sequencing


We’re Over Halfway There: Baylor's Richard Gibbs on Clinical Genetics

There’s a basic assumption in our field today that has been around for some time. We think of medicine as on a direct and even continuum with science. That discoveries in genomics, for example, will lead directly to breakthroughs in medicine. But the breakthroughs on the medical side have been much more rare to date than those coming from the study of biology and genomics.

Richard Gibbs is the Founder of the renowned Genome Sequencing Center at Baylor College of Medicine. He and his team were one of five worldwide sites contributing to the Human Genome Project (HGP). In today’s interview we find out what the sequencing pioneer has been up to since the days of the HGP and what his take is for how well genetic science is translating into clinical care.

In fact, Richard is willing to put a number on how far we’ve come.

“There’s a trajectory that began just about the time the Human Genome Project was being conceived through to this futuristic image of medical genomics where complete genomes are actually part of medical care,” he says. "That journey is not yet complete. We are somewhere between 50 and 90% there.”

Richard says that the HGP was actually a departure from what was typical in the field of human genetics. That it was a science project done more purely for the sake of science. Most of the history of human genetics research has been practical medical or clinical projects.

One of the areas where Richard’s team has made a big impact is in collaboration with the NHGRI's Center for Mendelian Diseases. The team is also participating heavily with the NIH’s Undiagnosed Disease Network. What is the difference between a Mendelian and a rare disease? What are the center’s solve rates for each of those areas?

We round out the discussion with a look at how Richard and his team get the 'best quality genomes' for their projects, an issue of utmost importance in the clinic.

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?

Luke Timmerman on His New Biography of Lee Hood

There is tons of life science journalism. Our coffee tables and inboxes fill up each week with that quarterly or that daily. We sift through headlines and product advertisements to assess what’s going on in our industry. It’s our job to know. In this age of several-times-per-day newsletters and 24 hrs a day Twitter, we catch what we can.

And occasionally, we come across a carefully written piece or a well done interview, and we take a moment to realize with some awe the history that is being made in our industry.

Occasionally. Which is why a new book out by veteran biotech journalist and the guest of today’s show, Luke Timmerman, is such a rare treat.

Hood is a thrilling ride through the life of the visionary biologist, Lee Hood, told by someone who is not afraid to show the shiny and the not so shiny. From his boyhood in Montana to being chair of the biology department at Caltech where he oversaw the invention of the automated DNA sequencer, to being recruited to Seattle by Microsoft’s Bill Gates, Hood’s journey becomes the perfect vehicle for Timmerman to probe into the messy corners of science and put an intimate, human face on the history of biotech. Covering Hood’s move to the University of Washington as a young Seattle based reporter, Timmerman has known Lee Hood for several years. It's a full scale biography, efficiently and confidently written with an insider's perspective and access. Timmerman says it's an “unofficial biography,” meaning Hood was supportive of the project, but Timmerman had full freedom.

Playing historian has been somewhat of a fantasy for the long time journalist.

"There are things that are happening in the moment which a journalist can call people on, but you don’t really get the whole story. There’s only so much people can say and there are not a whole lot of documents that come available when you’re on deadline. But when you’re a biographer, and you have the luxury of time, and people have moved on, things become a lot less sensitive. People become more willing to talk, and a whole lot of documents become available through the public record.”

Who is this man, Lee Hood, and how has he impacted our industry? In the book, we read of the time when Hood holds a press conference to announce his team has done it—they’ve got an automated DNA sequencer. But, standing at perhaps the pinnacle of his career, Hood forgets to mention the "team" part. It’s a flaw that will go on to haunt what by any measure has been a remarkably successful career.

What impact has the subject made on the author? And what does Timmerman hope for the book?

To round out the interview, we get Timmerman’s thoughts on his new gig, the Timmerman Report, and the recent Sarepta decision by the FDA.

August 2016 with Nathan and Laura

It’s the end of summer and end of another month. Joining us to discuss the genomics headlines of August are Laura Hercher and Nathan Pearson.

A recent study demonstrating that breast cancer patients with low genomic risk may not need chemotherapy is just what precision medicine is all about, isn’t it? Theral and Laura think the study is a big deal. Nathan’s not so sure.

Nathan is convinced though that Eurocentric studies have implicit racism. Laura agrees, saying the lack of racial diversity in biological databases is a major weakness that we must face head on.

Also, the FDA issued a report supporting Oxitec’s GM mosquitos for use in Florida. Laura is on board with the science but warns about smugness on the part of the scientific community. And George Church’s lab released a reengineered e. coli. Nathan imagines a new genomic language of 2 letter codons.

