By Mark Wanner, Writer for the HUGO-JAX Initiative, The Jackson Laboratory
Human Genome Organisation (HUGO) Council member Aravinda Chakravarti, Ph.D., has a listing at Johns Hopkins University that reflects his far-reaching contributions to research and medicine. It reads: “Professor; McKusick-Nathans Institute of Genetic Medicine; Departments of Medicine, Pediatrics, and Molecular Biology and Genetics at the Johns Hopkins University School of Medicine; Department of Biostatistics at the Bloomberg School of Public Health.”
A leader in human genetics research for decades, Chakravarti is now delving beyond gene discovery into understanding the molecular pathways associated with complex human disease. During a recent visit to The Jackson Laboratory, where he is a co-Director and faculty member at the annual Short Course in Medical and Experimental Mammalian Genetics, Chakravarti spoke about his current efforts and the directions in which he thinks human genetics research needs to go.
Q: You said recently that you were streamlining your research efforts. How so?
A: When you are a geneticist who studies humans, all phenotypes are of interest. As such, my research has spanned genetic studies of numerous human diseases and medical traits. Over the past two decades, we geneticists have become very proficient at disease gene discovery, and, like others, my laboratory has ended up mapping and discovering genes associated with many different diseases.
But while finding and localizing genes isn’t a big challenge any more, it is still very difficult to figure out what they actually do and how their malfunctions lead to disease. Clearly, one aim is to understand their normal function and another to figure out how changes in that normal genetic program leads to disease. For chronic diseases of humankind—cancer, heart disease, neurological diseases, anything—we still are largely ignorant of how genetic abnormalities lead to disease. That is still mostly a black box. That’s the part that many labs, including my own, are focusing on more closely and looking to solve. Unfortunately, this may require a disease-by-disease solution.
Q: Why is it so hard to figure out the function of a gene when you have localized it and already know the sequence?
A: Figuring out a molecular function of a single gene is straightforward, but typically a single gene has many alternative functional forms with many different functions. Understanding these functions across development and aging remains challenging since the universe of possibilities is so large. Moreover, few genes function by themselves and many functions are only evident by one gene interacting with another . . . figuring out this aspect is still in its infancy since the universe of these possibilities is even larger. One has then also to consider that the gene may have different functions in different cell types and tissues. That’s why it’s hard.
A good example of that is genetic research on sudden cardiac death that we’ve been doing for the past eight years. The prominence of sudden cardiac death is increasing as the common sources of cardiovascular disease owing to lifestyle factors are better controlled. It has remained medically elusive, with various possibilities of the pathology arising from structural (mechanical) or functional (electrical conductivity) problems in the heart. When we started studying this in 2005, we needed ways to distinguish between these hypotheses. This is where genetics and genomics can be surprisingly beneficial. My group was at the vanguard of developing and using SNP array technology for genomic studies and we performed one of the first genome-wide association studies of the QT interval from human EKGs to suggest NOS1AP variation as an intrinsic cause of sudden cardiac death. We published our finding in 2006, but moving from that genetic signal to figuring out precisely how cardiac physiology is affected has been a long road and taken over 7 years. We have a much better idea of the underlying NOS1AP function but there is much more to understand before we can intervene in humans to prevent disease.
Q: Even with the technology improvements? Why?
A: Even when we’ve localized the gene we need to create a cellular system where we can study the functions of this gene, by knocking its function out for example. For sudden cardiac death, we also need a cellular system that can simulate part of the cardiac physiology . . . that is, we should be able to demonstrate both molecular and electrophysiological disruptions by disrupting NOS1AP function. All of this takes time since the components are not “off-the-shelf.” Other problems are the development of new paradigms since it’s increasingly clear that, for complex diseases, many disease mutations are non-coding and we have to understand not the effects of a mutant protein but abnormal levels of a normal protein. We are at the beginning of understanding gene regulation from this viewpoint. What happens when there’s too much or too little of a protein? Why and how does this matter? What is the protein doing—or not doing—that affects cardiac physiology on such a rapid timescale? And we still have to figure out where the protein localizes in the cell and how varying its levels affects its functions.
Q: So finding the gene and knowing its sequence is just the start . . .
A: Yes, the sequence is necessary and reveals much, but it’s not sufficient. Finding a gene leads to many questions that still need to be answered. Where is it expressed? At what level? When during development? Where does the protein localize, in what tissue and where in the cell? All give clues to function. Geneticists and genomicists have been a bit slow in trying to incorporate biochemical and cell biological assays and technologies to solve problems in these areas. There need to be close collaborations with cell biologists and biochemists to understand gene function. And, of course, understanding some aspects of function in another species can be greatly helpful to its study in humans. Success in genetics shouldn’t be seen as an isolated success but rather as integrated with all other important aspects of biology.
