precision medicine

Modena, Italy is the town where one of the world's rarest cars were first developed and built: the Ferrari sports car. It’s also home to one of the world’s oldest universities where today’s guest spends his time studying rare human cells.

Andrea Cossarizza is Professor of Pathology at the University of Modena and Reggio Emilia School of Medicine and the President Elect of ISAC, or the International Society for the Advancement of Cytometry. He joins us today to talk about the role that improved cytometry technologies are playing in detecting rare cells and how this is being translated into better treatments for patients with cancer and other diseases such as immune disorders.

With the advent of immuno therapy has come a renewed interest in rare cells, or cells that occur with less frequency than 1 in 1000. Rare cells include the antigen specific T cells that we hear so much about with immuno oncology. But rare cells are also studied in many immune and inflammatory diseases such as HIV.

“This is a very new and interesting field which will have enormous importance in the future,” says Andrea, who wrote the chapter on rare cells in a new book on single cell analysis.

Andrea says that though new immuno therapies have shown such enormous promise, they only work on about half the patients. Being able to detect rare immune cells in advance of treatment will help clinicians to know which patients will respond.

What are the challenges that are emerging in this new field? When should the patient be tested? How does rare cell detection technology need to develop?

Join us as we lift the hood on the future of rare cell detection.

When we first talked with Tim Triche of LA Children's Hospital, we found out he was a bit of an outlier among cancer researchers. He was an advocate for poking around in the non-coding RNA.

Today we welcome Tim back to the show to talk about a new gene panel that he has designed specifically for childhood cancers. It’s a first of its kind and was modeled quite closely on the gene panel for the NCI’s MATCH trial. The new panel has both a DNA and an RNA component, and the RNA side is by far the biggest.

"There are 1,400 different amplicons on this panel looking for RNA fusions. Thermo Fisher tells me it’s the most ambitious RNA panel that they’ve ever undertaken," Tim says in today's interview.

"When 100 cancer patients walk in your office, then 100 cancer patients walk in your office," says Tim, quoting a common line in the field that points to the uniqueness of every cancer.

Yet even though every cancer is different, certain biological commonalities combined with better sequencing tools is enabling the design of new gene panels to guide in diagnosis and treatment. More and more a cancer is looked at based on the drug that might treat it rather than the organ in which it grows. The new panel can guide this treatment.

Some of the most important targets on the panel are RNA fusion transcripts. What are they, and why are they so important for helping kids?

Childhood cancers come from inherited mutations, whereas most adult cancers have to do with the skin or the linings of the organs due to mutations caused by environmental impacts. Fusion transcripts are very common in the youth cancers and have been a big part of routine diagnostics.

If a mutation is there early in life, is it likely to turn into cancer sooner rather than later? Yes, says Tim.

“If you look at the incidence of childhood tumors, there’s a big bump in the first months or year or two of life, and then they disappear thereafter."

Additional benefits from these new next gen sequencing panels are that they can work with very small “real world” samples of tumor tissue, and they can also be used as discovery tools. Tim says the panel, called OncoKids, is ready to go for frontline therapy, and is hoping to get the word out to oncologists everywhere.

Back in 2009, University of Washington professor, Jay Shendure, wrote a definitive paper offering up a roadmap for exome sequencing. Since then, the cost of sequencing has come down so far that many have debated whether or not to do whole genome sequencing vs. just the exome.  

As it turns out, the exome, as a unit, has been very fruitful for both clinicians and scientists, particularly in the area of rare disease discovery and diagnosis. Most genetic testing companies these days have the exome on their product lists.

In today's program, Jay says that we are still in the heyday of the exome; there is still much low hanging fruit.   However, some eight years after his landmark paper, he warns we will soon come to the end of that cycle.

“There clearly is a lot that we haven’t explained. But doing the same thing over and over again isn’t going to get us there. We’ve got to take a step back and systematically investigate the various explanations for the keys that aren’t clearly labeled and not under the lamppost.”

What are some examples of new hypotheses for decoding the genome? Jay points to searching in non-coding regions, epigenetic mechanisms, somatic mosaisicm, and di-genic mutations.

As we go ever deeper into the genome, what are Jay's thoughts on the need for going wider with lots of genomes? And is he on the same page with his UW colleague, Evan Eichler, when it comes to long reads?

Jay is a scientist's scientist. Coming out of George Church's lab at Harvard, he's worked over the years on new methods for genomicists. One of his latest projects dives into developmental biology. He says we've spent a lot of time looking at the "what" of genomics. Now it's time to look at the “how” and “why."

