single cell genomics


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?

Putting the Bench Next to the Bedside: Laurence Cooper, MD Anderson Cancer Center

Guests:

Laurence Cooper, MD, PhD, MD Anderson Cancer Center

Bio and Contact Info

Listen (4:55) When clinical science and bench research is one and the same

Listen (10:40) Single cell genomics enabling next level of immunotherapy

Listen (5:00) Marrying immunotherapy with gene therapy - Four clinical trials

Listen (4:18) Is this a new model for drug development?

Listen (8:30) Why has the war on cancer taken so long?

Laurence Cooper is one of those rare MD and PhD hybrids-what he calls a "'super nerd." Specializing in immunotherapy at MD Anderson Cancer Center, Dr. Cooper is a pediatric oncologist with a very important resource: he also runs a laboratory where he's able to study the basic biology underlining his patients' cancers.

"Clinical science and bench research are one and the same," he affirms in the interview.

This concept is nothing new. But that a doctor is able to treat his patients with therapy developed in his own laboratory is very rare.

Today's show with Dr. Cooper is the final program in our series on single cell genomics. He explains how the new tools for looking at and manipulating individual cells are transforming immunotherapy. Today, treatment for childhood leukemia has become much more targeted and way less toxic.

And Dr. Cooper is not limited only to naturally occurring stem cells in a donor to transplant to his patients. With genetic engineering, his lab is able to create or reengineer specific cell types for transplant. Currently the lab has four clinical trials going which enable Dr. Cooper and his team to treat his own patients with the latest therapies that are developed in the lab.

This marriage between the clinic and the lab is a powerful example of the translation of biomedical science. Could it be a model for drug development?

That depends a lot on funding, concedes Dr. Cooper. His lab is funded by MD Anderson, but also in large part through NIH grants. The interview ends with a discussion on funding for the "war on cancer" with a provocative comparison to the "war on terror."

On 9/11, 3,000 people died. Yet every two days, that many people die from cancer. Dr. Cooper wonders why "the outrage of 9/11 has not yet translated into outrage of still having 3,000 people die every two days."

We hope to have Dr. Cooper back on the program soon as part of our series on the "war on cancer."

Podcast brought to you by: Fluidigm - The leader in single-cell genomics and maker of the C1™ Single-Cell Auto Prep System. The path less traveled just got easier.

Alzheimer's a "National Emergency:" Larry Goldstein

Guests:

Larry Goldstein, PhD, Director, UCSD Stem Cell Program
Bio and Contact Info

Listen (2:50) Three stem cell projects

Listen (8:41) Single cell genomics some really cool technology

Listen (4:26) Alzheimer's will not be treated with a single drug

Listen (7:38) Alzheimer's a national emergency

Listen (2:59) Making a case for science funding

Listen (3:38) Thoughts about CIRM

Larry Goldstein came up quickly on the list for our series on Single Cell Genomics. Little did we know he would come on the show and make such a passionate case for biomedical research funding in general, and particularly for Alzheimer's. Early in the show Larry describes how he is using the "unbelievable, really cool technology" of single cell genomics in his lab. Director of UC San Diego's Stem Cell Program, Larry is using stem cells to study ALS (Lou Gehrig's Disease), Alzheimer's, and Neimann Pick Type C, a rare pediatric disease. Larry says that Alzheimer's has become a "national emergency."

"In the United States, the annual cost to the healthcare system of Alzheimer's disease is somewhere between $200 and $250 billion," he says in today's show. "The entire NIH appropriation is $30 billion." He goes on to point out that the amount of the NIH budget for Alzheimer's research--our only hope for alleviating the burden of the disease on the healthcare system--is $500 million. "The ratio of cost of research to cost of care is terrifying….This is insanity! We're bleeding money and doing next to nothing to stop the bleeding."

How is Larry making his case for Alzheimer's research and basic science in general? And what are his thoughts on CIRM (California Institute for Regenerative Medicine)? Goldstein is as eloquent a speaker as he is passionate.

A Great Time to Be in Biology: Steve Quake, Stanford

Podcast brought to you by: Ingenuity Variant Analysis - Identify causal variants from human sequencing data in just hours.

Guests:

Steve Quake, PhD, Professor, Bioengineering, Stanford
Bio and Contact Info

Listen (4:45) Bringing physics to biology

Listen (6:28) New technology driving the study of single cells

Listen (4:30) A great time to be in biology

Listen (4:32) Thoughts on privacy and incidental findings

Listen (4:05) What is holding back the adoption of genomic medicine?

Asked about how he comes up with so many inventions, today's guest, Steve Quake, replies that he is "impatient." It's a quick answer that leaves a lasting sting. Last year when Steve won the Lemelsen-MIT award for being such a mad-inventor, Jim Plummer, dean of the Stanford School of Engineering, wrote of Steve: “It is important to remember that, at just 43 years old, Steve Quake has introduced a number of inventions, any one of which most people would consider a lifetime achievement — and there’s more to come. The true measure of the man, however, is less in his remarkable productivity, but in the profound reach of his inventions".

Beginning with a discussion about the technology Steve developed and commercialized to drive the study of single cell genomics, our interview continues on into the realm of genomic medicine and and the future of biology. Is Steve a believer that we'll be living to 200 yrs old anytime soon? And what are his thoughts on the issue of incidental findings? Listen to Steve's latest ideas in today's program.

NOTE: Since this interview was taped, Steve was elected to the National Academy of Sciences. http://engineering.stanford.edu/research-profile/quake-elected-national-...

Garry Nolan: Trailblazing Single Cell Analysis

Podcast brought to you by: Fluidigm - The leader in single-cell genomics and maker of the C1™ Single-Cell Auto Prep System. The path less traveled just go easier.

Guests:

Garry Nolan, PhD, Professor of Microbiology and Immunology, Stanford University School of Medicine Bio and Contact Info

Listen (6:41) Why is the focus on the single cell so important?

Listen (5:18) Low hanging fruit from bulk analysis already picked

Listen (6:29) What has been the response to your work?

Listen (6:25) Commercializing work as diagnostics at Nodality

Listen (6:38) Biggest challenge is to simplify

Making a big decision several years ago that his lab would have the single focus on the single cell, Gary Nolan has become a global leader in a new discipline. In today's show, he shares his conviction that the next frontier in biology is to expand the number of parameters wherein the individual cell can be studied. "The low hanging fruit from bulk analysis has already been picked," he says. Gary is a founder of two companies, Rigel Pharma (publicly traded) and Nodality, wherein his research is being commercialized. Is 2013 the year of single cell genomics, we ask this trailblazer.



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