genomic medicine


May 2018 with Nathan and Laura: The Free Exome, California Database, and Mosaicism

Nathan Pearson and Laura Hercher are back for a look over a busy month of headlines.

May took us into the era of the free genome as Geisinger planted the genomic medicine flag on an even higher peak. And did you know California was keeping a genetic database for every baby born?

Meh. . . says Laura. Every state does it. Old news.

And mosaicism is old scientific news, says Nathan, but he likes the way Carl Zimmer brings it to light in a new book. Nathan and Laura then go above and beyond with their own elucidation.

It’s our final month-in-review before the break. Happy summertime!

I Won’t Rest Until We Have Quality Standards in Place for Biospecimens: Carolyn Compton, ASU

She’s a force of nature, and she’s back on Mendelspod. A decade ago, Carolyn Compton was hired by the NCI to solve a problem that has plagued the world of not just cancer research, but all of biomedical research. To this day, there are no standards in place for the acquisition, collection, storage, and delivery of human biological samples used for research. The leader of the NIH has acknowledged that this is a major part of biology’s non-reproducibility problem.

Yet Carolyn couldn’t solve it at the NCI. It took going to Arizona state where as part of the National Biomarker Development Alliance, she brought all of the stakeholders, government institutions, patients, private companies, and perhaps most importantly, the professional organizations such as CAP or the College of American Pathologists together, to put what in today’s program she calls “a basic floor” in place.

It was like the story of the blind men and the elephant.

"Despite the backgrounds of this broad swath of stakeholders who came to the conference—patients and regulators and scientists and physicians—they all had a certain knowledge of what was important. They all had knowledge of a certain part of the elephant, but they didn’t see the big picture until we came together. And what we came up with was astoundingly cohesive,” she says.

What has happened since? What changes has Carolyn seen toward the adoption of better standards and improving this immense problem that she simply calls, “garbage in, garbage out.”

We come in at around 25 min today.

You can find Carolyn’s referenced (free) article for Pathologist Magazine here.

Has Diagnostic Testing Plateaued? Alka Chaubey, Greenwood Genetic Center

If you’ve been in the field of genetic testing then you know about the Greenwood Genetic Center. With an address on Mendel Circle in Greenwood, South Carolina, this non profit diagnostic testing laboratory has basically written the book on diagnosing and understanding genetic disorders. Chances are, too, that you know the director of their cytogenetics lab and our guest today, Alka Chaubey. Her hunger for meeting new people and learning new science is matched only by her desire to share the Greenwood legacy.

The last time Alka joined us we talked about success stories in diagnostics. Today we’re talking about the limitations that our field is facing.

“If you look cumulatively at scientific discovery, definitely that is moving. But if you look sequentially at patient samples coming into our diagnostic lab, has our diagnostic yield increased? That number has not really made significant progress,” she says.

Now for the $64 million question, right? What can be done improve that number?

The Greenwood Genetic Center has a new program, TGEM (Technology and Genomics Enhancing Medicine) to spur innovation and partnership with technology companies. Alka talks specifically today about one of the six current initiatives in the program to bring BioNano Genomics' mapping technology into the lab’s clinical workflow.

We’ve talked with many scientists on the program lately about the new discoveries in structural variation. Alka's a clinical lab director who is not waiting for any dust to settle on those discoveries before making use of them in her lab. She’s already working on de novo mapping at the clinical level.

“This gives us way higher resolution than karyotyping. So we think that in combination with whole genome sequencing—because whole genome mapping is not a sequencing assay—this will give us more structural variation answers which we think play a significant role in that bucket of undiagnosed cases.”

We land the aircraft today at 23 minutes.

Editor's Note: Since this podcast was recorded, Alka took a new position at Perkin Elmer.

A New Way for DTC? Nathan Pearson, Root Deep Insight

You know him, but do you know what he does for a day job?

Over the past two years, Nathan Pearson has dazzled us with his broad knowledge of the genomics space on our regular monthly reviews. Today we’re talking to Nathan about his new company that he soft launched last December, Root Deep Insight, a venture into what he calls “direct-to-lay folk genetics.”

Nathan had a not undramatic debut in our field on the TEDMED stage with Ozzy and Sharon Osbourne interpreting their genome when he was at Knome. He would go on to become a lead scientist at Ingenuity and then a director of public outreach for the New York Genome Center.

In our show today, Nathan traces back his passion for unleashing the power of the genome to his childhood when he lost his mother to leukemia. He feels that had his mother had access to the greatly expanded bone marrow donor registries and involved patient data sharing options that we see today, the possibilities for her would have been much different. He’s driven by those possibilities for other patients.

