precision medicine

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 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?

Mike Snyder is well known in the genomics community for his iPOP (integrated personal omics profiling) study. Profiling himself with hundreds of thousands of measurements each day over a period of seven years and a group of a hundred others for about three years, he and his team at Stanford have shown that sequencing and other omics data can be used to predict Type II diabetes, cancer, heart problems and other disease. He’s also published numerous papers comparing NGS instruments. Now he is expanding iPOP with a whole new set of tools: over the counter wearable devices.

Though Fitbit’s sales may be down, Mike says wearables are hot. His team has found that there are over 1,000 health related wearable devices on the market today. He predicts that we will all be wearing them, using data that will be centralized onto the "dashboard" of our smart phones to drive our health decisions.

Those who have used wearables have used them mostly as “activity monitors,” and they tire of the devices after about three months. His lab, says Mike, is looking at wearables differently by using them as “health monitors.”

“The power of these devices is that they will measure continuously your basic physiological parameters, and we think that complements the other sorts of data that we’ve been collecting quite nicely. We actually think these devices can be used to tell when you’re getting sick.”

Just as when omics data predicted his own onset of Type II diabetes, Mike says wearables data helped him quickly diagnose his contraction of Lyme disease. The data in the recent two year study also showed when three others were getting sick—their heart rates went way up over baseline.

What about all the wild goose chases and the chance for hypchondria?

“I’m a believer in letting the data tell us what’s going on,” he says. "I didn’t know my blood oxygen level dropped on flights. In hindsight, it makes a lot of sense. And that’s what everyone says, 'it makes a lot of sense.' But most people didn’t know that. This could be a big issue for those with pulmonary illnesses.”

We end with a brief discussion of Mike’s new book: “Genomics and Personalized Medicine: What Everyone Needs to Know."

Rubbing shoulders at molecular medicine conferences these days one senses a sigh of relief when you talk about laboratory developed tests (LDTs). With the FDA’s decision to put regulation on hold coupled with the expected confirmation of Scott Gottlieb as FDA commissioner, those in the lab testing business seem to be confidently settling back to the status quo. And those who were arguing that all we need is a “beefed up” CLIA to hold labs to better testing standards don’t appear to be motivated to do so anymore.

Several questions arise when it comes to LDTs. First of all, if regulation was truly important for enabling this revolution we call precision medicine, then why couldn’t the Obama administration get it issued? In other words, is the status quo so bad? Secondly, without the FDA even threatening to regulate, will we see the “beefed up” CLIA that many labs argued is the best way forward? Without the stick of the FDA, is the carrot gone too?

Russell Garlick is the CSO of SeraCare, a private company that has worked to improve clinical laboratory standards for over thirty years. The company recently added a new business unit for precision medicine diagnostics, and Russell was brave enough to come on today and address these questions.

As for the status quo being good enough, Russell isn't happy.

“Many of the organizations undertaking clinical trials to recruit oncology patients have lost confidence because LDTs in one geography of the United States don’t perform the same as in other parts of the United States,” he says.

Russell has worked many years with labs on IVDs--the already regulated group of diagnostic tests. He sounds disappointed that the FDA has dropped their focus on LDTs, but is hopeful that existing organizations, such as the College of American Pathologists, or even private companies such as SeraCare might step in and seize an opportunity to improve things.

“There’s a lot of status quo. And frankly it’s a little bit disappointing,” he says, “because the laboratories can benefit from [improved standards]. It’s that inertia to do something new and different."

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?

The largest cut to NIH budget ever, rolling back genetic non-discriminatory law—the bad news continues to roll from Washington. But there was great news this month as well.

Both Nathan and Laura are fuming about HR 1313, or a Republican bill to roll back GINA protections. Laura points out that the proposed law builds on an exemption in GINA for wellness programs—a category difficult to define. And Nathan reminds us that families and children could be hurt by the new bill. Theral asks since when did privacy become partisan? GINA passed in ’08 with a vote of 95-0 in the Senate, 414-1 in the House (Ron Paul playing the weirdo there), and it was signed by George Bush.

Then on to some “game changing” drugs for multiple sclerosis and eczema and a successful gene therapy trial for severe sickle cell anemia. Not only are there new therapies, drug manufacturers seem to be getting the message on pricing.

Marc Edwards is telling a different story than the one most of us have been reading and hearing lately. But then he’s used to it.

Marc was the engineer from Virginia Tech who was called one day in September, 2015, by a resident of Flint, Michigan. A Ms Lee Ann Walters wanted Marc to check out her water. When Marc and his team got to Flint they uncovered super high levels of lead in the potable water, with over 100,000 people exposed to high lead levels and 12,000 people with lead poisoning. You know the rest.

