contents - Front Line Genomics

JANUARY ISSUE 2018 www.frontlinegenomics.com

File size/GiB 80

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NA12878J Illumina Hi-Seq-X 30x WGS human sample

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WELCOME I

I would like to kick off the first issue of the year by wishing you all a very Happy New Year! The arrival of a new year is always an exciting one for us at FLG, as it usually means that our very own Festival of Genomics London is right around the corner. We will be taking over the ExCeL Centre on 30-31 January, to discuss some of the most talked about topics in the field right now, brought to you by an impressive line-up of speakers. With the festival taking place in the heart of the UK, it only felt right to use this issue to celebrate all of the important work being carried out in Europe, and in particular London. That’s why nearly everyone included is in some way involved in the Festival. You’ll also notice that we have given our news pages a revamp. They have been transformed to reflect the four key themes: drug development, genomics in the clinic, enabling data and CRISPR. Here, you’ll be able to remind yourself of some of the biggest news stories from the past year, as well as discover what each theme means to our hand-picked guest contributors. For everything else festival related, head over to page 11. This time round, we felt that we’d use the preview as an opportunity to take a look back at what we’ve achieved so far. That’s why it acts as a reflection of where we are now, where we are heading, and why the festival is going to be instrumental in taking us there. We couldn’t possibly celebrate the genomics effort in Europe without discussing the contributions of Genomics England. Head over to page 17, to hear Sue Hill and Mark Caulfield talk about the impact of the 100,000 Genomes Project. As my own journey within the world of genomics continues, I find myself overwhelmed by the ongoing ambition, and drive within the field. This couldn’t be truer for the project, whose ambition to transform healthcare grabbed my attention from the very start. With their work

General Enquiries [email protected] www.frontlinegenomics.com

ultimately helping to deliver the benefits of genomics faster, just like our social mission, it was a real honour to write about a cause that impacts, and changes so many lives up and down the country. Through their Genomics Education Programme, and combined industry partnerships, they’ve really thought of it all, proving how they are indeed transforming healthcare for all. For me, the importance of collaboration rang true as I spoke to such a wide variety of organisations, both at a national and local level for this issue. Local non-profit organisation, Unique supports families across the world living with a rare chromosome or gene disorder. By connecting families and researchers through their global network, their work is essential in further understanding disorders. Although they are a smaller effort, one thing I’ve learnt is that every input is equally vital in contributing and making a difference to the wider effort of mainstreaming genomics. Go and check out their story on page 33. My excitement to attend my first festival on home turf is growing by the day. Sir Malcolm Grant, Chairman of NHS England, features in a number of interesting sessions relating to the integration of genomics – something I’m always eager to know more about. So, if you are reading this Sir Malcolm, I’d love to hear from you! The same goes for the rest of you, I can’t wait to hear your stories and ideas, so if you see me wandering the halls don’t hesitate to say hello. See you there! n

“WITH THE FESTIVAL TAKING PLACE IN THE HEART OF THE UK, IT ONLY FELT RIGHT TO USE THIS ISSUE TO CELEBRATE ALL OF THE IMPORTANT WORK BEING CARRIED OUT IN EUROPE, AND IN PARTICULAR LONDON.” Megan Humphrey Magazine Editor

Editorial Enquiries Carl Smith Ph.D. Managing Editor, Front Line Genomics E: [email protected] T: +44 (0) 207 384 7797 Advertising Enquiries Andrew Johnson Commercial Manager, Front Line Genomics E: [email protected] T: +44 (0) 207 384 7958

About Us Our mission is to help bring the benefits of genomics to patients faster. To achieve this, we work with the smartest people and organizations to produce a series of events and a free-to-access web portal & magazine for the genomics community. Our products are designed to support scientists, clinicians, business/research leaders and officials, from academia, research institutes, industry, healthcare and government organizations.

January 2018 / Front Line Genomics Magazine / 1

WANT TO HEAR MORE FROM OUR CONTRIBUTORS? THEN THIS IS WHERE YOU NEED TO BE, AND WHEN... GENOMICS 2017 – THIS WAS YOUR YEAR 30th Jan

13:00-13:45

BUILDING A GENETIC ATLAS OF (ALL) HUMAN POPULATION FOR PRECISION MEDICINE

Stage 4 30th Jan

Carl Smith Managing Editor

• Discussing the major talking points of 2017, and a look ahead to what 2018 has in store for the field of Genomics and Precision Medicine • Reviewing the results of Front Line Genomics first ‘Big Review of the Year’

Seán Ennis University College London

FOR PATIENTS, WITH PATIENTS: LEARNING FROM PATIENT EXPERIENCES TO MAXIMISE THE BENEFIT OF CLINICAL GENOMICS Beverly Searle Unique

31st Jan

13:20-14:15

Live Lounge

• Understanding the patient experience, and empowering patients and their families, and the professionals supporting them

31st Jan

11:05-11:35

Eran Elhaik University of Sheffield

31st Jan

14:50-16:05

Stage 3

• Discover ways to assess the performance of diagnostic tests

30th Jan

13:15-14:25

Stage 3

• State and international landscape of Personalised Medicine

31st Jan

10:50-11:25

Stage 2

Mike Stubbington • Understand the aims of the Human Cell Atlas Wellcome and the anticipated benefits Trust Sanger Institute

BEST PRACTICES FOR PREDICTIVE GENOMIC DIAGNOSTICS AND HOW TO ASSESS THEIR PERFORMANCE Miika Ahdesmaki AstraZeneca

• Discover the unique aspects of the Irish population as a resource for genomic discovery

THE HUMAN CELL ATLAS: HOW TO BUILD A HUMAN

Stage 4

• Variant classification is performed using approved guidance and agreed frameworks

Stage 3

BUILDING A GENETIC ALLIANCE OF (ALL) HUMAN POPULATIONS FOR PRECISION MEDICINE

AGNC SESSION: TOP TIPS ON VARIANT INTERPRETATION FOR COUNSELLORS

George Burghel Manchester Centre for Genomic Medicine

13:15-14:25

HERITABLE HUMAN GENOME EDITING 31st Jan Tony Perry University of Bath

14:50-15:15

Stage 2

• Appreciation of what heritable human genome editing is, and what it might become

TREE OF LIFE CAFÉ Feeling peckish? Then make your way over to grab something to eat. Alternatively, use the seating area to catch up with old and new colleagues for a drink.

LAUNCH PAD ZONE New for 2018. This dedicated area gives start-ups and small businesses the opportunity to showcase come of their latest products and services. Check out the exhibitors here to see some exciting innovations.

SPEAKER LOUNGE Dedicated especially to Festival speakers, it offers a place to network ahead of talks.

POSTER ZONES Check out academic authors presenting their posters, allowing you to interact and build relationships 1:1.

LIVE LOUNGE Pull up a bean bag and tune into bite sized insights from patients and clinicians and product demonstrations by leading solution providers and special features.

RECHARGE ZONE If you or your electrical devices are running out of energy, head over and you’ll be able to charge your devices for free and relax on some bean bags!

WELLCOME GENOME

STAGES 1,2,3 & 4 A collection of 20 minute keynotes from those doing the most essential work in the field; as well as complex issues channelled through multiple perspectives and experiences by panellists to illuminate the path forward.

Visit us for a chance to win a free conference registration to a Wellcome Genome Campus Advanced Courses and Scientific Conferences event in 2018 and get 20% off venue bookings at the Wellcome Genome Campus Conference Centre! Connecting Science: enabling the exploration of genomic science.

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CONTENTS JANUARY 2018 1 WELCOME

Magazine Editor, Megan Humphrey gives you the low down on this year’s Festival of Genomics London.

4 GENOMICS LENS

Take a look at Dame Sally Davies in action on last year’s festival stage.

5 MAKING THE MAGAZINE

Find out who helped put the magazine together and who contributed to the issue.

7 CRISPR

10 GENOMIC TECHNOLOGIES

8 GENOMICS IN THE CLINIC

11 FOG LONDON 2018

Hear how Tony Perry thinks genome editing has advanced.

What are the benefits of the Human Cell Atlas? Mike Stubbington gives his opinion.

George Burghel talks us through the opportunities of circulating tumour DNA (ctDNA).

We take a look at what this year’s Festival has to offer.

17 FLYING THE FLAG FOR UK

9 ENABLING DATA

Miika Ahdesmaki discusses the recent surge of NGS supported clinical data in oncology.

GENOMICS

Megan takes a look at the impact of the government-led, 100,000 Genomes Project.

20 IRELAND MAKES ITS MARK

24

Seán Ennis discusses the advantages Ireland can bring to genomic research.

24 SOLVING GENOMIC MYSTERIES

We gathered together an expert panel to talk all things data – what it is, what’s exciting, and what is it allowing us to do?

9

29 HOW OPEN DATA IS

CHANGING OUR PURSUIT OF DISCOVERY Oana Stroe explains how data is helping us satisfy our scientific curiosity.

32 CREATING A GLOBAL NETWORK

Find out how non-profit organisation Unique, are supporting families living with a rare chromosome or gene disorder.

34 BRIDGING THE GAPS TO

PERSONALISED MEDICINE Step into the world of Eran Elhaik, Lecturer at the University of Sheffield.

36 STAR WARS: THE LAST JEDI

After all the anticipation, and build up how did the new Star Wars movie compare to expectations?

10

BECOME A MEMBER

Sign up and become a Front Line Genomics member. It’s completely free of charge. Receive exclusive content and discounts on event registration. For full list of benefits and sign up, visit www.frontlinegenomics.com/become-member


Professor Dame Sally Davies, Chief Medical Officer (CMO) for England and Chief Medical Advisor to the UK government, speaking at last year’s festival.

4 / Front Line Genomics Magazine / January 2018

MAKING THE MAGAZINE JANUARY ISSUE 2018 JANUARY ISSUE 2018

www.frontlinegenomics.com

I

n keeping with the celebratory nature of this issue, and in honour of our very own Festival of Genomics, it was only right that the cover represented all things Britain. The genomics effort right now, specifically in the UK, is the most exciting it’s ever been. And, quite frankly it makes me proud to be British!

CONTRIBUTORS Megan Humphrey Magazine Editor Megan was fortunate enough to speak to two of the masterminds behind The 100,000 Genomes Project, as she put together an issue celebrating the work of genomics around Europe.

Seán Ennis University College London Seán took the time out of his busy schedule to talk to us about the cutting edge research Genomics Medicine Ireland is producing, ahead of his appearance at the Festival of Genomics London.

Oana Stroe European Bioinformatics Institute (EMBLEMBI) Oana, from the European Bioinformatics Institute discussed with us how open data is helping to satisfy our scientific curiosity.

ADVISORY BOARD

Jean-Claude Marshall Pfizer

Justin Johnson AstraZeneca

Gholson Lyon Cold Spring Harbor Laboratory

Dan Koboldt Nationwide Children’s Hospital

Alka Chaubey Greenwood Genetic Center

Nazneen Aziz Kaiser Permanente

Anna Middleton Wellcome Trust Sanger Institute

Neville Sanjana New York Genome Center

Kristian Andersen The Scripps Research Institute

Rong Chen Icahn School of Medicine at Mount Sinai

Wendy Rubinstein NIH/NLM/NCBI NIH Genetic Testing Registry

Ian Macaulay Technical Development Group Leader Earlham Institute

David Smith Mayo Clinic

Nan Doyle Massachusetts General Hospital

Eran Elhaik The University of Sheffield Eran let us in on what a typical day looks like for him in our Day in the Life feature, and even appeared as a panellist in our round table focusing on data.


