In-Situ Sequencing, CRISPR Patents, and Racist Milk Drinkers: February 2017 with Nathan and Laura

Commentators Nathan Pearson and Laura Hercher join us to look back on February’s genomics headlines.

Beginning this time with science, Nathan says we should be expecting great things from new in-situ sequencing. Laura found it encouraging that the National Academy of Sciences shifted to be more in support of genome editing. Theral asks what life forms are left to sequence for the Earth BioGenome Project?

Then it’s back to politics. Are the departure of Liz Mansfield from the FDA and Matt Might from the White House the beginning of a brain drain from government agencies in the new administration? We finish with some stories about racism that might fit under the heading “family genomics and black history month."

By Changing a Basic Lab Step, Acoustic Liquid Transfer Having a Broad Impact

Freeman Dyson famously said, “the great advances in science usually result from new tools rather than from new doctrine.”

Today we talk with Mark Fischer-Colbrie, CEO of Labcyte, a company which has made some waves--literally-- in the life sciences by changing a very fundamental laboratory procedure: liquid transfer. For some years now, Labcyte has been selling machines that move liquid around with sound. By eliminating the need for pipette tips and other “solid” surfaces, the machines guarantee much more precision.

“Science demands precision and in ever-increasing amounts,” says Mark at the outset of today’s interview.

Acting like a rifle shooting liquid straight up, the new acoustic technology has made inroads into most life science applications. Mark talks about the Finnish Institute for Molecular Medicine (FIMM) using the new technology to do truly personalized medicine, by ex-vivo screening of cancer patient cells against hundreds of available drugs. There is often precious little sample to work with, and the errors from traditional pipetting might mean the difference of life or death. The machine is also used widely by the pharma and synthetic biology communities for its ability to reduce costs.

“Imagine saving four months on a single drug discovery cycle,” says Mark.

Recently, Astra Zeneca has integrated acoustic technology into mass spectrometry, showing the potential to immediately upgrade other tools which have been around for some time.

Should everyone change over to acoustic dispensing?

Many Biologists Today Don’t Have Enough Computer Science to Use the Databases

Moray Campbell was for all intents and purposes an accomplished and successful cancer biologist at the renowned Roswell Park Cancer Center. Then one day he woke up and realized he was becoming irrelevant. He was a traditionally trained wet lab biologist who was getting left behind by computer science. Any scientist must keep up with their field, but this was different. A few conferences and journals--reading the news everyday was not going to be enough. Facing reality, Moray enrolled in a bioinformatics masters program at Johns Hopkins.

That was in 2013.

"Biology is genomics. And genomics is basically computer science,” says Moray at the outset of today’s program. “In 2013 I would have said I look at the epigenetics of prostate cancer. Now I say that I look at the epigenomics of prostate cancer. I’ve become genomically literate."

What was it like for Moray to go back to school mid-career with teachers and homework and finals? Did he doubt his decision when the going got tough? Is it harder for biologists to learn coding or coders to learn biology?

Moray is now finished with his degree and in the process learned that as a discipline, we're still struggling with how to teach genomics to biologists.

He gives the example of datasets such as TCGA that many biologists today don’t even know how to use.

“These data are there. And they’re being used very deeply,” he says. "But I suspect by quite a restricted community. If you don’t even know how to download a file, how are you going to be able to analyze it?"

It's been a dramatic transition for Moray. Looking back now he says, "biology is dead; long live biology."

Cardiologists Love Genomics: Euan Ashley, Stanford

Euan Ashley is one of the big names in genomic medicine that has been missing from our guest list. We’re happy to correct that today.

In 2010, he led the team who did the first clinical interpretation of a human genome--that of his Stanford colleague, Steve Quake. Since then Euan, an MD PhD, has been driving to make the use of new genomic tools and discoveries a routine part of medicine at Stanford, particularly in his own discipline of cardiology.

A regular speaker on the conference circuit, Euan titles his talks, "Genomic Medicine Is Here."

"There were these one off examples of great stories that captured everyone’s imagination,” he says at the outset "but somewhere in there, what happened is it just became routine. And we started sending exome and genome sequences on patients and using that information to help find a cause, and in some cases, treatment for their condition. We were all waiting for it to happen, but it just happened under our noses.”

At the same time, Euan acknowledges that he “loses sleep at night” over “dark corners of the genome.” What are these dark corners? What recent findings were made by new long read sequencing? How has genomics impacted cardiology?

We begin with the question, if genomic medicine is here, why are there still so many skeptics?

Join us in our first interview with one of the few jazz saxophonists in our field, someone who knew he wanted to be a doctor at age four but wasn’t inspired by science--that is, until a high school teacher handed him a copy of Richard Dawkins' “The Selfish Gene” after class.

People Told Us It Was Impossible: UCSC’s Mark Akeson on Nanopore Sequencing

Mark Akeson has been working on nanopore sequencing at UC Santa Cruz’s biophysics lab for twenty years. Up until the past few years with the launch of Oxford Nanopore’s sequencers, that work was mostly the methodical toil of the quiet inventor.

