genomic medicine


Know Then Thyself: Kari Stefansson, deCODE genetics

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.

Mukherjee Mess-up, the Secret Harvard Meeting, and Success in Gene Therapy: May 2016 with Nathan and Laura

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.

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.

March 2016 with Nathan and Laura: Genomic Jenga and the Creator, the Anti-Abortion Lobby and Genetic Testing, and Theranos, Again

Which company offers the gold standard of sequencing? Nathan starts us out with a metaphor to compare linked reads with real long reads. Then it’s on to this month’s “knockout paper” that moves us yet further from a deterministic view of genetics. Or is this genomic Jenga part of the “proper design of the Creator”? Laura links a new Indiana law banning abortion due to chromosomal abnormalities such as Down Syndrome to a larger effort by the anti-abortion lobby to go after all genetic testing. Theranos plays the Donald Trump of our industry.

It’s the end of March and time to look back with Nathan Pearson of the New York Genome Center and Laura Hercher of Sarah Laurence College.

Medicine and the Limits of Science with Michel Accad, MD

Are drug prices really too high? If so, how do we bring them down? Is precision medicine and the use of molecular profiles really making a difference in healthcare today?

These are questions that regularly haunt our industry and the journalists who cover it. But there will be no answers until we face the grand question of all, what today's guest calls the most nagging question in medicine: What is health?

Today we begin a new series focused on just this question.

When I came across Michel Accad’s recent blog, Why I Don’t Believe in Science, of course it provoked me to click. Either he would be a terrible nutcase, in which case I'd lose the time it takes to discover this, or it might turn out to be one of those disturbing points of the day when we have to actually do some thinking. What I found was a cardiologist based in San Francisco who was doing some deep philosophical thinking about medicine today. And, obviously, one savvy enough to get some click through. It turns out Michel does believe in science, but he doesn’t share the pervasive view that medicine is a continuum of science.

What are his thoughts about precision medicine? What is his definition of health?

We always jump at the chance to have a medical doctor on the program, and a doctor who is also a philosopher is a double treat. Today's interview takes us down a different path than our typical shows, and we'd like to invite the audience to send us your feedback by clicking here.

A Home Run on the First Hit: PacBio’s Jonas Korlach

Jonas Korlach is a natural storyteller—a rare trait in a scientist who is more comfortable presenting data than talking of himself. Jonas is the co-inventor of PacBio’s SMRT (single molecule, real time) sequencing, and we wanted to hear from him directly how it all got started, and also when the team realized that they had something big with long reads and close to 100X coverage. How many of us can boast of hitting it out of the park on our first try?

BioNano Genomics Stakes Out Sequencing Territory as They Discover Lots of De Novo Variants in Reference Genome Projects

If you attended or followed the recent AGBT conference about all things sequencing, you probably saw a few BioNano Genomics t-shirts with the slogan, “Back to the Map.” They’re referring of course, to a genome map. Just like Google Maps, a genome map consists of landmarks that tell scientists where on the genome they are. But unlike Google Maps and more like the maps North America that were made by European explorers in the 17th century, the map of the human genome is quite incomplete, the map of a frontier.

Erik Holmlin is the CEO of BioNano Genomics which offers unique genome mapping technology. In today’s interview, Erik points out that content is not the only king, context is pretty important as well.

“You can go back and look at some of the early discussions that were happening around the beginning of the Human Genome Project. And in fact a lot of the leading scientists of the time, Maynard Olson, Bob Moyzis, and others, emphasized that as we’re doing this sequencing it’s going to be very important that we put the sequence in context of the physical organization of the genome. Otherwise we’re never going to understand it,” Holmlin says.

After the market has become dominated by “short read” sequencing with the race to the $1,000 genome—a drive many say has been steered by the NHGRI—BioNano is now cutting out some territory for their genome mapping technology. Their flagship projects have no doubt been their work on the reference genomes. Erik says that in a recent trio sequencing project of genomes of Ashkenazi Jewish descent, they were able to find “a lot of de novo variants,” or variants which had not been found with other sequencing technologies.

Though Erik has always had his eye on the clinic—in fact, he came to the tools space from the clinical diagnostics industry because he felt passionately that we needed better tools to develop clinically actionable genomic data—he admits at the end of today’s show that his time at BioNano has pulled him more into basic research.

“In some respects I underestimated the need for more basic research,” he says. “And what really needs to happen is we need to get the translational research efforts to focus on the structural picture much more because that’s going to break through and lead to many clinically significant discoveries.”

Human Genome Turns 15: Mike Hunkapiller

We’re all familiar with the announcement in the year 2000 by US President, Bill Clinton, and the UK’s Prime Minister, Tony Blair, that scientists had completed the first draft of the human genome. It was a big deal. But the actual publications didn’t happen until the next year, February of 2001. Which means that this February is the fifteenth anniversary of the publication of the first human genome. For our commemorative show we’re joined by Mike Hunkapiller, the CEO of Pacific Biosciences.

Mike and his team at PacBio are coming off a great year. Their stock is up. Their long read sequencing technology is used for over a thousand scientific publications. And last year they launched a new better, faster, cheaper instrument, the Sequel, which are sold out through the first half of this year. PacBio is cool again.

How much were tool makers in the driving seat of the genomic revolution? And how much further can sequencing improve? Before asking Mike this, we explore some of his memories of those wild days when sequencing the human genome got presidents and prime ministers on the phone with their speech writers.



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