single cell genomics


We Can See Tumor Heterogeneity. Now What? We Ask Cathy Smith, UCSF

Cathy Smith counts herself among the Gleevec Generation after the landmark targeted cancer therapy. She’s an optimist who believes in the possibilities of precision medicine.

“We are outsmarting cancer,” she says.

Cathy is an Assistant Professor of Hematology/Oncology at UCSF where she is also an MD treating patients. Her area of expertise is in acute myeloid leukemia or AML. She joins us today to discuss a recent group paper and collaboration using new technology to track and monitor cancer evolution at the single cell level.

“It’s not that we didn’t know that this heterogeneity was under the surface, it’s just been hard to get at before we had this technology.” She is talking about single cell technology made by Mission Bio, a company based in South San Francisco.

As she looks forward to creating a first ever clinical trial using single cell data, Cathy says there are very hard questions to answer. It’s not totally clear what treatment decisions should be made when answer A comes back vs answer B. Still, she is optimistic that she and her colleagues will begin to find more answers for their patients.

“You don’t go into oncology if you’re a pessimist. You have to have hope that you’re going to get ahead of it. And the first step is to know what is going on."

Single Cell Analysis Shows Important New Detail in Key Clinical Study of AML: Koichi Takahashi, MD Anderson

The history of biomedicine goes something like this:

  1. A new tool is invented. 2. New tool is used in research labs to generate new data and new hypotheses. There is new science. 3. New tool is used in clinical setting to confirm this new science with real patients. 4. Then new tool is adopted into clinical use.

All the buzz these days, single cell DNA analysis instruments have just made it into step three.

Today we talk with Koichi Takahashi, Assistant Professor in the Department of Leukemia at MD Anderson and author of the largest clinical study to date using single cell analysis in the study of AML.

For years physicians and researchers have been testing patients for well known cancer driver mutations such as KRAS and BRAF with next generation sequencing tools, or what are now being called “bulk sequencers.” Koichi points out today that new single cell analysis tools are allowing researchers to see the unique genomic environment that lead to the common driver mutations and may be responsible for why each patient responds differently to the same therapies. Knowing each patient's individual tumor genomic environment--and not just the final driver mutation such as KRAS-could lead to effective tailored treatment.

“The development of cancer cells is like Darwinian evolution. They are adapting to the selective pressure of the tissue ecosystem. And by looking at the single cell clonal architecture of the mutations, we can actually build a phylogeny tree of how a particular patient's leukemia developed—like even before they were diagnosed with leukemia. Over the years how this leukemia was created—this single cell DNA sequencing can inform us of this history.”

Is this new scientific understanding able to impact yet how Koichi is treating his patients? What is next for this technology and for the field of AML research and treatment?

It’s a Gold Rush in Single Cell Genomics, Says Joachim Schultze, U of Bonn

The title says it all here. Herr Professor Schultze directs a major facility that he calls a single cell genomics platform. They have most of the single cell technologies available and partner with labs from all over the world on research.

Advances in single cell technologies are changing basic research and also delivering results for translational work in everything from immunology to obesity.

“Biology will never be the same again,” says Joachim.

Dr. Schultze is also heavily involved in epigenomics. He says that despite the ups and downs in this field, it still holds some exciting promise.

Talking to a leading genomicist in Germany, we ask for an outsider's view on our American approach to genomics.

Single Cell Sequencing Tailor Made for Nephrology, Says Vivek Bhalla, Stanford

Vivek Bhalla is used to the question, what’s a nephrologist? When we admitted we’d never had one on the program, he made his own admission, saying that the kinds of people who became nephrologists are the kinds of people who don’t seek out the limelight.

But Vivek, an assistant professor of medicine at Stanford, is changing that and speaking out on behalf of his profession. And he’s very excited about what single cell sequencing has done for the study of the kidney.

“The people who developed single cell RNA sequencing probably weren’t thinking about kidney physiology or kidney disease when they developed it, but they developed a tailor made technique for nephrology," says Vivek.

Why? It has something to do with the fact that kidneys are made up of nephrons which in turn are made up of a sequence of specialized cells. Because there are so many kinds of cells that run next to each other, it is difficult to extract one type of cell from another.

“That has hampered our understanding of how each of these segments work and has slowed the field compared to other fields where an organ is much more homogeneous, such as the liver or the heart where the bulk of the tissue is made of cardiomyocytes. In the kidney there are fourteen different segments along the nephron."

Sounds great. So what new possibilities in the science and in clinical applications are opened up by all of this?

With Immuno Oncology Comes a New Focus on Rare Cells

Modena, Italy is the town where one of the world's rarest cars were first developed and built: the Ferrari sports car. It’s also home to one of the world’s oldest universities where today’s guest spends his time studying rare human cells.

Andrea Cossarizza is Professor of Pathology at the University of Modena and Reggio Emilia School of Medicine and the President Elect of ISAC, or the International Society for the Advancement of Cytometry. He joins us today to talk about the role that improved cytometry technologies are playing in detecting rare cells and how this is being translated into better treatments for patients with cancer and other diseases such as immune disorders.

