genomic medicine

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.

OK, so we get it. Long read sequencing technology is cool. But how cool? Is it another great player on the field, or does it change the game altogether? 

The Mike Schatz lab at Cold Spring Harbor is well know for de novo genome assemblies and their work on structural variation in cancer genomes, so we were curious to hear how long reads have impacted their work. In todays show, lab leader, Mike Schatz, and doctorate student, Maria Nattestad tell of two new projects that include the de novo assembly of a very difficult but important flatworm genome and, secondly, making better variant calls for oncogenes such as HER2.

In the case of the flatworm, Mike says that the move to using PacBio’s long reads improved the assembly by more than a 100 times. That means the difference of looking at a super high resolution picture versus a fuzzy, blurry one, he says. With her work on cancer cell lines, Maria is seeing variants that just weren’t there with short reads. Will her work translate to lower false positive rates for HER2 in clinical diagnostics?

What will be the major headline for sequencing and informatics in 2016?

Mike says we’ll see many more reference genomes done, that the term “reference genome” itself is changing as we go from the one standard reference genome to multiple reference genomes representing the broader population. These new reference genomes are pushing bioinformaticians to come up with new ways to visualize and compare the genomes. Maria details her work into using “graph” assemblies as opposed to the linear approach made popular by the Genome Browser. She says that already a new generation of informaticians are rethinking genome visualization using graph assemblies. (Included below is an image representing her work.)

Neither mentioned it, so we ask at the end, what about Oxford Nanopore’s tech?

(The spectral karyotype of the Her2-amplified breast cancer cell line SK-BR-3. The original chromosomes are different colors, so this genome is a complex mixture of various chromosomes. The total number of chromosomes has also jumped from 46 to 80, and there is approximately twice as much DNA as in a normal human genome. Maria Nattestad and Mike Schatz are studying this genome to see how oncogenes like Her2 became amplified while all these changes took place in the big picture of the genome.)

Today’s story is one of a personal quest, of groundbreaking science, and the creation of a new movement in human genomics.

Jim Lupski is a professor at Baylor College of Medicine where he’s on the frontline of incorporating genomic research into everyday clinical practice. The story begins with Jim’s own genome, which is perhaps the most sequenced genome ever. Jim's life as a leading genomic researcher has been driven in part for a strong personal reason. He has a rare genetic disease named after three researchers who first defined it, Charcot Marie Tooth Neuropathy.

What began as a personal journey to uncover the source of his own disease led Jim to seminal work that launched the field of structural variation. Working first in the gene-centric mindset of the 90’s, Jim's team discovered the first gene known to be associated with CMT disease, PMP22. But while this gene is related to 70% of the cases, it wasn't the mutation responsible for Jim's own version of CMT. His discovery of that would be some years later, and from a much better picture of his genome.

Find out in today’s interview where Jim thinks we are now in genomic science, and why he says the goal in the clinic should be a de novo assembly.

Cliff Reid, CEO of Complete Genomics, is back on the conference circuit, touting a new product. After years of building his company to do sequencing as a service, Cliff presented data at last week's ASHG meeting on Complete's first sequencer as a product, or what they are calling the Revolocity supersequencer.

Cliff was a pioneer in developing the service model, offering only whole human genome sequencing. But after being bought out by BGI, who already had a service business in China, he was compelled to shift his business model to that of selling sequencers.

So where does this position Complete in an already crowded and mature sequencing tools market? And how does Cliff see the future of clinical sequencing? Cliff says that the new Revolocity offers the highest quality of any of the other sequencers. This is an impressive claim in a world where PacBio customers are saying they can get up to 100% accuracy with deep enough sequencing. As for throughput, the new supersequencer is similar to Illumina’s HiSeq X Ten system, producing about 10,000 whole human genomes per year.

However, Cliff says that high quality and high throughput are not the important part of the story here. “That's historically what people expected from us,” he says in today’s interview. "The most important thing we did with the Revolocity system is that we packaged it for clinical researchers and clinical use. The packaging is end-to-end.”

Strangely, in an age when longer sequencing reads have enabled genomic research to go to further heights, such as with HLA typing, the new Revolocity does not incorporate Complete’s LFR or Long Fragment Read technology. Long read sequencing is still a highly specialized effort, Cliff argues. Rather, he says, “we haven’t used the technology that we have today [short read technology]. What we need to do is sequence a million genomes."

K Thomas Pickard is not at all into sports cars. So when he hit midlife crisis, it wasn’t a Porsche or a golf club membership that would reenergize his quiet moments. Nope. K T got his genome sequenced.