Today we get to bring you a feel good story, one of the major achievements so far in precision oncology. Three large companies—Thermo Fisher, Pfizer, and Novartis—put aside their differences to come together for patients.

The patients are those who suffer from non-small cell lung cancer. In June, the FDA approved for the first time an NGS panel with multiple genes for multiple drugs that treat this kind of cancer.

“It’s groundbreaking for patients, because instead of having to wait for a hierarchal testing approach to their cancer, this one test could be able to give the answer for the patient."

By hierarchical, Annie Martin, the VP Global Head of Precision Medicine at Novartis, means the usual stepwise approach to testing for patients with this cancer. Typically patients are tested for first EGFR, followed by ALK, followed by ROS1, followed by BRAF. Now, thanks to a new NGS panel out by Thermo, all of these tests will be done at once and has been approved for various therapies.

In addition to Annie, we’re also joined by Thermo’s Joydeep Goswami, President of Clinical Next Generation Sequencing and Oncology at Thermo Fisher and by Hakan Sakul, VP of Diagnostics at Pfizer to talk about their collaboration.

How did Thermo decide on this panel, and what possible future uses to do they see? And how did the three large corporations—one diagnostics and two pharmas--come together to pull this off?

Join us with three of the industry’s leaders as we uncover the work behind a major milestone for precision oncology.

Invitae appointed their co-founder Sean George as CEO earlier this year. He joins us to share his bold vision for the field of genetic testing.

Sean mentions the word “scale” several times in today’s interview. Invitae was by no means the first on the scene, beginning in late 2013 (just after the Myriad Supreme Court decision), but with plenty of funding and talent they have sought to push the needle forward in a big way when it comes to genetic tests. The company has always exuded the message that there is all this valuable genetic information available now, and it’s just not getting to people who could benefit.

Sean says that this urgency is what drives him in a quest to “prevent unnecessary suffering that exists today by tearing down the barriers that are keeping this powerful and fundamental information from benefiting people’s lives.”

What are the barriers? Sean says cost is number one. That there are many out there who would buy genetic tests but can’t because of the price. In an age of astronomical drug prices, is it really that crucial to squeeze off a few dollars from a genetic test? And how does Sean and Invitae make the decision when to offer a test?

While Invitae has not gone the direct-to-consumer (DTC) route, Sean says they have a bit of a hybrid model where they market directly to consumers, but sell only into the clinic.

Sean agrees that the industry has had some “whiplash”, moving forward with excitement only to have big set backs. He says that in his company presentations, he likes to show two New York Times headlines:

The first goes, “10 Years after the Human Genome Project, What Does It Matter?” And the second headline taken from 1991: “Personal Computers: So Who Needs Them Anyway?”

The life science tools space is flourishing. Biomedical research output is at an all time high. Today’s guest says there are over 40,000 papers published each year on cancer biomarkers.

But very few of those become commercialized tests. Why?

Many had hoped the FDA would step in and save the diagnostics industry from itself, from a race to the bottom when it came to being able to reproduce clinically relevant tests. But that’s obviously on hold. In the meantime, others are stepping in. And there is one government agency which has no regulatory authority but some power to help out.

Kenneth Cole is the group leader for developing bioassay methods and standards at the National Institute of Standards and Technology. His group has just created a new set of standards and methods for HER2 testing which is available to the clinical lab community to help improve their own assays. It’s been said on the program that this very common test for use in cancer therapy has a false positive rate of 20 percent. That's too many patients getting told the wrong thing.

Ken’s group is now going to work on EGFR and other common tests, and they can help the testing community in several ways. First of all, Ken says, they have a “the luxury of being able to focus in on the measurement techniques and on examining all the sources of variability in an assay." They also work on characterizing cell lines, which have become “an essential part of modern biology.” Ken says a big part of the work at NIST is the education of the community and of the new crop of scientists.

Do you have an assay you’d like help with? Ken is easy to reach, and NIST welcomes your requests. They have set up many partnerships from loose collaborations to projects with IP protection.

Often the best place to find solutions is in going back to the basics.

They’re getting a lot of buzz this week. We’re pleased to have Justin Kao, a co-founder of Helix on the program today for the first time.

Launching formally yesterday, Helix has generated a good amount of enthusiasm—in no small part because they raised $100 million and are backed by Illumina. And the Helix business plan is definitely a bold one. They aim to become the DNA testing platform that supports and partners with direct-to-consumer (DTC) and clinical apps, offering genomic tests that are both medical and non-medical. Helix's part is to collect the samples, do the sequencing (exome plus), and be the app hosting platform.

