A New “Middle Way” for Genomics, with Physical Chemist, Yuval Ebenstein

“I love low tech,” says today’s guest.

It’s not your typical catch phrase for 2017. But then today’s guest is not your typical genome scientist.

A professor in the Department of Chemical Physics at Tel Aviv University in Israel where he runs the NanoBioPhotonix Lab, Yuval Ebenstein came to the genome from an unusual direction. As a physical chemist he started working with DNA as “just a material.”

The low tech is the method of visualizing genomes with microscopy, such as the old FISH or cytogenetic experiments. However, with the advances in imaging and single molecule analysis, he can now go far beyond these dated methodologies and "take dense chromosomes and stretch them out and read information along them in a very sensitive and informative way that is not accessible to other established genomics techniques."

“I love low tech and then giving it a little twist and turning it into high tech," he adds.

Yuval calls the twist a new “middle way” in genomics, between the large structural cytogenomics of the past and all the specific base calling going on now with next gen sequencing. Will his lab’s work turn into a new instrument able to be commercialized?

He says that PacBio, Oxford Nanopore, and BioNano are making headway in filling in this third or middle way, but that yes, there are new techniques that everyone should be able to use.

One specific paper Yuval’s group has recently preprinted is a method for isolating and cloning very long fragments of DNA using Cas9, or what his group calls CATCH (Cas Assisted Targeting of Chromosome Segments).

“This is a nice demonstration of taking low tech and reviving it,” he says.

It’s also an example of what Yuval says is the problem today with NGS, which is too much data.

To look at certain regions of the genome, such as BRCA, one does whole genome sequencing, or exome sequencing and ends up with a confusing amount of data. With CATCH, he suggests one can take advantage of CRISPR to isolate just the target DNA one is looking for. As our audience will know, most of the methods we use today, say in cancer diagnostics, are looking “under the lamppost,” using templates of known mutations rather than being able to discover what’s actually there.

“You could PCR out large pieces of the genome, but it’s hard and tedious, because you need a lot of primer sets. If it’s a very variable region like BRCA, you may have problems with your primer design, which won’t fit. This is another, hopefully more elegant way of taking out the intact region of interest of the genome and analyzing it very deeply,” he says.

Yuval’s lab is one to keep on our radar.

We've Become Too Single Variant Centric, Says Deanna Church on Genome Analysis

From 1999 to 2013, Deanna Church was a staff scientist at the NCBI where, for a time, she headed the Genome Reference Consortium. This was the effort to continually update, improve and maintain the reference genome. Then Deanna went into private industry, first to Personalis--a genome interpretation company, and now she’s Director of Applications at 10X Genomics--the tools company offering linked read sequencing technology. Deanna's work in the public and private genomics domains has given her a comprehensive and even profound knowledge of the human genome and an authoritative ease in communicating about it.

When we asked about the recent paper out by the 1000 Genomes Project—which includes her name as author—that brings to light hundreds of heretofore unknown structural variants, she says this:

“What I think would be really great is to see the community move toward the integration of structural variant calling and short variant calling. These still tend to be very separate. This paper, of course, only dealt with structural variant calling because it's a very challenging problem. Many times the [different] variant calls end up in separate files. What you’d really like to do is have a wholistic view. Analyzing the whole genome and thinking about how all the variants go together will be an important step for the community.”

Many of the scientists we talk to often begin at a tools company and then move on to an institution where they can work with an array of tools. Deanna has gone the other direction. But she says that working at 10X has “expanded her inner scientist.” There she has access to a lab which wasn't the case at the NCBI and is challenged by an array of hard scientific problems brought by customers of their linked read technology.

So what is new in the world of linked reads? What are Deanna’s thoughts on the incredible uptick in single cell sequencing applications? And in an age when the NIH’s budget has been threatened, how does she see the roles of private and public genomics institutions playing out?

It’s Deanna Church for the first time on Mendelspod.

Clinicians Show High Demand for Single Cell Sequencing, Says Bobby Sebra of Mt. Sinai

If today's guest were a super hero, he'd be High Resolution Sequencing Man.

Bobby Sebra is the Director of Technology Development at the Icahn Institute of Genomics and Multiscale Biology at Mt Sinai in New York. He has the complete arsenal of DNA sequencers in his lab. He specializes in long read applications, and today he goes into several of those spaces, including infectious disease and oncology.

How has sequencing changed since we last had Bobby on a couple years ago, and how does he see it changing in the next two years?

Bobby says the technology hasn't so much changed as the sequencing user has. The user is becoming more savvy, more knowledgeable and familiar with the diversity of options. And the biggest trend has been the uptick in single cell sequencing. Beyond that, Bobby has been surprised that the highest demand for single cell sequencing has been coming from clinicians more than from other scientists.

"I wouldn't have predicted it. The clinical community is excited about seeing it come their way for applications like liquid biopsy and the progressive and prospective surveillance of an individual over time," he says.

Finally, one might think that being located in a city like New York would mean access to the greatest variety and range of data for genomics research. But of course there is better. Bobby and his colleagues have formed a new company they're calling Sema4, to open up the data gates to the rest of the world.

September 2017 with Nathan and Laura: Venter Blunder, RNAi Returns, and Monthly Science Moments

To honor Laura's pentametric thirst,

We write the summary today in verse.


Was it a quake that had no epicenter,

That silly paper out by J. Craig Venter?


And after years of silencing the market

Has RNAi at last knocked out its target?


Then Nathan gives to yuppies devil's choice.

Which one libs: gluten dough or GMOs?


