About a month ago, I attended the ‘Beyond the Genome (BTG): Cancer Genomics’ meeting in Boston—my second conference as Chief Editor of Nature Protocols (my first was the 2014 ARR meeting at the University of Sussex). The BTG meeting grabbed my attention for several reasons; firstly, the topic was more-or-less within my comfort zone; secondly, there was a heavy focus on bioinformatics (a rapidly developing and important field); and thirdly, the line-up was fantastic. Fortunately, it was a small meeting so I was able to pin down several of the key speakers, including Fred Alt, Gad Getz, Peter Park, Nuria Lopez-Bigas, Mike Schatz, Nils Gehlenborg, and Rosalie Sears, and poke my head into some of their ‘labs’ (offices).

Given the bioinformatics focus of the meeting, it is perhaps unsurprising that many of them spoke about the need for easy-to-follow instructions for biologists branching out into bioinformatics and using complex computational tools for the first time. As Peter Park pointed out to me, “biologists and bioinformaticists speak different languages, and few journals seem to bridge this gap”. As it happens, some of our most popular protocols (e.g. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources, which has been cited almost 4,000 times) fit this bill perfectly, providing clear, concise, step-by-step instructions for using popular bioinformatics tools and software packages. Written by bioinformaticists, reviewed by biologists and bioinformaticists, and edited by (ex)-biologists, these protocols help researchers without a bioinformatics background to analyse their data themselves. Given the popularity of these protocols and the growing importance of bioinformatics within the biomedical sciences, this seems like an obvious area for expansion of the journal (so watch this space!)

With more than 40 talks over three days, a comprehensive overview of the BTG meeting is out of the question, so instead I will highlight a few of my favourites. On the first day, Gad Getz opened the talks with a discussion of MutSig, software developed by his group for identifying driver genes (by analysing lists of mutations and territory covered during sequencing) and building models of the background mutation processes that occur during tumour formation. Jan Korbel stepped up next, explaining the system he has set up for constructing maps of unbalanced SVs based on whole-genome DNA sequencing data. At the end of the day, Fred Alt spoke passionately about his recent work on high-throughput genomic translocation sequencing (HTGTS) strategies to identify translocations that arise from fixed DSBs, as well as sites of endogenous genomic DSBs.

The next morning, Rosalie Sears gave an interesting talk on the use of 3D tissue bioprinters to generate tumour tissue, as well as normal healthy tissue. Printer ‘ink’ 1 (consisting of endothelial cells, fibroblasts, and immune cells) is added first; printer ‘ink’ 2 (cancer cells) is then added to look at tissue distribution and assess cell interactions. Unfortunately, only a few labs have access to such advanced technology but this could change over the next 5-10 years as the set-up cost inevitably drops. Later that day, Lynda Chin talked about data she has collected using ChromHMM, a computational tool set up by Ernst and Kellis for predicting chromatin ‘states’ (based on combinations of chromatin marks) and characterizing their biological functions.

On the third and final day, Mike Schatz kicked off proceedings with a ‘bioinformatics challenge’ relating to single-cell CNV analysis. The challenge has become a regular feature of ‘Beyond the Genome’, encouraging students, postdocs, and analysts in the audience to get “down and dirty with data to solve an informatics problem as quickly as possible” (as Mike puts it). The task opened up to the floor this year (“should you chose to accept it”) was to resolve the population structure of a collection of cells, establishing which cells were in the same clone and, for each clone, which was the most highly amplified oncogene. Schatz provided data for simulated single-cell sequencing of a population of 9 cells with 250k reads per cell (all for chromosome 1 (not whole genome) at 0.5x coverage). He also provided a list of 100 candidate genes. As this coverage is too sparse to identify point mutations, the genome must be divided into “bins” (with 50-100 reads/bin) before mapping the reads and counting reads/bin. Copy number variations in a single cell can be identified as bins with significantly fewer or significantly more reads, and the population structure can be examined by finding cells with the same patterns of bin counts (see our Protocol on this).

After an initial flurry of activity as people rose to the challenge, the audience settled down to hear Nils Gehlenborg talk about the applications of StratomeX, an interactive visualization tool he developed in the Park lab to compare differences in molecular profiles across patient sets. Then, just after lunch, Schatz announced the winner of the bioinformatics challenge; René Böttcher, a PhD student in Guido Jenster’s lab in the Erasmus Medical Center in Rotterdam, was the first to solve the challenge in just over 1 hour (congratulations, René!). As the closing remarks drew nearer, Peter Park gave a fantastic talk on the different single-cell sequencing approaches, with tips on comparing data obtained using different techniques (e.g. GC bias with MDA sequencing, better read-depth stability at large scales with MALBEC than with MDA, more consistent depth at small scales with MDA, etc.). Shortly afterwards, a sea of smiling faces left the auditorium, with many promises to return next year.