23andMe co founder, Anne Wojcicki, said once on this program that “DTC testing is a whiplash culture.” This year, with a lighter hand at the FDA during the Trump administration when it comes to genetic tests, entrepreneurs are showing more boldness. This is one of those leaps forward.

“Consumer interest in DNA is exploding,” Justin says today. “The genealogy industry itself has been doubling every year for the past few years.”

Justin lists some of the app partners with which they are launching, and says they will soon be adding more, including a partnership with the clinically focused, InVitae. He says Helix has a CLIA certified lab and has been working with the FDA since they began.

Is there an inherent conflict in the attempt to host both medical genomic tests—such as the 59 ACMG recommendations--and tests that help us pick the right scarf or wine? According to the vision of Helix, DNA is DNA.

Justin compares the Helix platform to the basic enabling technology of GPS.

“What if I said to you, I’m going to the gym, and I’m going to do my standard 30 minutes on a treadmill because that’s what everyone does? In a few years, you’re going to turn to me and say, ’well that’s odd, your body and my body are different. Don’t you turn on your DNA?'"

When will we see the results of microbiome research in our every day lives? And what will that look like?

Rob Knight joins us for the first time today. He’s a professor at UC San Diego and Director of the Center for Microbiome Innovation. He is well known for co-authoring a paper showing that the microbial populations in the guts of obese mice differentiate from those in lean mice.

In addition to studies on obesity, Rob is also interested in the connections of the gut micriobiome with brain disorders, the possibilities for fecal transplants, and also the impact of microbial communities on drug interactions.

On the tools side we hear a lot about the success of single cell sequencing for human genetics; what impact are these new tools having on metagenomics? And if consent is often a thorny issue for studies in humans, what are the ethical issues studying microbes?

Rob says that in the next five to ten years we will be “taking control over our microbiomes,” meaning that we will be able to measure our microbial communities and use this information to improve our diet or to optimize a therapeutic. The big piece missing for translating microbiome research, he says, is better user interface or apps that would abstract away all the technical information. We need to go from the world of GPS coordinates to using Google Maps, he says.

Reports from ASCO, the nation’s biggest cancer conference, this year again were full of stunning stories about the success of older and new immuno therapies. The race has never been hotter for biomarkers to target patient groups. Most of this new class of drugs--which harnesses the immune system to go after the cancer--inhibit an immune checkpoint called programmed cell death protein 1 or PDL1. So frontline cancer treatment these days typically includes a test for the PDL1 biomarker. But there are a breadth of potential targets in the immune system that promise to make this class of cancer drug even more effective.

Today we talk with Mark Gardner, CEO of OmniSeq, who has just received approval from New York State (the company is in Buffalo) to launch their new Immune Report Card.

“The biology is complicated. Even for folks that are PDL1 high, in the majority of cases those patients are not going to respond to these drugs. The average number of responders is 20-30%. So we know something else is going on. It turns out we’ve known some of the mechanisms for how the tumors are achieving "immune escape.” What we’ve not had the ability to do is to simultaneously measure across the range of hypotheses for how that tumor is escaping."

Omniseq's Immune Report Card includes mutational burden and MSI testing, which is common practice today. The two additional “legs” of the report are copy number variation for PDL1 as well as RNAseq.

Let’s say you’re a biomedical researcher looking for a place to make your mark. You find out that there is still a major disease that affects more than 2 million people in the US, and we still know virtually nothing about this disease at the molecular level. Wouldn't that stand out?

It certainly has to today's guest, Ron Davis, who is also a father searching for answers for his son. Ron has been the Director of the Stanford Genome Technology Center for decades. He collaborated on the first DNA microarray and made a major contribution to the Human Genome Project. For five years now, Ron has directed his comprehensive skill set in bioengineering--and his vast connections--to work on a cure for ME/CFS, or Chronic Fatigue Syndrome, a disease which has ravished his son, Whitney Dafoe.

With no funding from the NIH so far (he says they're not good at starting things), Ron is working to characterize the disease at the molecular level. A new device developed at his center that he calls a "nano needle" could enable the first definitive diagnostic test for patients with CFS.

The history of this disease is of patients desperate with hope but always facing a major stigma. Many medical professionals are still not on board with diagnosing a patient with CFS. Ron says this stigma and lack of interest by the research community has created a big chance.

“This is a tremendous opportunity. Here’s a major disease which at the molecular level you don’t know anything about. This has got to be the last disease like this."

Find an extensive recent written interview with Ron here.