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CRISPR

EXPERT COMMENT Tony Perry, Reader, Laboratory of Mammalian Molecular Embryology, University of Bath: “The last year has seen continued advances in genome editing by the RNA-guided nuclease system, CRISPR-Cas9, including adaptations for epigenetic and transcriptional regulation. CRISPR-Cas9 also continues to find increasing application in the study and manipulation of plants, insects and vertebrates and Cas9 protein has been repurposed for base editing so that it can now exchange a single targeted nucleotide in genomic DNA for any other without introducing potentially hazardous double-strand breaks. The list of known naturally-occurring Cas9s has grown, with potential to add flexibility to the editing toolkit. For example, the Cas9 prototype is large, and new, smaller variants are more amenable to viral delivery. This is relevant to recent developments in somatic genome editing delivery systems in vivo that adumbrate clinical applications, and clinical trials using CRISPR-Cas9 are under way, mostly in China. Finally, two papers in Nature on embryo genome editing by CRISPR-Cas9 represent a notable technical step to evaluating heritable genome editing in humans.”

“MITALIPOV HAS REASSURED CRITICS THAT HIS TEAM OVERCAME ANY PREVIOUS DIFFICULTIES WITH THE TECHNIQUE BY “GETTING IN EARLY” AND INJECTING CRISPR INTO THE EGGS AT THE SAME TIME THEY WERE FERTILIZED WITH SPERM, PREVENTING EDITING ERRORS.“

HUMAN EMBRYOS EDITED FOR THE FRIST TIME IN U.S.

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team of researchers in Portland have for the first time attempted to create a genetically modified human embryo. The study was led by Shoukhrat Mitalipov from Oregon Health and Science University, and has been published in Nature. The method involved changing the DNA of a large number of one-cell embryos with the gene editing technique CRISPR. Mitalipov is thought to have broken new ground with his work, after American scientists have remained envious of scientists elsewhere who were first to divulge the controversial practice. He has in fact demonstrated that it is possible to safely and efficiently correct defective genes that cause inherited diseases. The process in question is known as “germline

engineering”; any genetically modified child would pass any changes that cause inherited disease on to next generations via their own germ cells. By altering the DNA code of human embryos, scientists hope to eradicate this possibility. However, the method has been heavily criticised with the opposition suggesting this could encourage the creation of “designer babies”. Mitalipov has reassured critics that his team overcame any previous difficulties with the technique by “getting in early” and injecting CRISPR into the eggs at the same time they were fertilized with sperm, preventing editing errors. The experiment is an exciting advancement paving the way that it is possible to safely and efficiently correct defective genes that cause inherited diseases. n

CRISPR USED TO INCREASE CROP YIELDS OF VEGETABLES Researchers have turned their hand to using the gene editing tool CRISPRCas9 to on crops and vegetables to increase crop yield. The team from Cold Spring Harbour Laboratory (CSHL) in New York developed a method to edit the genome of tomatoes using CRISPR. The results of which have been published in the journal Cell. In order to so, the researchers edited trait variations or major components known to affect yield rates in crops. They included the size of the fruit, its branching architecture, and the overall shape of the plant.


GENOMICS IN THE CLINIC

A SCALABLE APPROACH TO LIQUID BIOPSIES

“ADVANCES IN NGS AND DDPCR HAVE NOW ENABLED THE ANALYSIS OF CIRCULATING TUMOUR DNA (CTDNA) IN BLOOD. “

SUCCESS OF LIQUID BIOPSIES FOR CANCER SCREENING The quest for a simple blood test to catch cancer early has attracted big players from Bill Gates to Merck & Co. Now, scientists have the first major evidence that liquid biopsies hold promise for screening people for cancer, at least in certain circumstances. A study led by Hong Kong researchers and published this week in the New England Journal of Medicine, was led by Dennis Lo Involving nasopharyngeal cancer, the data presented “suggests that lives have been saved because of this screening.”

EXPERT COMMENT George Burghel, Principal Clinical Scientist, Manchester Science for Genomic Medicine

“T

herapies targeted according to the genetic profile of common cancers is expanding rapidly in routine healthcare and resulting in improved patient survival and quality of life. For many solid tumours, such as colorectal and lung cancer, profiling of ‘druggable’ somatic mutations in DNA from pathology samples is a routine practice in oncology. However, biopsies are invasive and pathology samples suitable for genetic testing are not always available. Advances in NGS and ddPCR have now enabled the analysis of circulating tumour DNA (ctDNA) in blood. ctDNA testing or ‘liquid biopsy’ is an exciting and rapidly growing area in oncology genetic


profiling. ctDNA mutational analysis provides an alternate, non-invasive method that complements genetic testing of pathology samples with the advantage of ease of access and the potential for ongoing sampling and testing, allowing early detection and monitoring of cancer. “In Manchester, ctDNA testing for EGFR mutations in lung cancer patients has been successfully used for over a year. For some patients where ctDNA testing has been used, access to new targeted drugs would not have been possible as biopsies were not available. Further developing ctDNA based cancer testing will greatly help the fight against cancer.” n

An accurate, scalable approach for monitoring cancer using a patients’ blood sample has been developed, which has the potential to help diagnose and monitor cancer patients more effectively than with tissue biopsies. The research, published in Nature Communications, was the result of collaboration between the Broad Institute of MIT and Harvard, the Dana-Faber Cancer Institute (DFCI), the Koch Institute for Integrative Cancer Research at MIT, and Massachusetts General Hospital. Traditionally, tumour genomes have been studied using tissue biopsies, when part or the entire tumour is surgically removed and DNA is harvested from the sample. This ensures that sufficient DNA is available for sequencing, but biopsies can be difficult, expensive, and painful for the patient, particularly if the tumour is in an inaccessible location. A suggested alternative is to use liquid biopsies instead, which detect tumour DNA in the bloodstream that has leaked out of cancer cells (known as circulating tumour DNA (ctDNA)).

ENABLING DATA

METASTATIC BREAST CANCER DATA RELEASED The Metastatic Breast Cancer (MBC) Project has completed its first public data release, an event that coincides with the Project’s second anniversary and the recruitment of their 4,000 participant. The dataset, which is available through the MBC Project’s website, contains participants’ de-identified genomic data, treatment history, medical records, and personal accounts of their treatment. This release is planned to be the first of a regular release cycle, with new data being published every six months. The project is a crowd-sourced, social media-driven attempt at involving a large number of patients in research directly by making them partners in the process. It quickly became apparent that the patients were keen to involve themselves, as evidenced by the 2,000 US participants who signed up in the first seven months of the project. “Patients have had an enormous impact on the project’s evolution, including its design and implementation, from even before it had a name,” said Corrie Painter, PhD, Associate Director of Operations and Scientific Outreach for the project.

EXPERT COMMENT Miika Ahdesmaki, Associate Directory Bioinformatics (Precision Medicine and Genomics), AstraZeneca:

“OUR AI TECHNOLOGY IS TODAY BEING DEPLOYED IN 350 HOSPITALS THAT ARE ALL CONNECTED TO EACH OTHER BY A SOFTWARE SERVICE PROGRAMME, TO DIAGNOSE ABOUT 8,000 PATIENTS PER MONTH”

SOPHIA GENETICS RAISES $30M TO ACCELERATE DATA-DRIVEN MEDICINE

S

OPHiA GENETICS has raised $30 million in Series D funding in a bid to accelerate its mission of democratising data-driven medicine worldwide. The company’s universal technology, Sophia AI accurately analyses and detects all types of genomic variants to help clinicians better diagnose and treat their patients. The new round of funding will not only enable the company to continue with its mission, but also use the necessary resources to further develop its technology. CEO and Co-Founder, Dr Jurgi Camblong told Front Line Genomics: “Our AI technology is today being deployed in 350 hospitals that are all connected to each other by a software

service programme, to diagnose about 8,000 patients per month and have analysed over 125,000 patients in 53 countries to date.” “Back in 2014, when we first launched the platform we decided to focus first on Europe and now that we have demonstrated that the technology works effectively independently we will be raising deployment in hospitals outside of Europe. Part of the money will be used for that extended network of users. We will continuously improve our technology to better support the patient workflow in patient oncology, not only in molecular imaging data but as well as being able to use the platform so that pathologists will be able to communicate with oncologists regarding the treatment patients receive.” n

“In the last year, there was a surge of NGS supported clinical data in oncology showing the benefits of, for example high tumour mutational burden and microsatellite instability in predicting response to immune checkpoint inhibitors. Important developments were seen in both tumour FFPE and circulating tumour DNA applications. There still remains a lack of alignment in how these measures are properly quantified, what cut off points to use and which sample types these can be applied in. I look forward to exciting developments in 2018, in terms of understanding better the merits and limits of these new predictive molecular diagnostics, as well as extensions into finer grained algorithms such as mutational signatures.”


GENOMIC TECHNOLOGIES

EXPERT COMMENT: Mike Stubbington, Principal Staff Scientist, Wellcome Trust Sanger Institute:

10X GENOMICS PARTNERS WITH THE HCA PROJECT 10X Genomics and the Human Cell Atlas (HCA) International Consortium have announced a new partnership, aimed at enabling HCA pilot projects. The partnership, which is non-exclusive, will allow researchers within the HCA project to buy 10X ChromiumTM Single Cell 3’ and 5’ RNA analysis solutions at discounted prices. “The Human Cell Atlas will impact almost every aspect of biology and medicine, ultimately leading to a richer understanding of life’s most fundamental units and principles. The project has implications for a vast range of scientific applications and disease areas, and will benefit research and discovery around the globe,” said Dr. Teichmann, Head of Cellular Genetics at the Wellcome Trust Sanger Institute.

“THE BIOHUB IS AN INDEPENDENT NONPROFIT CREATED TO CONNECT SCIENTISTS AT STANFORD, UC SAN FRANCISCO, AND UC BERKELEY.”

CHAN ZUCKERBERG INVESTS IN CELL MAPPING TO FIGHT DISEASE

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lthough an ambitious thought, one day we all hope to live in a world where every disease can be cured, prevented or managed. And it seems we are taking steps in the right direction, with the help of Facebook founder Mark Zuckerberg and his paediatrician wife, Priscilla Chan. The end goal involves the mapping every cell of the human body, which is regarded as the highest priority for most scientists. According to neuroscientist and president of science for the Chan Zuckerberg Initiative, Cori Bargmann outlines that the Human Cell Atlas, which is on the same type of scale as the Human Genome Project, is looking at 30 trillion cells to identify properties and patterns, the way cells relate to each other, and the effect of demographic differences.


The Biohub is an independent nonprofit created to connect scientists at Stanford, UC San Francisco, and UC Berkeley – and one of its projects is work that supports the broader Human Cell Atlas effort. “The brain power of these three institutions is tremendous, but they’ve never done a research project together. There’s such an opportunity to bring people together to solve problems, and that is what the Biohub is trying to do,” Dr Bargmann told the audience at the Big Data in Biomedicine 2017 Conference. Three-way collaboration is considered a rarity, explained Euan Ashley, MB ChB, DPhil, associate professor of medicine and genetics at Stanford University. “USCS has medicine and Berkley has math and engineering, whereas Stanford has both.” n

“The Human Cell Atlas (HCA) is a large, international consortium that aims to create comprehensive reference maps of all human cells as a basis for understanding fundamental human biology and diagnosing, monitoring, and treating disease. The consortium will use single-cell genomics and spatially-resolved gene expression measurements to define all human cell types in a variety of ways. All data will be made openly available, to transform our knowledge of health and disease. “The planning process for the HCA began in October 2016 and culminated in a white paper that details how this transformative global resource will be built. Excitingly the project has now moved into pilot projects and work towards the first draft of the Atlas which will begin with the release of data from the first one million immune cells collected under the HCA. We’re looking forward to the ever-increasing progress that will occur over the next year and beyond.”

