Craig Venter on Genomics’ Past and Precision Medicine’s Future
By Allison Proffitt
March 9, 2023 | Kevin Davies and Craig Venter sat down together to celebrate thirty years of the Molecular and Precision Med Tri-Con this week in San Diego on Monday night. Davies—the founding editor of Bio-IT World, Nature Genetics, and most recently The CRISPR Journal as well as author of several books—gave a guided tour of human genomic research and sequencing since 1991 with Venter offering first person color commentary along the way.
Craig Venter has been a driving force for human genomics from the earliest days. Davies highlighted some of his career milestones including the 1991 Science paper on Expressed Sequence Tags (DOI: 10.1126/science.2047873), 1998’s launch of Celera, and the 2001 cover of Science announcing the first human genome in published simultaneously with the International Human Genome Consortium (DOI: 10.1126/science.1058040).
Of course, Venter shared plenty candid insights along the way, including his wholly altruistically suggestion that Francis Collins sequence the mouse genome because Celera had made such progress on human genomes. He also recalled the “complex diplomatically negotiated truce” to appear with Collins and President Bill Clinton at the White House in 2000. Venter called it a “moment of pragmatism” that angered both his Celera team and his wife. “The best thing for the public and the best thing for science was to have the truce, even though anybody who knows me know that’s not in my nature.”
He almost didn’t attend, though, after reading a draft of Tony Blair’s prepared remarks suggesting that companies shouldn’t be sequencing genomes. In response to Venter’s objections, “The White House science advisor said, ‘You’re asking me to change a foreign head of state’s speech. We can’t do that.’” Venter recalled. “I said, ‘Well, if you want me to show up, you will.’” Blair’s speech was changed.
After the initial fanfare, Venter was key in catalyzing the full breadth of sequencing discovery, Davies pointed out, with a $500,000 Genomic Technology Prize in 2003. “It mostly just served as a wake-up call for people that sequencing was just beginning. It wasn’t over. It took a year or so to really turn around people’s thinking, but then some pretty cool technologies came up,” Venter said.
Algorithms as Truth Serum
While he’s happy to receive credit for Celera’s first published human genome assembly, Venter reserves any plaudits for a “finished” genome. The genome has been finished, “so many times I’ve lost track,” he quipped. The task won’t be finished, he challenged, until each of us has our own, diploid genome.
Venter’s own diploid genome was published—anonymously—in 2007 in PLOS Biology (https://doi.org/10.1371/journal.pbio.0050254). “It’s the most complete diploid genome sequence that’s published,” he said, but, “It still has lots of gaps and doesn’t have telomeres. It was using long-read ABI [Applied Biosystems] sequencing at the time so it could actually be assembled as a diploid genome.”
From there, Venter shifted to exploring the idea of a “minimal genome”, publishing a bacterial genome of 473 genes in 2016 (Science, DOI: 10.1126/science.aad6253) and then shifted his focus to metagenomics and his ocean sampling efforts.
Early in his work at The Institute for Genomics Research (TIGR), Venter said, he received a clinical sample from Norway. When sequenced, the sample assembled into two separate genomes. “It doesn’t matter what you think you have in the genome… the nice thing about the algorithms: it will sequence whatever’s there because every species, every organism has a unique mathematical solution,” Venter said.
Now, with assembly algorithms acting as “truth serum,” Venter could tease apart complex mixtures of genomes. Where to apply that capability? An around-the-world sailing trip, of course, gathering 200 liters of seawater every 200 miles or so and shotgun sequencing it all. Venter recounts that adventure and its discoveries—both scientific and diplomatic—in his latest book: The Voyage of Sorcerer II: The Expedition That Unlocked the Secrets of the Ocean’s Microbiome, due out in September 2023.
Yet for all of his pioneering efforts in genome sequencing, Venter advocates a deep dive into the phenotype for real precision medicine advances today. He was asked recently what he would choose if given the choice between a whole-body MRI and whole genome sequencing. Practically, he said, he’d pick the MRI, though he conceded that the future will be combination of the two.
That’s the mission of Human Longevity, a company he launched in 2013 to build the world's most comprehensive database on human genotypes and phenotypes, and then subject it to machine learning so that it can help develop new ways to fight diseases associated with aging. Venter sits on the scientific advisory board of Human Longevity now, and he was an active proponent of the genome + phenome approach during the Q&A session that followed his conversation with Davies.
Human Longevity customers believe they are healthy, Venter emphasized; it’s not a healthcare service for the already-ill. Yet of those worried (wealthy?) well, Venter reports that 50% have a “major discovery” made by the platform. Venter, himself, has a complete workup every six months, he reported, and credited Human Longevity with catching his advanced prostate cancer six year ago. “The interpretation of everything except the genome keeps getting better,” he said.
The Next Frontier
In fact, sequencing, interpretation, and the entire genomics pipeline keep getting better, reported his panel-mates. Molly He, CEO and cofounder of Element Biosciences introduced her company’s new sequencing platform, the AVITI System, which is delivering $200 genomes. Alex Aravanis, CTO at Illumina, announced this week’s deliveries of NovaSeq X, the company’s newest sequencing platform touted as “the most accurate genome, short and long reads, multiomic analysis, in a single flow cell, on a single run, on one instrument.” And Euan Ashley, a professor of genomics and precision health and medicine at Stanford, currently holds the Guinness World Record for the fastest genome sequencing from blood draw to diagnosis at a mere five hours and two minutes on an Oxford Nanopore platform.
While all of the panelists were undeniably positive about the future of precision medicine and genomics, the route there was not a consensus. Ashley, a cardiologist, said that genomics by middle age is pretty boring. Anything shocking will have already revealed itself, and other genomic impacts—polygenic risk scores impacting complex diseases, for example—we don’t successfully incorporate into healthcare yet.
Aravanis jumped in to defend the utility of the genome. “Between carrier screening, pharmacogenomics, PRS [polygenic risk scores] scores, and hereditary cancer, about half of people find something clinically relevant either to family planning or their own health or their own risk,” he said.
Ashley is much more positive about the genome’s clinical value in newborns and babies. Every step of the sequencing and interpretation process has been improving in the past few years, he said, and now genomes are enabling diagnoses for children every day. Though the “last mile” is still fairly manual, Ashely said, sequencing is now cheap, accurate, and fast enough to routinely change lives in pediatrics.
But at the other end of the spectrum, Ashley still recommends improving your diet, exercise, and sleep to impact aging. “That’s the answer regardless of how many MRIs or genomes you have!”
Venter disagreed: “You can exercise all you want, sleep all you want, eat 10 pounds of kale a day. You can think that you’re healthy. But only a clinic like HLI and ones like it can tell you whether you’re healthy or not,” he said. “The genome can lead to false information—false ideas—that without phenotype information for verification is dangerous.”
More data are key, Venter believes, not terribly surprising from a man who set out to sequence the ocean.