Nathan is a bone marrow donor volunteer. And he found a few years back that he can ask for his genomic data back from the registry. Particularly his HLA data. All bone marrow donors can. But this data comes back undecipherable. Enter Root Deep Insight. Their vision is to make all this free data not only available but readable and valuable to the donors, or those who might volunteer to be donors.

Is this DTC? Yes, a new kind. First of all, it’s free.

“We’re learning the lessons from consumer genomics. HLA can already tell you really fun things, not just about your ancestry—and it really goes quite deep there—but important things about potential drug responses, for example.”

We get to other questions. What role does the genomicist play in society today? Do they look at the rest of us as just walking data points? And what are Nathan’s thoughts on the new generation of block chain companies such as Nebula and Luna?

It’s Nathan Pearson for an hour.

Genetic Testing in the Age of Trump: Hank Greely, Stanford

"In a world turned upside down, this is an area where I don’t think he’s had much effect. I don’t think he knows how to spell “DNA.”"

So begins Hank Greely in today’s interview on genetic testing in the age of Trump. Hank is a Professor of Law and, by courtesy, Professor of Genetics at Stanford.

The first order of business today is the boom in DTC testing. Hank is actually pretty cool with this, including the new DTC BRCA testing. He expresses some concern with Sema4’s recent newborn screening panel which he calls “quasi DTC." He is very happy with the current FDA director and thinks that the FDA is treating DTC the way they would have in the previous administration.

“There’s been an evolution, not a revolution."

So what’s turning Hank’s crank these days? Well, remember that article out in Tech Review a few weeks back about our genes predicting our intelligence? Hank is starting to wonder if the science really is that good. No. Really. He’s also feeling a bit chagrined about liking the bio hacker more than he should.

He’s funny. He’s thoughtful. And he’s on your speakers right now. Hank Greely for 36 min. Enjoy.

Eric Schadt and Sema4 Try the Consumer Model with Newborn Screening Panel

"We like to refer to it as consumer initiated, but physician supervised,” says Eric Schadt today when asked if his new test is direct-to-consumer.

Eric is the Dean for Precision Medicine at the Icahn School of Medicine at Mount Sinai in New York and since 2016 has served as CEO of Sema4, a spinoff that he founded out of the Mount Sinai Health System. Sema4 launched a newborn screening panel, Sema4 Natalis, in February of this year covering over 190 disorders.

With 400 people already employed, Sema4 is based largely on genetic testing, data science, bioinformatics, and software development teams that were built up at Mount Sinai prior to the spinout. New panels will be marketed directly to parents around the country, many of whom have already bought other prenatal screening tests from Sema4.

From 2011 to 2017, Eric served as the Founding Director of the Icahn Institute for Genomics and Multiscale Biology at Mount Sinai. He says he founded Sema4 to achieve a greater scale than could be had within a single hospital system. For him and Sema4, the end game is to "partner with" tens of millions of patients for ongoing studies. He calls it his "growth hack" strategy.

The Natalis panel is a practical place to start. Many of the additional rare childhood disorders that expand the panel beyond the conventional heel prick testing of 30-50 disorders are the result of new research and the latest technology and are a no brainer. This will bring some uniformity across states. And the new testing can be done from a cheek swab rather than the more invasive heel prick.

Still, some argue, Sema4 Natalis really amounts to doing research on parents. For the panel includes cancer risk tests as well.

Does Eric plan to do any follow up studies with parents? Mount Sinai is the sole owner of Sema4. Has any other major healthcare provider made a play similar to this?

State of Sequencing 2018 with Keith Robison, Omics! Omics! Blogger

Sequencing geeks are fresh off the trail from AGBT, and it’s time for our annual look at the sequencing tools space. This year we sit down with the longtime Omics! Omics! blogger, Keith Robison, who not only can answer all your questions about the topic, he even knows which sequencer you’re using right now, and in which department.

Keith jauntily runs through the Big 3--Illumina, Pac-Bio, and Oxford Nanopore--and has a few odds and ends to say about the "niche developers."

We finish by asking Keith what new trends and new instruments he's looking at. He says his son is a senior in high school where Keith has offered to go in and demonstrate the MinIon nanopore sequencer.

"Imagine if the next generation of kids all learns sequencing on this little device. It starts becoming a practical reality where kids in high school--even middle school--learn sequencing and then learn data analysis."

The Flongle Generation, anyone?