PREVIEW

THE UK FINDS ITSELF IN A VERY EXCITING POSITION RIGHT NOW. YES, WE ARE A SMALL ISLAND BUT IN THIS INSTANCE SIZE DOESN’T MATTER. WE ARE LUCKY ENOUGH TO HAVE A NATIONAL HEALTH SYSTEM THAT SEES THE VALUE IN THE EFFORTS OF GENOMICS, AND WHO ARE DRIVING IT FORWARD TO BECOME A VITAL PART OF HOW WE TREAT PATIENTS. NOT ONLY THIS, BUT WE ALSO HOUSE A NUMBER OF RESEARCH INSTITUTES ACROSS THE COUNTRY WHO POSITION THEMSELVES AT THE FOREFRONT OF SUCH WORK. January 2018 / Frontline Genomics Magazine / 11

PREVIEW

Our Founder, Richard takes a look back at FLG’s progress so far

H

owever, as all of you no doubt are aware the implementation of genomics into routine clinical care is a slow process; and it does come with its challenges. But, that’s where the Festival of Genomics can step in, and offer a place for everyone working on different parts of precision medicine to come together; and have the opportunity to exchange ideas, and find out what everyone is up to. Ahead of the London Festival, happening on 30th-31st January at ExCel London, we have gathered together some of the key people directly involved with the creation of the event, as well as sat down with the one man who holds the cause very close to his heart. But first, it wouldn’t be right to inform you about this year’s event without talking to you a little about how Front Line Genomics was born. The inspiration came to our Founder, Richard Lumb after the death of his father in 2009. He sadly passed away from mesothelioma, a rare form of cancer commonly caused by exposure to asbestos. “We now know that in an estimated 70% of mesothelioma cases, a gene called the BAP1 gene has become damaged or mutated,” explains Richard. “In simple terms, if your gene carries the mutation, you’re very much more likely to go on to develop mesothelioma.” “It’s entirely possible that my father carried the BAP1 gene mutation from birth. What we do know is that the technology is available to undertake risk assessments on people like my father, and manage their risk of developing certain types of cancer by reducing their exposure to asbestos. If we can radically improve our understanding of the genome’s influence on disease and treatment, then we can make incredible advances in medicine and improve the lives of everyone on the planet.” This is an extremely exciting prospect, and thanks to rapid technological developments we have made more progress than ever before. However, sometimes these advances are slow to get into the hands of the people who can use them to make a difference. “So, the question is, how do we first, speed up progress in genomics, and second, narrow the gap between advances being made, and getting them into the hands of people who would benefit,” explains Richard. And it is with that in mind that Front Line Genomics was launched in 2014, a media and events organisation, accompanied with a social mission of delivering the benefits of genomics faster. We try to address the above in a few simple ways, these include educating and engaging; pushing people towards the cutting edge; bringing people together to make progress and bring new technology to practitioners. Richard continues, “Within a month of existing we created a website that educates and keeps people up to speed with what’s happening in genomics. A couple of months later we published our first magazine in digital and print format. In June 2015, we had the first Festival of Genomics.

12 / Frontline Genomics Magazine / January 2018

“If we can radically improve our understanding of the genome’s influence on disease and treatment, then we can make incredible advances in medicine and improve the lives of everyone on the planet.” “Overall, we’ve had almost 10,000 people through the door at our festivals. Our e-books, website content (like webinars), and magazines have reached many more times that number – I would estimate over a quarter of a million people. In the middle of day-to-day operations, and the next big sales target, it’s sometimes easy to forget how many people we’ve actually helped. We should be very proud.” Carl Smith, Managing Editor, believes that as a media organisation, there is an opportunity to take a critical look at what we can do. “We’re not going to find a cure for cancer within FLG, but we can do our best to make sure the people who might be able too are getting all the information they need, meeting the right people, and making the connections they need to collaborate and get there faster,” he says. Now that you are up to speed with our back story, and what it really is that drives us day in, day out we can now turn our attention to what’s going on at our London Festival. The key themes being presented this year are drug development; genomics in the clinic; enabling data; and CRISPR. For this issue only, we thought it’d be useful to adapt our usual news pages at the start of the magazine to represent each theme. In doing so, we have gathered two of the most popular news stories about each one over the past year, and spoken to an industry expert to get their perspective the topics progress. Some of them are even walking these halls right now.

PREVIEW

“Overall, we’ve had almost 10,000 people through the door at our festivals. Our e-books, website content (like webinars), and magazines have reached many more times that number – I would estimate over a quarter of a million people.” Thanks to popular demand, the graffiti wall makes a return this year

We caught up with our Festival Directors, James Bell and Laura Rae to find out what the Festival really means to them. “Once a year, we create a melting pot of the best and brightest genomics work in the country – and it becomes the place to go if you want to learn about the status of genomics in this country and want access to insights or feedback to shape your work,” says James. “We’ve become a vehicle for top level strategic initiatives to be launched – for the last two years that’s been via the CMO and CSO, and this year we’re very fortunate to welcome Sir Malcolm Grant and Sir John Chisholm to the stage, notes Laura.” Joining a long list of impressive speakers, James is “really excited to welcome Professor Sir Munir Pirmohamed to chair a session that considers the vital role genomics plays in he flipside of the drive for efficacy: safety.” “Around 25% of drugs fail clinical development of account of safety issues and for the 2018 Festival we’re presenting a kaleidoscope of perspectives covering MHRA, academic and industry strategy from Roche and GSK to discuss how regulating innovation and genomics can enable faster delivery of drugs to market, how to establish relevant gene networks and stratify patients for adverse events from drug labels and critically how using genetic tests to help define drug dose and choice to reduce the likelihood of adverse reactions.”

A theme prevalent throughout this issue is the incredible genomics work happening right here in the UK, so it’s of great importance to mention that at the event, we will be assessing whether we can fully integrate genomics into the NHS within five years. “Following the release of the generation genome report, there was a lot of buzz around how we could achieve the proposed dates,” adds Laura. “Could genomics really be mainstreamed into the NHS within five years? It’ll be interesting to bring together the different viewpoints in this panel, and to hear from individuals like Sir Malcolm Grant and Chairman of the NHS and Sobia Raza, Head of Science for the PHG Foundation on what they perceive to be the biggest strategic and technical challenges and opportunities for the genomics community over the next 12 months.” As always at the festival, we try to offer those in attendance a break from the predictable format of most life science events. Last year, we introduced the graffiti wall, which thanks to popular demand is returning. Adding to the list of features, we are very excited to introduce the Pipette Wars, kindly being supported by Eppendorf. Visitors will be able to compete against Eppendorf’s epMotion 5070 to see who is quickest on the draw. Above all, when we asked Helen Curl, Group Event Director what her favourite thing about the Festival is, she replied, “my favourite thing is overhearing the conversations happening in the aisles of the exhibition.”

January 2018 / Frontline Genomics Magazine / 13

PREVIEW

“IT’S SOMETIMES EASY TO FORGET HOW MANY PEOPLE WE’VE ACTUALLY HELPED. WE SHOULD BE VERY PROUD.”

“MY FAVOURITE THING IS OVERHEARING THE CONVERSATIONS HAPPENING IN THE AISLES OF THE EXHIBITION.”

Richard Lumb

Helen Curl


PREVIEW

“I’M LEADING A PANEL WITH SOME OF OUR FLG FAVOURITES ON DAY 1.”

“COULD GENOMICS REALLY BE MAINSTREAMED INTO THE NHS WITHIN FIVE YEARS? IT’LL BE INTERESTING TO BRING TOGETHER THE DIFFERENT VIEWPOINTS IN THIS PANEL.”

Carl Smith

Laura Rae

January 2018 / Frontline Genomics Magazine / 15

PREVIEW

The festival will be taking over the ExCeL Centre in London, on 30th-31st January

The poster zones and café; those moments of serendipity when individuals meet and realise they can help each other in their projects. Bringing everyone together for an event is ultimately about just that – helping people to make valuable connections.” Speaking of making connections at our events that stand the test of time, Carl adds, “Going to see Sir John Chisholm talk to the public in Oxford about the 100,000 Genomes Project was one of the first things I got to do here at FLG. “Now I get to have a chat with him onstage. He’s got a great way of framing all of this in the context of the big picture. I think he’s going to inspire a bunch of people in the crowd. I’m also leading a panel with some of our FLG favourites on Day 1. We’re going to be looking over some of the big stories from 2017 and talking about what we want, and expect to see moving forward. It’s something we tend not to see too much of at the Festival, but open discussion is always good. We have some strong personalities on there, so I’m curious to see where the session takes us. I’m just worried about keeping it all down to 25 minutes.” Despite this year’s London Festival shaping up to be one of our best yet, we are always looking for ways to improve, and it seems like the right time to share a view of those ideas with you. “Right now, the business is responding to changes and challenges we’re seeing in the market,” explains Richard. “We’re seeing that the appetite for digital content is rising rapidly. So we have exciting plans to develop better, more useful and interesting content in that space. We’re also working on meeting formats that bring similarly minded people together to work on very specific problems – for instance, R&D heads in big pharma, or medical data experts across healthcare and industry. “We also see the opportunity for technology providers and practitioners to come together to educate each other, to ensure that products are truly fit for purpose, and to ensure that practitioners are getting the most value out of new technology. There are lots of physical meetings and digital ways in which we are seeking to make that happen.” With all that in mind, when writing previews comes with it the chance to reflect and assess how our event has grown; and what more we still need to do. Richard continues, “Aristotle said, “the more you know, the more you know you don’t know,” That’s certainly the case with genomics. Our understanding is moving forwards at a rapid


“Within a month of existing we created a website that educates and keeps people up to speed with what’s happening in genomics. A couple of months later we published our first magazine in digital and print format.” rate. Yet it feels like we’re only a few hundred grains of sand into the beach. Certainly, technologies like machine learning look set to keep us moving at a rapid rate, and the possibilities of genome editing are mind-blowing. But I’m sure, for sure, that we’ll never solve all of the mysteries. For every one we solve, we’ll uncover ten more. That’s something we should all be excited by, because using these new technologies, the opportunities to advance our understanding, and treatments, will increase exponentially. “So where does that leave Front Line Genomics. It’s not clear to me that the world would benefit from a festival on every continent. Or through helping to educate and engage another quarter million people. “I would like to see us move beyond the successes we’ve had with broad education and also have much more impact with smaller pockets of people – to get much more specific and focused in our impact.” So, there you have it, everything you need to know ahead of this year’s London Festival. Now it’s time to go and explore, network and learn! On behalf of us all here at Front Line Genomics, we really hope you have a great two days. n

GENOMICS ENGLAND


GENOMICS ENGLAND

“A

cross my career I have never seen a transformation project that has achieved quite so much in so little time, and the passion and commitment that’s been shown by individuals and services is a testament to the commitment to keep the NHS a world-leader, in this important area of medicine.” Those are the words of Sue Hill, Chief Scientific Officer for Genomics England, as she recalls the impact of The 100,000 Genomes Project. It goes without saying that attempting to transform healthcare is one huge task, having to deal with a number of difficulties, and having to juggle science, infrastructure, administration and business can be tricky. But The 100,000 Genomes Project was far from intimidated. The project began with the desire to transform healthcare, and genomic medicine in the National Health Service in England, as well as to bring both health and wealth on rare disease, cancer and infection, to the clinic. But as time has gone on, they have in fact provided so much more. Before we expand on that, let me take you back to April 2003, to a time when one of the most significant scientific breakthroughs of modern times was made. After years of research, finally the genetic code of a human being – their genome – had now been published. Such work meant that The Human Genome Project had opened a never before explored door, one that would allow some of the most important discoveries about DNA to be turned into a potentially life-saving reality, for NHS patients across the country. It was this very concept that spurred the then Prime Minister, David Cameron after being urged by scientists of course, to recognise the enormity of genomics. With 1,000 genomes having already been successfully sequenced, it felt right to aim to sequence another 100,000 by 2017. It was then; in late 2012 that the government-led 100,000 Genomes Project was born. “We felt at the time, from the knowledge of sequencing costs that the best benefit would be to go for a very large number, we knew that if we stated this as the ambition that we would drive the technology market to provide us with the right infrastructure to be able to do the program,” explains Professor Mark Caulfield, Chief Scientist of Genomics England. “It would allow us to make well powered observations that make the argument for adoption in healthcare. The ambition was to leave no hanging lingering doubt that we should do this within healthcare, and that’s exactly what’s happened. The focus of the number is to drive the project to success in essence.” “The project has been tremendously successful in establishing the proof of concept for the use of whole genome sequencing in routine care,” notes Sue. “It has seen the diagnostic yield for rare disease increase 4-5 times above existing genetic testing, bringing an end the diagnostic odyssey that has lasted for decades in some patients. In cancer, early results have shown actionable genes in 65% of patients who have been through the project.