It was my first visit to the Emerald Isle, and most definitely worth it. However short, my three-day permanence in Belfast to attend The 15^th International Meeting on Human Genome Variation and Complex Genome Analysis (HGV2014) was fruitful and thoroughly enjoyable.

I flew from London Gatwick to Belfast International Airport on an early morning flight on September 17^th, never a good start of the day; not for me at least, given my long-term experience with low-cost flights that leave REALLY early in the morning bound for my native Sicily from London, the city I have emigrated to, and where Nature Protocols is based. You’ve got to suffer to go Sicily, it seems — and be mildly uncomfortable to go to Ireland.

Well, the discomfort did not last long. As soon as I climbed onto a cab just outside Belfast Airport, the friendly cabbie exclaimed “Culloden? It’s the best hotel in Northern Ireland, sir. Five stars, you know?” Culloden Estate and Spa was to double as the venue of the conference and my hotel accommodation. That review by an undoubtedly knowledgeable local sure felt nice to hear. Time to relax on the back seat of the car and take in the scenery on that drizzly morning as the cab drove for about 35 minutes through the Irish countryside, skirting downtown Belfast, before arriving at Holywood, the Belfast suburb where Culloden Estate and Spa is located. The castle-resembling hotel is immersed in quite spectacular greenery, both within and without the hotel grounds, and the hilly locale overlooks Belfast Lough, the deep inlet of the Irish Sea at the end of which is located Belfast, with its harbor. When the cab pulls over by the main entrance of the Culloden, a man in impeccable grey tail-coat and top hat opens the car door for me with a smile. Wow, that’s not the kind of treatment the average former chemistry researcher is accustomed to…

Time to check in, undo my suitcase in my room, and walk to the event room to register for the conference. There, I am handed my name badge “Baldo Lucchese – McMillan Publishers” by Sinead Lawlor, the über-efficient overseer of the conference organization. She explains to me that the conference will be attended by 126 participants, ten of them exhibitors (I think I am included among those ten), and there will be 54 research poster presentations. A pretty manageable conference size-wise from my standpoint. Among the participants are also three researchers who have written protocols for our journal, Dr. Ido Amit of the Weizmann Institute, the corresponding author of High-throughput chromatin immunoprecipitation for genome-wide mapping of in vivo protein-DNA interaction and epigenetic states, and doctors Yves Moreau and Thierry Voet of the University of Leuven, co-authors of Microarray analysis of copy number variation in single cells. Always nice to find one’s footing in that sense at a conference.

Time to dive into the talks. We are welcomed to HGV2014 by this year’s conference organizer, Dr. Mark Lawler of Queen’s University Belfast, who has also been instrumental to my attendance. As he will explain to me the next day, he moved from Dublin’s Trinity College — Mark is actually a native Dubliner (don’t they say “Dub”?) — to Belfast’s Queen’s University barely a year and a half ago, so it has been quite the struggle for him to organize HGV2014 in his new hometown. You surely wouldn’t have guessed from the results, however. I couldn’t be happier with my accommodation, the conference will progress smoothly and the talks will prove excellent.

HGV2014 is articulated into seven sessions distributed over three days, which will include a total of 36 talks and three round-table discussions. Of the 33 speakers from academia and the three from industry, the vast majority hail from either the British Isles or the US, although there are also a total of eight speakers from Canada, Italy, Belgium, Germany, and Israel.

The first of talk of the first session, “Interpreting the Human Variome”, is given by Dr. Pui-Yan Kwok of the University of California San Francisco, a member of the organizing committee and a veteran organizer of this conference. The talk, “Structural Variation in the Human Genome”, seizes my technique-oriented, Nature-Protocolly (warped?) mind. One of Dr. Kwok’s group research focuses is the study of structural variations of the human genome, variations like gene deletions, insertions, duplications, inversions and translocations. Many of these features are associated with particular diseases and disease phenotypes, but they are often hard to identify and define using whole-genome analyses, which rely on the mapping on short DNA reads ‘chopped’ from the full length genomic DNA and matched to a reference genome. This approach can provide ambiguous information when it comes to identifying, for instance, the number of times a gene is repeated in sequence along a stretch of genomic DNA, a rather important parameter to measure in some research and clinical contexts.

