With the Festival of Genomics London just around the corner, we thought it was the right time to turn our attention to the key themes being presented this year. The themes include: CRISPR; Genomics in the Clinic; Enabling Data; and Drug Development (which we have given a little twist). We have gathered together some of the key people within each theme, as well as some speakers, to get the low down on what’s been happening over the past year. To show just how much these themes are progressing, we have even given you a slice of some past news stories that we previously published on our site. One last thing, don’t forget to keep your eyes peeled for the below in the London edition of the magazine, which will be hitting your desks in the New Year!

Theme 1: CRISPR

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 (with a report in November) 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.”


Human Embryos Edited for the First Time in U.S.

A 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, 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”.

An issue experienced prior by Chinese publications found that CRISPR caused editing errors and that the desired DNA changes were taken up not only by all the cells of an embryo, but just some. This effect, known as moasaicism, made way to arguments that germline editing would be an unsafe way to create a person. But, Mitalipov’s team are said to have shown that it is possible to avoid both mosaicism and “off-target” effects, as the CRISPR errors are known. The team overcame earlier difficulties by “getting in early” and injecting CRISPR into the eggs at the same time they were fertilized with sperm.

The experiment is an exciting advancement paving the way that it is possible to safely and efficiently correct defective genes that cause inherited diseases.

CRISPR Used to Increase Crop Yield of Vegetables

Researchers have turned their hand to using the gene editing tool CRISPR-Cas9 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.

CRISPR was then used to make multiple cuts inside three genome sequences in tomatoes. The sequences are called promoters, which are DNA areas close to the gene that regulate when, where, and at what level the actual “yield” genes become active. The CSHL scientists were also able to include a wide range of changes in the three targeted traits mentioned by introducing multiple sets of mutations on the promoter gene sequences.

Lead researcher and CSHL professor Zachary Lippman explained in a press release, “What we demonstrated with each of the traits was the ability to use CRISPR to generate new genetic and trait variation that breeders can use to tailor a plant to suit conditions. Each trait can now be controlled in the way a dimmer switch controls a light bulb.

The team received better results when they targeted regulatory sequences as opposed to the actual “yield” of genes. As a result, they were able to achieve a subtler impact on the quantitative traits. “Traditional breeding involves great time and effort to adapt beneficial variants of relevant genes to the best varieties, which must continuously be improved every year,” said Lippman.

He added, “Our approach can help bypass this constraint by directly generating and selecting for the most desirable variants controlling gene activity in the context of other natural mutations that benefits breeding. We can now work with the native DNA and enhance what nature has provided, which we believe can help break yield barriers.”

CRISPR has been used to improve crop yield in the past, and in doing so could eventually be used to solve world hunger. The method in question which can be used in all food, feed, and fuel crops such as rice, maize, sorghum, and wheat can definitely contribute.

“Current rates of crop yield increases won’t meet the planet’s future agricultural demands as the human population grows,” concluded Lippman. “One of the most severe limitations is that nature hasn’t provided enough genetic variation for breeders to work with, especially for the major yield traits that can involve dozens of genes Our lab has now used CRISPR technology to generate novel genetic variation that can accelerate crop improvement while making its outcomes more predictable.”

Theme 2: Genomics in the Clinic

George Burghel, Principal Clinical Scientist, Manchester Science for Genomic Medicine:

Therapies 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.”


An Accurate, Scalable Approach to Liquid Biopsies

An accurate, scalable approach for monitoring cancer using patients’ blood samples 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 this week, was the result of a collaboration between the Broad Institute of MIT and Harvard, the Dana-Faber Cancer Institute (DFCI), the Kock Institute for Integrative Cancer Research at MIT, and Massachusetts General Hospital.

Traditionally, tumour genomes have been studied using tissue biopsies, when part or all of the 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)).

As liquid biopsies only require a blood sample from the patient, the cost and difficulty of the procedure is greatly reduced. The technique also means that it can be carried out irrespective of the cancer’s location in the body.

“Our ultimate hope is to use blood biopsies to exhaustively search for and characterize even the smallest remnants of tumours,” Viktor Adalsteinsson, PhD, co-first author of the study and Group Leader at the Broad Institute, told MIT News. “And, as tumours evolve in more advanced stages of cancer, developing resistance or becoming metastatic, we might access timepoints that could be pivotal in deciding which therapies are right for that patient.”

There are problems with liquid biopsies that have held the technique back, however. The most prominent issue relates to the quantity of tumour DNA in each sample; in order to compile a whole exome from circulating DNA fragments, at least 10% of the cell free DNA present needs to be tumour DNA. Unfortunately, the percentage of ctDNA in each patient’s sample varies dramatically and this can restrict the utility of liquid biopsies.

The technique also traditionally relies on screening the accumulated cell free DNA for known cancer mutations and as such, any tumour DNA present that doesn’t carry those mutations will not be detected.

A novel technique developed in this study, called IchorCNA, avoids this problem by instead screening for mutations patterns that are universal to nearly all cancers. The team also wanted to develop an unbiased approach to calculating the quantity of tumour DNA present in each sample before attempting whole exome sequencing, reducing lost time from failed sequencing attempts.

