genomic medicine

They’ve been called the “unsung heroes” of our age. They are primarily women. And when the trend for most of us is to become specialists, they have been generalists.

Today we begin a special series on genetic counselors. Our first guest, a genetic counselor herself, is a name familiar to our audience. Laura Hercher is one of our regular month-in-reviewers, and today it’s all about her. She is on the faculty at Sarah Lawrence College where the first genetic counseling program was begun in 1969 and where half of the nation’s genetic counselors have been trained.

Like many other fields, there are different schools of thought when it comes to genetic counseling. In today's show, Laura says that the older method was for the counselor to decide what genetic data was good for the patient. It was thought that "genetic information is super explosive, and you have to treat it like non-exploded ordnance all the time and be very very careful what you give out."

Now, Laura says, the trend in genetic counseling matches that in the world at large "where people expect a free flow of information," and more is left up to the patient. "The early studies we've gotten have suggested that people can handle information."

What makes a good counselor? And is there a difference between counseling in the clinical setting and counseling for industry?

These are a few of the questions we cover in Part 1 of the interview.

Listen to Part 2.

Today’s show with Jonathan Hirsch, the President and co-founder of Syapse begins a couple years ago. We first featured him on the program in January of 2014 with the headline, Is this the Omics-to-Clinic Site We’ve All Been Waiting For?

It turns out, in many respects it is. Syapse has had some big wins with some of the more progressive healthcare companies in the U.S., including Intermountain and Stanford. This year Syapse announced the creation of the Oncology Precision Network for data sharing in cancer care among several major institutions. The company even got a shout out from Vice President Biden in one of the recent White House confabs.

Over the years we’ve featured various bioinformatics and clinical informatics companies who had the aim of bringing omics data to the clinic. Syapse is emerging as a leader in that field demonstrating strong traction, particularly in cancer care. Today Jonathan explains the company’s Precision Medicine Platform, on top of which sits their oncology application.  He gives an example of just how this platform is changing cancer care at Intermountain in St. George, Utah, a small town with some big expertise.

And has the Veep’s Cancer Moonshot been changing things up?

“Everyone focuses on the money, but it’s not about the money,” Jonathan says. "It’s about how you use the power of the presidency to knock heads together and bring people together in collaborative relationships that they might otherwise not have entered. We’ve seen a measurable change in attitudes around clinical data sharing from this initiative."

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.

Today's guests have been separately on the program recently. And we've asked them, both Brits, to come back on for a discussion of the Brexit. Clare Turnbull is Clinical Lead for the 100K Genomes Project Cancer Program at Genomics England. Hadyn Parry is the CEO at Oxitec, a company based in Oxford which is already selling their genetically engineered mosquitos into Brazil to deal with viral diseases like Zika and Dengue Fever.

The first question we throw at them is whether they are still in shock over the outcome of the vote. Clare resides in London, and Hadyn in Oxford—both places that voted overwhelmingly to remain in the European Union. In fact, Hadyn says he doesn’t know a single person who voted “leave.”

Clare says Genomics England is funded through 2020, so in the short term, the 100K Genomes Project is secure. She also has a role in academia where most genomics research takes place. There, she says, they are being hit with an immediate impact. 10-15% of grant funding in the British system comes from the EU.

“People are on grants which are running. People have won grants that not yet been awarded. And people are looking to collaborate on grants in the medium term future. And one becomes a pretty unattractive collaborator on an international, pan-European grant when it’s uncertain whether or not we’ll be in the EU. The uncertainty is pretty immediate,” says Clare.

Hadyn says the uncertainty is certainly affecting business in the short term. But points out that in the longer term, the UK is solid. They have a great tradition of science, and they have four of the top ten universities in the world. And their entrepreneurial culture is strong. It’s much easier to do a startup biotech company in the UK than in the rest of Europe.

“The longer term, I’m quite comfortable with,” he says. "It’s all about the uncertainty in the short term. The sooner we move to understanding the rules of the game, the sooner the short term uncertainty can be removed.

For now, both see a country still in shock and denial.

Kari Stefansson is a name well known in the field of human genetics. His founding of deCODE genetics in his native Iceland in 1996 took our field into a new frontier with the unique opportunity to work with not only a homogenous population but also to integrate with a large centralized healthcare database. It also surfaced a huge ethical debate about genomic privacy.

We’re very happy to welcome Kari to the program for the first time to talk about his vision for deCODE now that the company has been bought by Amgen. The company has continued to publish papers revealing major findings of rare variants associated with common diseases. Just last month Kari and deCODE published a paper in the NEJM with the discovery of a gene called ASGR1. The gene lowers the risk of heart disease by a substantial 34%.

Kari is passionate about discovery for the sake of discovery.

“All life on earth is rooted in information that lies in the simple code of As and Gs and Cs and Ts of DNA,” he reminds us. “Some of our discoveries are knowledge for the sake of knowledge. It is man studying man.”

But he also points out that as soon as they made the discovery of the ASGR1 heart-protective gene, researchers at Amgen went to work immediately on a drug discovery program. And, he says, he knows that many other pharma companies have already begun similar programs.

deCODE is perhaps best known though for their project to create a genomic database unlike any in the world. And for the ethical issues this has brought up. Last year deCODE announced that they had sequenced enough individuals to impute the genomes for the entire population of Iceland. This could lead to a new kind of preventative healthcare system that would be a model for other countries everywhere. It’s also left Kari and his colleagues scratching their heads over whether, for example, they have a social obligation to find out who in Iceland carries the dangerous BRCA mutations.

He shares some dramatic statistics that reveal their dilemma:

"Women who carry this mutation have 86% probability of developing a lethal cancer. They have 72% probability of developing breast cancer. They have a life expectancy that is twelve years shorter than non-carriers. They are three times more likely to die before the age of 70 than the non-carriers. And most of this risk could be mitigated by preventative surgery, for example.”

The interview goes well over our typical target of 20 minutes. But Kari is a deliberate thinker and an eloquent speaker. Enjoy.

Today we look back on the genomics headlines over the past month (and a few days). To do this we’re joined by our regular commentators, Nathan Pearson and Laura Hercher.

First we take on the science journalism kerfuffle of the year. When Pulitzer Prize winning author, Siddhartha Mukerjee, got epigenetics wrong in his New Yorker piece, scientists came out en masse to denounce it. Nathan reassures us that scientists aren’t afraid of writers.

Then on to that secret meeting at Harvard, HGP-Write. Laura gives it two thumbs down, saying it’s very normal for folks to be scared of the idea of synthesizing a human genome from scratch. So don’t make it more scary with a secret meeting and total lack of transparency.

Finally, we review some positive success stories for gene editing, specifically some gene therapies which have been approved or undergoing new trials.

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.

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.

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.