Direct RNA-Seq Project Shows Nanopore Sequencing Can Reveal New Insights into Basic Biology: Winston Timp, JHU

Nanopore sequencing has arrived. Passing test after test this past year--including one we discuss today--this technology which was being hyped decades ago is delivering on its promise.

Winston Timp joins us today. He's an assistant professor at Johns Hopkins and one of the leaders on a recent large scale project to directly sequence RNA on an array of nanopores. Winston's is the first in a series of shows we've lined up with users of Oxford Nanopore's technology.

Why RNA-seq? Hasn’t this been done for years?

Yes, says Winston, but in the past no one has been looking at the RNA itself. They’re usually making cDNA from the RNA and sequencing that.

“One of the big advantages to nanopore sequencing, is that you can characterize any polymer you can put in the pore.”

Nanopore sequencing is polymer agnostic.

So what good does it do to look at the RNA directly? Ever heard of epitranscriptomics? Winston has worked for a while on DNA methylation in his lab. Now he’s looking at RNA methylation. Not only is he seeing basic biology that we've never seen before (unique isoforms, exon connectivity that has been imputed by informatics but never seen directly), he’s coming up with new translational questions for health and disease.

When we started Mendelspod seven years ago, the next gen sequencing race was in full swing. It was all about the push to bring down the price of sequencing. The lower cost brought an excitement to the world of biology with all the new projects it made possible. But we found out there were was a major limitation to the technology. Read length. Over the past couple years, PacBio paved a whole new world with their long reads that enabled many new genomic projects. BioNano gave us the big picture with their optical mapping. Today users of nanopore sequencing are generating reads of 1 megabase and the versatility of the nanopore is giving scientists even newer views of biological activity. The race is still very much on.

The Global Business of Reproductive Genetic Testing with Gary Harton, Igenomix

Reproductive testing is one of the hottest fields in which genetics is going mainstream, a field hurdling us rapidly into the future. It’s an area we’ll be following closely in 2018.

Gary Harton serves as the Chief Operating Officer in the US for Igenomix, a company in the reproductive testing space with a vast global presence. The company has labs in the US, Japan, India, Turkey, Rome, Brazil, Mexico, Canada, and are headquartered in Valencia, Spain.

This international operation across so many cultures and national borders has its logistical and regulatory challenges, but it also offers the company an opportunity to introduce tests to cultures which are early adopters in a field fraught with big ethical and cultural decisions. With these more open cultures, the company can develop new tests and supporting clinical data.

The company’s most common test is preimplantation genetic screening (PGS) where embryos are checked during an IVF cycle for chromosomal abnormalities. According to Gary the test has gone mainstream in the US, but not in Europe. Yet in Europe, there can be wide variability. Spain and Italy tend to be early adopters and open to new testing technologies, whereas France is highly regulated.

One of Igenomix's newer tests is preimplantation genetic diagnosis (PGD). This offers parents who have a disease such as Huntington’s or cystic fibrosis--or are disease carriers--to eliminate that disease from their embryos through genetic testing. There is widespread support for PGD being used for this purpose. However the test can also be used for enhancements, or the grey area between disease and enhancements. Here, of course, decisions get much more complicated. For example, Gary says that recently the company had a request from deaf parents to select for deafness with their embryos. Should the company offer such a test?

How does Igenomix decide which traits to select for? Are there governing regulatory bodies that issue guidelines? A year ago we interviewed Hank Greely, author of The End of Sex, who argued that in 20-40 years parents would not use sex to reproduce. Does Gary agree with Hank's bold prediction?

We also talk with Gary about some less thorny issues. Years ago, the industry used FISH technology for testing then switched to arrays. Now most everything is done with NGS. How has NGS and new automated liquid handling technologies impacted the field? Has this raised the quality of testing?

It's a rare glimpse into life for some pioneers taking genetics into the future, and Gary is open and transparent.

The State of Genomics 2018 with Nathan, Laura, and Misha

Our first show of the year is an outlook on genomics for 2018. To do this we’re joined by our regular commentators, Nathan Pearson and Laura Hercher, and also by a special guest to mix things up a bit, Misha Angrist, Associate Professor at Duke University and Editor in Chief of Genome Magazine.

Misha wrote a seminal book on the rise of next gen sequencing and personal genomics (Here is Human Being: At the Dawn of Personal Genomics). After working at Knome, Ingenuity, and the New York Genome Center, Nathan recently founded his own company, Root, which works closely with tissue donor registries to give back DNA information to consumers for free. Laura is recognized as a leader in the field of genetic counseling, being a counselor herself and training many of today's working counselors.

Join us as we ask, where are we in genomics today?



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