Introduced to genomics through a super computing company he worked at twenty-five years ago, K T went on to make a career for himself in medical imaging. Yet always in the background lurked a curiosity to know more about genomics. K T's inner geneticist found satisfaction in the past couple years. First he got his 23andMe data and then participated in Illumina’s Know Your Genome program, eventually doing trio sequencing on his wife, his daughter and himself. K T has written peer reviewed articles on his findings.

What was the process like for K T? For example, how did he get his genome analyzed once it was sequenced and what did he learn? How does K T compare genomics to the more established field of radiology where he had his day job?

K T’s genomics hobby has led to founding a non-profit to advocate for “neurodiversity” and the San Francisco Bay Area chapter of Genomics Coffee.

Classes for the school year begin this week at Stanford University. New to the faculty is Carolyn Bertozzi, an American chemist who made her name across the bay at Berkeley and was wooed to Stanford by a chance to do research and teach chemistry in a new interdisciplinary institute known as ChEM-H. The institute will bring chemists, engineers, biologists and medical doctors together to understand life at a chemical level. We’ve often heard of biology and engineering institutes, or bringing bio and IT. This institute ups the ante and includes chemistry and medicine.

Carolyn is an outspoken scientist who feels that chemistry gets short shrift in a time when biology is considered the queen of the sciences. She points out that the National Insittues of Health tend to be lead and run by biologists. We usually call it biomedical research, not chemical-biomedical research. And yet, she argues, it is chemistry that will give us the answers going forward.

“This is a bit of semantics, but I’d say that what we don’t understand about biology is what happens at the level of molecules. What we don’t understand about biology is the chemistry of it. It is hard to see. You need a different set of tools and technology to see what happens at the molecular scale. And that is the chemistry,” says Carolyn in today’s interview.

Does Carolyn think there’s too much hype around genomics? Would she like to see a revival of chemistry?

As the editor-in-chief of a new open access journal, ACS Central Science, Carolyn will be publishing much more on the topic, making louder and prouder the voice of the chemist.

Diagnostics can be a tough business. The FDA is making a strong push to bring more oversight. Obtaining reimbursement can be outright Sisyphean. And clinicians are slow on the uptake. All of which makes today’s story so good.

Located at 106 Gregor Mendel Circle in Greenwood, SC, the Greenwood Genetic Center became the first lab to partner with Affymetrix to commercialize their recently FDA cleared CytoScan Dx assay. This test is the first-- and so far the only--FDA cleared whole genome test to aid in the post-natal diagnostic evaluation of constitutional disorders, such as developmental delay.

In today’s interview, Alka Chaubey, director of the cytogenetics lab at GGC, explains why this array-based test has become so successful.

It’s taken some time, but the NCI is finally sponsoring a big time clinical trial for cancer where the patients are organized by the genomic pathway that defines their cancer rather than the organ type.

"Instead of being a breast cancer trial, or a colorectal cancer trial, or the usual construct that’s been used, this one is obtaining biopsy specimens from patients with a whole variety of differing tumor types, evaluating them with a standardized platform to identify abnormalities, and then linking those abnormalities to arms in the trial with drugs targeted to those abnormalities. This is a completely new way of doing a clinical trial and becomes an important step in moving forward a precision medicine cancer therapy approach,” says today's guest, Stanley Hamilton, head of Pathology and Laboratory Medicine at MD Anderson Cancer Center.

How are the four centers participating in the trial going about selecting patients for this new trial? And what pathways does Stanley foresee dominating the trial?

Stanley’s lab has chosen to use Thermo Fisher’s Ion sequencers to characterize the patients’ genomic pathways. Why? Find out the answer to these questions in today’s interview with one of the leading PI’s for this unique clinical trial.

Nathan Pearson, formerly a genome scientist at Ingenuity and Knome, has been doing public outreach for genomics at the New York Genome Center for about a year now. In today’s interview, Nathan says he always wanted to be able to speak directly to the larger public about the great science he’s been involved in.

“Ever since graduate school, I’ve wanted to take insights from our field to the public more directly. Not just through the ivory tower--the education system that is set up to train scientists—but to help other people out there who won’t be professional scientists. They can benefit from the insights that science brings societally, and can also increasingly contribute to those insights by investing their own data on behalf of science," he says at the outset of today's show.

Nathan offers first an overview of the mission at the NY Genome Center and lists examples of their collaboration projects. Then the interview runs a bit like a review of genomic medicine as of summer 2015.

What are Nathan’s thoughts on the debate over how much of the genome is functional? What is Nathan doing to reach out to the general public? And is he concerned about the ‘hyperbolome,' or the over hyping of genomic discoveries and technologies?