Clouds of witness: Type 2 diabetes in the modern world
Interview with Mark McCarthy
By Mark Wanner, Writer for the HUGO-JAX Initiative, The Jackson Laboratory
Type 2 diabetes is a growing medical problem, but unlike many complex diseases there is an easily identifiable foundation for its cause—our modern lifestyle. Its emergence as a serious threat to health therefore poses significant challenges in a variety of fields beyond clinical medicine, including research and public health.
HUGO Council member Mark McCarthy is on the front lines of both the research and clinical fronts. His dual roles are effectively captured in his two U.K. bases of operations in buildings about 400 meters apart in Oxford: at the Oxford Centre for Diabetes, Endocrinology and Metabolism and at the Wellcome Trust Centre for Human Genetics. In the lab at the Wellcome Trust he works to tease out the root genetics of susceptibility to type 2 diabetes, seeking pathways that can be targeted for improved therapies. In the clinic he specializes in diabetes, helping patients manage their existing disease.
One recent late spring morning McCarthy discussed the behavioral versus genetic aspects of type 2 diabetes, how technology advances are aiding his work, the difficulty of capturing the human condition in the lab, and much more.
Q: You originally trained as a medical doctor. How did you become so involved in genetics research?
A: I was doing the equivalent of a residency and received a fellowship to do some research in diabetes genetics. At the time I was mostly looking to move up the medical ladder, and a higher degree in research would help. But I enjoyed it, and in the mid 1990s went on to do post-doctoral work with Eric Lander at the Whitehead Institute before returning to the U.K. to continue my research using family-based studies to find genes associated with diabetes. I still practice medicine, but over the years I’ve done progressively more basic research and less clinical work.
Q: Type 2 diabetes is strongly correlated with behavior and environment—what techniques are you using to find the genetic associations?
A: We are focused on finding the components of disease risk, which is driven by genetic differences. We are using a range of different approaches to identify this genetic component. Over the past few years, genome wide association studies have provided a powerful approach to identifying genetic loci, and we’ve identified around 65 for type 2 diabetes. Given these associations, we’re now increasingly trying to understand the whole chain of causation from variant to disease, something that has proven quite challenging.
Q: Have model organism studies been effective?
A: Well, we’ve seen over and over again that we struggle to recapitulate the true disease situation in model organisms. We can use them to discover basic biology and test pathways, but type 2 diabetes is so heterogeneous that we have to bring it back to the human for most clinical discovery.
Q: Heterogeneous? Part of the promise of genomic medicine is to treat patients as individuals, not part of large population averages. How does this figure in to type 2 diabetes therapies?
A: Type 2 diabetes is the result of multiple factors coming together, and it is likely that the balance of factors involved differs subtly from individual to individual. That opens the door to more precise, personalized approaches to treatment and prevention. One of the main challenges is that, once people have diabetes, the disease and/or its treatment gets in the way of characterizing the changes that led to the diabetic state. So those kinds of studies need to be done in people before they develop diabetes, for example by performing detailed phenotyping of the earliest stages of disease.
Q: Much of the blame for the type 2 diabetes epidemic rests in behavioral and environmental factors, and some people say we should put our effort and investment into education and behavioral modification instead of genetics and pharma research. What are your thoughts?
A: In principle, we know how to stop the diabetes epidemic in its tracks—through changes in diet and exercise for example. However, in practice those behavioral modifications are incredibly hard to sustain. We can already identify many of the individuals destined to develop diabetes based on their family history and ethnicity, but it has proven very difficult to achieve the sustained lifestyle changes that might reduce their risk.
In terms of more specific interventions, it might be possible to target energy-dense foods as one possible culprit contributing to the rise in diabetes. It’s also possible that research will turn up other factors that have contributed to the rise in diabetes worldwide. Could it be, for example, that widespread antibiotic use in early life has led to changes in the gut microflora that are important? That’s purely speculative at the moment, but indicates the kind of factor—amenable to intervention—that might emerge from ongoing research.
