history of science

Editor's Note: Theral's mic malfunctioned in this interview. Fortunately the not as good backup mic did work and John has a good mic.  Our apologies.

John Greally joins us today. He is the founding Director of the Albert Einstein College of Medicine’s Center for Epigenomics. He’s a pediatrician and a clinical geneticist with appointments in both at Einstein.

Last month, he was the lead author of a significant new publication in PLOS Genetics, titled Using Egpigenomics to Understand Cellular Responses to Environmental Influences in Diseases.

After summarizing the paper, John shares his journey in epigenomics over the past decade including a “crisis of faith” in the field. After taking a sabbatical from his own center and some cross-pollination with colleagues, John’s view of epigenomics evolved, particularly in the era of single-cell genomics.

Yes, says John, the environment impacts the genome, but the chain of causality is less direct than was previously thought. He and his co-authors on the new paper show that a larger cast of characters is involved.

Last month the American Society of Human Genetics (ASHG) took a quite remarkable step, putting out a formal statement of apology for its past history of involvement with eugenics. Some say it’s long overdue while some of us didn’t know about this history.

Along with the statement, the society issued a full report which is part of the Facing Our History - Building an Equitable Future Initiative. Here to discuss the statement and the initiative is the President of ASHG, Dr. Brendan Lee. Dr. Lee is also a Professor and Chairman of the Department of Human Genetics at Baylor College of Medicine.

Dr. Lee says the society, which is the largest of its kind in the world, has been working on diversity and equity as part of its recent strategic planning initiative. But he also acknowledges that the issue became more urgent after the events around the death of George Floyd which rocked America.

How well is this history known by ASHG members? Some members have commented that politics should be kept out of science—what are Dr. Lee’s thoughts about this response? The Initiative is not only about an honest reckoning with the past, but bold changes for the future. What will that look like?

It’s the age of multi omics. Or multi comics, if you don't catch spell check. A few weeks ago at the annual meeting of the American Society for Human Genetics, we were pleased to find not only genomics companies but some proteomics outfits finding a home. As we chatted with one of these, Olink Proteomics, we were blown away to hear that they were announcing the publication of 1,000 scientific papers. It wasn’t so long ago that genomics companies were boasting this kind of milestone. Has proteomics finally achieved scale?

Here to tell us is Dale Yuzuki, Director of Digital and Strategic Marketing Communications at Olink. He says in today’s interview that the proteome is now delivering on the original promise of the genome.

“There’s going to be a flurry of very significant findings with regard to the development of new drugs, new diagnostics, a new understanding of disease, new ways of prevention because of the genome project—ALL from new ways of analyzing the proteome at scale."

Dale is a return champion here on the program. He has worked for major life science tools and diagnostics companies, including Qiagen, Illumina, and Thermo. We ask him today why it took proteomics so long to scale? Olink is a Swedish company with a rich history in life science. They have just published a large scale study using the UK Biobank’s rich data resources.

Today spatial biology company, Vizgen, makes their debut on on the program.

When Vizgen CEO Terry Lo was first involved in developing what we now call spatial biology at Perkin Elmer, he admits that he never thought it would have a genomics side to it.

“What was really interesting for me is that for many years as we were building this spatial biology field, we always thought this would be a protein play. We didn’t think that spatial genomics would be feasible as a product. So when I started picking out some of these publications from Xiowei’s laboratory called Merfish—this ability to do this high-plex, single-cell genomics in tissue was really unheard of. That’s what got me excited. This was the first time something could be developed into a real product on the genomics side,” says Terry.

Terry would then follow this first product from Perkin Elmer to Akoya Biosciences where the term "spatial biology" would be coined. Now at Vizgen for two years, Terry says their product, MERSCOPE, is the industry's best spatial genomics platform, showing gene expression for up to 1,000 genes for a single tissue section.

As spatial biology takes us into the biological frontier, “spatial laboratories” are now popping up around the world, that is labs that are set up specifically for the purpose of mining the benefits of this new technology. Join us today as we delve into the early history of spatial and understand how a newcomer is making waves with their own genomics approach.

Where is Vizgen finding success? What does Terry find to be the sweet spot for multiplexing? And what is this Mouse Brain Map that everyone is talking about?

Dr. Eric Green has been the Director of the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH) since 2009. Two years ago, he and his colleagues at the Institute came up with a strategic plan for the next ten years. Today we discuss the plan with the director and get his outlook on the future of human genomics.

Dr. Green says human genomics can be roughly divided into four chapters.