Q: With all of those questions left to answer, how can genetics and genomics help disease research and medicine?
A: Human diseases are affected by many different genes, as well as currently unknown aspects of lifestyle and environment. There will be various stages of understanding as we unravel these factors one by one, but we can impact therapy without understanding it all. Primarily, genetics and genomics can accelerate our understanding of the molecular basis of human disease and thereby point to therapy avenues that are currently nothing more than guesses. This is where professional organizations like HUGO can help, through international data sharing across populations, diets, environments, behaviors and cultures so that we can make faster progress from diverse viewpoints. It’s important to bring together different people and make it a truly global effort. HUGO can also play an important role by focusing attention on rate limiting factors and working with funding agencies to maximize what we can accomplish.
Q: What are some of those issues?
A: The major issues are sharing of samples, sharing of data, and access to technologies. Then there’s the challenge of computation. A biologist used to be able to collaborate with a quantitative expert and be able to answer their question, but that’s not good enough any more. Since current data sets are very large, we need to query these data sets to even pose the questions. Thus, we need to be computationally trained to ask the right questions in our research and be able to address the issues of handling huge data sets and analyzing them. In a way biologists need to be multi-lingual and be able to understand the language of computing as well as biology.
On a related topic, we also need to address education and make sure quantitative and computational training are significant parts of the whole educational process. We need to get away from the “soft” science thinking—biologists aren’t naturalists running around with butterfly nets any more—and train all students in the “hard” quantitative techniques.
Q: It sounds like it will take a while to change the field.
A: Moving forward, we in the field who are interested in human disease will have to master three areas: biology, computation and clinical science. Although so much of current education is geared to training specialists, it is the educated generalist who can traverse all three of these areas that will be successful. It can be done—we just need to act on it.
Prof. Chakravarti has been recently been named by The American Society of Human Genetics (ASHG) as the 2013 recipient of the annual William Allan Award. The award will be presented on 25 Oct 2013, during ASHG’s 63rd annual meeting in Boston.
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.
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.
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.
By Hsien-Hsien Lei, PhD, HUGO Matters Editor
One of the the most rewarding experiences I’ve had since I began writing about genetics and health is the opportunity to meet interesting and inspiring characters in the field, whether virtually or in-person. Dr. Misha Angrist aka Genomeboy is someone who I’ve learned a great deal from over the years. His candidly astute (astutely candid?) observations on genetics and life and his participation as one of the original study subjects of the Personal Genome Project mark him as someone to watch as the genome revolution unfolds. Once you’re done reading this interview, hop on over to Twitter and follow Dr. Angrist’s stream of consciousness. You’ll be glad you did.
HUGO Matters: On your profile page at the Duke University Institute for Genome Sciences and Policy, it says you’re Assistant Professor of the Practice. What does that mean and how did you end up going from an MFA from the Bennington Writing Seminars to an MS in genetic counseling to a PhD in genetics to Assistant Professor of the Practice?
Dr. Angrist: I actually got the MS in genetic counseling first, had so much fun doing research that I went for a PhD in genetics, and then years later, after burning out as a postdoc and floundering a bit in the real world, decided to get an MFA. After that I took a job at Duke as a science editor and eventually became Assistant Professor of the Practice. “PoPs” are full-time faculty who are non-tenure-track. They generally teach more than they do research, although that’s not always the case. I enjoy both and am fortunate that I get to do both. I teach, I write grants, I do research, I write papers, and I have written what I hope will be the first of several books. (You can read about PoPs here: http://chronicle.com/article/For-These-Professors/31149/)
HUGO Matters: You’re currently working on a book, Here Is a Human Being: At the Dawn of Personal Genomics, that’s due for release in November 2010 about personal genomics and the characters involved in the development of the field. Can you tell us more about the process of writing a popular science book?
Dr. Angrist: Writing “HiaHB” was both the most gratifying thing I’ve ever been paid to do and the hardest. Despite having an MFA, I’m not convinced that anything could have prepared me for it. I made many, many mistakes and I continue to make them in the editing process.