Q: But losing weight has such a direct impact . . .
A: Its clear that humans generally do a great job of matching energy input and output. And even in those who become obese, the imbalance between those two factors is relatively modest.
Q: How has HUGO contributed to your work?
A: My research depends a great deal on international collaboration, and many of our projects use samples collected in diverse parts of the world. HUGO has contributed hugely to good practice in this area, and in the promotion of genomic research across the globe. This has really opened doors to new international collaborations that would not otherwise have been possible.
Q: Looking ahead, is there any chance we’ll be able to find a cure for type 2 diabetes?
A: It is certainly possible. The best hope lies in identifying the processes most fundamentally involved in diabetes pathogenesis, such as those revealed by genetic studies, and then by developing novel preventative and therapeutic interventions which can reverse those changes.
Q: What about using genetics to predict onset?
A: On their own, the predictive power of genetic variants is modest, and it may well be that genetics alone will never provide a sufficiently strong predictive signal for clinical purposes. But by combining genetics with measures of other contributors to disease risk—such as epigenetic changes, or the cumulative effect of environmental exposures collected on hand-held devices—I am hopeful that clinically useful stratification of risk will be possible in the years to come.
Mark McCarthy will be presenting at the upcoming HGM 2013 / 21st ICG, held from 13 – 18 April 2013 at The Sands Expo & Convention Center, Marina Bay Sands, Singapore.
Interview with John Mattick
By Mark Wanner, Writer for the HUGO-JAX Initiative, The Jackson Laboratory
Human Genome Organisation (HUGO) Council member John Mattick has a history of balancing ahead-of-its-time research with leadership of research institutes.
Mattick was the first to propose that the RNA transcribed from the enormous amounts of intronic and intergenic DNA that doesn’t code for proteins in the genomes of humans and other complex organisms may constitute another level of genetic information important for development. Two decades ago this was a radical concept, as most investigators called it “junk” and looked no further. Now the importance of non-coding RNA is widely accepted, with research into its roles ongoing. Mattick received the 2012 recipient of HUGO’s Chen Award for Distinguished Academic Achievement in Human Genetic and Genomic Research for his innovative research.
Mattick also led the Institute of Molecular Bioscience at the University of Queensland for many years, growing it to a 500-person institute before stepping down to re-focus on family and research. He returned to a significant administrative role again in January 2012, when he became executive director of the Garvan Institute, one of Australia’s leading biomedical research institutions.
Recently, Mattick was kind enough to take time out of a busy morning in Sydney to discuss everything from non-coding RNA transcripts to the vagaries of healthcare delivery around the world to induced pluripotent stem cells.
Q: The activity shown in the non-coding regions of the genome from last year’s ENCODE papers seemed to catch the mainstream media’s attention, but it must have been old news for you. How did you start looking into non-coding RNA and what did you think of the new data?
A: It’s been obvious for 35 years now that most of the genome is transcribed to RNA. That brings up two possibilities—the non-coding transcriptions are either junk, meaning that the genome is full of rubbish, or that another type of information is being put into the system. The second possibility struck me as much more interesting than the assumption that it’s all junk, and it became clear as crystal to me as more data came in over time that it’s much more likely to be functional than not.
The ENCODE project looked at things that have been on the table for years, but it’s nice to get some extra detail. Unfortunately, many still seem to cling to the notion that most genome biology in humans is driven by proteins. ENCODE is curiously silent about the implications of the massive transcription of RNA and the signatures of functional organization across these non-coding regions, preferring perhaps to duck the question of whether it is all relevant or largely “transcriptional” noise.
The intellectual and cultural problem is that if this non-coding RNA is functional—and all the emerging evidence points in this direction—the entire conception of gene regulation has to be reconstructed. The field has assumed for a long time that protein regulators, transcription factors of various sorts, drive the regulation of the system. But now we have to figure massive amounts of regulatory RNA into our understanding. Transcription factors are very powerful stage-specific effectors of gene expression, but my feeling is that much more information is required to supervise architectural organization—the shapes and positions of different muscles, bone and organs.