"Each chapter has come out of similar strategic planning processes. The first chapter was the human genome project, a very valuable start for the field of genomics. In 2003, we asked what next and we published a plan which was about the first use of this information that was provided by this first genome. Now we had to understand what the 3 billion letters of the genome meant. It was a new era for genomics and it was wide open. That was chapter 2 from 2003 to 2011, and it put us on a solid trajectory to get to the $1,000 genome. We sequenced a lot of people and a lot of animals. Then published in 2011 was the strategic plan for chapter three which would bring us into the clinic where all of a sudden we could see how genomics could be used in a powerful way to understand human disease but also other applications in genomics that would become part of medicine. And right now we are writing the story of chapter four of human genomics."

Though he is hesitant to name the fourth and current chapter ("you never like to write your headline until you've lived it out"), we do tease this out of him: "Making genomics mainstream and equitable in medicine."

Now that we have high accuracy long reads, would Dr. Green like to see larger population studies done with better quality? Where is the NIH at with the All of Us project? And how does the director see his mandate when it comes to balancing between basic and translational research?

On that last question, Dr. Green says being a physician, he may have pushed the translational side heavily, but overall he tries to keep a very diverse portfolio.

"We do not have the best technology for sequencing DNA. They need to be better. We don't want a $1,000 genome, we want a $100 genome, and maybe eventually get a $10 genome. So we want to continue to develop new technologies. And then on top of it, I need to study things in the clinic to see how they work. And the hard part will always be that balancing act. There's never quite enough money. You're just trying to figure out where am I going to get the biggest bang for my buck. And keeping your eye on the landscape because it's not all about NIH. Lots of people are doing genomics research, and what can we do better than others and what should we cede to others to do."

We finish with some personal questions about Dr. Genome, his name among colleagues.

There was a tweet thread at the end of the recent Advances in Genome Biology and Technology (AGBT) conference where researchers took a moment of silence for all the sequencing companies that have announced big plans at the conference and then died. It was clearly aimed at this year’s sequencing tools entrant and buzz-generating Ultima Genomics. The company emerged from stealth the week before AGBT announcing the $100 genome with a purse of $600 million backed by funders including Khosla Ventures, Andreessen, and Founders Fund.

Leading this ambitious newcomer to the sequencing field is Gilad Almogy, a former engineer at Applied Materials. As with others we have met here on the program who have crossed over from tech to healthcare, he believes that sequencing must continue to scale at least in the way computer chips have to achieve more clinical breakthroughs.

What is not being done now that might be done with a $100 genome?

Gilad says, “it’s about getting sequencing back to Moore’s Law. Moore’s Law is not only about getting computer chips cheaper. It’s about people knowing that they will. It’s not only about discounting sequencing costs by 10. It’s about all those folks--scientists and researchers—making trade-offs, should I sequence this or that, this gene panel or that exome, or can I do exome plus? All those trade-offs that are constantly slowing folks down. We just want to say, hey, you don’t have to. Stop thinking within the constraints. Moore’s Law has two sides. Us delivering the lower costs, and folks believing us and others that the costs are coming down and developing applications that make full use of those lower costs.”

"It doesn't make sense that every hospital has an MRI and a CT and maybe a PET scan and doesn't have a sequencer."

We talk about where the company is now, when Ultima will offer their commercial release, and what challenges they face in meeting that date.

It can be quite easy for those of us who have watched this space for some time to slip into skepticism, sensing a mature market. It’s also still very easy to remember when Illumina was making their name in arrays and DNA synthesis or when Oxford Nanopore raised suspicion with talk of handheld nanopore sequencers.

For Gilad, and perhaps for us all, it's still early days in DNA sequencing.

"Scientists have been putting RNA into cells through a lipid delivery system for 44 years,” says Elie Dolgin. “And that’s ultimately the vaccine that has gone into millions of arms.”

Elie is the author of a recent piece in Nature magazine, The Tangled History of mRNA Vaccines.  He joins us to talk about his quest to uncover the winding journey that led to the cure that is moving the world forward.

“The path to mRNA vaccines drew on the work of hundreds of researchers,” he writes in the piece. One of those scientists, and the first to take notes and write down some early IP, was Robert Malone, a grad student at the Sulk Institute. Elie comes back to him again and again in the piece and shows a fascination for him in the interview.

The story moves on to modified RNA and the two star companies, Moderna and BioNTech. Elie moves beyond his article at the end of the show with some suppositions about the future of mRNA technology. Will a new mRNA flu vaccine come next?

It’s been a year since the coronavirus breached American shores. Here to look back with some perspective is New York Times science writer, Carl Zimmer. Carl has authored thirteen books on science, including Planet of Viruses which includes an essay titled, "Predicting the Next Plague."