Exploring the Exome and the Future of Genomics with Jay Shendure

Back in 2009, University of Washington professor, Jay Shendure, wrote a definitive paper offering up a roadmap for exome sequencing. Since then, the cost of sequencing has come down so far that many have debated whether or not to do whole genome sequencing vs. just the exome.  

As it turns out, the exome, as a unit, has been very fruitful for both clinicians and scientists, particularly in the area of rare disease discovery and diagnosis. Most genetic testing companies these days have the exome on their product lists.

In today's program, Jay says that we are still in the heyday of the exome; there is still much low hanging fruit.   However, some eight years after his landmark paper, he warns we will soon come to the end of that cycle.

“There clearly is a lot that we haven’t explained. But doing the same thing over and over again isn’t going to get us there. We’ve got to take a step back and systematically investigate the various explanations for the keys that aren’t clearly labeled and not under the lamppost.”

What are some examples of new hypotheses for decoding the genome? Jay points to searching in non-coding regions, epigenetic mechanisms, somatic mosaisicm, and di-genic mutations.

As we go ever deeper into the genome, what are Jay's thoughts on the need for going wider with lots of genomes? And is he on the same page with his UW colleague, Evan Eichler, when it comes to long reads?

Jay is a scientist's scientist. Coming out of George Church's lab at Harvard, he's worked over the years on new methods for genomicists. One of his latest projects dives into developmental biology. He says we've spent a lot of time looking at the "what" of genomics. Now it's time to look at the “how” and “why."

Will This New Nano Technology Be the Microarray of Genomic Structural Variation? Barrett Bready, Nabsys

Barrett Bready is back on the program. He’s the CEO of Nabsys, a company with some new technology for genome mapping.

Originally Nabsys had been working to develop nanopore sequencing, but after a recent reboot has become focused on scaling up scientists' ability to read structural genomic information. Barrett compares Nabsys’ new multiplex technology for genome mapping to the improvement of arrays over single nucleotide (SNP) detection.

"When we first started we were using solid state nanopores. And we realized that there were limitations to nanopores. Nanopores don’t multiplex well. If you have two nanopores very close to each other and a DNA molecule goes through nanopore number one, the signal in nanopore number two will be effected. So we developed our proprietary nano-detector that can be multiplexed at really high density.”

With long read sequencing now gone mainstream coupled with a growing interest among genome scientists in structural variation, Barrett says Nabsys has a chance to enter the marketplace competing on price and throughput and will have their instrument ready for beta testing early next year.

George Church on What Comes After CRISPR

George Church joins us today. He’s the Robert Winthrop Professor of . . . . well, he’s George Church. And he confirms that, yes, a movie called “Woolly" is being made about his lab. In the next breath, he reminds us (and himself?) that less than 1% of his press is about the woolly mammoth.

George was honored this year as one of Time Magazine's "Time 100 List", and we’re curious about what topics of conversation come up when he’s with non-scientists. What does he think of Trump (or what he calls “the new politics”)? Is he tempted to join the wave of scientists running for office?

“In China, about 80% of their top government officials have a degree in science or engineering, while in the United States it's closer to 1%,” he deadpans.

We cover some scientific ground today as well. George says CRISPR has been overhyped as the step between Zinc Fingers/Talens and the next gene editing tool. So what is the next CRISPR? And what ever came of his 3-D sequencing?


We Need a Google Maps for Metagenomics, Says Rob Knight, UCSD

When will we see the results of microbiome research in our every day lives? And what will that look like?

Rob Knight joins us for the first time today. He’s a professor at UC San Diego and Director of the Center for Microbiome Innovation. He is well known for co-authoring a paper showing that the microbial populations in the guts of obese mice differentiate from those in lean mice.

In addition to studies on obesity, Rob is also interested in the connections of the gut micriobiome with brain disorders, the possibilities for fecal transplants, and also the impact of microbial communities on drug interactions.

On the tools side we hear a lot about the success of single cell sequencing for human genetics; what impact are these new tools having on metagenomics? And if consent is often a thorny issue for studies in humans, what are the ethical issues studying microbes?

Rob says that in the next five to ten years we will be “taking control over our microbiomes,” meaning that we will be able to measure our microbial communities and use this information to improve our diet or to optimize a therapeutic. The big piece missing for translating microbiome research, he says, is better user interface or apps that would abstract away all the technical information. We need to go from the world of GPS coordinates to using Google Maps, he says.

On Bioinformatics Data Sharing and Collaboration: Andrew Carroll, DNAnexus

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.

Green Light for DTC, Blood Mammograms, and Ancient DNA: April 2017 with Nathan and Laura

For genomics nerds, April 2017 will be remembered as the date when the FDA adopted a more open policy towards 23andMe and direct-to-consumer (DTC) genetic testing. What does this decision mean, and just where is the FDA drawing the line? A genetic counselor herself, Laura found the decision “head turning.”

“There’s lots of reasons why some genetic counselors are not going to be thrilled to deal with everyone’s 23andMe results,” she says.

For the “cool new studies” section of today’s show, Laura is excited about a research project announced by Grail, a spinoff from Illumina working on a pan cancer screening test. And Nathan points out that the trend for researchers to look back at ancient DNA sharpened this month with two new studies that not only open up the possibilities for historians and archeologists but also have relevance to human health longterm.

“We’re getting much better at doing it,” he says. “So look for more of this ancient meta genomics where we can find little fragments of DNA outside of cells but intact in sites like soil. They’re very diverse, but we're starting to figure out really what was going on at a place some time in the past."

We finish with a couple stories that are giving pause to researchers working on gene therapy and immunotherapy.

It’s commentators Nathan Pearson and Laura Hercher joining Theral to talk genomics for April.

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