Q: Architecturally? You mean a larger regulatory framework?
A: Yes, people haven’t really considered whether additional information is needed for developmental architecture, and how the transcription factors might be integrated into this larger narrative.
The genome has an outpouring of RNA during development, with over 90 percent of the genome differentially transcribed in different cells at different stages. The major function of these transcripts appears to be to orchestrate the superstructure of the genome in a very precise way, by directing the site-specificity of the epigenetic complexes that modify the DNA and the proteins around which it is wrapped—an extraordinarily complex secondary code. Exploring that is a journey we’ll have to go on to understand development.
Q: Your own journey has led you back toward a more administrative role, however. Why did you take over as executive director of the Garvan Institute?
A: Well, Garvan has an excellent neuroscience program, and lately my research has transitioned to looking at the RNA-based plasticity in the brain—that is, how it is able to reprogram itself in response to external signals for learning and memory.
But mostly I saw an opportunity to construct a next-generation research institute that embraces genomics as a way to gain better insight into complex biology and complex diseases. Here we can introduce genomics as not just a technology but also as a way of thinking, a philosophy that provides a new and holistic approach into the way complex human characteristics are studied. This in itself represents a transition from reductionist to system-wide approaches, with a marriage between genetics and genomics and their interplay with cell and molecular biology likely to lead to the next great advances.
Genomics has clearly made enormous inroads in understanding cancer on a molecular level, and we need it to understand other complex diseases: diabetes, osteoporosis, neurological disorders and so on. We need to embrace genomic tools and perspectives to usher in the next generation of science and medicine.
Q: What is Garvan’s association with St. Vincent’s Hospital?
A: Garvan was actually born of St. Vincent’s Hospital, which is quite famous and much-loved in Australia. The setup here most resembles Johns Hopkins Medicine [in the U.S.] in style, with basic research conducted in close alliance with a leading hospital. It’s a great place to introduce new ideas, findings and technologies to translational research and medicine.
Q: Applying genomics in the clinic still faces challenges around the world, such as lack of actionable understanding, accuracy and quality control, data management issues, reimbursement problems and so on. How quickly do you see it happening in Australia?
A: Well, you can’t predict the future, even what will happen in the next five years, let alone ten years. Things are changing so quickly, and the pace of change is accelerating—all you can say is that whatever happens will probably happen faster than you think! Nonetheless I believe the march toward genomic medicine is unstoppable.
Australia has a mixed public/private health and health insurance system—in my opinion one of the best in the world—which delivers a quality of medicine comparable to the USA at a much lower cost, with equal access. The more practical genomic medicine becomes and the more value it delivers, the more healthcare systems will embrace it, and the more it will be used in practice. Physicians in Australia don’t yet know much about genomics, just like everywhere else around the world, but they’re not resistant, and the College of Pathologists here is already running genomic education programs.
There are challenges, but people power, bottom-up advocacy, will solve the acceptance problems faster than mandates. A cancer patient will find a doctor who will arrange for a genomically informed diagnosis of their tumor. People will become very savvy and advanced about their options.
Q: What has being on the HUGO Council meant for you?
A: HUGO is very special. It was created by the pioneers of human chromosome mapping, and for years it was the only organization to embrace genomics. It remains the best place for people who are interested in understanding the many dimensions of the human genome and genomic medicine.
I just love HUGO as an organization and the Human Genome Meeting as a conference, because it’s the gathering place for the leaders in the field from around the world. It’s so helpful for seeing the whole of the system, the way human genome information can be used and the different perspectives, challenges and opportunities that surround it.
HUGO has the trust of governments across the world because it has always taken a very ethical view. It’s not seen as having a national bias or focus but rather as a highly successful international scientific organization, of great stature and integrity. It also reaches out very actively to developing communities, to promote égalité, which is most important.
Q: What do you find most interesting and exciting as you look to the future?