Today it is quite ordinary to see a sequencer the size of your wallet being taken out into the field for DNA work. But for years, the naysayers dominated.

“Back in the day, the skeptics outnumbered the proponents 99 to 1,” Mark says in today’s show.

In his beginning-of-the-year blog, NIH Director, Francis Collins, called nanopore sequencing one of the four breakthroughs of 2016. And the NIH deserves some credit.   Mark says they were constant in their funding and belief in the technology.

With the success of nanopore sequencing technology has come legal battles to secure the IP.   Both Illumina and PacBio have sued Oxford Nanopore—the Illumina suit is now settled. And at the end of last month, Akeson’s lab (meaning the University of California) sued Genia, claiming that they owned the patents for Genia’s technology.  Genia was founded in 2009 and we have interviewed them several times since 2011.

“There's the old adage about once something succeeds, there’s all sorts of people who claim to have invented it,” says Mark.  

So what’s next for Mark? Is he on board the “long read train?” How much more can sequencing improve?


Genomics in 2016: Nathan and Laura Name Their Top Stories

From new CRISPR trials in humans to mitochondrial transfer therapy, from the spinout by Illumina of two new genomics health companies to the complete and utter failure of Theranos, from the approval by the FDA of GM mosquitos to the FDA giving up on LDT regulation as a result of the election, the genomics headlines of 2016 didn’t fail to dazzle, deliver, and disappoint.

Hear which stories our regular commentators, Laura Hercher and Nathan Pearson, chose as their top and also most underreported of the year in today’s look back on 2016.

How to Scale Cancer Genomics, with Marco Marra, UBC

Back in 2009 at the annual AGBT meeting for sequencing, Marco Marra presented one of the first cases of cancer treatment using whole genome sequencing.

We caught up with Marco at his office at the University of British Columbia where he heads the Department of Medical Genetics. Marco also directs the Genome Sciences Center which is part of a very special organization called the BC Cancer Agency.

In 2012 Marco and his team began a pilot project at the agency to scale up their work from just a one off case to more routine treatment. While doing whole genome and whole transcriptome testing is not yet “standard of care” for cancer patients, the scientists and researchers at the agency have the opportunity to sit down with oncologists on a weekly basis and explore its use with several patients at a time.

What are the major questions and challenges Marco has encountered in scaling? How is the regulatory environment for genomic testing in Canada? And which camp does Marco adhere to when it comes to whole genome sequencing: quantity or quality?

Join us as we talk to the number two cited scientist in all of Canada.

Why Diversity Is the Only Path Forward: Sarah Tishkoff on African Genomics

Are you lactose tolerant? If you’re of Northern European ancestry this is because of a stretch of DNA in a gene enhancer that developed some 9,000 years ago. That's the same time Northern Europeans began domesticating cattle for milk. If you’re of African ancestry, you may have one of three mutations which appeared independently of the European mutation--and of each other--about 6,000 years ago, again when dairying began.

The genetics around lactose tolerance are a great example of how diverse human populations evolved and how this diversity impacts our health. While many in our field are feeling chagrin at not being able to unlock more secrets in our biology that will lead to medical breakthroughs, some leading researchers are pointing to the need for more diversity in our genomic databases, with a particular emphasis on structural variation.

Sarah Tishkoff began studying African genetics back in graduate school on some cell lines that had been collected and started years before. It was at a conference in Cape Town, South Africa with other geneticists and archeologists and members of the local population where she was asked a question that began her career in Africa. Why are the populations up in Tanzania--those people who speak with clicks--so different from the people not far to the south? Sarah went to Tanzania to find out.

“I had no idea what I was doing at the time. I went to Tanzania and just did it. It was quite an experience going as a woman and leading a team of Africans who were just not used to working with a female leader.”

Since then, the dramatic improvement of sequencing technology has allowed Sarah and her team to do some groundbreaking genetic work, much of which has medical implications. For example, her research into the G6PD gene has shown that for certain African populations common malaria drugs can be toxic.

Because Africans are more genetically diverse and have the oldest genetic lineage, African genetics plays an important part in all human genetics research. It's important that our databases include this diversity. Sarah says the recent work to improve the human reference genome is “a great start” but there’s much more to be done. The three African genomes we pointed out in a recent program, she says, are actually from a common regional ancestor. They only reflect a fraction of the African diversity.

Sarah agrees with those in our field lately who have observed that there are still many mysteries in the genome which have not been unlocked because we’re missing important structural variants.

“I believe that some of these structural variants are going to be functionally super important. They’re going to impact normal variation and disease risk. If we had a more diverse set of reference genomes, then that would be great. People could then go ahead and use short read sequencing and map it back to all these diverse reference genomes. And that’s going to help people in terms of personalized medicine."

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?

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