bioinformatics

“To be fully honest, I think some of these tests are scary tests. I’ve had the luxury of testing myself . . . some of this needs to have the physician and the genetic counselor involved.”

That’s Pouria Sanae, a newcomer to our field via Yahoo and Helix. He’s also a Swede which gives him a fresh perspective on American genomic culture. Last month Pouria and his co-founders launched ixlayer, a new platform that integrates many of the players in the genomic medicine space: DTC companies, clinical labs, and physician/providers.

Pouria’s big vision here is close to the familiar dream of bringing genotype and phenotype together that we’ve heard on this program before. Maybe this outsider will pull it off in a big way. His approach is bold and comprehensive. Obstacles he’s facing?

Health data is more sensitive than anything he's encountered before. And there is not the same “buy in” in the healthcare space that he saw in software.

But as he asks, “isn’t this something we need to do?”

Our end-of-year special guest is one of the U.K.’s top genomicists, Ewan Birney, Co-Director of the European Bioinformatics Institute at EMBL. He is also the non-Executive Director for Genomics England.  Ewan's perhaps best known for his work with the ENCODE consortium.

We begin by following up with Ewan on a popular blog he co-wrote in October on race and genetics that responds to some of the latest trends on this topic. What does he think of “racial realism? How does he like being called “woke?” But there were issues not covered in the blog: if indeed race is cultural, what are DNA scientists doing talking about it?

We move on to general questions about genomic medicine in the UK. Ewan gives a nuanced answer on whether or not to do BRCA screening and paints a context for genomics which is different than we see in the U.S.

In a year when major genomic medicine companies have faced the chopping block in America—Human Longevity, Arrivale, UBiome— the field seems to be having a rosier time in England.  One of their health ministers just announced plans to sequence all babies at birth--a plan Ewan admits is aspirational, but "a credible aspiration."  Ewan says England and all the Nordic Viking countries enjoy strong support and interest in genomics. And in the U.K., he says, doing and believing in genomics is rooted deep in a tradition of science that goes beyond politics or any current resident of Downing Street.

Did he mean for his recent piece in the Guardian DNA is not our destiny,  it's just a very useful tool to be a correction to over hype? 

"Yes!  I'm afraid there's a very messy middle here.  It's not the case that genomics is going to somehow solve or radically alter medicine.  That's just not the way it works. But it's also not the case that it's useless.  It is a very useful tool.  It's very similar to radiology.  For certain scenarios, it is really transformative.  It's a core part of medicine.  But it's not the case that all of medicine was completely changed by X-rays."

It’s the kind of plot that makes great science.

There are genes that have been hiding in plain sight, undetected until now. They’ve gone unseen, that is, by short read sequencing. Today’s guest and his colleagues call them “camouflage genes,” and a couple in particular may play functional roles in Alzheimer’s disease.

Mark Ebbert is an Assistant Professor of Neuroscience at the Mayo Clinic where he is using long read sequencing technology and computational biology to study neurodegenerative diseases, including Alzheimer’s and ALS.

“For years, the field has know that there are regions of the genome that remain dark when you are using short read sequencing data,” says Mark. "But up until recently, there had been little work characterizing how big the problem was. And as we were working on some studies on Alzheimer’s disease and ALS, we started to bump up to some genes that completely surprised me that they were dark, or what we now call camouflaged. It turns out that 26% of CR1 is camouflaged. I’ve been in Alzheimer’s research for seven years now, and in all that time I hadn’t noticed, and I’ve never heard anyone else mention that CR1 is camouflaged.”

Which leads us to ask, again, why wouldn’t all scientists doing discovery work use long read sequencing? What is the cost of missing an important gene?

If you’re not on the long read sequencing train, you’re not landing in the world of genomics.

A new paper out begins, "Structural variants contribute greater diversity at the nucleotide level between two human genomes than another form of genetic variation.”