With the advent of immuno therapy has come a renewed interest in rare cells, or cells that occur with less frequency than 1 in 1000. Rare cells include the antigen specific T cells that we hear so much about with immuno oncology. But rare cells are also studied in many immune and inflammatory diseases such as HIV.

“This is a very new and interesting field which will have enormous importance in the future,” says Andrea, who wrote the chapter on rare cells in a new book on single cell analysis.

Andrea says that though new immuno therapies have shown such enormous promise, they only work on about half the patients. Being able to detect rare immune cells in advance of treatment will help clinicians to know which patients will respond.

What are the challenges that are emerging in this new field? When should the patient be tested? How does rare cell detection technology need to develop?

Join us as we lift the hood on the future of rare cell detection.

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.

Known for Medical Devices, 116 Yr Old BD Makes a Bold Move in Genomics

Talk to someone who attended this year’s AGBT, and you’ll know the big buzz was about single cell genomics. One of the exciting new platforms came from a new player in the genomics space and yet from a very old company.

Founded at the end of the 19th Century, Becton Dickinson (BD) has been one of America’s great medical device innovators. They made the first syringe designed specifically for insulin injections. Their BD Vacutainer became the standard for blood collection in the U.S. They designed the first “intelligent” insulin pump. At this year’s AGBT conference, BD showed up with a new genomics division announcing their new Resolve(TM) Single-Cell Analysis Platform.

Today we talk with the VP of BD Genomics, Stephen Gunstream. Stephen says life science researchers already know BD through the BD Biosciences unit which over the past thirty years has been perfecting flow cytometry for their single cell analyzers and sorters. Acknowledging that BD has been going through “a culture shift the past five to ten years,” Stephen says their history with flow cytometry made their recent move into single cell genomics tools a natural one.

“People talk about a resurgence in single cell genomics, but I wouldn’t really call it a resurgence,” says Stephen. "We’ve been analyzing cells for 30 years with flow cytometry. What has really changed is that the capabilities of next gen sequencing has allowed us to do this in a highly parallel manner at a cost which is a lot more affordable.”

So how will BD stand out in a rapidly maturing marketplace? What research does Stephen think the new platform will most impact? And perhaps most importantly, will BD with their century old history of experience with clinical products be able to significantly help guide genomics research products into the clinic?

People Told Us It Was Impossible: UCSC’s Mark Akeson on Nanopore Sequencing

Mark Akeson has been working on nanopore sequencing at UC Santa Cruz’s biophysics lab for twenty years. Up until the past few years with the launch of Oxford Nanopore’s sequencers, that work was mostly the methodical toil of the quiet inventor.

Today it is quite ordinary to see a sequencer the size of your wallet being taken out into the field for DNA work. But for years, the naysayers dominated.

“Back in the day, the skeptics outnumbered the proponents 99 to 1,” Mark says in today’s show.

In his beginning-of-the-year blog, NIH Director, Francis Collins, called nanopore sequencing one of the four breakthroughs of 2016. And the NIH deserves some credit.   Mark says they were constant in their funding and belief in the technology.

With the success of nanopore sequencing technology has come legal battles to secure the IP.   Both Illumina and PacBio have sued Oxford Nanopore—the Illumina suit is now settled. And at the end of last month, Akeson’s lab (meaning the University of California) sued Genia, claiming that they owned the patents for Genia’s technology.  Genia was founded in 2009 and we have interviewed them several times since 2011.

“There's the old adage about once something succeeds, there’s all sorts of people who claim to have invented it,” says Mark.  

So what’s next for Mark? Is he on board the “long read train?” How much more can sequencing improve?

 

How Good are Linked Reads? Serge Saxonov, 10X Genomics

When 10X Genomics launched their GemCode sequencing instrument at last year’s AGBT conference, what they offered seemed too good to be true. 10X was promising researchers a machine that could generate long reads using Illumina’s short read technology at a price lower than what PacBio could offer with their “real” long read instruments. A year earlier, Illumina had announced they were buying Moleculo, a company that promised to offer long read data out of the short reads. But good data with the Moleculo platform failed to materialize.

10X Genomics hasn’t had that problem of Moleculo, and was in fact declared the “winner” at AGBT this year when they presented de novo human data.

Today, for the first time, the CEO of 10X, Serge Saxonov, joins us to talk about their technology and the company’s stellar rise.

The question everyone wants answered from Serge is how well the 10X linked reads stand up to so called “real” long reads. PacBio has spent years co-discovering with their customers applications where their long reads provide significant advantage over short reads, at a price. And even though PacBio released a cheaper-faster-better machine, the Sequel, late last year, some researchers have been wondering whether 10X might come through and "clean house" with their inexpensive system?

“Now you can get the information that people were hoping to access in maybe five or ten years--you can get it now. And in fact you don’t need to make a tremendous new investment and change your workflow radically,” says Serge.

While 10X is enabling Illumina customers to generate long reads, are there still limitations of the short read machines that can’t be overcome?

Serge and 10X have already launched a second system, the Chromium, which offers single cell analysis. How big is the single cell market, and what are Serge’s thoughts on the future of sequencing?



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