“Most importantly, the project has established the infrastructure and driven the transformation of systems and services to produce and handle significant volumes of genomic samples and to allow comprehensive delivery of cutting-edge genomic technologies across the entire health system.” In doing so, the project has continued to be supported centrally through the Department of Health, with particular investment coming in key elements of infrastructure. “A key element of the project recognised that genomics must become ‘business as usual’, so significant contributions and business decisions have been made by system partners such as NHS England, who funded the creation of 13 population-based NHS Genomic Medicine Centres and payment mechanisms for sample recruitment,” says Sue. “Likewise individual hospital organisations have made their own decisions and investments around developing infrastructure.” Right now, there are up to 3,000 front line NHS staff working on the project every week, in approximately 19 NHS organisations across England. All of which wouldn’t be possible without industry partnerships, with the likes of Edico, Novogene, Congenica and GlaxoSmithKline, that all help contribute the best possible interpretation of genomic data. One particular partnership however, was crucial to the project’s development, and that was with Illumina in 2016. Striking up a collaboration with the world’s leading sequencing company was exactly what the project needed, Illumina’s reputation of driving down the cost of sequencing to proliferate the adoption of NGS, was able to help steer the project to success. “This has had a big impact on the feasibility of this project,” emphasises Mark. “It has made it both affordable in a healthcare setting, but also brought to bear the weights of the world’s most successful company in this area.” Outside of sequencing, there are still other factors that need attention, and one of the obvious ones for any healthcare system is trying to embed changes into practice across all sites. Sue tells, “The move to using fresh-frozen handling of cancer tumours, because of the disruptive effect of formalin on DNA structure, has involved unpicking a way of working that has been built up over decades. “Inevitably changing this, particularly in smaller hospitals, involves concentrated efforts including emphasising the scientific case for change coupled with peer support to demonstrate the practicality of the new approaches.” It is no secret that the implementation of genomics into routine clinical care still presents problems, and that’s why it’s vital that scientists, geneticists and doctors are sufficiently trained to interpret data and understand what it means for a patient’s medical condition. Having this ability is crucial if patient outcomes are going to be improved as a result of genomic data. However, with technologies advancing so rapidly it is of the upmost importance that when they arrive into the hands of people who can help, that they are equipped with the knowledge to implement them quickly. Luckily, the project is working to ensure this is the case. “Since the project’s inception,” says Sue. “There has been a tailored Genomics

GENOMICS ENGLAND

The 100,000 Genomes Project in Numbers 100,000 70,000

Education Programme (GEP) offering up-skilling, education and training to the entire 1.1 million workforce of the NHS, to support all staff to be confident and capable in harnessing the power of genomics for patient benefit.” Going one step further to ease the pressures of such a challenge, the project has recognised the need for a cross-sector approach. This will ensure that routine care and treatment is closely linked through to clinical research, academia, industry and international collaboration to support ongoing learning from genomics and promote the development of new treatments and

genomes

patients and family members

21

Petabytes of data. 1 Petabyte of music would take 2,000 years to play on an MP3 player.

13

Genomic Medicine Centres, and

85

NHS Trusts within them are involved in recruiting participants

1,500

NHS staff (doctors, nurses, pathologists, laboratory staff, genetic counsellors

2,500

researchers and trainees from around the world

interventions. It is important that full-scale integration is maintained, this isn’t always about diagnosis, and instead is about feeding data back into the database to boost basic science too. Sue furthers, “This will develop and strengthen these relationships for mutual benefit, with a requirement for the system to collaborate with academic and industry partners and participants encouraged to provide broad consent for their samples and information to be used for research purposes, when suitably de-identified.” There is no doubt that the project has highlighted the ability of the health system

“THE PROJECT HAS BEEN TREMENDOUSLY SUCCESSFUL IN ESTABLISHING THE PROOF OF CONCEPT FOR THE USE OF WHOLE GENOME SEQUENCING IN ROUTINE CARE.”

to provide high quality samples and rich data sets for rare disease and cancer. “The 100,000 Genomes Project is unashamedly ambitious and has seen a significant commitment from individuals and services throughout the NHS to deliver to the project deadline and for all the families involved,” concludes Sue. “We’ve seen exponential growth in recruitment of participants and sample collection and are currently seeing around 5,000 new recruits every month, with new clinics and services come online all the time. Even in the areas where there have been technological challenges, such as with cancer samples, we are now moving at pace.” Right now, the project has sequenced a total of 41,582 genomes, marking a huge achievement for not only healthcare, but the whole of the genomics community. Although the target to sequence 100,000 genomes by the end of 2017 was ambitious, measuring the project’s success by focusing on just the number would be a disservice. Instead, it is their ambition that is the very measure of their success; after all it’s making all of their work worthwhile. It installs people with the hope that one day genomics will be part of routine care, and that patient outcomes for all will see a dramatic improvement. On reflection, I know for one that I am incredibly proud that the UK is flying the flag for genomics, and are doing a very good job at it too. n


COMMENT

SEÁN ENNIS CO-FOUNDER AND CHIEF SCIENTIFIC OFFICER GENOMICS MEDICINE IRELAND & DIRECTOR UNIVERSITY COLLEGE LONDON

SEÁN TELLS US WHAT ADVANTAGES IRELAND CAN OFFER GENOMICS RESEARCH

IRELAND MAKES ITS MARK GENOMICS MEDICINE IRELAND (GMI) IS PIONEERING CUTTING-EDGE RESEARCH THAT WILL NOT ONLY BENEFIT IRISH PATIENTS ALONE, BUT HAS THE POTENTIAL TO MAKE A SIGNIFICANT GLOBAL IMPACT.

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enomics Medicine Ireland (GMI) was founded in 2015 with the objective of solving diseases of genetic origin by creating largescale, population-based medical research studies on the island of Ireland to examine the relationship between genetics, health and disease. We’re building a powerful, disease-specific database which will be used to develop new insights into life-changing diseases affecting people in Ireland primarily, but which we anticipate will have an impact around the world. This database will give academic researchers, clinicians and global pharmaceutical researchers the ability to more efficiently identify the relationship between genetics and disease and lead the way for new treatments and new diagnostics … and in some cases even cures. We’re still a very young company but already in the last year we have launched several research studies into a range of diseases in collaboration with a number of Irish hospitals, such as Brain Tumours, Rare Disorders, Inflammatory Bowel Disease and Multiple Sclerosis. The recruitment for and analysis of these studies will take a number of years to complete, but the ball is now rolling on potentially making a significant impact on these conditions. We’ve already seen early results in the field of Rare Disorders where the whole genome sequencing we’ve conducted has facilitated diagnosis of a number of patients who had previously been undiagnosed; in one particular instance involving a child, the diagnosis led to a treatment which is already showing great promise. We’re also seeing a lot of enthusiasm for our GenoFit research study which we are undertaking with the University College Dublin Institute for Sport and Health. With GenoFit, we hope to provide a comprehensive view of the potential genetic factors contributing to fitness and health. It is well accepted that our health is influenced by a wide variety of factors such as age, nutrition, sleep quality and fitness as well as psychological and environmental factors. Our health, fitness and likelihood of developing certain diseases is also influenced by our genetics. Currently, we don’t fully understand how much of a


contribution each of these factors makes to our health and disease risk. The GenoFit study will allow us to gain a more detailed understanding of individual risk factors and how much of a role they play will help to develop and deliver more personalised health management. The study launched last September and was originally launched for open enrolment to all adults on the UCD campus but will be rolling out nationwide this year. We’ve had a massive response to this and some early signs are very promising in terms of results. It’s still very early but we certainly have high hopes for greater discovery in several of the disease and wellness areas we’re studying. IRELAND AS A GENOMICS ‘CENTRE OF EXCELLENCE’ Ireland offers many advantages for genomic research. First and foremost, we have a large and relatively homogenous population when compared to other Western cultures - this translates to less noise in the data making disease-relevant variations easier to identify. Ireland also has statistically relevant incidence in the population of a wide range of currently medical conditions such as Multiple Sclerosis, Inflammatory Bowel Disease, Alzheimer’s and other chronic complex diseases. This means a significant number of relatively accessible patients with a variety medical conditions that we hope to draw on for our studies. From a research perspective, Ireland’s universities and hospitals have a history of close collaboration, and this, together with our concentrated clinical infrastructure, simplifies the logistics of conducting large-scale, population-based research studies. We’re fortunate to have the support of world-class investors which include ARCH Ventures, Polaris Ventures, GV (Google Ventures), and Irish sovereign investment through the Ireland Strategic Investment Fund (ISIF) which represents significant endorsement for our approach. Twelve months ago, we also entered into a 15-year alliance with AbbVie which further validates our vision for genomics in Ireland to have lasting impact and hopefully, resulting in therapies

COMMENT

to benefit patients both here in Ireland and around the world. Finally, we’re really hopeful that GMI’s establishment will encourage a cluster formation for a Next Generation Sequencing ecosystem in Ireland that will further attract additional foreign direct investment in life sciences and IT. I think the future is really bright for genomic research in Ireland. IRELAND’S IMPACT ON THE WORLD Genomics has the potential to be Ireland’s “moon shot”. What I mean by this is that here in Ireland we are pioneering cuttingedge research that will result in better therapies not only for the Irish patients on which the research is based, but it should

also be relevant to the roughly 80 million people around the globe who make up the Irish diaspora: that’s nearly one per cent of the population of the world. So, if we find something significant here, it’s likely to have some sort of impact worldwide. We believe that the unique characteristics of the Irish population make it an ideal place to carry out this type of research and power precision medicine. What GMI is doing here is scientifically very ambitious because we are curating and validating the data, collecting and sequencing it to the very highest standard, and doing deep analysis on the genomic samples and phenotypic data from a large group of people, so it’s a very rich dataset.

Seán has life-long experience in research in medical genetics. He has led and been involved in establishing collaborative approaches to investigating chronic conditions such as Motor Neuron Disease (ALS), Autism Spectrum Disorder and, more recently, Rare Diseases. He has extensive published research studies and is a frequent speaker in the area of genomics. Seán holds a PhD in genetics from University College Dublin. He is a lecturer at the School of Medicine & Medical Sciences at UCD, Investigator with the National Centre for Medical Genetics and National Children’s Research Centre. He is director of the UCD Academic Centre of Rare Diseases (ACoRD).


COMMENT

“I THINK THE FUTURE IS REALLY BRIGHT FOR GENOMIC RESEARCH IN IRELAND.”

NOT WITHOUT ITS CHALLENGES As ideal as Ireland is for genomic studies, there are still some limiting factors here that we need to navigate. For example, while the health services executive is piloting an electronic health records system, the medical records are still largely paper-based. We’ve also found that resources within the clinical environment can be limited with shortages in the availability of specialist research nurses. Additionally, consultants here are already quite stretched in terms of their workload – hardly a problem unique to Ireland but it does compound the situation somewhat. In spite of this, we’ve found the clinical teams to be very supportive and keen to get involved in these studies. By the nature of studying chronic complex diseases, many of the people living with the conditions we’re examining are very unwell, therefore, making it difficult for them to participate in the study in spite of the fact that they are, in most cases, very motivated to do so. But my attitude from the start was - rightly or wrongly - that either we do something big in Ireland or it’ll happen elsewhere. SHOOTING FOR THE MOON We’re very excited to announce that we’re currently putting the final touches on our next generation genomics sequencing centre at our headquarters in Dublin. It will be the island’s first purpose-built genomic sequencing centre and really puts Ireland at the forefront of genomics research globally. Long term, our ambition is to sequence a minimum of 10% of the Irish population – 600,000 individuals – across 50 disease areas starting with 20 currently complex disease areas. Broadly, by 2020 we aim to see some significant early results in key rare diseases and multiple novel targets identified for complex diseases, and by 2030 we hope to have a diagnosis of these in addition to multiple new drugs in development. In 2018, we are also going to rollout several new studies in additional complex chronic diseases, as well as expanding existing studies by bringing further hospitals and research centres on board.


