commercializing diagnostics

We speak directly with the Oracle today. It's Keith Robison, blogger at Omics Omics. Your All Knowingness, we ask, what has happened in the world of sequencing technology this year?

“The companies may need a mulligan,” he quips and laughs.

But then, maybe, not. It turns out the great Pandemic has driven sequencing technology in its own way. There’s been an explosion of sequencing based diagnostics. That trend was already happening, but the pace was mightily booted along. And all of the technologies have been involved—some new entrants as well--used for their own strengths, to track the powerful virus and all its speeding variations.

We take the flagships one by one, from 10X to the small Genapsys, asking the Oracle in the end whether there is any more room for a shakeup in this mature space. We finish with an impressive story of clinical sequencing for rare disease diagnosis at a world record speed. Oh, Oracle, tell us the future.

We’ve interviewed several CEOs over the years since the Theranos fiasco who avoided any mention of the blighted company whenever the comparison came up. But today’s guest, Murielle Thinard McLane, the CEO of Ontera, jumped at the chance before Theral could get to it.

"Some people might say, well that's the Theranos model. They (Theranos) didn't get it wrong. The demand for a fast, comprehensive point-of-care solution near the patient is there. Where they got it wrong is that you need a technology that is sound to do that!"

Ontera is a spinout from UC Santa Cruz, and they came on the scene with a nanopore device/platorm that was so versatile that perhaps the biggest challenge they faced out of the gate was in choosing just what to do with it first.

And what makes it so great? It is small. It is fast. It can read any molecule. RNA, DNA, proteins, small molecules.

Think of the applications. It can be taken anywhere. Out into the field for agricultural testing. On location in Africa or South America for Zika virus testing or TB testing. Or, and this circles back to our earlier point, to your local Walgreens for basic diagnostic tests where you will receive immediate results.

The company has new leadership after a round of funding that includes Silicon Valley's forward thinking Vinod Khosla, and can boast already of partnerships with the Gates Foundation, IARPA, and Bayer.

April was a tough month for some genomics companies. The FBI raided the offices of uBiome and two other pioneers in the field failed. Are there broader implications?

Nathan and Laura have returned to first give us some facts and then to throw their hats in the ring.

Lots happened this month in the world of DNA. Tune in and catch it all.

Talk to anyone who’s been around diagnostics or blood sampling for long, and they’ll tell you that nanotechnology is nothing new.

Today’s guest, Brett Goldsmith, the Chief Technology Officer at Cardea, says he was involved in the nano revolution that was and then wasn’t 20 years ago. (The older veterans among us might date it back even further, to forty years ago.) So what are Brett and Cardea buzzing about early this year in a new Nature paper?

Biosensors.   They say thier new--and significantly cheaper--ones are capable of integrating the world of biology and digital that will give us instant access to the networks of biological information used by our bodies.  The sensors bypass our existing testing gadgets that use labels and lights and measure directly the biological interaction.  One can imagine "Googling" biological data about yourself.   The argument here isn't new, nor is the technology.  What is new and shown by the Nature paper is a dramatically changed economy of scale for producing the biosensors. Brett claims it is something along the lines of going from $120K down to just $20-30 each.

If you look at Moore’s Law and the dramatic reduction in the price of sequencing as what fed two revolutions, it does appear there’s a case to be made for a similar revolution to be had with biosensors and the possible applications they could enable.

What are the details of the paper? How do Cardea’s sensors work? To whom are they selling them now?

And what kind of data does Cardea have to put out to show the world that they are not Theranos No. 2?!

Time is health. Take certain blood cancers, for instance. When a patient is seen in a doctor’s office, they are then sent to a central lab for testing, and the results can take a few days. With blood cancer patients, these few days can be vital.

For years a holy grail in diagnostics has been to get diagnostic tests to the point-of-care based on just a few drops of the patient’s blood that could give immediate results.

Today we talk to Danny Levner, the co-founder of Sight Diagnostics, a company that has been working carefully and methodically toward this goal, first with a malaria test and now a CBC, or complete blood count, point-of-care test using just a couple drops of blood. The new CBC test is CE approved and commercially available in Europe and on track for FDA approval soon.

Danny says there are CBC point-of-care tests on the market in the U.S. already, but that they compromise on the quality that one gets from a central lab test.

“The physician has a question in front of him or her: Do I want the result now, or do I want it done well? And what we resolved to do in the beginning is to offer a no-compromise test,” says Danny.