A: A world of discovery is awaiting everyone from the massive genome sequencing studies being done. Across the world there is a huge data avalanche, providing a tremendous opportunity for scientists everywhere to roll up their intellectual sleeves and start looking through it in different and creative ways.
The advances in the stem cell field, especially induced pluripotent stem cells (iPSC), are also very exciting. There are many projects looking at the dynamic molecular transitions in these cells and how they can be reprogrammed. Wonderful insights into the whole process of differentiation are beginning to flow, providing a fresh impetus to investigating the normal and abnormal processes of human development. We’re doing this in our lab. You can obtain iPSCs from patients with neurological disorders, reprogram them into neurons, and they show, amazingly, some of the characteristics of the actual neurons in the patients themselves. So you can do your research in real human cells that mirror the disease—it’s just incredible.
The big frontier is, of course, the brain, and its complexities will be peeled back by genomics, epigenomics and transcriptomics. The 20th century was just the warm-up.
David Cox 1946 – 2013
By Mark Wanner, Writer for the HUGO-JAX Initiative, The Jackson Laboratory
David Cox was among the HUGO Council members I was excited to interview and profile on this page at some point in the months ahead. His extraordinary career helped change human genomics from an intriguing concept to an important reality. His contributions to genomics research and medicine are immeasurable.
Sadly, this post is a memoriam. David Cox’s recent passing means that I will not be able to speak with him and share the excitement and warmth he shared with so many others. I can, however, present some of what he accomplished and share a few of his words, and those of others, to show what he meant to HUGO and the genomics community.
Recently, Cox worked in the private sector, focused on translating research progress into useful therapies. At the time of his death he was senior vice president at Pfizer, where he was credited with helping shift emphasis there toward the discovery of more targeted drugs. A company statement said, in part, “As the company’s lead geneticist based at our Rinat facility in San Francisco, David was a driving force in shaping Pfizer’s strategy on Precision Medicine, as well as our vision for the future of biomedical innovation.”
But perhaps his most enduring legacy is contained in the simple citation: Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Cox DR, et al. Initial sequencing and analysis of the human genome. Nature 2001;409:860-921. Cox was one of the innovators, one of the true pioneers in human genomics, and it is fitting that his name appears on the Nature paper announcing the draft sequence. Indeed, the lead author on the other paper announcing the draft sequence, J. Craig Venter, paid tribute via social media: “David Cox one of the early genomic leaders and a good man dead at 66. [A] real loss to genomic medicine and the scientific world.”
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Cox’s education followed a linear path at first. He received B.A. and M.S. degrees from Brown University and set out for graduate school at the University of Washington, earning his Ph.D. in genetics then proceeding to medical school there, graduating in 1981. As documented in a wonderful interview he gave at Cold Spring Harbor in 2003 while at a symposium to celebrate the completion of the draft human genome sequence, his perceptions changed on the road to his M.D. “[I] always just wanted to be a doctor and I got sucked into research early on in college. And so when I was in the process of finishing medical school I realized that we didn’t actually understand how anything worked.”
Cox’s drive to understand how “anything” worked never waned. Having studied genetics, he was quick to appreciate that learning more about DNA biology would lead to better medicine. His medical specialty was pediatrics, but it was always enmeshed with his genetics research. After his pediatric residency at Yale, he completed a research fellowship in genetics and pediatrics at the University of California, San Francisco, then became an associate professor in pediatrics at UCSF in 1980. By 1991, he was a full professor in psychiatry, biochemistry and pediatrics as well as co-director of the UCSF Human Genome Mapping Center.
Soon after his research fellowship, Cox began thinking big. He said of that era: “So it was at that time in the early 1980s, that my dream from the point of view of medicine would be to have the entire sequence of the human genome so that we could basically know the DNA . . . But I thought it was crazy and everybody else thought it was crazy too . . . I realized it was possible and even though it seemed unlikely I got on board right away.”
