genomic medicine


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.

Is Population Medicine Failing Us? Michel Accad

Is health the same thing for an individual as it is for a population? This question goes to the foundation of how we practice medicine today and that of most of genomic research.

Michel Accad is a cardiologist in San Francisco and the author of a new book, Moving Mountains: A Socratic Challenge to the Theory and Practice of Population Medicine, in which he uses Socrates to spar with Geoffrey Rose, a British physician and one of the architects of modern medicine.

As early as the 1950’s, Rose advocated for the idea that individuals should be treated based on bell curves of an entire population, essentially risk based medicine. This philosophy would lie at the heart of not only the British National Health Service but many public health programs. It informed the famous Framingham studies here in the U.S. In fact, the term “population medicine” is a very positive term for those working in healthcare today. Genomic medicine has been an outgrowth of population medicine.

Michel says this philosophy is failing us at the level of individual health. Third party payers, be they governments or insurance companies, are in their offices working a system based on large datasets. They develop algorithms using all kinds of risk studies. But these payers have little to no contact with the actual patients. Ironically, he says, we call it personalized medicine. Michel points to hypertension, a disease area where sixty years after Rose pushed for risk studies, cardiologists are still divided into camps over whether to treat a patient if their blood pressure lies above the average. Michel argues that population medicine is utilitarian and ultimately utopian. What are framed as scientific studies are really social engineering.

What about clinical trials, we ask Michel. Don't population studies bring doctors and patients many good drugs?

In the second half of the interview, Michel points out that a mechanistic view of biology dominates clinicians and scientists today. It’s true. Our guest last week, a well known geneticist from Stanford, compared people to cars, arguing for the need to wear health data gathering sensors.

"Right now among philosophers of science, there’s a recognition that “mechanism” is inadequate to explain cellular organisms."  The study of biology also has often been developed with tautologies, he says.  "For example, say you’re studying the beaver and you ask what is a beaver. The standard answer is to go to the genetic sequence. From the genetics, you say you have a beaver. But you have to know what beavers are in the first place in order to study a beaver. It’s a circular argument."

So what other models might we use in biology? And what can we do in healthcare if we’re not using large population studies--go back to blood letting?

(Amazon link)

Homo Sapiens (D)Evolves into Homo Medicus

A well known science and medical author, Wades Tudeep, has proposed an upgrade to a famous Shakespeare quote from Hamlet:

“What a piece of work is a man! How noble in reason, how infinite in faculty! In form and moving how express and admirable!  In action how like an Angel!  In apprehension how like a god! . . . [proposed addition] . . . In DNA, what an  encyclopedia of disease!"

The Story of Geisinger and Doing Genomic Medicine at the Right Pace

Mike Murray and the crew over at Geisinger are making the implementation of genomic medicine look down right easy.

In today’s interview, Mike explains GenomeFIRST Medicine, a program at the Geisinger Health System in Pennsylvania to offer care “that is based on an individual’s DNA sequence.” The healthcare provider boasts its own biobank and has partnered up with Regeneron’s Genome Center to offer exome screening to self selected patients. As of DNA Day last year, April 25th 2016, 100,000 recruits had signed up.

What has made Geisinger, who was selected to join the nation Precision Medicine Initiative, so successful with genomics? Mike points to the leadership.

“We have incredible support from the highest levels of the organization. As we’ve rolled out genomics, they are supportive and interested. As long as we’re there to explain what we’re doing and why we’re doing it, we have them on our side,” he says.

Has there been any pushback from doctors or patients?

Mike says one of the challenges they hadn’t really considered has been a “naming issue.” Sometimes one of the variants a patient tests positive for “puts their clinical story together.” But other patients may test positive for something like lynch syndrome, for example, who haven’t really had any problems.

“They really don’t have lynch syndrome, “ he says, "they have a genetic variant that goes with it. Until they have problems associated with it, they just have risk for lynch syndrome. So the problem is how do you keep something like that high enough on the radar that people and their providers know what to look for, but not so high that insurers or other entities might say, we’re going to treat them like our standard approach to lynch syndrome?”

In fact, Mike and his team have thought quite far through this challenge of how to report genomic findings back to patients. He explains what they’ve come up with in this beautifully clear interview about one of America’s most genomically experienced and progressive health systems.

Cardiologists Love Genomics: Euan Ashley, Stanford

Euan Ashley is one of the big names in genomic medicine that has been missing from our guest list. We’re happy to correct that today.

In 2010, he led the team who did the first clinical interpretation of a human genome--that of his Stanford colleague, Steve Quake. Since then Euan, an MD PhD, has been driving to make the use of new genomic tools and discoveries a routine part of medicine at Stanford, particularly in his own discipline of cardiology.

A regular speaker on the conference circuit, Euan titles his talks, "Genomic Medicine Is Here."

"There were these one off examples of great stories that captured everyone’s imagination,” he says at the outset "but somewhere in there, what happened is it just became routine. And we started sending exome and genome sequences on patients and using that information to help find a cause, and in some cases, treatment for their condition. We were all waiting for it to happen, but it just happened under our noses.”

