clinical genomics

One of the popular questions on the program this past year is how those doing sequencing decide between the quality of Pacific Bioscience's long reads and the cheaper short read technology, such as that of Illumina or Thermo Fisher. Today’s guest provides the most clear and dramatic answer yet: use the PacBio system exclusively.

We heard this from Steve Marsh, the Director of Bioinformatics at the Anthony Nolan Research Institute in London. Established in 1974 by the mother of a boy with a rare blood disease, the Anthony Nolan Institute is a world leader in blood crossmatching and donor/patient registries. Steve and his team at the Institute have dramatically improved the resolution of HLA typing, one of the methods for matching a donor’s blood tissue with that of the transplant recipient.

Thirty years ago when Steve entered the field, HLA typing was performed with serology and there were just 119 HLA antigens that were known. “We thought 119 was a lot of diversity,” says Steve. With the advent of genomic tools in the 90’s, HLA typing moved to the level of the genetic allele, done first with PCR and then with sequencing. “We knew that the HLA molecules were polymorphic, but now we know they are hyper-polymorphic. . . For example, 'A2' is a specificity, and serologically we recognized the specificity 'A2,' and that was it. We now recognize that there are over 500 different variants of A2,” Steve explains.

Knowing more about the incredible diversity of blood types can make achieving a donor/patient match seem all the more prohibitive. More variables mean fewer candidates. But research at the Anthony Nolan is now paying off and is robust enough to make a difference in the clinic. Ideally blood registries will provide precise matches and do so immediately.

All this explains why Steve is so keen on the PacBio system. In a field where the quality of the sequencing makes the difference between the right match and not, the increased price of the longer reads is worth it.

Finally, it should be said that we recorded this interview with Steve just before PacBio announced their new higher throughput Sequel Sequencer. This new smaller footprint instrument is promised out in 2016 at half the price, seven times the throughput and with the same high quality long reads. The decision between quality and price in the world of sequencing will soon be easier.

Though recent guests at Mendelspod say we're not quite to the $1,000 genome, we're close enough to use that benchmark in genomics discussions. But what are we getting for that almost $1,000?

Mark Gerstein is the co-director of the Yale Computational Biology and Bioinformatics program where he focuses on better annotation of the human genome and better ways to mine big genomics data. He has played a big role in some of the large genomics initiatives since the first human genome project, including ENCODE and the 1,000 Genomes Project.

“I’m very enthusiastic, of course, about the thousand dollar genome, but I don’t think that a true human genome has arrived for a thousand dollars,” Mark says at the outset of today’s interview. "The great excitement of next generation sequencing—which is deserved—has also obscured that there are a lot of very deep technical questions in terms of really assembling the tricky parts of the genome and really being able to conceptualize the more complex bits of human genetic variation that need to be tackled.”

So what are those tricky remaining parts? Mark shares his interest into the importance of structural variation, and says there is much more to learn from the overlooked non-coding portion of the genome. He’s particularly interested in pseudogenes.

We took some audience questions for Mark which lead us into a discussion of how best to query and mine big genomics data. As with several other leading bioinformaticians on the show, Mark agrees that privacy is the big issue for genomics and for society at large.

If you haven’t already, check out the inaugural Festival of Genomics being held in Boston later this month.

Billed as “a rigorous, fun, and transformational forum,” the unusual get-together will feature the who’s who on the genomics speaking circuit, including Craig Venter, George Church, and Eric Green. Based more on a music festival than a science conference, the Festival of Genomics offers a chance for folks from all around the genomics community to perhaps connect in a new way. And did I mention the disruptive price? Tickets are going for as low as $150 to enable more diverse attendance.

Who is this new media company, Front Line Genomics, that is producing the show? And what is their goal?

We talk to CEO, Richard Lumb, and Managing Editor, Carl Smith about the new company, the first festival, and their overall vision.

“We’d love the festival to be something that people genuinely look forward to and think: ah great, time to get out of the office and have some fun, meet old friends and see what new exciting research and new opportunities are out there,” says Carl in today’s show.

The Festival of Genomics takes place at the Boston Convention Center, June 22-24.

If you followed the news from the recent show of the American Association for Cancer Research (AACR), no doubt you heard about the exciting potential of liquid biopsies. These new blood-based tests, made possible by better tools and analysis techniques, offer a non-invasive way of understanding various cancers. Traditionally, with non-hematological cancers, solid tumor biopsies are obtained through surgical recession or an invasive needle.

It’s been known for some years that there are biomarkers in the blood -- circulating tumor cells (CTCs), for example -- which would give us information about a diagnosed -- or undiagnosed — cancer, but it is just recently that scientists and pathologists have tools with high enough resolution and specificity to detect them. With these new tools, the potential to change cancer treatment and detection has those in the field almost giddy in anticipation. Not only would a non-invasive method replace existing tests, but earlier detection and diagnoses would be possible.

