the Luzp2 and Siglec-H loci, and we show that overall mRNA levels of Luzp2 in TgPWS and TgAS brain are significantly reduced by 17%. Intriguingly, 5' Chrna7 shows 1.7-fold decreased levels in TgPWS and TgAS brain whereas there is a ≥15-fold increase in expression in neonatal liver and spleen of these mouse models. By isolating a Chrna7-Tg fusion transcript from TgAS mice, we mapped the telomeric deletion breakpoint in Chrna7 intron 4. Conclusion Based on the extent of the deletion, TgPWS/TgAS mice are models for PWS/AS class I deletions. Other than for the first gene promoters immediately outside the deletion, since genes extending 5.6–9.1 Mb away from each end of the deletion show normal expression levels in TgPWS brain, this indicates that the transgene array does not induce silencing and there are no additional linked rearrangements. Using gene expression, non-coding conserved sequence (NCCS) and synteny data, we have genetically mapped a putative Luzp2 neuronal enhancer responsible for ~33% of allelic transcriptional activity. The Chrna7 results are explained by hypothesizing loss of an essential neuronal transcriptional enhancer required for ~80% of allelic Chrna7 promoter activity, while the Chrna7 promoter is upregulated in B lymphocytes by the transgene immunoglobulin enhancer. The mapping of a putative Chrna7 neuronal enhancer inside the deletion has significant implications for understanding the transcriptional regulation of this schizophrenia-susceptibility candidate gene.

Cells are able to sense the level of oxygen in their environment and can adapt by rapidly altering expression of various genes. This capacity has both positive and negative implications; following ischemic injury, it can help promote blood vessel growth and recovery, but in cancer, new vessel growth helps sustain developing and metastasizing tumors. In the 1990s, William Kaelin Jr. and Gregg Semenza (Figure ​(Figure1)1) revolutionized the understanding of cellular oxygen sensing by identifying many of the molecular players involved. Their continuing work in the field has led to the development of successful therapeutic strategies. In April, their contributions will be celebrated as they receive the 2012 ASCI/Stanley J. Korsmeyer Award. The JCI recently spoke to Kaelin and Semenza about their path to this prize.

Chronic myelogenous leukemia (CML) was the first cancer to be linked to a clearly defined genetic defect, a chromosomal translocation that generates a constitutively active tyrosine kinase. In the 1990s, Brian Druker and Charles Sawyers (Figure ​(Figure1)1) collaborated to develop the targeted therapies that transformed CML from a fatal disease to one that boasts a 90% cure rate. Their work has been widely recognized as revolutionizing the molecular treatment of cancer, and in April their contributions will be further celebrated as they receive the 2011 ASCI/Stanley J. Korsmeyer award. The JCI recently spoke to Druker and Sawyers about their research careers and this latest award.

Poliovirus invades the nervous system, resulting in paralysis and occasionally death. In 1988, a global initiative was launched by the WHO and partners to eradicate the virus by mass immunization. The effort was largely successful; the number of polio cases fell by 99%, and today the virus remains endemic to just four countries: India, Pakistan, Afghanistan, and Nigeria (1). However, in November and December of last year, hundreds of polio victims were identified in the Congo, and an estimated 40% of those cases were fatal. The JCI recently spoke to Vincent Racaniello, selfdescribed “virus guy” and polio expert at Columbia University, about the outbreak. JCI: Is the poliovirus currently circulating in Africa different from that seen in the rest of the world? Racaniello: There is no evidence that the poliovirus circulating in Africa (specifically in the Congo) has changed in any way. The Congo strain appears to have come from India via Angola, possibly spread by migrant workers. It is a wild-type 1 strain, not a vaccine-derived strain that has caused outbreaks in other countries. JCI: Most of the victims in the Congo are teenagers and young adults, and the fatality rate is high; does that signal that the virus has changed in some way? Racaniello: The high prevalence of infection among teenagers and young adults is likely related to gaps in immunization. The last case of polio in the Congo was in 2000; hence immunization has lagged. When polio is acquired at a later age, the disease tends to be more severe. JCI: How far do you think this latest outbreak is likely to spread? Racaniello: Mass immunizations will probably restrict the outbreak to the Congo. However, consider that only 1% of poliovirus infections are paralytic. That means in the current outbreak, where 476 cases of paralytic disease have been recorded, there have been a total of 47,600 infections, 99% of which have gone unnoticed. Therefore the potential for spreading the infection to neighboring countries is high — unless those countries maintain high levels of immunization. Migrant worker travel can also cause distant spread of infection. In 2004, there was an outbreak of polio in Nigeria; the virus spread to other countries in Africa and then to Indonesia. JCI: How should vaccination policy change to prevent future outbreaks? Racaniello: All countries need to maintain high levels of immunization coverage until the disease has been eradicated. In the US and other developed countries, this is done by routine immunization at birth. In underdeveloped countries, this is difficult due to poor health care systems, unstable political situations, and armed conflict. Hence, mass immunizations are used to improve coverage. As long as countries such as the Congo allow immunizations to lag, there will be outbreaks.

On September 8, Johnson & Johnson awarded the 2010 Dr. Paul Janssen Award for Biomedical Research to Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the NIH, and Erik De Clercq, professor emeritus at the Rega Institute for Medical Research in Belgium (Figure ​(Figure1),1), in recognition of their work on HIV and AIDS. Named for physician and chemist Paul Janssen, known affectionately as Dr. Paul, the award honors active scientists who have made contributions to the improvement of human health. The JCI recently spoke to Fauci and De Clercq about the award, their careers, and the future of AIDS research.

The Antonio Champalimaud Vision Award was established by the Champalimaud Foundation to honor major contributions to vision research and organizations that work toward the global alleviation of vision problems. In June, the foundation recognized two American scientists for their contributions to visual neuroscience, J. Anthony Movshon, director of the Center for Neural Science at New York University, and William T. Newsome, a Howard Hughes Medical Institute investigator and professor at Stanford University (Figure ​(Figure1). 1).