Dr. Kwok’s laboratory, in collaboration with BioNano Genomics Inc., a company based in San Diego, California, has developed “Genome Mapping in Nanochannels”, a technique that is particularly suited to identifying structural variations in the genome. In this approach, instead of being reduced in size, long stretches of human DNA are first nicked at several positions on only one DNA strand using a nicking endonuclease expected to nick about 12 times every 100,000 bases. These nicks are then repaired using fluorescent nucleotides and the full-length DNA molecules are then uncoiled and forced to pass through narrow parallel nanochannels, in which only one DNA molecule can fit at a time. The DNA molecules are then photographed as they move along the nanochannels. Given that the nucleotide sequence recognized by the nicking enzyme is known, that a reference genome exists, and that one obtains clear images of where the fluorescent nucleotides have been inserted along the genomic DNA stretch, a researcher can now, for instance, literally count on a photograph the number of repeats of a particular gene. Using this approach, Pui-Yan Kwok’s research group believe to have closed some of the sequence gaps in the human genome, its ‘grey areas’ of ambiguous sequence assignment that are probably due to the presence of structural variations.

The following Session II, “Tracing and Targeting the Tractable Cancer Genome”, was in principle a bit too focused on clinical research from the standpoint of Nature Protocols remit; nevertheless, it did rouse my curiosity. The lecture by Dr. Lillian Siu of the University of Toronto was particularly thought-provoking from my layman’s point of view. Lillian Siu’s research focuses on the study of inter-patient and intra-tumor genomic heterogeneity in the context of cancer. It has been known for years that cancer patients with specific genetic signatures tend to respond (or not respond) to specific drug treatments in a somewhat predictable fashion. Such genetic heterogeneity is the basis of the so-called personalized medicine approach to treatment. Dr. Siu sketched for the audience the clinical trial designs that take into account genetic heterogeneity. At one end is the ‘umbrella trial’, in which all participants share the same tumor type (for instance lung cancer), according to histology results, and they are assigned to different drug treatments based on their relevant genetic aberrations. At the other end is the ‘basket trial’, in which patients with different cancers based on histology are pooled together into treatment groups based only on their genetic aberrations, irrespective of histological evidence. Finally, she described the N-of-1 trial design, which consists of a comparison of the results of two different treatments applied to the same patient: in this trial design, time-to-progression in a patient on a genotype-matched treatment is compared to the same parameter in the same patient when he/she was on a prior, and presumably non-genotype-matched, treatment.

At the end of this talk, a calculatedly provocative question from a member of the audience rang: “So, are randomized, controlled trials a thing of the past?” Well, given my background as former associate editor at Nature Reviews Nephrology and Nature Reviews Gastroenterology and Hepatology, this question made me sit up: aren’t they the gold standard for medical trials? Lillian Siu clearly did not want to be drawn into sweeping generalizations, but she explained that, in a genotype-matched drug clinical trial, tumor responses may be sufficiently significant and objective for conditional drug approval of the drug to be granted in some cases. In this context, she thought that, prospectively, randomized trials are likely to become less and less prevalent, given how exhausting they can be for research resources as well as for patients. It sure was a treat to witness this exchange…

The next day’s morning session was entitled “Phenomes, Genomes and Archaeomes: Solving the Conundrums”. I have had a small obsession for studies on ancient DNA genomics for a while, so it came to no surprise to me that I found the talk “Ancient Population Genomics: Do It All or Not At All” by Dr. Dan Bradley of Trinity College Dublin, particularly exciting. As Dan Bradley reported, a key difficulty when working with ancient DNA is that when collecting DNA from a typical ancient human bone sample, only about 1% of it is DNA from the original owner of the bone, the rest is leftover from various contaminations. He and his research group have used bioinformatics tools that enable researchers to sift through the sequencing data from ancient DNA that does not need to be particularly pure to infer which sequences pertain the individual to whom the biological sample belonged and which are, instead, due to contaminants.

Dan Bradley reported results from his group and collaborator’s research that help shed some light onto the population and cultural changes that Europe underwent between the Mesolithic through to the Iron age, via the Neolithic and Bronze age. One of the overarching questions his group has been trying to address is whether age-defining technological/cultural innovations were exchanged ‘osmotically’ between populations or whether such dramatic changes, for instance from a hunter-gatherer culture to an agricultural one, are associated with new human populations displacing the previously resident ones. Although their data on this subject appears to be a bit of a mixed bag, evidence seems to indicate that in most cases an age-defining technological or cultural shift also coincides with a population replacing or pushing aside another. Well, it does make sense in a sad sort of way.