I think for me what clinched the decision to go forward with the book was meeting George Church–such a fascinating, charismatic, eccentric, visionary and brilliant guy. And extremely warm and generous, too. He made my job so much easier than it would have been had I chosen to focus on someone else. And indeed, I was blessed to be able to talk to/follow around dozens of other compelling people inside and on the fringes of the personal genomics world. I imagine any writer of a narrative nonfiction/journalistic book relies on the kindness of strangers–I certainly did.
HUGO Matters: As if all the above weren’t enough, you’re also the fourth subject in the Personal Genome Project. Why did you decide to make your personal genome public? Do you think we should all do the same?
Dr. Angrist: I decided to make my genome public because I thought I needed to walk the walk. I’m someone who decries genetic determinism and says we shouldn’t be afraid of this stuff, so I thought I should put my DNA where my mouth was. Does that mean everyone should do it? Absolutely not. I think one of the things about personal genomics that gets lost sometimes, particularly by some of my colleagues in the humanities, is that it’s personal. You should be free to share or hide as much of yourself as you want; it’s not for me to say whether it’s appropriate or not. It’s none of my business. The fact that I chose to do it is a decision I made for me, not for anyone else.
I have heard the objections: “What about your family? Aren’t you exposing them?” Yes and no. I have young daughters and a family history of early-onset breast cancer. So yeah, I wanted to see whether I carried a mutation in BRCA1 or BRCA2 before I went public. (My BRCA genes are clean as far as I can tell.) Not because I didn’t want my daughters to know what might be in their genomes, but because I’m their Dad and if their risks were high I wanted them to learn about those risks from me and their Mom, not from the internet. But still, I would rather know than not know. If their children were at risk for a late-onset disease, some parents might not want to know–I respect that. But I would. As for the public aspect, I still maintain that genomes are probabilistic things and we learn about these same probabilities to some extent every time Uncle Joe can’t remember where he parked his car or Grandpa needs angioplasty.
I suspect that within a few years the power of these arguments will diminish. Anonymous genomes will always be hard to keep anonymous and their usefulness will be limited by their anonymity. Perhaps even more important, my generation (I’m 45) and its qualms about genetic information will have been overtaken by the Facebook generation and its willingness to let it all hang out.
By Hsien-Hsien Lei, PhD, HUGO Matters Editor
Several years ago, I became acquainted with Dr. Keith Grimaldi who was then Chief Scientist at Sciona, a company offering nutrigenomic tests. Nutrigenomics is the study of the interaction between genetics and diet. Nutrigenomic tests are genetic tests that are used to help people determine the ideal diet for optimizing their health.
Interest in nutrigenomics started around 2003 and peaked in 2005 (around the time I started blogging about genetics). This was the time before direct-to-consumer, personalized genetic testing became the attention-grabbing industry that we are familiar with today which includes tests for specific disease-related genetic mutations to SNP analysis to whole genome sequencing. Nutrigenomics has now claimed a corner of consumer genetic testing and Dr. Grimaldi, who holds a PhD in Clinical Biochemistry from the University of Cambridge, is spearheading the nutrigenomics movement in Europe as Scientific Director of Eurogene, which we’ll learn more about in this interview.
I hope you’ll find this interview enlightening. Dr. Grimaldi has had an interesting career in the field of genetic testing and has much to share. Don’t miss his comments about science and social networking below the fold! If you have any questions for Dr. Grimaldi, please leave a comment.
HUGO Matters: Eurogene is an interesting endeavor in that it’s personal genomic/nutrigenomic testing supported by a consortium of partners. Can you tell us how Eurogene came about and some of the project’s immediate and long-term plans?
Dr. Grimaldi: At the time the project began I was working with Sciona, we had been involved with a number of EU consortium research grants and had also worked for several years with the Biomedical Engineering Laboratory at the National Technical University of Athens (BEL-NTUA) with a group of excellent software and systems developers. A call came out from the EU under the eTEN programme for market validation products. The scope of the call was to use the funds to overcome barriers to market facing new technology products and services that could be useful in society. We put together a small consortium – Sciona, BEL-NTUA, three clinical partners in Italy, Germany and Spain, plus a marketing / business development company from the UK. Fortunately we were one of the chosen few and our project was to use e-technologies to improve the product – to transform the existing largely paper based nutrigenetic test (hardcopy questionnaire and report) into electronic format and develop an interactive website for individuals and practitioners to manage their genetic & personal data and create their own personal reports.