But you may not know that a very similar story to Flint played out in the nation’s capital in 2003. A Washington DC water crisis led to a hearing in which Congress found that the CDC had released “scientifically indefensible” reports on the water.

Marc Edwards exposed those reports and lost a contract with the EPA over it.

Aghast at the world of academic science which he says is "gamed by a system of quantitative incentives" and at government agencies who often overlook the truth, Marc now takes aim at the whole system of science. Last year he co-authored a report Academic Research in the 21st Century: Maintaining Scientific Integrity in a Climate of Perverse Incentives and Hypercompetition. The report warns of a tipping point where science “itself becomes inherently corrupt and public trust is lost, risking a new dark age."

The integrity of science has been a major theme here on the program, so while Marc is not a biomedical researcher, his experience in exposing bad science resonates within our own life science community.

In line after quotable line (“The idea of science as a public good is getting lost. In science our product is truth, and our brand is trust. The greatest proportion of truth seekers are not going into science as opposed to other human endeavors."), Marc fillets today’s scientists in government and academia, arguing that the system of science is skewed towards quantitative markers rather than quality: the pressure to publish more papers each year, citations, how much funding, etc.

Marc thinks things have gone so wrong that the war on science today (and yes, he does think there is a war on science), is more the fault of the scientists than any political movement. Somewhat with irony, but more with sadness, he says:

“The Flint water crisis was so bad it restored my faith in politicians. I mean that’s how screwed up it was. The politicians behaved themselves really well. The people who have been indicted are the scientists and engineers."

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.

First of all, watch the video below.

A Santa Cruz company is now previewing a nanopore device that could be a major disruptor in molecular testing. The device is the size of a glucometer and could take all kinds of testing—perhaps someday even cancer-tracking liquid biopsies—into the home with its ease of use and ability to work with thousands of different assays.

Two Pore Guys, named for the pores not the guys, is a spinout from UC Santa Cruz and one of a growing biotech community on the west side of Santa Cruz, CA. The company has yet to do beta testing and is focused now on scaling up manufacturing of the small, relatively simple devices. CEO, Dan Heller, says Two Pore Guys has no plans to develop their own tests but will stay focused on the platform.

“We could make ten or fifteen assays and go to market with them, but why not let others make thousands and thousands of assays?” Dan asks. "They’ve already spent billions of dollars and decades developing primers or capture molecules for antibodies. Why not just give it a new life and let them sell it into the market? It's a revenue share."

So what tools might this replace? Dan lists the standard lab machines for PCR, HPLC, and mass spec. “There’s many uses of existing lab equipment that could be done on our device more quickly, cheaply, easily,” says Dan.

Based on recently developed nanopore technology, the small device looks remarkably straight forward. A molecule—just about any molecule-- is pulled through a nanopore by an electric current. The impedance of the current is the measure of the molecule. Though the device does not currently sequence DNA, its possibilities to replace other large life science tools does seem all the more real in a time when Oxford Nanopore’s small sequencing devices--also partly developed at UCSC—are proving themselves powerful tools.

Listening to Dan, the broad range of molecules and applications becomes dizzying: diagnostic testing such as liquid biopsy tests for cancer (the company is currently doing a study with UC San Francisco for a KRAS liquid biopsy test), infectious disease, border security, agriculture, animal health, and environmental testing.

It leaves us with this question in the end: why was this not done before?

Freeman Dyson famously said, “the great advances in science usually result from new tools rather than from new doctrine.”

Today we talk with Mark Fischer-Colbrie, CEO of Labcyte, a company which has made some waves--literally-- in the life sciences by changing a very fundamental laboratory procedure: liquid transfer. For some years now, Labcyte has been selling machines that move liquid around with sound. By eliminating the need for pipette tips and other “solid” surfaces, the machines guarantee much more precision.

“Science demands precision and in ever-increasing amounts,” says Mark at the outset of today’s interview.

Acting like a rifle shooting liquid straight up, the new acoustic technology has made inroads into most life science applications. Mark talks about the Finnish Institute for Molecular Medicine (FIMM) using the new technology to do truly personalized medicine, by ex-vivo screening of cancer patient cells against hundreds of available drugs. There is often precious little sample to work with, and the errors from traditional pipetting might mean the difference of life or death. The machine is also used widely by the pharma and synthetic biology communities for its ability to reduce costs.

“Imagine saving four months on a single drug discovery cycle,” says Mark.

Recently, Astra Zeneca has integrated acoustic technology into mass spectrometry, showing the potential to immediately upgrade other tools which have been around for some time.

Should everyone change over to acoustic dispensing?