FESTIVAL OF GENOMICS LONDON I’m really looking forward to participating at the Festival of Genomics where I’ll be touching on the richness of Ireland as a centre for pioneering genomics research and the potential for us to become a centre of excellence for genomics internationally. I’ll also be discussing the rapid evolution of genomics and the potential to research much larger populations in a deeper and more meaningful way to fuel discovery. In addition, I plan to speak to GMI’s work on developing an Irish Reference Genome. Already we’ve seen some results related to this published by researchers at the Royal College of Surgeons in Ireland in the Scientific Reports journal called ‘The Irish DNA Atlas; Revealing Fine-Scale Population Structure and History within Ireland’. The landmark study provides the first fine-scale genetic map of the island of Ireland, revealing patterns of genetic similarity, so far in ten distinct clusters, roughly aligned with the ancient provinces as well as with major historical events including the invasions of the Norse Vikings and the Ulster Plantations. I will elaborate further on this in relation to our work in the field of medicine and the potential for this in identifying linkages. n

“IT’S STILL VERY EARLY BUT WE CERTAINLY HAVE HIGH HOPES FOR GREATER DISCOVERY IN SEVERAL OF THE DISEASE AND WELLNESS AREAS WE’RE STUDYING.”

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ROUNDTABLE

SOLVING GENOMIC MYSTERIES HOW CAN WE INTEGRATE DIFFERENT DATASETS TO GAIN A BETTER RESEARCH PERSPECTIVE? OUR EXPERT PANEL DISCUSSES ALL THERE IS TO KNOW ABOUT BIG DATA.

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ata is continuously being generated across the whole spectrum of genomics, and other –omic fields. The pace of innovation has become so rapid, that we are constantly raising new questions to investigate. In addition, we have also seen technologies from other data-centric fields find interesting applications within our own work. Our panel of experts go through the big questions being asked, and even ask some of their own. FLG: With so much –omic data, real world data, and electronic health records, what are the realistic short and long term opportunities to really do something useful with all of it? Pete White: Make no doubt, the –omic data that has been produced to date has already been transformational for many diseases. For example, we’ve seen great advances in identifying pathogenic variants in thousands of rare genetic disorders, with many being either actionable or providing clues to better diagnostics and biomarkers. However, the long-term opportunities allow us to truly understand disease in all of its molecular and phenotypic complexity. In coming years, we should be able to delve in at the single-cell level across the entirety of a disease course, which will provide us with better ways to model interventions, as well as to predict new therapies. When combined with clinical, environmental, and social data, this information will allow us to model disease in a highly specific way. Mark Gerstein: In the short term, the goal is to get a better knowledge in genetics by analysing and annotating all the omics data, such as the gene regulatory networks, the functions of noncoding sequences, the relationship between genotypes and the phenotypes, etc. In the meantime, by integrating the real world data and electronic health records, people are working on developing personalised medicine and accurate prediction of potential diseases. In the long term, we would like to know the functions of all the genome components so that we can reliably predict any influence of genetic variants. Furthermore, we might get to know how DNA sequences lead to complex organisms like human beings and the evolutionary relationships between different organisms. Eran Elhaik: I think that people have long awoken from the illusion that Big Data will provide long awaited answers and realised that, if anything, it raises new questions. Karl Popper essentially predicted this in 1934, claiming that the process of scientific discoveries is not systematic or methodological and requires talent, imagination, and intuition, which brings us back to the human factor and the need to train people who can connect all these data. In the short term we will probably see “Meta-datasets” – the stashing of datasets generated by different groups in a hope that their combined size would compensate for the disadvantages of batch effects and other biases. Personally, I am sceptical about such datasets. In the long term, we


will see smart integrative systems that know how to correct for these biases and assimilate multiple inputs to produce clever predictions. Assim Siddiqui: In the short term, while there is a lot of data, it is poorly organised and structured. You can spend a lot of effort organising and cleaning data without much to show for it, so it is important to carefully define the question and identify tractable opportunities that can be realised quickly. There are numerous publications where through careful choice of datasets and focused questions, the authors were able to derive a result that validated in the lab. Some of these studies have resulted in the launch of commercial ventures such as our company. The failure rate in drug development is high so even small improvements can be significant from a patient outcome and financial perspective. In the long term, as we get better at structuring data and gather more of it, new types of analysis become possible and we’ll be able to make more precise informatics predictions and improve the success rate of drugs. FLG: A lot of this data sits in disparate sets. Without a consistent cohort across all of it, can it only be used in isolation? PW: The more we can harmonise this data, the more we will be able to learn from it. Initiatives such as the UK Biobank and the All of Us program have realised this notion and have tremendous potential as they move forward. Of course, there are many barriers—mostly self-imposed—that are hindering our ability to develop such a consistent cohort. Historically, we have embraced a culture of distributed innovation, which has been quite successful at solving certain biomedical problems, but has been much less effective at making progress for complex diseases. I think we would be wise as a community to focus more on the social challenges that keep disparate datasets apart, such as the ways in which research is funded and awarded, as well as the considerable role that academic and clinical centres play in data accessibility. MG: The human genome is so complex that it is regulated in multiple levels. It is essential to integrate different datasets, including genomic, transcriptomic, epigenomic data and even clinical results, to get a better understanding of any research interest. Various innovative algorithms and approaches are being developed to archive this end, such as network-based methods, multiple-kernel learning, multiple step analysis, etc. In our current work, we are also trying to use the deep Boltzmann machine to interpret different datasets within a same framework. EE: For the time being – yes, but only until more fundamental work is done to understand which of these datasets represent the “truth” and how to correct for the biases in the other datasets to take advantage of their measurements.

PANELLISTS Pete White Riveschl Professor and Chair of the Department of Biomedical Informatics, University of Cincinatti College of Medicine, & Division Director of Biomedical Informatics at Cincinatti Children’s Hospital In these roles, Pete oversees informatics research and resources at both institutions, including leading the academic, educational, data services, technology development, and Research IT missions. As co-director of Cincinnati Children’s Center for Pediatric Genomics, he also serves in a leadership capacity for establishing enterprise-level solutions to genome-based precision medicine.

Mark Gerstein Co-director of the Yale Computational Biology and Bioinformatics Program Mark has published appreciably in the scientific literature, with over 400 publications in total, including a number of them in prominent venues, such as Science, Nature, and Scientific American. His research is focused on bioinformatics, and he is particularly interested in data science and data mining, macromolecular geometry and simulation, and human genome annotation and cancer genomics.

AS: Data can be combined with care. This requires close attention from those with expert knowledge in statistics and genomics and careful curation of the input data sets. This can be a manually intensive process and that’s why as I said earlier, it is important to define the question carefully so to not waste effort. Once data has been curated and integrated, it can be used multiple times and that increases its value. FLG: What kind of impact can Machine Learning have on precision medicine, and how far are we from that? PW: I would argue that we have solidly been in the Machine Learning era for at least 10 years, but the acceleration of how these approaches have been used in biomedicine is truly remarkable. Machine learning, deep learning, AI, precision analytics—these currently ubiquitous buzzwords indicate that unsupervised, self-learning algorithms have been beneficial for an increasing number of

Eran Elhaik Lecturer The University of Sheffield Eran’s recent work includes the development of the GPS technology that identifies and dates the origin of genomes and promotes a new understanding of cot death and mental disorders.

Asim Siddiqui CTO NuMedii Dr. Siddiqui has over 20 years of experience in bioinformatics and software engineering. Prior to joining NuMedii as Chief Technology Officer, he served as Vice President of Product Development at Natera where he built Natera’s product management and program management functions. Dr. Siddiqui drove improvements to Natera’s NIPT diagnostic including its cloud strategy and cell free cancer program. Prior to that, he served as the Director of Bioinformatics at Life Technologies where he was awarded the Life Technology Inventor Award for his work on NGS bioinformatics.

researchers and biomedical problems. Their use will only increase as the data gets deeper and broader, as their predictive abilities are largely tied to the volume and disparity of data they are fed. This will have great impact on some of our most challenging problems, such as computational drug design and prediction, understanding disease course, and modelling organoids. MG: Machine learning in statistical analysis is obviously very useful when dealing with large amounts of aggregated data. These techniques collectively allow one to find subtle patterns in data that are not immediately apparent by eye. They're particularly useful with the high dimensional omics data and phenotypic data where many different types of data sets are being put together. This capability of machine learning is essential for developing precision medicine. It can not only analyse different treatment results but also keep track of all the information of a patient, like his/her weight, age, blood pressure, etc.

“I THINK THE DAY IS COMING WHEN A RESEARCHER CAN GO TO THEIR COMPUTER AND, WITH THE PROPER AUTHORISATION, BE ABLE TO INSTANTANEOUSLY QUERY ACROSS ALL SIZEABLE MOLECULAR, CLINICAL, AND ENVIRONMENTAL DATASETS GENERATED WITH PUBLIC FUNDS.”


EE: Machine Learning has the potential to boost the field of diagnostics. Take for example diagnosing rare diseases in children. What is extremely challenging for humans can be done faster and more accurately with Machine Learning applications, like Face2Gene, as long as the diseases are clinically well defined.

“MACHINE LEARNING, DEEP LEARNING, AI, PRECISION ANALYTICS—THESE CURRENTLY UBIQUITOUS BUZZWORDS INDICATE THAT UNSUPERVISED, SELF-LEARNING ALGORITHMS HAVE BEEN BENEFICIAL FOR AN INCREASING NUMBER OF RESEARCHERS AND BIOMEDICAL PROBLEMS.”

AS: We are already beginning to see the impact of ML (Machine Learning) on precision medicine in limited use cases e.g. radiology and ophthalmology image analysis. In our field, we use ML approaches to model response to drugs and have made discoveries in this manner. However, there is still need for human expertise and we are a long way until full automation of this process. FLG: From the infrastructure side of things, how do you go about future proofing as best you can, so you don’t end up having to reinvest in a new set up a few years down the road? PW: This is an especially tough challenge, as the pace of innovation necessitates that technologies will develop more rapidly over time. We know the data deluge will only strengthen in intensity, and there will always be the need to scale data compute, storage, and exchange as fast as possible. I do think that these things tend to be in balance with other factors. For example, look at the Internet—there is always the desire and push to make it faster than it actually moves, and to make browsers better in order to handle, for example, high definition video. But we have moved quite quickly, and the rest of the scientific process also needs to evolve. We need to invent better ways to use and to ask relevant questions of big data. We also need to determine how to resource larger infrastructures and that tends to play a substantial role in modulating progress. MG: One way of dealing with the rapid obsolescence of technology is to rent the infrastructure as opposed to buying it. This is one of the main impetuses behind cloud computing, where one is essentially renting cycles or purchasing them on the fly rather than buying computing equipment. EE: This is a question of vision and habits. There is never enough time to do things right the first time and never enough money to do them right the second time. Unfortunately, it is very common to prefer tech-gurus (maybe because they are harder to understand) over the expert scientists only to hear a year down the road that an application is unfeasible because the system was not designed to support it. By then, of course, the tech-guru has already left for a better job and we are stuck with a dysfunctional system. To minimise costs in the climate of uncertain funding and rapid innovations, infrastructure should be as centralised as possible. AS: You scale the parts of the infrastructure that are stable keeping everything else nimble. Our algorithms need to remain nimble, but basic concepts such as genes and proteins remain largely constant. Also, it is important to keep an eye on your end customer of the infrastructure. For us, the end customer is internal and as such can tolerate changes more easily than an external one and so not overbuilding the system is another means of handling this. Hardware systems are another source of change and updates. In today’s world, this has been greatly simplified for consumers of hardware through the use of cloud technologies. Cloud vendors innovate rapidly and have made it easy for us to transition to new hardware and try new technologies such as GPUs without large investments.


the new normal, and that’s a good thing. To create better models of biological system, we need more data. Effective organizations have already determined how to use this data and incorporate it into their workflows. Those that have not need to partner with others else they risk getting left behind.