Cox contributed greatly to the sequencing effort over the years in many ways, including through the development of radiation hybrid (RH) mapping. RH mapping is used to construct long-range maps of mammalian chromosomes by creating random x-ray breaks in chromosomes to determine distances between DNA markers and their order on the chromosome. In the days of Sanger sequencing, RH mapping provided genomics researchers with a powerful method to begin stitching together the relatively minute DNA sequence reads attainable at the time in the correct order. Cox and his colleagues first documented the technique in Science in 1990.
In 1993 Cox moved to Stanford University, where he served as professor of genetics and co-director of the Stanford Human Genome Center. His work at Stanford helps trace the arc of the human genome project, including gene mapping progress and new methods for detecting DNA sequence variation mixed with specific disease gene discovery research.
Cox’s influence extended far beyond his laboratory, however. In 2000 he co-founded Perlegen, a pioneering consumer genomics company. He was elected as a member of the Institute of Medicine, National Academy of Science, in 2001. He was also one of the founding members of HUGO, serving three terms on its Council while at Stanford and was serving a fourth term through 2014.
Cox is described by fellow HUGO Council member Mark McCarthy as “a powerful advocate for human genomics,” and his influence is seen in the very formation of the human genomics field. Upon completion of the draft reference human genome sequence, Cox said, “Now that we have it though I want to be alive to be able to use it in this correlative way.” And he was able to use it, to apply systems and genomic biology to therapy development and see the advent of genomic medicine.
In his tribute, HUGO President Edison Liu wrote: “The HUGO family is saddened by the tragic and sudden loss of our friend, colleague, and ardent supporter of HUGO, David Cox. David was not only a superb scientist, an institutional leader, and a driver of innovation, he was also a warm and supportive friend who had kind and helpful words whenever such were needed.” He continued, “Rarely in the course of a scientific development are there champions who bring such a confluence of talents that David Cox offered– fundamental science, clinical medicine, academia, industry, selfless commitment, kind heart.” David Cox will be missed.
HUGO Researchers Are Pushing The Boundaries Of Human Genomics
By Mark Wanner, Writer for the HUGO-JAX Initiative, The Jackson Laboratory
Upon the founding of HUGO 24 years ago, human genome research was in its infancy. It was, one might say, a field whose potential was recognized by a select few, many of whom served on the first HUGO Council.
The current HUGO Council continues to drive progress, but in a different context—it is a time when the practical implementation of genomic research findings is now possible. It is of paramount importance to increase understanding of the human genome, and the work is of relevance to a growing number of people worldwide.
You will meet many members of the HUGO Council from around the world in HUGO Matters in the months ahead. They will discuss their outlook and their work, including current challenges and future goals. Combined, they will reveal a wide spectrum of genome biology and how it relates to us, our health and medicine.
I am excited to introduce the HUGO Council through these posts and facilitate an ongoing exploration of the human genome. I have covered genomic research and clinical genomics in “Genetics and Your Health” for The Jackson Laboratory for three years, and I look forward to expanding my coverage in HUGO Matters. There has been tremendous progress in the field lately, and it will be fascinating to see what develops in the coming years.
The first interviews will build toward the 2013 Human Genome Meeting in Singapore this April. I hope you will return to meet some of the most influential human genome researchers in the world.
Globalization of Science
Edison Liu, President and CEO, The Jackson Laboratory
March 2012 | The past ten years have seen tremendous changes in the power and utility of sequence information, and in the pace of globalization. The advance of genomics technologies has dramatically increased the impact of genetic information on biological investigations. Gene hunting is no longer a molecular exercise but a computational sport and the scale of the studies have elevated from single gene analysis to whole genome reconstructions. Just as analytical firepower from computers enabled robotics thus moving analysis to action, genomics is enabling synthetic biology, which promises to be a game-changer.
The second trend, globalization of science, has more important social and political ramifications. In the last 10-15 years, the balance of scientific productivity has equilibrated to include Asia. Science and innovation is no longer just the domain of North America and Europe. In fact, in certain areas, Asia is potentially leading. The location of the world’s most powerful genomics center—BGI in China—was inconceivable just ten years ago. More than the simple production of data, this means that innovation, which is the fuel for the new economy, will be found in the East.