Using 1,439 blood samples from 520 breast or prostate cancer patients at DFCI, the team tested IchorCNA to establish how accurate and effective it was. They found that in 33-49% of samples, more than 10% of the cell free DNA present was ctDNA and thus the sample was suitable for whole exome sequencing.

The team also wanted to investigate how IchorCNA compared to traditional tissue biopsies, so they contrasted the results of 41 patients who provided both a blood and tissue sample. They found that the genetic data from both sample types was very similar for many genetic features, including an 88% match for clonal somatic mutations and an 80% match for copy number variations.

“Our study has demonstrated that we can get a cancer whole exome reliably, from blood; that it reflects the matched tumour biopsy; and that it can be done for a significant fraction of patients with metastatic cancer,” said Adalsteinsson. “This validation suggests that we can use blood biopsies for large-scale genomic characterization of disease in patients with metastatic cancer.”

The results of this study are already being used to actively work with patients as part of the institutions’ direct-to-patient research efforts. These efforts include a number of collaborators, notably the Metastatic Breast Cancer project, which is supplying saliva, tissue, and blood samples from volunteer cancer patients.

“With this work, we now have a framework for the precise measurement and quality control of tumour DNA in the plasma, enabling the genomic analysis of blood biopsies with high technical accuracy,” said Matthew Meyerson, MD, PhD, Professor of Pathology at DFCI and Harvard Medical School, and an Institute Member at the Broad.

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, who is known for discovering that fetal DNA can be found in a mother’s blood, which launched a new era of non-invasive testing for pregnant women.

A Good Test Case for DNA Screening

The study involved nasopharyngeal cancer, which is a very common form of cancer in middle-aged men in South China. This type of cancer is aggressive, and forms at the top of the throat and behind the nose, where early detection matters a lot. About 20,000 men were tested, and 300 patients who tested positive twice were given in depth examinations such as magnetic resonance imaging, or MRI, which led to 34 cancer diagnoses.  

This shows that one in ten men who tested positive actually had cancer unknowingly. 

The data presented “suggest that lives have been saved because of this screening,” Richard Ambinder, a professor of oncology at Johns Hopkins School of Medicine who wasn’t involved in the study, wrote in an accompanying editorial in the journal.

The results could help the commercial prospects for Grail Inc., a Silicon Valley startup that has raised more than $1.1 billion since its 2016 launch, from investors including Bill Gates, Merck & Co, Jeff Bezos and Arch Venture Partners. At the time of launch, Baselga said: “If this pans out, this could be a real game changer.”  Not more than a week ago, GRAIL announced leadership changes to support the company’s next phase of growth as it moves towards commercialisation of early detection products.

Earlier this year, GRAIL merged with Cirina, a small startup founded by leader of the study, Dennis Lo, which is drawing it closer to commercialization by bringing in a number of important patents. 

Lo said in a statement that his blood test isn’t commercially available in Hong Kong as of yet, while Grail has declined to reveal its commercial timeline. 

“It’s our aspiration to create a commercial test” for nasopharyngeal carcinoma, Grail’s president, Ken Drazan told the Washinton Post. If successful, the test, to be marketed in Southeast Asia, would be Grail’s first product.

 Preventative Health Care Causing Eager Investors

It’s been predicted that non-invasive tests could revolutionise cancer care, with the rise of technologies like genetic sequencing. Detecting disease early is something that could make treatment more effective, making investors eager to fund ventures focused on such preventative health care. 

Lo and his team seem to have proven that liquid biopsy testing works, however, nasopharyngeal cancer is a special case. 

The researchers estimate that, overall, it cost a total of $28,600 to identify each cancer case. “It may be worth it in Hong Kong, but maybe not in places like the U.S. where the disease is rare, and more people would have to be screened at a greater cost to find each case,” said

Dr. Richard Ambinder of Johns Hopkins School of Medicine, who wrote a commentary in the journal.

Before bringing any test to market, GRAIL would need to show extremely low rates of both false positives and false negatives, the former could lead to unnecessary treatment, while the latter could give patients a mistaken sense of security, writes the Washington Post. 

Round Table: Transforming Cancer Diagnosis 

If you’re only broadly aware that ctDNA is something people are talking about, then read on.

ctDNA stories are some of the most popular stories we publish on our website. If any of you missed our liquid biopsies webinar with Gary Pestano, that’s a great place to start familiarising yourself with the basic premise and how it’s applied to diagnostics. Broadly speaking, ctDNA is single- or double-stranded DNA released by tumour cells into the blood. It can be detected in tiny amounts, and offers several advantages over traditional tissue biopsy methods. Using it as a biomarker makes for a highly sensitive and specific tool to not only detect cancer earlier, but also change how we approach tumour management.

Theme 3: Enabling Data

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

“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.”


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 MBC Project was launched in October 2015 by the Broad Institute of MIT and Harvard, the Dana-Farber Cancer Institute, and a coalition of non-profit partners, with the intention of promoting patient involvement in research. There are currently around 155,000 women in the USA with metastatic breast cancer and the disease is responsible for roughly 40,000 deaths each year, accounting for 14% of female cancer deaths.