If arrays and short read sequencing lead to the discover of many point mutations, or SNPs, which no doubt advanced genomic science a long ways, long read sequencing is now in its heyday with the contribution of structural variation detection. And according to the aforementioned paper, said structural variation is no small matter.

Mark Chaisson is an Assistant Professor in Quantitative and Computational Biology at USC. He cut his computational chops in the lab of Evan Eichler and is now etching his own name into the genomic literature. We discuss two such papers today.

It’s the question of the moment Are we living in the age of AI? Or is it still just hype?

When it comes to the latest research in immuno therapy, computational modeling is helping to answer key open questions, such as which patients might respond to which drugs.

"If you were to ask me last year about deep learning, I would probably say, aaah, most of the algorithms that are published are not really answering the important questions yet. But I think this year I am converted. We are starting to use deep learning, and we are starting to see interesting results.”

Shirley Liu is a Professor of Biostatistics at Harvard and the Co-Director of the Center for Functional Cancer Epigenetics at the Dana Farber Cancer Institute. Her lab has very recently put out three algorithms, TRUST, TIMER, and TIDE which represent some very exciting ways that bioinformatics is empowering not only cancer research but treatment decisions.

As a computational biologist, Shirley has found herself highly in demand today as the latest genomic tools such as single cell sequencing generate new amounts of data and as public databases such as TCGA make their rich cohorts available.

In today’s interview, she details these three new algorithms and makes the case that computational modeling has arrived for cancer genomics.

What does it take to collaborate in genomics?

A platform, for one thing. Over the past few years bioinformaticians have been speculating about a dominant "go to” site that would serve the software needs of those in genomics. Would it be a private company, a Google of genomics? Or would it be a non profit consortium? Would it be created at the government level?

Today we talk to Andrew Carroll, the VP of Science at DNAnexus, a company which has come about the closest of any to being that community platform. Over a year ago, they won a challenge to host PrecisionFDA, a community platform developed for exploring just how to evaluate and regulate NGS assays.

Beginning as a cloud storage company for genomics back when Amazon was just beginning to look to the sky, DNAnexus then evolved into an iTunes-like platform for various genomics software apps. One bioinformatics software on the platform might be great at variant calling, while others specialize in tertiary analysis.

“From the visibility I have, I estimate around a four to five fold increase year over year in the volume of sequencing," says Andrew. "Bioinformatics has grown to the point that it doesn’t pay to be a jack of all trades. A few years ago a project that was a thousand or ten thousand exome scale was a big deal. These days projects are coming up on hundreds of thousands of exomes, even hundreds of thousands of whole genomes."

DNAnexus’ platform isn’t just about a bunch of bioinformatics apps, it’s also a portal where different kinds of organizations can find each other and collaborate; for example, a healthcare provider and a sequencing center. In addition to PrecisionFDA, DNAnexus has been announcing these partnerships, one after another: Regeneron/Geisiner, Rady Children’s Institute for Genomic Medicine, Stanford Genomics Center. The company hasn’t sat back and waited for customers, but have been cultivating a proactive vision for genomic medicine by helping organizations be as open and collaborative as possible with their data.

"The work that we do through our partners actually tells the best story," says Andrew.

Freeman Dyson famously said, “the great advances in science usually result from new tools rather than from new doctrine.”

Today we talk with Mark Fischer-Colbrie, CEO of Labcyte, a company which has made some waves--literally-- in the life sciences by changing a very fundamental laboratory procedure: liquid transfer. For some years now, Labcyte has been selling machines that move liquid around with sound. By eliminating the need for pipette tips and other “solid” surfaces, the machines guarantee much more precision.

“Science demands precision and in ever-increasing amounts,” says Mark at the outset of today’s interview.

Acting like a rifle shooting liquid straight up, the new acoustic technology has made inroads into most life science applications. Mark talks about the Finnish Institute for Molecular Medicine (FIMM) using the new technology to do truly personalized medicine, by ex-vivo screening of cancer patient cells against hundreds of available drugs. There is often precious little sample to work with, and the errors from traditional pipetting might mean the difference of life or death. The machine is also used widely by the pharma and synthetic biology communities for its ability to reduce costs.