“THERE IS NEVER ENOUGH TIME TO DO THINGS RIGHT THE FIRST TIME AND NEVER ENOUGH MONEY TO DO THEM RIGHT THE SECOND TIME. UNFORTUNATELY, IT IS VERY COMMON TO PREFER TECH-GURUS (MAYBE BECAUSE THEY ARE HARDER TO UNDERSTAND) OVER THE EXPERT SCIENTISTS ONLY TO HEAR A YEAR DOWN THE ROAD THAT AN APPLICATION IS UNFEASIBLE BECAUSE THE SYSTEM WAS NOT DESIGNED TO SUPPORT IT.”

FLG: There’s a lot that has, and continues to be, said about the looming tsunami of data. At what point does the conversation shift from ‘how are we going to manage all of this data, effectively?’ to ‘how are we using this data in our workflows?’ PW: I think this somewhat depends on perspective and the magnitude of the problem. We’ve had a tsunami of data for some time but have managed to use the data quite well in certain cases, such as in the ENCODE and TCGA projects. I think the difference now is that more people are affected, to the point that everyone in the space needs to have solutions. Hospitals, academic institutions, disease groups, educational programs, research funders—those organisations that realise that they are in the data business, and accordingly plan for enabling their constituents to use data effectively, will be best positioned for success. MG: On the tsunami, one of the key issues in dealing with largescale data is dealing with progressive summarisation of the data. For instance, for images one often does not deal with the raw files, but deals with compressed JPEGs and MPEGs. Likewise, for human sequences, instead of dealing directly with BAMs and reads, one might often deal with VCFs and eventually even just haplotypes. Similarly, for the sequence annotation, one would look at peak files and various annotated blocks, such as enhancers, rather than looking at raw signal tracks or the result of an RNAseq experiment. These summarisations are a much lighter way than the raw data and much easier to deal with. In this way, we do not need to worry about the data management problem but focus on using them. In addition, they often have much of private information shorn. EE: I am not sure such a shift would occur. The rate of data generation is a direct outcome of technological maturity and new technologies allowing the generation of new data types, like single cell or metagenomes. This will not stop just like the need to solve crimes and understand the molecular mechanisms of complex disorders will not disappear. Whether we are utilising the best possible resources to address these problems is a question for reviewers. Perhaps it is worth discussing how to best inform the community of the availability of these datasets and their maturity? AS: It already has (or should have). A tsunami is not a wave of data with ebb and flow but a constant on-going increase in data. This is

FLG: Ownership of data is something that gets brought up by the public frequently. Should patients and consumers own their own data, or does it sit best at an organisational level? PW: Research should be an inclusive exercise, where all stakeholders contribute for greater awareness and better outcomes. The concept of learning health systems has not yet impacted greatly on genomic research, but the principles of coproduction and trust engineering apply quite well to genomics, especially clinical genome diagnostics and therapeutics. I believe that patients and the community have important strengths that researchers and clinicians can better leverage. Stronger community engagement, including in underserved areas, can bring new ideas, establish partnerships, and educate the public about the value of genomics. As this occurs, we should see positive evolution of our social understanding of genomics, and as a result, many of the ownership issues will begin to dissipate. MG: The ownership of data is a complicated issue. Essentially it makes sense for the individuals to own their own data. However, researchers like me are getting many data sets from many individuals and constantly processing them and being asked to reuse data in various formats. It's very complicated to do so over many individuals and one would have to imagine some sort of intermediate program mechanism to be built so that the data can be available for research but also keep the individual’s privacy intact. EE: I believe that people have the rights to their own data and that only they can decide what to do with them. AS: Data from a single patient has no (or very little) value. What has value is the amalgam of integrated data from many individuals, and the quality of questions being asked of the data. There needs to be more outreach to the public to help them understand our only hope of tackling complex disease such as cancer is for the data to be shared. This needs to be brokered by a trusted party, but accessible in some confidential manner to all. Whether the consumer or organisation owns the data is less important to companies like ours than is there a straightforward manner for us to access it to enable discovery. FLG: What needs to be considered when dealing with data policy issues, and can technologies such as block-chain help with this? PW: Data policies will need to continue to evolve. As compliance and privacy footprints grow, the challenge for the research community will be how to best balance protection with utilisation for appropriate risk. To date, IT and compliance groups have focused more on protection, in large part because minimal or no risk solutions are more easily quantifiable and justifiable than those with “acceptable risk”, which is impossible to precisely define. At some point, this may make research intractable to conduct. It may make sense to better define what risks are acceptable, and to work with each other to come to consensus. While technologies like block-chain will help, ultimately it is human behaviour that poses that greatest risk and need to adapt.


MG: Block-chain is a popular new technology for keeping a secure ledger. However, it is not well-suited to directly interact with large amounts of private data, such as the reads and BAMs from genome sequencing. Nevertheless, it might be useful for tracking modifications to these files, as far as looking at the metadata. One can imagine a metadata history of a file being dealt with in terms of a block chain. EE: There are many issues to consider, but I believe that the most important ones are that the policy should be short and understandable and explain the risks in donating data. Block-chain technologies can help in protecting and securing the data and I can envision that they will be adopted for sensitive data. AS: Data policy questions centre around ownership of the data and data privacy. Data policies can help formalize the rules for sharing and technology can help implement those rules, but more fundamentally there needs to be an understanding at a societal level of the value and application of this data. There is a lot of hype around block-chain right now. It has the potential to help, but like all new technologies must be evaluated on its own merits. FLG: As much as it is a technical challenge, data sharing is also a social challenge. How can you get people into the habit of wanting to share their data? PW: In my experience, the best way to get people to share is to understand their particular uncertainties about sharing. These may vary—desire for attribution, perceived compliance risks, effort expenditure. Understanding these uncertainties can help to determine a behavioural economic strategy to overcome obstacles. Opportunities for direct engagement of data providers in the process—such as participating in developing standards, involvement in pilots utilising data that has been aggregated together, acknowledgement of participation— can help. Finally, focus on those who do share, as the sharing will drive the research and capabilities forward; don’t dwell on those who do not or cannot, which can be an exercise of diminishing returns. MG: Obviously, data sharing has issues related to data ownership, privacy and so forth, which are general societal questions and have to be dealt with. One of the key issues here is to keep the individual from being harmed by the sharing and this requires various protections. Obviously, there is health insurance protection for genomic data sharing but there might be also various social protections against stigma, which would be important for sharing a full description of an individual. EE: One of the very first written texts was a self-promotion message written by King Hammurabi. This is no different than any animal in nature showing its strength, beauty, or skills. However, after that peacocking message came the first laws, which separated us from the animals. So while sharing may be ingrained in our DNA, perhaps more strict laws are the solution. AS: That’s exactly right. I see it as more of societal challenge than a technological one. Once we figure out the rules, the technology piece is (relatively) easy. Outreach is key. We must be able to explain to the public why this data is needed, its value and the potential for societal good. Understanding that any individual piece of data has low value by itself is key. We also need to put in place the right rewards for people to share their data. When people share social information on sites like Facebook, they do so because it provides them with a value they recognize. We need to determine the equivalent structures for medical data that will promote sharing and disclosure of their medical records.


FLG: What are you most excited about for the future? PW: I think the day is coming when a researcher can go to their computer and, with the proper authorisation, be able to instantaneously query across all sizeable molecular, clinical, and environmental datasets generated with public funds. We are working towards that vision here at Cincinnati Children’s with a project called VIVA, which aims to provide a catalogue of all molecular, biomaterials, imaging, and clinical data across our academic health center. Our aim is to organize our data at the institutional level, rather than just by disease or cell type, and link this with similar data compilations from other institutions. I’m excited about the new possibilities that this data immediacy and democracy will bring, in terms of discovery potential, shortening the R&D cycle for improved health, and improving team science cohesion to tackle our most pressing and complex disease challenges. MG: The most exciting part about the future is the application of advanced AI technology in the genomics field. It will help us to tackle all the questions above and solve the mysteries in genomics. Eventually it would help us find treatments for diseases that are currently incurable, automatically monitor the dynamic change of individual patients and adjust their therapy accordingly. EE: I am terrified about the future. I do hope to see more women in science and more children interested in STEM. AS: The ability to create and test predictive models that can be used to accelerate drug discovery and drug validation/approval in an accelerated manner. With more data, our capabilities will only improve to the point of reducing and one day potentially even removing the need for large clinical trials with most results being computed in silico. n

COMMENT

OANA STROE COMMUNICATIONS OFFICER EUROPEAN BIOINFORMATICS INSTITUTE (EMBL-EMBI)

OANA TELLS US HOW EMBL-EBI IS HELPING ANSWER SCIENTIFIC QUESTIONS

HOW OPEN DATA IS CHANGING OUR PURSUIT OF DISCOVERY HOW IS DATA HELPING US SATISFY OUR SCIENTIFIC CURIOSITY?

I

n the 16th Century, a cabinet of curiosities was a popular way to show off one’s private collection of extraordinary objects. Animal specimens, skeletons, minerals, unusual handmade objects and intriguing antiquities from the New World could all be revealed with a flourish, and rouse in visitors a keen sense of curiosity in this new Age of Wonder. Over time, cabinets of curiosities morphed into modern museums. Both feed two profoundly human tendencies: curiosity, and the desire to collect and preserve knowledge. These same tendencies are driving a sea change in science: disruptive technology, a tsunami of data and the democratisation of access. Now, curious visitors to the European Bioinformatics Institute (EMBL-EBI) data resources can gaze into a new kind of menagerie: the wonders of the molecular world carefully tended in public databases that anyone can access. A MULTIDIMENSIONAL CABINET “Traditional cabinets of curiosities organised items by type, so in a sense they were like an ontology of shapes, because they classified artefacts according to what they looked like,” says Chuck Cook, Scientific Services Manager at EMBL-EBI. “You could draw a parallel with the modern database, which organises biological data resources in a similar way – into categories. In the database, information and categories are interlinked, so in a way the database is like a ‘smart’ or multidimensional cabinet of curiosities.” Even as technology advances at breakneck pace, science is more accessible than ever. The sublime combination of high-tech visualisation, collaborative software programming and open data is truly democratising biology.