Session IV “Answering the Global Genomics Challenge — Time to Step up to the Plate”, late morning on September 18^th included talks that focused on ongoing international efforts to sharing genetic data across research centers and across countries to share evidence about genetic mutations and how they may be associated with the onset of, or the predisposition to, disease. Dr. Anthony Brookes of the University of Leicester, among other projects, recounted the design and purpose of Cafe Variome project. This project in particular stuck to my mind because the previous day I had had the chance to talk about it with Dr. Owen Lancaster from Brookes’ lab, who was presenting a poster describing Cafe Variome.

As Owen also clarified for me, Cafe Variome tries to shift the basic nature of the problem of accessing data on mutations and phenotypes that, despite their high potential usefulness, are currently not being openly shared due to legal, ethical or competitive reasons. Cafe Variome tries to clear this roadblock by providing a platform whereby the existence rather than the substance of the data is made accessible to subscribers. Once these discovery ‘hits’ are achieved, the platform facilitates exchange of the data in the form the most suits the relationship between data requestor and data owner: data summaries, data displays, data links, data owner contact details, or a form for data automated data request and subsequent provision.

Presently Cafe Variome, which is hosted by the University of Leicester, supports networks of rare disease diagnostic laboratories or research consortia that share an interest in certain causative genes or diseases, know and trust each other to different degrees, and wish to have a full picture of what records and information exists across the collaborating network. Six such federations are currently trialing the platform, and, Owen explained, one of them will be shortly opening up their content also for public discovery. Well, fascinating stuff for someone like myself who is a bit obsessed with data sharing and privacy, particularly when it comes to genetic make-up. Sooner or later I should write a post on that too…

Session V, “Improving our Health: Time to Get Personal”, was particularly engaging. In the first talk, “Personalised Cancer Medicine: Are We There Yet?”, Mark Lawler described the efforts and purpose of the European Alliance for Personalised Medicine, of which he is a member, an international association that aims to promote personalized medicine and its delivery in the health systems of European countries and to develop patient-centered European translational research platforms. It was clear how much enthusiasm and personal stake Mark has in promoting personalized medicine in the context of cancer treatment, but from the last talk of the session it was also clear, at least to me, that he does not take himself overly seriously, and he is quite open to discussion.

The last ‘proper’ talk of this session, aside from being quite entertaining, was rather unusual in that it was given by Professor Timothy Caulfield, a researcher in the area of health law, biotechnology policy and bioethics. The title of talk, “Marketing the Myth of Personalized Prevention in the Age of Genomics”, already conveys a lot of the tone of this presentation. Timothy Caulfield is a bit of a skeptic of personalized medicine, and he started his lecture by thanking Mark Lawler for inviting him to talk at the conference despite his stance and, presumably, he implied, as a way to kick-start a lively discussion. Caulfield does not believe that the prevention of common diseases is likely to be affected by personalized medicine. Progress in genetic research, he argues, has been hailed as heralding a ‘revolution’ for decades now. But this revolution has yet to materialize. He is also rather offended by what he calls ‘science-ploitation’, via which for-profit companies, even those commercializing beauty creams, for instance, claim that their products can be targeted and tailor-made to suit the personal needs of customers based on their genetic make-up. A number of sleek commercial ads with portentous ‘scientific’ claims succeeded each other on the screen at various times as Caulfield gave his presentation.

The core of his objecting to the promotion of, for instance, widespread genetic testing in the healthy population in the wake of the personalized medicine ‘revolution’ lies in the research that points to the fact being made aware of a predisposition to a particular condition or disease does not change the behavior of individuals to any significant or measurable level. Focus on genetic testing and personalized approach when it comes to public health policies, he argues, shifts responsibility from the political and social level to the individual, when it is proven that only ‘general’ policy decisions can spur changes in social attitudes and, ultimately, change the behavior of individuals. To drive home the point about science-ploitation of the concept of personalized medicine, Caulfield recounted how he had had his genome sequenced by an American commercial company. Caulfield shared with the audience some of the results he had obtained, which meant that he had a slightly elevated predisposition, compared to the average, to a few medical conditions. The ‘bespoke’ advice that he received from the commercial company was to exercise, drink in moderation and not smoke… So much for the personalized prevention regime; point made, I’d say. Science-ploitation… That’s a word that I’ll end up using a lot, I’m guessing, sorry Professor Caulfield.