“Imagine saving four months on a single drug discovery cycle,” says Mark.

Recently, Astra Zeneca has integrated acoustic technology into mass spectrometry, showing the potential to immediately upgrade other tools which have been around for some time.

Should everyone change over to acoustic dispensing?

Moray Campbell was for all intents and purposes an accomplished and successful cancer biologist at the renowned Roswell Park Cancer Center. Then one day he woke up and realized he was becoming irrelevant. He was a traditionally trained wet lab biologist who was getting left behind by computer science. Any scientist must keep up with their field, but this was different. A few conferences and journals--reading the news everyday was not going to be enough. Facing reality, Moray enrolled in a bioinformatics masters program at Johns Hopkins.

That was in 2013.

"Biology is genomics. And genomics is basically computer science,” says Moray at the outset of today’s program. “In 2013 I would have said I look at the epigenetics of prostate cancer. Now I say that I look at the epigenomics of prostate cancer. I’ve become genomically literate."

What was it like for Moray to go back to school mid-career with teachers and homework and finals? Did he doubt his decision when the going got tough? Is it harder for biologists to learn coding or coders to learn biology?

Moray is now finished with his degree and in the process learned that as a discipline, we're still struggling with how to teach genomics to biologists.

He gives the example of datasets such as TCGA that many biologists today don’t even know how to use.

“These data are there. And they’re being used very deeply,” he says. "But I suspect by quite a restricted community. If you don’t even know how to download a file, how are you going to be able to analyze it?"

It's been a dramatic transition for Moray. Looking back now he says, "biology is dead; long live biology."

The race to the $1,000 genome has been full of breathtaking advances, one after the other. But is next gen sequencing reaching maturity? Will there be that many more significant innovations?

Yes, says our first guest in today’s program, Andy Felton, VP of Product Management at Thermo’s Ion Torrent division. Andy presented Thermo’s two new sequencing instruments, the Ion S5 and the Ion S5XL at a press conference today. While their numbers (accuracy, read length, throughput) don’t look that significant an achievement over the stats of their predecessors--the Personal Genome Machine (PGM) and the Ion Proton--the S5 and S5XL perhaps lead the industry now in ease-of-use.

Integrated with Thermo’s new sample prep station launched last year, the Ion Chef, and robust bioinformatics software, the workflow from sample to report is impressively simple and straight forward. Only two pipetting steps are required. The genomics team at Thermo is betting that this attractive simplicity will open a new market. "Genomics for all," they boast.

Does this just catch Thermo up with Illumina, or does it put them in the lead for clinical sequencing, we ask our second guest, Shawn Baker, CSO of AllSeq. (See Shawn's own blog here.)

Last year, pharma giant Roche went on a buying spree, picking up one company after another. In December, when it was announced they had bought out Bina Technologies, many of us were playing catch up. Who is Bina, and how do they fit in the overall bioinformatics space?

Today we hear from Bina's CEO, Narges Bani Asadi. As with many new bioinformatics companies, Bina has changed their service and product since they spun out of Stanford and UC Berkeley four years ago. Narges says that the biggest demand from customers is to provide a comprehensive solution for the entire organization. Often, she says, she encounters brilliant bioinformaticians working at customer organizations who are completely overwhelmed by all of the various informatics tools available. Many of these tools are offered free over the internet, and, she says, it’s creating “open source overload.”

Bina has been a very ambitious company from the start, working to provide NGS users with a comprehensive informatics solution, from beefy, fast infrastructure to an interface for the various kinds of users in an organization, to high powered analytics. And Narges is excited about the Roche buyout, saying that it will speed up their plans. Indeed, just providing bioinformatics solutions to Roche in both their drug and diagnostic divisions is already a huge project.

What was Bina doing so well that attracted Roche, and what will the future NGS informatics ecosystem look like? Join us for an inside look at the world of bioinformatics with one of the space’s most dynamic leaders.