In the years ahead, I predict that we will be using massive biological data that includes genomic, transcriptomic, and metabolomic data to reconstruct complete systems. Understanding and harnessing biological/genetic complexity will provide more nuanced (and correct) medical predictions, and will allow us to reconstruct complex biological systems for production. The latter will give us whole organism solutions to crop improvements, environmental remediation, and biomass conversion.
Medical solutions for sustaining health will now come from a systems understanding of disease. The systems comparisons between disease models in the mouse and the human will be the key to new medicine. For example, why a mutation causes disease in one species and not the other provides the genetic clues for new cures. Moreover, the understanding of disease mechanisms will be used to reconstruct the necessary components to enhance an individual’s robustness against disease and infirmity—which will be the foundation for future preventative medicine. This shift from data generation to complexity analysis, to systems reconstruction will require deep understanding of model systems such as the mouse.
What will the key challenges be for the entire biomedical research community? I project that they will be mainly cultural, managerial, and pedagogical. Indeed, limiting resources because of economic austerity are challenging. But, many of our systems are outdated and insufficiently forward looking. Our Ph.D. programs will need to be more quantitative, modular, and less domain intensive. This means that fewer individuals should be trained as focused cancer biologists but as individuals who use cancer biology as a model system to answer fundamental biological and technological problems. Our promotion systems that reward isolated brilliance will have to accommodate collective contributions. As a community, we will need to find ways to establish enabling infrastructures that will position us for future strength rather than to support historical biases. All this means that some old structures must be taken down to allow for new ones to be built. This is never easy.
But what would the benefit be? The 21st century will be among the most challenging for humanity as food and energy become scarcer, as our populations age, and as the environment continues to degrade. It will be innovations in biosciences—and their implementation—that will save us all.
National Institutes of Health epigenomics public data resource now available!
Researchers in the Reference Epigenome Mapping Consortium, part of the NIH Common Fund’s Roadmap Epigenomics Program (http://commonfund.nih.gov/epigenomics), have begun creating a community resource of genome-wide epigenetic maps in a variety of human primary cell and tissue types. The data currently represent more than 100 samples including adult and fetal cells and tissues, and embryonic and induced pluripotent stem cells. The majority of reference epigenomes being generated contain information about DNA methylation, a core set of histone modifications, chromatin accessibility, and gene expression. A subset of reference epigenomes will also contain an expanded set of at least twenty additional histone modifications. The Consortium’s website (http://roadmapepigenomics.org) provides information about protocols developed by Consortium members, information about data standards, and links to a variety of sites where the epigenomic data can be visualized in a genome browser or downloaded for subsequent analysis.
Are Alcoholic Habits Determined by Genes?
A recently published study has revealed that a gene related to autism, called autism susceptibility candidate 2, or AUTS2, is linked to increased alcohol consumption.
To read more, please go to www.mgrc.com.my/genomics_news/AUTS2.shtml
12th International Meeting On HUMAN GENOME VARIATION AND COMPLEX GENOME ANALYSIS (HGV2011)
Date: 8th-10th September 2011
Place: Claremont Hotel Club and Spa, Berkeley, CA, USA
Website: http://www.hgvmeeting.org/hgv2011
Abstract deadline: 31st May 2011
Registration deadline: Open until all delegate places taken
* Topics to be covered include methods/strategies for utilisation of different types of DNA variation (e.g., SNPs and copy number variations-CNVs), functional genomics applications, population genetics, bioinformatics, databases, algorithm development, personal genome sequencing, The 1000 Genomes Project, and the study of human disease.
* Postdoctoral fellows, junior faculty member, and under-represented groups can apply for meeting grants to help minimise their attendance costs.
HGM 2011 on City TV News
Catch City TV News report on HGM 2011 here. The HGM 2011 news segment is between the times 03:47 and 06:42.
HGM2012 Sydney video on YouTube
View HGM2012 Sydney video on YouTube now: http://www.youtube.com/watch?v=T2utMRLGFy0
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