This session was capped by a round table discussion entitled “Prime Time for Personalised Medicine”, which had a TV talk-show format, in which the chair, conference co-organizer Dr. Stephen Chanock of the National Cancer Institute, Maryland, moderated the discussion of a five-membered panel that included also Timothy Caulfield, Mark Lawler, and Lillian Siu. Of course different points of view and opinions were shared during the discussion, but the panel ultimately agreed that the sensationalization and mis-representation by the general interest and popular press and by commercial companies of the results and implications of genetic research are a significant problem for the scientific community. However understandable sometimes, these tendencies could ultimately harm genetic and genomic research itself. A tentative solution proposed by several of the panelists and a few members of the audience was for scientists to become more actively involved in the public discourse about genomic and genetic research, so as to offer additional means for the public to correctly frame this discussion and interpret the significance of research findings. Proposals were made that scientists should try, for instance, to make themselves more savvy and effective in the use of social media like Twitter, although some confusion immediately ensued this proposal as some panelists and members of the audience couldn’t initially agree on the character limit of twitter feeds. Nevertheless, it was an encouraging start all in all, given that the matter was eventually correctly settled: that limit is 140.

An excellent conclusion of the day’s lectures, before the gala dinner of the conference, which took place at the Titanic Signature Building, an attraction that opened to the public in 2012 and is located in the section of Belfast harbor where the RMS Titanic was built. This building, which is exactly as tall as the Titanic’s highest tip, hosts a multi-storey, multimedia museum themed on the building and ultimate sinking of the Titanic. Us conference participants were taken on a guided tour of the museum that chronologically followed the Titanic (mis)adventure and that culminated in a viewing of the striking underwater footage of the wreck of the Titanic shot from a deep-sea submersible in the 2004 expedition undertaken by marine explorer Robert Ballard together with the National Oceanic and Atmospheric Administration (NOAA). Naturally, a very fancy and very satisfying dinner followed, made particularly enjoyable by light conversations with my table mates, researchers from Spain, the Philippines via California, Britain, and Sweden.

The last day of the conference was dedicated to sessions VI, “Understanding the Evolving Genome”, and VII, “Next-Gen ‘Omics and the Actioanable Genome”. It was also the day of two Sponsor Presentations, one of which was by BioNano Genomics Inc.’s Dr. Han Cao, “Towards the True Contiguity Resolving the “Dark Matter” of Genome”, which covered also the technique already introduced on the first day of the conference by Dr. Pui-Yan Kwok for Genome Mapping in Nanochannels, and that BioNano is currently applying also to the study of non-human genomes. As mentioned, pretty fascinating stuff from the point of view of a technique-biased scientific reporter.

Talking about techniques, the last day of HGV2014 was also dedicated to giving awards to the best posters. In advance of my attendance of the conference, Nature Protocols had proposed to award a one-year online personal subscription to the journal to the presenter of the poster describing the most interesting technique, and Mark Lawler had been immediately enthusiastic and supportive of the idea. As I walked around speaking with poster presenters, I also got to chat with Nature Protocols authors Ido Amit and Thierry Voet. They were possibly being nice, but they both told me that they enjoyed their experience as authors of our journal, and they considered Nature Protocols a very useful resource. It may not be statistically significant with just two subjects, but they both ended up putting more work than they had anticipated into their Protocols, but they felt it was entirely worth it. A quiet sigh of relief on my part welcomed the conclusion of their reflection. Surprisingly, both of my interlocutors, to whom I spoke separately, by the way, also felt that it would be of great help if Protocol authors could submit video tutorials alongside their manuscripts. Fact is, however, that authors can already do so, and a minority of the Protocols we publish do come with supplementary information in the form of videos. Clearly, we must do more to make our authors more aware of this possibility.

Going back to the posters, maybe unsurprisingly, Nature Protocols, in its yours truly incarnation, decided to award the prize for the poster describing the most interesting technique to Dr. Angel Mak, a post-doc in Puy-Yan Kwok’s University of California San Francisco laboratory, for the poster entitled “De novo genome assembly and structural variations detection by genome mapping in nanochannel arrays”. Of course, the technique described in the poster is none other than Genome Mapping in Nanochannels, already described in Dr. Kwok’s lecture two days earlier. My sincere congratulations on your research work Angel! But I had a wonderful time looking up all the posters and talking to several of the presenters. Very exciting work being presented by each poster, and thank you to all the researchers I spoke to, none of whom let transpire any disappointment at the dumbness of some of my questions.

It was Friday after 4 pm by the time I announced the winner of Nature Protocols’s prize, and it was time for me to catch a cab to go to the airport. I had to give a miss to the Irish Night — Whiskey Tasting Experience and Culture Night Performance Including Broadway Acclaimed Actor Eilin O Dea, organized for 5.30 pm that evening. A London night was beckoning for me; not that I had anything special planned, in fact I had nothing at all planned, but even with my relatively early flight from Belfast, I did not reach home till 11 pm that night. Sadly, I’m too old for anything more lively than that. And hey, now I’ve got an excuse to go back to Belfast and complete the Northern Irish experience…

Thanks a lot Mark and thanks a lot HGV2014 participants for the excellent time all around!