Building an open access forum for N of 1 studies
Ahead of the launch of new journal Molecular Case Studies, Editor in Chief Elaine Mardis told us the story behind this new journal.
Launched this month, Cold Spring Harbour Molecular Case Studies, to give the journal its full name, presents genomic and molecular analysis of individuals or cohorts alongside their clinical presentations and phenotypic information.
“With so much individual sequencing going on in so many places, we have created a new type of journal designed to rapidly communicate studies that utilize ‘omic’ data to solve patient diagnoses and uncover new treatments,” said Elaine Mardis, MCS Editor-in-Chief. Dr. Mardis currently also serves as Robert E. and Louise F. Dunn, Distinguished Professor of Medicine, and Co-Director of the McDonnell Genome Institute at Washington University.
This interview first appeared in issue 3 of Front Line Genomics.
A lot of individual sequencing is taking place. It’s about time that these ‘N of 1’ studies had an open access home. Elaine Mardis has added to her, already impressive, list of achievements and done just that – creating a new journal, molecular case studies, with CSHL press.
Elaine Mardis is one of the true ‘Rock Stars’ of genomics. But what elevates someone to that status? A big part of it is seeing the opportunity to go further with what’s available.
She was at the very forefront of cancer genome sequencing in the mid 2000’s. This was a big paradigm shift at the time, and one of the major steps that has defined modern genomic practice. Having learned so much from one genome, it’s no surprise she also recognises the value of today’s N of 1 studies.
We spoke with Elaine to find out how and why she came up with the concept of Molecular Case Studies – the new journal she now takes charge of as Editor In Chief.
FLG: Elaine, looking through your impressive biographical notes, it seems clear you were destined for the world of science from an early age.
EM: I’ve always had a love of science, even from a young age. I recall finding one of my father’s textbooks from his college days, on Zoology, and seeing a picture therein of the duckbill platypus, for the first time. I was captivated by that enigmatic creature, and years later we sequenced the genome of the platypus. So, that brought me full circle, I suppose!
FLG: Your undergraduate degree in Zoology, and PhD in Chemistry and Biochemistry, (both obtained at the University of Oklahoma) is where your curiosity in molecular biology can be traced back to. I guess this led to you becoming interested in DNA sequencing?
EM: During my senior year at OU, I took a course in Biochemistry that was taught by Bruce Roe. I was so captivated by the notion of biochemistry and molecular biology, especially the way he taught it, that I began to visit during his office hours to discuss more. Bruce had recently taken sabbatical in Fred Sanger’s laboratory at the MRC about three years after the 1977 paper describing the Sanger dideoxy method. He was passionate about DNA sequencing and really set up one of the first labs in the US to pursue the Sanger method. I was really just one of many people trained by Bruce who have pursued DNA sequencing in their careers. Perhaps the best other example is my current “partner in crime” at the McDonnell Genome Institute at Washington University, Rick Wilson, who got his PhD a couple of years before I did.
FLG: Having finished your PhD in 1989, when the notion of sequencing the human genome was just gaining traction, alongside hard work, how important a role would you say luck has played in your career – of being in the right place at the right time?
EM: I would say that luck has played a major role in my career! Other than knowing I wanted to be in science for my life’s work, I had no other concrete plan as to how this might be achieved. I feel like my life has been a series of incredibly lucky events and I still feel like the luckiest person in the world to get to do this for a living.
FLG: In 2008, you produced your breakthrough paper in which you reported whole genome sequencing of a tumor genome. Can you take us through that journey?
EM: Absolutely. We had begun a program project funded by NCI with Tim Ley to uncover the genetic underpinnings of acute myeloid leukemias (AMLs), that involved PCR and capillary sequencing of candidate genes. After three hard years of work, we hadn’t uncovered too many new genes and this was coincident with our betatesting of the Solexa 1G sequencer (that later was bought by Illumina). So, Tim, Rick and I began to discuss what it would be like to simply use the Solexa instruments we had and take an unbiased look at the AML genome—rather than trying to predict which genes we thought would be mutated, we would instead let the genome tell us what had gone wrong. So, we worked with our colleagues to devise a proposed coverage (we settled on 30-fold) that should cover the genome, and we wrote 10 genome pairs (tumor + normal) into our next five years of the project budget (2 per year). Of course, this was not reviewed favourably and we were asked to resubmit. Realizing this was much too “soon” for conventional funding, we turned to a local philanthropist, Alvin J. Siteman, and asked for the $1M we thought would give us sufficient funding to sequence one patient. That was AML1, our first patient and the subject of our Nature 2008 manuscript. It was only a single case, but we learned so much!
FLG: You’ve recently taken on the role as Editor-In-Chief of Molecular Case Studies. Launched in the Spring of this year, the journal’s stated aim is to bring a more rapid peer-review process to publication. Can you give an overview of the fields covered and, indeed, what prompted you to become involved with the project?
EM: The journal was an essential concept that I had come to, seeing how much individual sequencing was going on in so many places for different reasons, and knowing that a mechanism to communicate “N of 1” studies was going to be vital to helping these different sites stay abreast of what other sites were generating to helping everyone understand new variants that were being identified, treated, and used in diagnosis. I brought the idea to several entities in the scientific publishing business, and the folks at CSHL Press did some investigational work and came back to me with the proposal to start the journal. This is not a sequencing-only journal, as we encourage other reports that utilize “omic” data to solve patient diagnoses or to uncover new treatments, etc.
FLG: There is a growing weight behind the call for more open access publications. Are we finally seeing a gradual change toward this?