“It has been shown that people were able to detect cancer metastases [with liquid biopsies] about six months earlier than with imaging,” says today’s guest, Milena Cankovic, the Director of Molecular Pathology and Genomic Medicine at Henry Ford Hospital in Detroit. She’s the co-author of a recent paper offering a snapshot of just where the field is at today, "Do Circulating Tumor Cells, Exosomes, and Circulating Tumor Nucleic Acids Have Clinical Utility?”

Milena says her lab is currently doing studies of liquid biopsies alongside their traditional solid tumor work. She says the lab plans to offer their first blood-based cancer tests later this year. What tests might those be, and what is involved in ensuring they are ready for prime time? Find out in today's show.

Just as biomedical research is experiencing a surge of translation into clinical application, so too must the stories of this research and its impact in the lives of patients be translated to a larger audience.

Genome magazine is a new forum for patients to learn about the rapidly advancing field of precision medicine. Published by a two time breast cancer survivor, Susan McClure, Genome is sent out to an audience of more than 325,000 each quarter for free. With four editions published, the magazine has featured stories on a multitude of diverse topics around the core theme of genomics: prenatal diagnostics, cancer care, the microbiome, and many more.

Jeanette McCarthy is the editor of Genome and joins us today to talk about her vision for the publication. She describes the audience — the magazine is as popular with doctors as it is with patients — and her efforts to find the right tone for a wide audience.

"Our vision is really to bring patients into the conversation about precision medicine," she says.

When President Bill Clinton stood with Francis Collins and Craig Venter in 2001 to announce the sequencing of the genome, the genome wasn’t really done.

So is it done now? And if not, when will it be done? What does ‘done’ even mean? That first human genome sequence that represented the work of Venter and Collins improved each year and became what geneticists refer to as the reference genome. In 2009 the Genome Reference Consortium, a group of various institutions, was set up for the purpose of finishing this reference genome. And every few years a new version is published. The latest goes by the sexy name of GRCh38.

Valerie Schneider, a scientist at the National Center for Biotechnology Information (NCBI), is the leader of the team working on the reference genome. In today’s interview, she tells us about the ongoing work to improve the reference genome, and why it’s important to science and medicine.

Will tech companies like Google and Apple be good at life science applications? We pursue this question today with Dale Yuzuki, the avid life science blogger, scientist, and now a marketing manager at Thermo Fisher. (See his recent blog, The Core Competency of Google Is Not Life Sciences.)

In addition to his personal blog, Dale is developing a blog for Thermo called 'Behind the Bench' where among other topics, he tracks the latest in sequencing. We ask Dale what happened to the Ion Proton, whether the recent trend toward long reads makes the Proton vulnerable, and just how his customers go about deciding which sequencer to buy. Adept on both sides of the bench, Dale is comfortable on both sides of the interview table as well.

More than with any other major disease, the understanding and treatment of cancer is being transformed by genomics. And these are early days.

John McPherson has been involved in sequencing since the original Human Genome Project. He now directs the Genome Technologies Program at the Ontario Institute for Cancer Research. John chaired a panel on cancer genomics at the recent AGBT, or Advances in Genome Biology and Technology conference, and shares his thoughts on this year's meeting.

Like many others, John is excited about the new possibilities gained by long read sequencing, particularly in showing structural variations of various cancers.

We ask John which platforms he likes, and most importantly--in this day with increasing sequencing instrument options--how he decides how much to spend on sequencing to answer a specific question.

"Our goal is to be as accurate as we can," he says. "For single nucleotide variants (SNPs), we see about a 93-95% verification rate. And we’re pretty happy with that. The question becomes how many samples you do, and not what you do to a sample. Depending what question you’re asking, the number of samples affects your power overall.”

John works in Ontario. We ask him about the state of clinical genomics in Canada, a country with a single payer system.

Go about anywhere in the life science industry, and you’ll run into someone who once worked at Affymetrix. Since the founding of Affymetrix and the development of what’s come to be known simply as the Affy chip, the company’s history has been intertwined with that of biotech and the genomics revolution. But what has become of the company today?

In the present heyday of DNA sequencing, some have predicted the death of Affy’s chip or microarray, a platform celebrated in it’s time for the ability to see thousands of genes in one assay. But a recent deal with the prenatal diagnostics company, Ariosa, signals that the array is anything but dead.

Today we talk with Affymetrix CEO, Frank Witney, who has engineered a certain comeback for the company. In the Fall of 2013, Affy's stock hit a low point of $3.01 per share. They had just purchased eBioscience for their flow cytometry technology in an effort to diversify. But Affymetrix was dangerously low on cash. Since then, though, the stock price has quadrupled and quarterly earnings are consistently beating analysts' expectations.

What happened? What is the future of arrays? Will they actually come behind sequencing and be the main workhorse for translating genomics into the clinic?