“With a traditional cabinet of curiosities, the collector was the ultimate authority,” adds Andy Yates, Team Leader of Ensembl Genomics Technology Infrastructure at EMBL-EBI. “EMBL-EBI keeps its “collections”, or services, open to the researchers everywhere. In doing so, we’re making the contents – and ourselves – open to reanalysis and review. It’s a necessary move if we want our resources to be truly useful. “We work within the scientific community, and that means we are open to critique – at a speed that would have been unthinkable even 15 years ago. Previously, we would have probably published the latest version of the Ensembl genome browser on a CD, sent it off in the post and that was it. There was no instant feedback, no self-regulation, nothing. It’s only in the past few years that this kind of openness has become workable, due to improved communication channels, and now it is actually expected by our users.” OPENING UP THE CABINET “Data accessibility is crucial for anybody doing science, which is a massive change,” continues Yates. “Cabinets of curiosity were private collections with limited accessibility. Some owners opened their doors to the public, but it was still only a small number of artefacts – the most peculiar ones – that were on display. Most things were indexed and locked away.” EMBL-EBI hosts many tens of petabytes of data, and a big part of its work relates to making datasets easy to find. Without indexing, there is no way of knowing what is in a database, or how it got there. Indexing is as central to public data resources today as it was to early collections. Data curation and annotation activities are intense at EMBL-EBI. Once you have generated a sequence and identified a gene, you have to search that gene against a huge amount of pre-existing data. The curation process includes labelling and describing datasets consistently


COMMENT so that any researcher can discover and make use of the data for their own experiment. This helps research communities build knowledge and make connections between different studies and disciplines. Without descriptions – also called metadata – samples and sequences are cast adrift in a sea of data. “Without metadata, exploring a database is like wandering through the basement of the Louvre blindfolded, hoping you’ll find the Mona Lisa,” says Yates. FAIR POINT To be useful, research datasets must be put into context and linked to the paper that describes them. To make sure these hard-earned datasets can be reused by other scientists, text miners and data curators at EMBL-EBI check data submissions, ensuring they meet the necessary requirements. EMBL-EBI works hard to develop tools according to FAIR Guidelines. The FAIR data movement aims to make research data Findable, Accessible, Interoperable and Re-usable. It has gained momentum in the life sciences, where hundreds of thousands of scientists throughout the world are generating diverse datasets of all sizes. FAIR data articulates the central needs of data-driven research, as access to accurate, up-to-date information is required to formulate good hypotheses.

“MUCH LIKE THE COLLECTORS WHO SET UP THE FIRST CABINETS OF CURIOSITIES, SCIENTISTS ARE STILL METICULOUSLY CATALOGUING EVERYTHING THEY LEARN ABOUT THE FORM AND FUNCTION OF LIFE.” Image Credit: Spencer Phillips, EMBL-EBI

ASKING QUESTIONS So how is data availability changing the way we answer scientific questions? According to Chuck Cook, “people are going to become more dependent on big data, and scientists who can’t use big data will be left behind professionally. As we become more specialised, running isolated experiments is becoming more difficult. To delve deeper into research, we will need to collaborate with people from lots of different backgrounds. And to do that we need a common language – that’s something we are actively working on.” “Biologists have to turn into programmers, to a certain extent,” agrees Yates. “That’s how the scientific questions are changing. The researcher will come up with a hypothesis and then prove or disprove it through data mining of large data resources. That requires some degree of programmatic knowledge. The questions may be similar, but they can be much more complex. We will still repeat, and repeat, and repeat our questions and analysis, gently refining the answers we get.” “The time it takes to go from scientific discovery to application is becoming much shorter,” adds Rob Finn, Team Leader for Sequence Families and EMBL-EBI’s Metagenomics resource. “This is partly because the data is connected, so you get the whole biological context rather than just looking at one thing in isolation. That means you’re better informed to design your next experiment.” Finn is no stranger to exploration. He is involved with data from the Tara Oceans expedition, which sailed a research schooner more than 300,000 kilometres in a five-year circumnavigation of the globe. Scientists on the voyage systematically collected samples of plankton from all the world’s oceans and shipped them back to land for DNA sequencing and analysis. “Sequencing the samples from Tara lets us ‘see’ some of the diversity of life in the oceans,” continues Finn. “The first set of 40 million genes identified in Tara Oceans samples are mainly prokaryotes – bacterial species we haven’t seen before. But in the second wave of data, we have identified over 117 million eukaryote genes so far – and there is still a long way to go. There’s a huge amount of genetic data to study out there. What do all these genes do, what species do they belong to? How does it all fits into the bigger picture? Those are the really intriguing questions we’ll be exploring for years to come.”



COMMENT

Oana Stroe is Communications Officer at the European Bioinformatics Institute (EMBL-EBI). The institute shares data from life science experiments, performs basic research in computational biology and offers an extensive training programme supporting researchers in academia and industry.

“TO BE USEFUL, RESEARCH DATASETS MUST BE PUT INTO CONTEXT AND LINKED TO THE PAPER THAT DESCRIBES THEM.”

MAPPING THE LIFE SCIENCES In light of this ever-growing influx of data, what are the big challenges facing biology in the coming years? “The big change I see in biology is that molecular scientists now have the capacity to look genome-wide and species-wide,” says Janet Thornton, Director Emeritus of EMBL-EBI and Senior Scientist. “Before open data, a scientist worked on one protein, gene or experimental system, possibly for their entire career. Seeing the bigger picture was practically impossible. Today, we can make genome-wide and species-wide observations. “This shift also poses the biggest challenge, which is that, despite the unity of biology (in that all living systems are coded by the genetic code), truly important discoveries in biology still lie within the nitty gritty details. In genomics, we have seen the impact of technological development to drive innovation. Certainly, recent developments in imaging for cell biology will allow researchers to develop highthroughput experiments that change the questions we can ask. “Biology is still in the discovery phase, and slowly moving into the theoretical explanation phase. There is so much left to understand. As always, our science will follow the ‘Map, Quantify and Model’

roadmap. It’s like before the world was mapped - we are only just properly mapping biology now. Initiatives like the Human Cell Atlas are very good examples of all the missing details we still need to understand before we begin to explain how things work. The next step will be to translate this knowledge into everyday areas, such as medicine, agriculture and biodiversity.” TOOLS FOR A CURIOUS MIND Much like the collectors who set up the first cabinets of curiosities, scientists are still meticulously cataloguing everything they learn about the form and function of life. But at EMBL-EBI, the work is about more than just recording and describing data. Linking it all up to facilitate further discovery is another area of intense focus. By working with users, helping set standards and curating data, EMBL-EBI creates resources that other scientists can build on well into the future. Programmers and scientists at the institute also develop a broad range of analytic tools, from complex machinelearning methods to computational models for testing hypotheses, or simply satisfying curiosity, and applying new knowledge to real-world questions. n


CREATING A GLOBAL NETWORK UNIQUE SUPPORT FAMILY’S ACROSS THE WORLD LIVING WITH A RARE CHROMOSOME OR GENE DISORDER. THE CHARITY PUBLISH INFORMATION GUIDES, IN A NUMBER OF DIFFERENT LANGUAGES TO HELP FAMILIES UNDERSTAND WHAT IT IS LIKE LIVING WITH ONE OF THESE DISORDERS

FLG: Tell me about Unique’s history and main mission? BS: Unique’s mission is to inform, support and alleviate the isolation of anyone affected by a rare chromosome or single gene disorder and to raise public awareness. We support families worldwide living with a rare chromosome or gene disorder, and the professionals supporting them. Unique was founded in 1984 by Edna Knight MBE as a Trisomy 9 Support Group. Putting pen to paper, families with trisomy 9 were able to share their experiences and support each other. The group steadily expanded to include families of children with any rare chromosome disorder. In 1993, the group gained its charity status and adopted the Unique logo. Alongside the help of my husband, Trevor, who worked as a database specialist, Unique launched its database to collect the lifetime histories of families living with a rare chromosome disorder. When our first website launched, we had just 1192 registered families. With the progress of genetic testing technology from karyotyping to array CGH analysis, and now next generation sequencing, we currently have over 16,000 member families, representing over 18,000 affected individuals in more than 100 countries worldwide. FLG: What services do you offer? AP: We understand what life is like with rare chromosome or single gene disorder, and the isolation and mixed emotions they can bring. To relieve the isolation of our families, we have our listening ear telephone and email helplines. We connect families with each other on the basis of their rare chromosome or single gene disorder or symptoms. We have our social media pages and groups to enable families to speak to each other, wherever they may be in the world. Over the years we have developed a network of local contacts to help bring local families together for support and friendship. Our information guides are medically verified and provide detailed and descriptive information about many of our rare chromosome and single gene disorders. They are family friendly and many are available in multiple languages. For professionals such as clinicians, we can produce anonymised phenotypes on request using our confidential offline database. Where appropriate, we also connect researchers with patients for research projects.

guides. Once we have reached a critical mass of families with a specific disorder, we undertake a medical literature review and seek professional experts and researchers. We also request families to complete additional detailed surveys, which allows for the inclusion of helpful tips and stories from families living with the specific disorder. Once the guides are developed, they are medically verified. We have now produced over 200 disorder-specific information guides with many more in the pipeline. The final guides include phenotypic information about the disorder, as well as information about education, social life, development, behaviours and ongoing research. New guides about chromosome and single gene disorders are translated into many different languages are continually added. Unique is very grateful to the many geneticists, paediatricians and developmental specialists who have already helped us by writing or reading through and verifying the texts of the group’s guides on individual conditions. All information guides are available to download from our website free of charge. FLG: What are some of your biggest challenges right now? BS: Part of the new GDPR law, due to be implemented in May 2018, will strengthen rules around consent. This means, however, that rare disease patient support groups like Unique could be restricted by the Data Protection Bill in using health-related data from their patient registries for patient care and research.

FLG: You write information guides, what do these entail and where are they distributed? AP: We know that families need more than just a list of medical problems that could be associated with a rare chromosome or single gene disorder. They need to know what daily life entails and what to expect when living with such a rare disorder. Unique has been collecting the lifetime histories from families living with specific chromosome disorders, and more recently single gene disorders, in our comprehensive offline database for over 30 years. Since 2003 we have spent many thousands of hours producing family-friendly, medically-verified, disorder-specific information


Image Credit: Arusha Images Photography

“OUR INFORMATION GUIDES ARE MEDICALLY VERIFIED AND PROVIDE DETAILED AND DESCRIPTIVE INFORMATION ABOUT MANY OF OUR RARE CHROMOSOME AND SINGLE GENE DISORDERS. THEY ARE FAMILY FRIENDLY AND MANY ARE AVAILABLE IN MULTIPLE LANGUAGES.”

Patient-provided data on the natural histories of rare diseases, an invaluable resource for clinicians, the NHS and the international research community, may have to be destroyed or anonymised unless they fall under an exemption or unless the data is regularly re-consented by patients. In many cases re-consent will be impracticable where the data has been collected over many decades. This could hinder research, public health policy decisions and patient support.

regularly hold free regional family days and conferences for families. At these events we encourage professionals from different backgrounds, including clinical geneticists, molecular and cytogeneticists to attend the events and give family-friendly demonstrations about genetics. This also provides a unique opportunity for clinicians and families to interact in a non-clinical situation, and also for our lab technicians to meet the families whose samples they are testing.

FLG: With genetic disorders being felt all over the globe, how do you connect with as many people as possible?

FLG: In your opinion, what needs to be done to allow for the increased implementation of genomics into the clinic?

AP: Unique supports families worldwide in more than 100 countries. Due to the rarity of the disorders at Unique, it’s important we’re able to connect with families and professionals anywhere in the world to help us understand the effects of rare chromosome and gene disorders on daily life. Thankfully this is now much easier with access to the internet and social media. We have a network of over 200 local contacts worldwide to connect local families with each other, who occasionally organise coffee mornings and other social events. This helps to support families locally and also raises awareness of Unique and the support we can provide to families and professionals.

BS: Increased awareness and education of the benefits genomics can bring to care of patients and their families is vital. The implementation of genomics in clinical

care and the possibility of securing a diagnosis through DNA sequencing is essential to supporting families living with the consequences of a rare chromosome or gene disorder. For many Unique families, receiving a genomic diagnosis means access to a prognosis and possibly to personalised medical care and support. We regularly deliver presentations to and hold discussions with policymakers, paediatricians, medical students and primary healthcare professionals to increase awareness of the importance and impact of receiving a genomic diagnosis and provide a patient perspective. Through the annual international rare chromosome and gene disorder awareness week we aim to raise the public’s and professionals’ awareness of Unique and the impact on families of rare chromosome and gene disorders. n

Arti is an Information Officer at Unique. Her role is to answer queries from new and existing family members and professionals, to provide information about specific rare chromosome and single gene disorders and to help match up families on the basis of their rare chromosome or gene disorder, symptoms or treatments. She also responsible for the production of the Unique magazine.