That was the immediate plan but the project evolved along a slightly but significantly different course. It began in January 2008 and phase 1 EU funding saw it through until October 2009. Due to the economic downturn, when Lehman went bust etc, in December 2008 Sciona failed to secure some required funding and had to drastically reduce its operations (and sadly ceased trading a few months later). Sciona left the project and I left Sciona, becoming a member of BEL (it was great, I returned to being an academic and got to be in Athens a lot!). The direction of Eurogene changed then because suddenly it was no longer tied to one product or service – we outsourced genotyping of the remaining patients to a European genetics lab and carried on. One of the interesting findings, in the current debate, was that although Eurogene was set up to deliver both DTC and through practitioners, it was largely the latter market that was more receptive for this type of product/service in Europe and we ended up avoiding DTC. Regarding longer term plans, I think I’ll answer that as part of the reply to the next question
Dr. Grimaldi: As Eurogene was conceived it could have been seen as a sort of competitor to these companies, but it was really complementary. The Eurogene concept is to deliver highly personalised information based on genetics plus diet & lifestyle and other biomarkers such as traditional blood analyses. The aim is to integrate personal genomics with the rest of the person’s lifestyle and health status. We don’t do whole genome scanning or sequencing and restrict the genetic analysis only to those SNPs (and indels, copy number variants, etc) that are relevant for a particular purpose, e.g. a type 2 diabetes (T2DM) profile which we are working on at the moment. The companies you mention do the genotyping and provide quite a lot of interesting information in their reports but it’s not highly personal and is of limited use for clinical decision making. On T2DM for example the information is general, does not quantify, for the individual, the effects of diet, lifestyle, biomarkers and family history on the T2DM risk, nor does it enable personalised treatments, based on all those parameters, to be devised – Eurogene will do all that. A loose analogy could be financial information – if you are a small investor maybe you find enough information for free on Yahoo finance, or with a small subscription to get a bit extra. If you are a serious investor concentrating on a particular sector you will pay a subscription to someone like Reuters or Bloomberg to receive highly specific, detailed information targeted to your sector of interest which will be an important factor in your investment decisions – Eurogene is more like the latter in a healthcare setting (but rather smaller at the moment!).
As the project developed though, the situation has changed subtly, and here come the longer term plans. We are no longer tied to a single commercial genetic test provider and when Sciona left we had to decide whether to continue along the same lines and develop our own tests. We decided not to – there are plenty of genotyping companies out there already and we decided that with the infrastructure and systems that we had developed that our core competency was information interpretation and secure, confidential delivery.
The software tools that we have developed, the Eurogene “Rules Toolset” include several components, the kernel of which is the Modeler – this takes genetic data plus ANY other kind of data (diet, exercise levels, blood analysis markers such as lipids, insulin, glucose, etc) and creates a personal report. The rest of the Toolset includes modules for safe data encryption, transmission and storage; real time generation of updated personal reports managed by the practitioner or customer, through web services, and continual quality control of the algorithms to make sure that the data in is interpreted correctly in the personal report / advice that comes out. The QC module is a very important piece as it also creates a log of all the advice statements created for each report – we think that this sort of exhaustive QC data collection, where we can go back and check what advice / results were given in any particular report from any date will be a key requirement in future regulations (and mistakes can be made – see Daniel Macarthur on decodeme). The system handles information and the end report can be as broad or as specific as needed, it is also interactive so that when you change you diet, or get new blood test results you can create updated personal reports – e.g. it would quantify the risk change for T2DM based on the parameters that change. Of course being an EU project it is also multilingual (the system will also handle Chinese, Japanese, Hebrew, etc), one cool thing about that is that if you happen to require a medical visit while travelling in a different country you can access your account and, with a few clicks, create your personal reports in the local language.
I think you could describe the Eurogene Toolset as a sort of operating system for the application of personal genomics in healthcare, either direct to the consumer or via a practitioner. So now we are even more complementary to 23andme etc. I mentioned above a T2DM model – we are developing this more as a demonstration than as a product – it will allow anyone who already has their results to register with the website (anonymously), input their genetic data plus other personal information (diet, biomarkers, etc) and produce a personal report based on all the elements, not just the genetics. The system can handle all sorts of complexity, I have always been closely involved with NuGO (in fact we held our 2nd workshop at Nugoweek in Italy last year) and we have made sure that the Rules Toolset will be compatible with all the “omics” data once that begins to have clinical applicability.
So longer term…we are a small consortium and the phase 1 funding is over. We are now deciding whether to pursue private funding (we have created a business plan) or whether to look for more public funding, both have their pros and cons. But as we are very clear about what we are and we expect to work with other companies who have, or want to develop, personal healthcare services for which we would provide all of the infrastructure and systems for interpreting data and delivering services. It allows each partner to concentrate on its expertise, we have built a complex set up that would cost several €100,000s and a couple of years to reproduce and we will make it available to companies who want to deliver their expertise through healthcare personal services.