A Maniacal Commitment to Science: Peering into Regeneron’s Genetics Center with Jeff Reid

Today we feature a pharma company that has been around for some time but recently getting more media coverage for the impressive scale of their new genetic center. Regeneron Pharmaceuticals, insiders joke, has been an overnight success that took 25 years.

One might think every big pharma company has their own genetic center for internal R & D. But today’s guest, Jeff Reid, Executive Director of Genome Informatics at the Regeneron Genetic Center (RGC), says that actually deep genetic research is often outsourced.

In just two years, the RGC has built an impressive sequencing lab and announced large partnerships with healthcare systems and academic centers that rival major government projects. One such collaboration with Geisinger Health System involves the sequencing of 100,000 genomes. Already, the RGC has sequenced over 100,000 exomes and has plans to sequence 500,000.

“What we’re doing is quite different,” says Jeff. "We are envisioned as a large scale academic genome center embedded in a pharma company."

Jeff says the strategy is to not only go wide with studies of large numbers of patients for the purpose of finding very rare variants, but to go deep as well. Big numbers can be distracting, he points out, saying that some times they get more insight off a small project, such as the treatment of children with a rare genetic disease.

“There are strategies all across the spectrum of project size,” he says.

Set up in an age when compute and data storage are no longer an issue, the RGC has become the first large scale genetic center to be entirely in the cloud. What is the major informatics challenge for Jeff and the center? And what does having such a large scale genome center mean about Regeneron and where we are today with genomic medicine?

FDA’s Liz Mansfield on New NGS Guidances

On July 6th, as part of the President’s Precision Medicine Initiative, the FDA issued two new draft guidances for the oversight of next gen sequencing (NGS) tests. The first guidance is for using NGS testing to diagnose germline diseases. In the second, the FDA lists guidelines for building and using genetic variant databases.

To help us understand just what the guidance is and what led to its release, we’re joined by Liz Mansfield, the Deputy Office Director for Personalized Medicine at the FDA.

It’s unusual for the FDA to issue guidance around a single technology, but Liz says that NGS is “transformative” and is eclipsing so many of the older technologies. The biggest challenge is that NGS is a technology used for discovery and has the power to test for so many things at once.

How does the new NGS guidance relate to the much talked about guidance on LDTs that came out a couple years ago? And does the new guidance represent a more incremental, step by step approach for the FDA in dealing with the explosion of today’s molecular testing field?

“No, it’s not an attempt to break down into smaller bites the issue on LDTs. It’s to address this particular technology, regardless of who the developer is,” says Liz.

The two guidances are for very specific purposes and Liz anticipates further NGS guidances to be issued in the future. For example, guidelines for dealing with somatic mutations rather than germline mutations.

June 2016 with Nathan and Laura: GMO Labeling, Misspelling CRISPR, Sequenom Patent Loss, SmidgIon

Today's show was recorded July 1st, the first day that Vermont’s GMO labeling law went into effect. Just how big a win was this for the anti-GMO crowd, we ask our two commentators, Nathan Pearson and Laura Hercher. They have a surprisingly optimistic take, suggesting that the GMO labeling could become a positive marketing tool.

Laura says the scale and ease of CRISPR vs the older technology of zinc fingers is like going from manuscript writing to the printing press. She insists, therefore, that the approval of the first ever CRISPR trial is a big deal even though we’ve already been doing the same cell replacement therapy with zinc fingers. She also points out that the new trial is funded by Sean Parker’s foundation which is moving along at a Silicon Valley pace.

"The tech industry has never had their moment where it killed someone to move too fast.”

Last week the Supreme Court killed off Sequenom’s patent for prenatal screening. After Laura and Theral hotly debate whether there should be such patents, Nathan suggests there is a right balance.

“It’s sort of like tuning a carburetor,” he says. "Patents can encourage people to invest, but they can also inhibit the development of technology.”

And lastly, DNA has a new mascot. It’s called the SmidgIon.

Genomics Is Oversubscribed, Says Creator of BLAST

One of the original Celera team that worked on the Human Genome Project, Gene Myers is now setting up the new Center for Systems Biology at the Max Planck Institute of Molecular Cell Biology and Genetics.

However, unlike many others such centers, the main focus of this institute will not be genomics. Rather Myers is going for microscopy.

“Genomics is only about 20% of it,” he says in today’s interview from his office in Dresden, Germany

Myers feels that genomics is overcrowded. He wants to look at the “rest of the stuff” which he finds to be “the most important." Seeing that human genomics was more a matter of scaling after the Humah Genome Project, Myers scientific curiosity led him into microscopy where he seeks to take images of transgenic constructs in the cell and build computer models of basic biology.

