Interview with John Mattick: On RNA, the rise of genomic medicine and more

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 DNA that doesn’t code for proteins in the genomes of humans and other complex organisms may constitute another level of genetic information that was 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 HUGO Chen Award for Distinguished Academic Achievement in Human Genetic and Genomic Research for his innovative approach.

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.