Because many metastatic breast cancer patients receive treatment at clinics that do not support tumour tissue research, previous studies of the disease have struggled to amass large enough patient cohorts. 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 7 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. “Their enthusiasm had a ripple effect that allowed us to expand far beyond what we had originally thought we could do.”

Now, more than 3,900 patients have completed the project’s survey for gathering demographic and medical information. Over 2,400 of those participants have given permission for the researchers to access their biological samples and 1,400 of those have provided the team with saliva samples. It is using data from these participants that the team have put together their public release. The first dataset, which is freely available in the public, consists of whole exome sequencing data for 103 tumours from 78 patients, alongside the patients’ self-reported experience information.

This release is an important milestone for the project, and indicates how successful the project may be in future at furthering metastatic breast cancer research.

“At two years, we can now say that we have all the pieces, and all the pieces work,” said Nikhil Wagle, MD, Director of the MBC Project and Medical Oncologist at Dana-Farber. “We can engage, register, and obtain consent from patients. We can access and abstract medical records. We can take in, process, and sequence tumour tissue and saliva. And we can put the end deliverable – data – out there for the world to use. Everything is feasible, which two years ago was not obvious.

“Going forward we have to push to scale up and start making discoveries. We feel the urgency, we want to go faster. And we know the patients are willing to go with us as fast as we’re able to take them.”

SOPHiA GENETICS Raises $30m to Accelerate Data-Driven Medicine

SOPHiA 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. The company will continue to recruit top talent and accelerate hospitals’ adoption of clinical genomics testing, regardless of whether they are equipped with a next-generation DNA sequencing lab or not.

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.”

With more and more hospitals adopting Sophia AI the company has in turn created the largest clinical genomics community, which enables the hundreds of institutions in the network to safely and anonymously share their findings and knowledge while ensuring patient data privacy.

“I think that the beauty is that all hospitals today are capable of doing precision medicine by just using AI,” explains Dr Jurgi. “That is really the magic; through the use of technology we use a barrier for hospitals who want to jump into genomic medicine by enabling every hospital in the world who can afford it to be as good as every university hospital.”

Theme 4: Genomic Technologies (The theme at the Festival is Drug Development, but we gave this one a little twist, so that we could talk about the important advancements in the Human Cell Atlas.)

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

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.”


Chan Zuckerberg Invests in Cell Mapping to Fight Disease

Although 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 cell atlas is an international effort to map and characterise all cells in the healthy human body. It is led by the Wellcome Trust Sanger Institute and the Broad Institute, in collaboration with leaders from across the international scientific community.

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.”

Dr Ashley believes that the cell atlas has worldwide potential. He added, “I love the investigator-centred approach to funding science. This has been shown time and again to encourage high-impact, risky research that wouldn’t be funded through other mechanisms.”

In order to highlight the capability of the project, Dr Bargmann noted that the end of the century is 83 years from now and we should remember what has happened in the 83 years since 1934. Back then there were no antibiotics, statins, or blood pressure drugs, as well as no understanding of the link between smoking and cancer.

This gentle reminder of how far we’ve come definitely encourages us to get excited about the future, and in hopefully squashing disease. 

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 HCA project is the largest undertaking of its kind. The goal of the project is to map out all the cells within the body to an unprecedented level, characterising the environment and gene expression profile of all different cell types. The consortium is guided by an organising committee that consists of 27 scientists from 10 countries, co-chaired by Sarah Teichmann, PhD, Head of Cellular Genetics at the Wellcome Trust Sanger Institute, and Aviv Regev, PhD, Director of the Klarman Cell Observatory and Cell Circuits Program at the Broad Institute.

“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.

“The Human Cell Atlas is one of the most important scientific research undertakings since the Human Genome Project,” said Dr. Regev. “Recent advances in single-cell technology have allowed us to look at cells with a clarity and depth of analysis that we have never been able to achieve before, making this ambitious project a reality within reach.”

This new partnership was established to help the HCA consortium to launch pilot projects more easily, with the help of 10X Genomics’ high-throughput gene expression analysis solutions.

“We are excited to participate in this important project, which will have an impact on our understanding of basic human biology and disease, similar to what the Human Genome Project did for our understanding of genetics,” said Serge Saxonov, CEO and Co-Founder of 10x Genomics. “Our innovative technology enables massively parallel scRNA-seq analysis of hundreds to millions of individual cells, which is a revolutionary change in how gene expression experiments can and should be performed. We hope to see more ambitious projects tackle such massively complex biological problems, leveraging the scale and throughput our technology can provide.”

Round Table: Single Cell Sequencing

With high throughput and high levels of data at the single cell level, we are now gaining a new order of magnitude of information. This is helping to make single cell sequencing one of the most exciting technologies in genomics, today. To understand where the field is today and where it’s heading, we gathered together an expert panel to discuss all this and more.

Register for your free pass to the Festival of Genomics London, January 30-31, here!