EM: I quite agree. For MCS, open access is critical to the mission and success of the journal, allowing engagement from scientists, clinicians, and patients. All of the papers will be published continuously online and can be read by anyone, facilitating the rapid dissemination of potentially clinically relevant insights into disease and treatment options. To be clear, we are keen to publish open access n of 1 studies, but of course we must balance this with respect for patient anonymity and other legal restrictions on sharing patient data. In general, we’ve seen only positive feedback for these central tenets of our approach.
FLG: With advertising and subscription revenues supporting publications, there are many who feel submission fees are unjustified. The purpose of peer reviewed publishing, is to create a critical forum for knowledge sharing, is there a risk of the commercial element working against that goal?
EM: It’s a fair question, but I must point out that for MCS, there are no subscription or submission fees, and all articles are free online for anyone to read. To cover the costs associated with publication, the authors pay an Open Access fee per paper, which is on a sliding scale. Since CSHL is a not-for-profit research and educational institution, the launch of MCS is fully in-line with their mission.
FLG: It’s easy to see the publisher as ‘the bad guy’ in some of this, but often times there is some naivety around what goes into producing a journal. Is there anything that has surprised you or that you think would surprise people about the work that goes on behind the scenes?
EM: Other than it’s a lot of hard work? I guess there probably isn’t anything too surprising other than the difficulty in getting people who you really think would be good to volunteer their time for the peer review. It’s a fundamental worry that I think a lot of us have, that ensures the science being presented is rigorous and well controlled.
FLG: The ultimate goal of an n-of-1 trial being to determine the optimal, or best, intervention for an individual patient using objective data-driven criteria. Now that there is a publishing home for this kind of study do you believe n-of-1 trials will have an increasing role in clinical science?
EM: I think the primary impact of “N of 1” studies will initially be to generate a recognition that the pursuit of these studies can and will have clinical utility, to help patients receive appropriate therapy or diagnosis or both. Perhaps the underlying value of these studies will be to emphasize how much better the collective sharing of information can make our medical pursuit of excellence for every patient.
FLG: Coordinated n-of-1 trials have the potential to radically change the way in which evidence-based and individualized medicine is pursued, how do you foresee the development of benefits going forward in terms of patient care?
EM: The primary benefit will be to emphasize the clinical utility that is brought to bear on individual patients by these trials. There already are groups accruing the data and evidence to support this clinical utility. However, we are experiencing many of the same barriers to effective implementation and one hope is that open access information sharing will ease at least a few of these barriers to implementation. Here, I wish to emphasize that even negative results that could be informative to others are of interest at MCS.
FLG: With your work at Washington University continuing to help refine the completion of the human genome, in close collaboration with the NCBI (National Center for Biotechnology Information), how do you perceive the next steps in the sequencing project’s future?
EM: The continued improvement of the reference genome, the generation of additional high quality reference genomes should tell us collectively what we miss by alignment of short read data to a fixed reference. I think future-forward that our large-scale studies will be accelerated by these genomes-to-genome comparison data and will help us think of new and accelerated analysis paradigms.It’s much like high-energy physics, which has a penchant for only keeping data from new, never-documented events that occur in the superconducting supercollider, and throwing out the events that already were seen. At some point this might be our approach to genomics as well.
FLG: Do you have any advice for you scientists embarking along a career path in respect of technological development and its applications in translational research?
EM: I think the best advice I could offer is as follows: 1) be a good collaborator by having respect for the expertise others bring to bear on the problem you all care about solving, and 2) insist that they do the same regarding your contributions. Team or collaborative science can be such an amazing enterprise when everyone respects each other and everyone contributes equally, with enthusiasm and a shared set of goals.
FLG: There is increasingly wider attention on female representation within the genomics field. Bioinformatics is one area in particular that is heavily male dominated. When you ask people who the most famous female in genomics is, you’re almost always the first name people think of. In contrast, people will give a list of names when asked from prominent men in the field. Is this still an artefact of slow changing social prejudices? What should we be doing to make the field a more attractive career path for women, and ensure that they get the same opportunities to take on leadership positions?
EM: So, firstly that is surprising to me—there are many, many successful women in genomics besides me. I always have felt that genomics had an advantage over engineering or physics in that it is a relatively “new” discipline and was therefore quite attractive to women because established roles and gender domination wasn’t yet a problem. I am sensitive to the fact that women tend to not stay in science due to their desire to fulfil other roles such as that of primary caregiver to children (and sometimes to aging parents). I’m not sure how that can be fixed, however. It’s a complex problem.
FLG: Despite some of the discontent felt at times, Genomics is an exceptionally exciting field at the moment. Whether it is the advances in technology, the applications they open up, or the new influx of expertise from computer sciences, there’s a lot to get excited about. What is capturing your imagination most at the moment?
EM: The most interesting thing to think about is how many different groups of very smart researchers are focused on the many aspects of precision medicine, and how interdisciplinary these pursuits have become. It’s an educational opportunity for those involved to learn about new areas of expertise, to share the collective intellectual pursuit of a problem, and to hopefully break new ground in how medicine is practiced. I am personally captivated by work going on that fuses genomics with cancer immunotherapy, and I think there will be dramatic advances in this area over the next few years.
FLG: Thank you so much for your time. You’re reputation as not only a rock star of genomics, but also one of the nicest people around, is very well deserved. Before we wish you the best of luck with Molecular Case Studies, is there anything else you would like to say?
EM: Only that the success of MCS will be due to the many contributors of research reports to our journal. I sincerely hope everyone will consider submitting their case studies, so we can achieve our mission whilst effectively, quickly and freely communicating the results.
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