At the same time, Euan acknowledges that he “loses sleep at night” over “dark corners of the genome.” What are these dark corners? What recent findings were made by new long read sequencing? How has genomics impacted cardiology?

We begin with the question, if genomic medicine is here, why are there still so many skeptics?

Join us in our first interview with one of the few jazz saxophonists in our field, someone who knew he wanted to be a doctor at age four but wasn’t inspired by science--that is, until a high school teacher handed him a copy of Richard Dawkins' “The Selfish Gene” after class.

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 to Scale Cancer Genomics, with Marco Marra, UBC

Back in 2009 at the annual AGBT meeting for sequencing, Marco Marra presented one of the first cases of cancer treatment using whole genome sequencing.

We caught up with Marco at his office at the University of British Columbia where he heads the Department of Medical Genetics. Marco also directs the Genome Sciences Center which is part of a very special organization called the BC Cancer Agency.

In 2012 Marco and his team began a pilot project at the agency to scale up their work from just a one off case to more routine treatment. While doing whole genome and whole transcriptome testing is not yet “standard of care” for cancer patients, the scientists and researchers at the agency have the opportunity to sit down with oncologists on a weekly basis and explore its use with several patients at a time.

What are the major questions and challenges Marco has encountered in scaling? How is the regulatory environment for genomic testing in Canada? And which camp does Marco adhere to when it comes to whole genome sequencing: quantity or quality?

Join us as we talk to the number two cited scientist in all of Canada.

Biomarker Panel to Predict Type 1 Diabetes

When we talk precision medicine on Mendelspod, we’re usually talking about oncology. But today we shift our focus to diabetes.

Raghu Mirmira is an MD PhD at Indiana University who is working on a panel of biomarkers that would predict Type 1 diabetes. That’s right. Predict.

Having already found a DNA biomarker candidate which detects dying beta cells using the new technology of digital PCR, Raghu is now working to improve the panel with other metabolites.

Will we some day have a Myriad Genetics for diabetes? Raghu says, yes. But he warns that we must also develop new treatment options to go along with a predictive blood test.

“Before we get to the point where this is a commercially available test, we need to be doing further studies to figure out what’s the outcome of individuals who test in a particular way. And what kind of interventions could improve those outcomes in some way.”

Reference Genome Making Major Strides in Ethnic Diversity, Says Valerie Schneider, NCBI

A couple months back, we reported on a study showing that genetic tests for an inherited heart disorder were more likely to come back with false positive results for black Americans than for whites. The study provoked many in our industry to urge scientists to incorporate more ethnic diversity in their studies. So far, biology has been too Eurocentric—the databases are implicitly racist, they argue.

Perhaps no dataset for human genomics is referenced more than the human reference genome, or the GRCh38. This is the "Rosetta Stone” of genomics used by scientists and clinicians everywhere who are assembling and studying genomes. Valerie Schneider is a scientist at the NCBI who works everyday on the GRCh38. She says major strides--enabled in part by better sequencing technologies--have been made lately to add diversity to the GRCh38 and to create other reference genomes for various populations around the globe.

The populations represented with these new projects include a Han genome, a Puerto Rican, a Yoruban, a Columbian, a Gambian, a Luhya, a Vietnamese, and one or two more Europeans.

“The sequence from these genomes is planned for correcting errors and adding new "alt loci" to the reference genome. But these new assemblies are also intended to stand on their own as complements to the reference,” says Valerie.

Valerie reminds us that it’s still early days in genomics. There’s so much diversity in the human population that her team is not sure whether having a single reference for each of these ethnic groups will be sufficient.

With more reference genomes comes the challenge of how best to compare and visualize them. There is a major need for tools that can show large nests of sequence as opposed to a linear reference, she says in today’s interview.

What is Valerie's take on the term “reference quality genomes”, and how will a better reference genome improve precision medicine?

Erica Ramos on Her Pioneering Role as Genetic Counselor for Industry

For the next installment of our series on genetic counseling, we’re joined by Erica Ramos. She’s the president-elect of the National Society of Genetic Counselors and was the second genetic counselor hired at Illumina where she’s been for four years. Illumina now has 15 genetic counselors.

Erica has been a trail blazer throughout her career. Before joining Illumina, she was the first ‘cancer counselor’ in the city of Las Vegas, Nevada. Her time at Illumina has been a prime example of the evolving role of the industry counselor.

“Genetic Counselors are starting to be recognized more and more as experts in bridging gaps between physicians and researchers, patients and physicians, and now even companies and their customers,” she says at the outset of today’s interview.

When asked about the tension between the commercial pressure from her company to sell tests and the actual needs of the patients, Erica says Illumina wants to sell the right tests and she quotes Illumina’s new CEO, Francis de Souza: “sometimes you need to go slow before you can go fast.” Erica says that it’s good for business to engage the genetic counselor early on in product development so that the right product is chosen.

We finish the interview with a preview of the upcoming National Society for Genetic Counselor's annual education conference, Sept 28 to Oct 1 in Seattle, Washington.



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