"Now that we have reference quality genomes of a number of model organisms, we can do transgenics at scale,” says Myers. "We can take any protein or any promoter and see where it’s being expressed in the cell, and in which cells. And that ability--to basically watch any given protein of interest--has been a huge accelerant to the discovery of biological phenomenon."

With much improved imaging—from better, cheaper cameras to the availability of digital storage—Myers envisions that microscopy will be the breakthrough new platform for biological discovery, similar to what sequencing has been.

“It’s my belief, that if I can build that platform, that people will come and look at transgenic constructs over and over again until we have a very complete atlas of what’s going on in the cells at each point in time,” he says.

What is the biggest challenge to developing such a platform? Myers says the key will be adaptive optics, imaging technology that can adapt for the limitations and aberration of light in the cell.

With 10K Genomes Sequenced, Genomics England in High Gear: Clare Turnbull, Clinical Lead

We’ve heard on the program over the past few years that genomic medicine will probably take off first in a country with a centralized health service. And when the U.K. announced their 100K Genomes Project at the end of 2012 with the creation of Genomics England in 2013, it was certainly a bold visionary move to do just that—to put the entire country on a progressive path toward precision medicine for all.

So with 10K genomes sequenced, how is the project going?

“We’re still early days in the program in delivering it,” says today’s guest, Clare Turnbull, Clinical Lead for the Cancer Program. "Because the National Health Service in England is a single health care provider, it is possible to leverage carrots and sticks to make sure things happen. This gives us a lot more opportunity to effect change than in a more disparate service such as in the U.S.”

What are those carrots and sticks? What new paradigm shifts must take place, and what are the biggest challenges?

Beginning with rare diseases and cancer in this first project, the overall goal, Clare says, is to bring next generation sequencing technologies "full scale in their entirety into our healthcare service, and build all the structures that are necessary to use these types of tests--in particular, whole genomes--as routine investigations in every patient in every hospital within our service.”

Clare says she is a fan of Mendelspod because we provide "a very American perspective" on the same challenges and opportunities.

A Sneak Peek into the Future of Clinical Genomics with Ben Solomon, Inova

We hear from some that soon each baby's genome will be sequenced at birth. This vast amount of genomic information will be stored in a person's medical record for life and be referenced for personalized healthcare, be it for a diagnostic, a prognostic, or a prediction. But others say that it is still way too early to be generating so much information on each person when we know so little about the genome. This camp argues that we should deal with patients on a case by case basis using a more targeted approach.

The Inova Translational Medicine Institute offers us a glimpse into questions such as the whole genome vs targeted approach. A unique not-for-profit research institute, they are using genomic information from patients in the Inova Health System’s five hospitals to move them closer to personalized medicine. With this direct access to patients, solid funding, and a location in the Washington/Baltimore government research hub, the institute is no doubt the envy of anyone working to implement genomics into the clinic. Add to that, Inova’s CEO is a former NCI director, John Niederhuber, who has hired some of the best and brightest in genomics.

We talk today with Ben Solomon, who was hired out of the NIH to be leader of the institute’s Medical Genomics Division. He says that one of their first studies looks at the genomes of over 1,000 pre-term birth babies and could be a model for clinical sequencing on a larger scale.

“We enroll folks about halfway through pregnancy," says Ben in today's show. "We generate whole genome sequencing on the baby when the baby is born, but we start collecting samples from mom and dad before the baby is born. Then we do whole genome sequencing on the full trio. And we follow them longitudinally, hopefully throughout their whole life. The oldest patients are four to five years old now. We re-consent them at a certain age.”

The study is an example of staying away from any bias that comes with looking for a particular disease. In fact, Ben says, in the age of genomics, the classical presentation of disease is drastically changing. A longitudinal study like this is about finding the "natural history" of many different conditions.

This particular study uses whole genome sequencing, but much of the work the institute does is targeted sequencing. Ben says that though it's often a blurred line, his team first determines whether the case is research or clinical. If it's a clinical setting, he says the first line approach is to go with a targeted panel, pointing out that the use of panels has grown tremendously over the past few years replacing the "one-off" genetic testing.

"A few years ago when someone was coming in with a question of hereditary breast and ovarian cancer, the standard was BRCA1 and BRCA2 testing. And very quickly that has changed into almost always larger panel testing. And even the panels offered are getting much larger."

Ben says there is often resistance to the growing size of panels - including from both genetics professionals as well as other clinicians and patients -because with larger panels, the likelihood of seeing variants of unknown significance increases and with that the challenge of interpretation.

This question of targeted vs whole genome leads to a discussion about how much genome interpretation Ben and his team do in house, demands of a bioinformatics infrastructure, and costs.




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