HUGO Matters: What are the major challenges facing the field of nutrigenomics?
Dr. Grimaldi: Although in Eurogene we are moving away from a strictly nutrigenomics field to more broadly cover personal genomics the challenges are similar, and familiar:
Regulations – we need some framework and we need it sooner rather than later. At Eurogene we researched this quite a lot (a review will be submitted for publication soon) and there is basically no real regulation of any sort anywhere except in some isolated cases like the recent German legislation. Even with the strict (widely criticised) German legislation it’s hard to see how it will stop DTC sales into the country over the internet. Our position is that we strongly support self-regulation as I describe in more detail on my blog and the main reasons are time and flexibility – we would be happy to work with any government regulation but that will take too long and will probably be obsolete by the time it comes into force. Look at the reports from the recent #AGBT Conference, sequencing cost is tumbling – what will it be like in 3-5 years time? Our longer term view at Eurogene is that soon there will be so many people with their own DNA results that it will no longer be necessary to offer genotyping to start up a personal genomics company. All you will need is a website and an internet connection to start selling interpretation services – can you imagine the free for all that will happen? Even now with the significant start up costs there have still been some very dubious companies appearing over the last few years, imagine what it will be like when the start up costs will be low. Actually they will be low to start up a poor service, the costs will still be high to provide a real service, providing personal healthcare information and interpreting results is not cheap or easy if it is done properly, but is if it is done badly. We urgently need some movement on self-regulation so that the public (and professionals) will be able to identify who are the credible companies; we need it for the protection of ALL the stakeholders (except the scam companies).
Credibility – this is essential of course but we have all taken hits over the years plus anything involving nutrition is vulnerable. We have to be open and transparent; the companies mentioned above are very transparent but there are several unmentioned who are not. We all have to be careful about our marketing and claims. Episodes like the recent press release of a conference presentation of a trial to support a weight management genetic test does not help. The test may or may not be valid, but weight loss is such an exploited area that much more care is needed and I don’t agree with press releasing a conference presentation to claim scientific validity to help sell a test, any test let alone a genetic test. Until the data are available for scrutiny either online or written up and published then there is no basis for using them as support for sales – I know it goes on all the time in the supplement industry but maybe that’s precisely the point, personal genomics and especially nutrigenomics has to be a long way from the level of the supplement industry – the bar is much higher, maybe artificially higher because of the G-word, but that’s the reality we have to live with.
These are the two main barriers I think – there are many others, e.g. reaching levels where there is undisputed clinical utility & demonstrating it, educating healthcare professionals and providing them with the tools to integrate genomics, to name a couple, but without overcoming the main barriers any long term growth will be painful.
HUGO Matters: Once whole genome sequencing becomes affordable and efficient, how do you think the field of nutrigenomics will change?
Today, I’m pleased to share an interview with Trish Brown, Vice President of Clinical Affairs at DNA Direct. Trish is a board-certified genetic counselor who has extensive experience in personalized medicine and has authored over 45 peer-reviewed posters, publications, and presentations.
DNA Direct is a genetic services company that recently announced their acquisition by Medco Health Solutions, Inc. to further their strategy to bring personalized medicine to the general public. DNA Direct provides genetic counseling support to physicians and patients and also offers direct-to-consumer genetic tests, paternity & family tests, and DNA Archive DNA storage that makes it possible to store DNA at room temperature.
In January, Trish presented at the Personalized Medicine World Conference in Silicon Valley. Her slides are also included below.
HUGO Matters: What do you think are the biggest challenges facing personalized medicine?
Trish: Lack of personalized medicine experts, and lack of access to available experts. DNA Direct has created information technology tools combined with a national call center of experts to provide education, decision support tools, and expert availability.
HUGO Matters: How do you think direct-to-consumer genetic testing and personalized medicine should be regulated?
Trish: DNA Direct is committed to providing responsible, reliable genetic information services and access to testing, when appropriate. We have developed guidelines and services to help ensure appropriate testing for all stakeholders across the healthcare continuum. We believe the industry should be focusing on the delivery of quality healthcare to improve outcomes.
Please leave any comments or questions for Trish in the comments!