This is not all that sets the company apart. From the get go, working under the ever present shadow of Theranos, Sight Diagnostics has been meticulous about doing clinical trials and publishing their data.

Danny also shares today how the technology works, combining machine vision and AI to digitize blood with an easy to use application kit for the average operator in the doctor’s office. Members of Sight’s team came from the automotive machine-vision company, Mobileye. Levner trained in George Church’s lab.

They’re working at it in methodical steps. They’re publishing their data. This time it looks like the real thing.

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.

The Personalized Medicine Coalition advocates for a wide group of constituents, including scientists, health care providers, entrepreneurs, payers, and patients. Which is why we’ve often wondered how the organization can be absolutely clear in their priorities.

Today, PMC President Edward Abrahams joins us to answer that question.

For example, take the topic of laboratory developed tests. The country is currently experimenting with an anti-regulatory political direction. Is Ed happy that the FDA has dropped their guidance for LDT regulation? With such a disparate constituency, what does he think is the best way forward? What about the CMS announcement recently that there wouldn’t be any reimbursement for diagnostic tests that weren’t FDA approved (isn’t this at odds with anti-regulatory policies?)—does Ed have any insight here? Also, is the current boom in direct-to-consumer testing a boon or bane for the industry?

When Obama’s Precision Medicine Initiative was launched, many organizations which had been using “personalized medicine” in their nomenclature were pressured to change their names. Ed says he’s still happy with the old term and in fact is working in congress to create the first Personalized Medicine Caucus.

We come in at around 27 min today with one of those unique industry veterans who can talk science with scientists, can talk real with patients, and carries clout on The Hill.

“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.

When we first talked with Tim Triche of LA Children's Hospital, we found out he was a bit of an outlier among cancer researchers. He was an advocate for poking around in the non-coding RNA.

Today we welcome Tim back to the show to talk about a new gene panel that he has designed specifically for childhood cancers. It’s a first of its kind and was modeled quite closely on the gene panel for the NCI’s MATCH trial. The new panel has both a DNA and an RNA component, and the RNA side is by far the biggest.

"There are 1,400 different amplicons on this panel looking for RNA fusions. Thermo Fisher tells me it’s the most ambitious RNA panel that they’ve ever undertaken," Tim says in today's interview.

"When 100 cancer patients walk in your office, then 100 cancer patients walk in your office," says Tim, quoting a common line in the field that points to the uniqueness of every cancer.

Yet even though every cancer is different, certain biological commonalities combined with better sequencing tools is enabling the design of new gene panels to guide in diagnosis and treatment. More and more a cancer is looked at based on the drug that might treat it rather than the organ in which it grows. The new panel can guide this treatment.

Some of the most important targets on the panel are RNA fusion transcripts. What are they, and why are they so important for helping kids?

Childhood cancers come from inherited mutations, whereas most adult cancers have to do with the skin or the linings of the organs due to mutations caused by environmental impacts. Fusion transcripts are very common in the youth cancers and have been a big part of routine diagnostics.

If a mutation is there early in life, is it likely to turn into cancer sooner rather than later? Yes, says Tim.

“If you look at the incidence of childhood tumors, there’s a big bump in the first months or year or two of life, and then they disappear thereafter."

Additional benefits from these new next gen sequencing panels are that they can work with very small “real world” samples of tumor tissue, and they can also be used as discovery tools. Tim says the panel, called OncoKids, is ready to go for frontline therapy, and is hoping to get the word out to oncologists everywhere.

Back from summer vacation, Nathan and Laura are smoking hot as they look back over some exciting headlines.

The summer boiled over with plenty to talk about, but it was just this week that delivered most of the news for our discussion today. Novartis’ gene therapy based on CAR-T technology was approved Wednesday, making it the first gene therapy to be approved ever in the US. Analysts will be trying to figure out how high high is when it comes to the price tag, but Nathan and Laura explain why this therapy is a big deal for patients.

As for the first gene editing of embryos in the US that happened earlier in August? Nathan says, yes, it’s a first, but the big story is how "strikingly reliable the CRISPR edit is in germline vs the rest of the body."

Finally, we heard a few days ago that genetic testing provider, Invitae (recently featured here on the program) had sent out a large batch of false negative tests. Laura, a genetic counselor, says that in the absence of FDA regulation the system is operating on trust.

“And I want to say,” she adds, “ I trust Invitae. They’re a good lab, and I think they’re handling this well.”