Dr Beverly Searle is the Chief Executive of Unique. She has passionately been involved with the charity since the birth of her daughter Jenny in 1990, first as a volunteer and since 1999 as a staff member. Jenny was born with a chromosome deletion and was profoundly disabled and very medically complex; sadly Jenny passed away at 21 years old but continues to make a difference to all who know of her.

FLG: Bridging the gap between families and professionals is essential in further understanding disorders, how does your organisation approach this? AP: One of the aims of Unique is to bridge the gap between families and professionals to enable deeper understanding and efficient team work. We know that care works better for people living with rare chromosome and gene disorders when families and professionals are able to work together. We often link researchers who are interested in particular chromosome or gene disorders with families who are living with the disorder. Funding permitting, we


A DAY IN THE LIFE

BRIDGING THE GAPS TO PERSONALISED MEDICINE DR. ELHAIK COMPLETED A PH.D. IN MOLECULAR EVOLUTION AT THE UNIVERSITY OF HOUSTON, STUDYING THE EVOLUTION OF MAMMALIAN GENOMES. HE THEN COMPLETED TWO POST-DOCS AT JOHNS HOPKINS WORKING ON POPULATION GENETICS AND MENTAL DISORDERS. AS A LECTURER AT THE UNIVERSITY OF SHEFFIELD HE FOCUSES ON MEDICAL, EVOLUTIONARY, AND POPULATION GENETICS. ERAN ELHAIK, LECTURER, THE UNIVERSITY OF SHEFFIELD

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r. Elhaik’s recent work includes the development of the GPS technology that identifies and dates the origin of genomes and promotes a new understanding of cot death and mental disorders. This is what a typical day looks like for him in his own words.

By now I have been working for the past 2-3 hours, which technically makes me a night person. Together with a US colleague, we develop infographics to represent the relationships between various cultures through time and space using ancient DNA. Anthropologists have already classified them as “hunter-gatherers” (HGs) or “farmers” and similar. Such names allow our minds to construct very clear images of bare-foot hippies dancing around trees in the nude and grabbing fruits from the low branches, or of people dressed for work in some primitive overalls and straw hats, their backs painfully arched as they clear the stones from their field and sweat is pouring from them. No doubt which of those are our ancestors – our mind tells us. It is the same mind that tells us that the well-dressed lady on the train works in a bank and the gentleman with paint-splattered trousers is a housepainter. It’s called

typology, and it is one of the gravest dangers in science. Anthropologists cannot tell us how genetically related these HG and farmers are. After all, farmers were yesterday’s HGs and some HG’s would be tomorrow’s farmers. Are they really that different? At first scientists thought that they are, but now they are not so sure. I try to imagine the encounter between these people, since there is little doubt that the ripening fields attracted the HGs at some point. Did the farmers give the HGs some seeds (why would they? Why help the competition?)? Did they enslave them (maybe some, but what of the others?)? Paid them off (probably, but to what end?)? Paid them to ruin the competitor’s field (this would invite retaliation)? Most of these are not questions for geneticists, of course, but they are useful nonetheless to develop hypotheses.

I am taking on some light reading before getting really tired. Nowadays it is the history of the Near East and Mesopotamia with an emphasis on Jewish history. Here we have “The Great Sea” (David Abulafia), “Babylon” (Paul Kriwaxzek), “The Beginnings of Jewishness: Boundaries, Varieties, Uncertainties” (Shaye Cohen), “The Construct of Identity in Hellenistic Judaism: Essays on Early Jewish Literature and History” (Erich S. Gruen), “Identity of the Diaspora: Jews in Asia Minor in the Imperial Period” (Krystyna Stebnicka), and “Jewish Communities in Asia Minor” (Paul Trebilco). Most of these books strictly depend on typology, although as I explained above, they cannot say for sure. They assume, and are probably correct, that cultures far away from each other are genetically distinguishable, but what about crossroads like the Near East where people of different origins have been mixing for generations. Is there a point to distinguishing people as Jewish or Greek in a mixed society? What if they are of the same gene pool but with different names? Some of these books won’t be as long, that’s for sure.

I am flipping over the headlines to make sure the world is still in one piece and that we don’t need to run to the nearest bunker. If we do I’ll take my chances in the woods. UK bunkers got stuck in their WWII version. Fortunately, we have at least one more day here.


A DAY IN THE LIFE

Ignorance of population genetics has dire consequences on epidemiological studies. Allele frequencies can vary tremendously even within the UK. To demonstrate that I analyse an enormous genomic database for which we were provided data on people’s place of birth. The GPS algorithm we published in 2014, predicts the place of birth from the genomic data with impressive accuracy. By large, northern and southern people emerged from different founding populations, most likely northern Europeans and Southern/Western Europeans, respectively. It is easy to use GPS Origins on English genomes to see where people migrated from. Had we knew that, we would be in a much better position to study their drug response, drug metabolism rate, and other pharmacokinetic traits necessary to develop personalised medicine. It would also allow us to perform epidemiological and clinical trials much more accurately without the risk of stratification bias (mismatched ancestries). Two emails come in from the GPS Origins customer support one after the other. The first congratulates GPS Origins for pinpointing their origins 50km away from their home. The second is much more furious – condemning GPS Origins for the very same reason. I can see now why people stay away from this field.

Overnight I got 30 emails from Google Alert and Google Scholar Alerts mentioning news and scholarly articles covering all my fields of interest from Sudden Infant Death Syndrome (SIDS) to Genetic Genealogy. This happens every day. Together with journal alerts and, of course, Twitter, each day starts with a hefty pile of papers to read. No point sighing, it won’t make it go away.

A 3rd year student walks in. He chose bipolar disorder as his topic for a 4000-word project and got excited after finding a marker that appeared in all 42 GWA studies he analysed. It is an intronic variant with odds ratio (OR) of about 1.5, at best. I explain the meaning of these terms and encourage him to search for markers with larger effect size. The next time he comes he is far less excited. Yes, there are variants with higher ORs, but they don’t replicate across studies, that is the literal definition of GWAS. I recall how one of my colleagues got manic with excitement when he found out that olfactory receptors came up high in our work on bipolar. It was followed by depression. Now, here comes the eternal question – “what should I do now?” I explain that everyone has their own “grandma recipe” for finding variants, so as long as he is consistent and making reasonable assumptions, it is OK. He is not happy about it, he would much rather “find something,” but science is not about being happy. It is pretty much about failing miserably and tweaking it to appear like a great achievement. Success is either accidental or the result of very hard work.

Lunch time. Lunch is probably the best time to exchange ideas and meet new colleagues, but we don’t have a luncheon room so I just eat at my desk. If it wasn’t for the university’s emails we would be practically cut out from the rest of the university. If only they would be as informative about newcomers as about those who passed away, there would be a point in regretting not having a luncheon room.

A conference call with a company involved in clinical trials. I explain that our newer GPS-based tools – allow optimize case/treatmentcontrol matches using both demographic and genetic criteria to minimize stratification bias. In this manner, trials can be more accurate and, hopefully, more likely to be show the real effect of the drug or treatment. The neat thing about the tool is that, even if the trial has failed, it allows you to genetically characterise the groups of responders to identify any personalised effects that the treatment may have. The company reps are impressed. A follow up call is scheduled.

Jetlag is hitting me now since I just returned from Australia. I was advised to give it a few days, but in a few days I’ll be in Finland and then Israel. How many jetlag’s can one person have? Do they cancel each other out? I am taking a quick walk in the freezing weather. If it worked for Elijah of Vilna, it should work for me too. Upon my return I review my postdoc’s work. I try to pinpoint the mistakes, but the more tired I am the more likely I am to just correct the mistakes myself. I am a bit surprised that no one at my lab picked up on this pattern. If they had, they would have gotten me a hammock by now. Their loss. This study deals with the environmental factors associated with autism. We are looking at some factors that have been largely ignored in the literature in an ecological link study. I wonder how many more such factors are there that our culture trained us to ignore. Mental disorders are considered “complex,” that is, the product of genetic and environmental factors. Applying one’s “grandma recipe” to search for pathogenic variants is rather simple. Accounting for the nongenetic components is a completely different story. That’s the “low hanging fruit” paradigm of genetic studies.

I head home with extreme care. The problem is not with the long walk or even the hill, but with the slippery road – pretty much like science.


REVIEW

STAR WARS: THE LAST JEDI Carl Smith & David Smith (no relation)

AFTER ALL THE ANTICIPATION, BUILD UP, AND CHILD-LIKE EXCITEMENT HOW DID THE NEW STAR WARS MOVIE COMPARE TO EXPECTATIONS?

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.J. Abrams, arguably, pulled off the impossible with 2015’s The Force Awakens. Star Wars was back in our lives, and reunited us with some old friends, banishing memories of Jar Jar Binks for good. December saw Rian Johnson’s The Last Jedi take on impossibly high expectations and build on modern day mythology. DS: Finally, after waiting a generation, there is a new Star Wars movie that measures up to The Empire Strikes Back! After the total lack of originality in The Force Awakens, The Last Jedi

takes off in a completely different direction and breaks new ground!

development makes no sense and contradicts a lot of established Star Wars lore.

CS: I completely disagree. While not a total remake like the last one, this borrowed heavily from Empire Strikes back and continued to walk us down an all too familiar path. The bad guys are on the verge of dealing a crushing blow to the good guys in a big battle, there’s a big reveal about one of the bad guys, there’s a focus on Jedi training, there’s a betrayal by a rogue… I could be describing Last Jedi or Empire Strikes Back! Don’t even get me started on the weird side quest to casino planet and the ham fisted insistence to give Poe Dameron some ‘personal growth’.

CS: I just don’t get how she can be so evenly matched with Kylo Ren despite him benefiting from all that training with Luke and more under Snoke.

DS: I think you’re taking it a little too seriously. It was still a fun movie. The pacing was a little off in places, but it was great fun and easily the best looking Star Wars movie out there. I loved the whole package of action, humour, visuals, mixing the old with the new… CS: I couldn’t agree more on the visuals. Some of those set pieces were stunning. I found the humour a little off, in that it’s not something we’ve seen in the previous 7 (8 counting Rogue One) movies. I also felt the movie lacked some subtlety in its reverence to the originals. Especially scenes with Luke- they all seemed to have a reference to the original trilogy. Old versus new seemed to be a big theme in this one, and it got a little too ‘meta’ for me. DS: One thing did really bug me though. I love Rey as a character, but her character

Editorial credit: / Shutterstock.com

VERDICT: GREAT/OK

PROS

CONS

Amazing visuals

Leia flying through space

Andy Serkis delivers another great performance

The main antagonists seem pretty incompetent

Leaves us in a very new place for Star Wars

Leaves us in a very new place for Star Wars


DS: I think they got all of that wrong. The more training these two get, the weaker their powers seem to get. But my big thing is this: Star Wars has always been about destiny, and family destiny. Even in the prequel trilogy young kids are tested for potential aptitude in using of the force. Here Rian Johnson starts to lead us down a different path where anyone can use the force. We wave goodbye to Jedi’s, we wave goodbye to the Sith, it’s all open to anyone now. Where do you go from that without invalidating everything that’s come before it? CS: I could talk forever about everything I didn’t like about this movie, but it should be remembered that it’s a near impossible task to take on a classic like Star Wars and put something together that’s universally loved and venerates what’s come before adequately. It was still better than a lot of other movies out there. DS: I still really liked it. I think you’re being way too cynical on this one. I can’t believe I’m going to have to wait two years for the finale now… So there you go. The love/hate battle surrounding The Last Jedi made it to FLG as well. Go see it and tell us what you think! n

DAVID’S RATING

8.5

6

CARL’S RATING

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