A career in genetics and genomics isn’t necessarily limited to the bench or clinic. Attorney Daniel Vorhaus has made a career practicing law in the areas of biotechnology and genomics among others. Mr. Vorhaus is a graduate of Duke University and was a Fullbright Scholar at Lancaster University where he received an MA with Honors in Genetics, Culture and Society. He received his JD from Harvard Law School and is currently practicing law at Robinson, Bradshaw & Hinson. Dan is also ELSI Advisor to the Personal Genome Project and Editor of the widely-read and greatly respected Genomics Law Report.
HUGO Matters is pleased to share the following interview with Mr. Vorhaus. If you have any questions, please leave a comment!
HUGO Matters: How did you arrive at a career in law specializing in genomics and personalized medicine?
Dan Vorhaus: After I finished my undergraduate degrees, I studied with Ruth Chadwick in the UK, which is where I first tacked in earnest the ethical, legal and social issues – as well as the science – associated with human genetics. That was a fascinating time for me and I showed up at Harvard Law with a ton of excitement about becoming a genomics lawyer.
There wasn’t much of a curriculum there in genomics or biotechnology at that time (although that really changed a few years ago when the Petrie-Flom Center opened) but, fortunately for me, I ran into George Church who was just getting the Personal Genome Project up and running. For those that know George, he is tremendous at saying “yes,” even with near-total strangers. I asked if I could help out with the PGP, which struck me as a truly innovative model across a number of dimensions, and George not only said yes, he started handing me substantive projects right away. It was a bit of a crash course but the PGP presented so many interesting legal questions to consider – as it still does today – that it really accelerated my learning curve.
My other big break was coming to work for my current firm, Robinson, Bradshaw & Hinson, here in Charlotte, NC. RBH has been unwavering in its support of my work over the past several years. In addition to continuing to support my work with the Personal Genome Project, they also encouraged me to develop our genomics and personalized medicine practice, which included the launch of the Genomics Law Report last spring. It has been a lot of work over the past few years, but the support from my colleagues at RBH has made it possible.
HUGO Matters: What do you think are the most interesting and important legal issues currently facing the field of genomics and personalized medicine?
Dan Vorhaus: One of my favorite aspects of this job is that it is so dynamic. The underlying science and technology evolves so rapidly that, at this point, law and policy have little hope of keeping pace. That’s created a patchwork quilt of law and regulations surrounding genomics and personalized medicine. A lot of what I do for clients, particularly the researchers, entrepreneurs, companies and investors that are at the leading edge of personal genomics, involves mapping out a development strategy that minimizes risk by both addressing existing laws and regulations and anticipating where new changes or complications are likely to arise. So the issues are really quite different depending on which client I’m working with in a given day.
That said, there are a few key challenges facing the field today. One is the intellectual property landscape in biotechnology, particularly within the personalized medicine space. There are ongoing legal and policy battles over the future of biotechnology patents, including the gene patents that are the subject of so much discussion in the Myriad Genetics litigation. There is also considerable uncertainty, at least in the United States, about when agencies such as the FDA are going to take a more active role in regulating personal genomics technologies, particularly the growing array of what are known as Laboratory Developed Tests (LDTs).
More fundamentally, as personal genomics begins to play an integral role in the lives – not just the medical care, but the day-to-day lives – of more and more individuals, the issue of how to manage individualized genomic information safely and responsibly is going to come increasingly to the fore. The United States enacted the Genetic Information Nondiscrimination Act (GINA) in 2008, and that was an important step in the right direction, but it’s only one piece of the puzzle. I think most individuals, policymakers and regulators that are looking at personal genomics are still trying to figure out how to sensibly collect, store and communicate genomic information. That’s going to become an increasingly pressing issue as the cost of genomic sequencing continues to fall and more people gain access to personalized genomic information.
HUGO Matters: What advice would you give to students and young scientists interested in a career outside of the ivory tower?
Dan Vorhaus: Don’t be intimidated if you don’t immediately see the opportunity you’re looking for. With all of the social media tools out there now it’s easier than ever to network and explore until you find something that catches your eye. And if you have a lightly traveled (or completely novel) career path in mind, look for people that are good at saying “yes” and that are willing to let you take chances.
Also, if you do decide to explore the world outside of the “ivory tower,” you should be certain that you know how to find your way back for frequent visits. I spend a lot of time meeting with academics – as well as reading scientific journals – in my attempt to keep current with the basic science, which is important because that’s invariably what will serve as the basis for one or more new companies in a year or two. I think you can get away with being largely insulated if you intend to stay in academic, but it doesn’t work the other way. If you go out into the public or private sector it’s important to maintain close ties with what’s happening in academia.
Thank you for the interview, Dan! Please feel free to leave comments and questions following this post.