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Scientists Completed the First Human Genome 20 Years Ago. How Far Have We Come, and What’s Next?

If the Human Genome Project (HGP) was an actual human, he or she would be a revolutionary whiz kid. A prodigy in the vein of Mozart. One who changed the biomedical universe forever as a teenager, but ultimately has much more to offer in the way of transforming mankind.

It’s been 20 years since scientists published the first draft of the human genome. Since its launch in the 90s, the HGP fundamentally altered how we understand our genetic blueprint, our evolution, and the diagnosis and treatment of diseases. It spawned famous offspring, including gene therapy, mRNA vaccines, and CRISPR. It’s the parent to HGP-Write, a global consortium that seeks to rewrite life.

Yet as genome sequencing costs and time continue to dive, the question remains: what have we actually learned from the HGP? After two decades, is it becoming obsolete, with a new generation of genomic data in the making? And with controversial uses such as designer babies, human-animal chimeras, organs-in-a-tube, and shaky genetic privacy, how is the legacy of the HGP guiding the future of humanity?

In a special issue of Science, scientists across the globe took a deep dive into the lessons learned from the world’s first biomedical moonshot. “Although some hoped having the human genome in hand would let us sprint to medical miracles, the field is more an ongoing relay race of contributions from genomic studies,” wrote Science senior editor Laura Zahn.

Decoding, reworking, and potentially one day augmenting the human genome is an ultramarathon, buoyed by potential medical miracles and fraught with possible abuses.

“As genomic data and its uses continue to balloon, it will be critical to curb potential abuse and ensure that the legacy of the HGP contributes to the betterment of all human lives,” wrote Drs. Jennifer Rood and Aviv Regev at Genentech in a perspectives article for the issue.

An Apollo Program to Decode Life

Big data projects are a dime a dozen these days. A global effort to solve the brain? Yup. Scouring centenarians’ genes to find those that lead to longevity? Sure! Spitting in a tube to find out your ancestry and potential disease risks—the kits are on sale for the holidays! Genetically engineering anything—from yeast that brew insulin to an organism entirely new to Earth—been there, done that!

These massive international collaborations and sci-fi stretch goals that we now take for granted owe their success to the HGP. It’s had a “profound effect on biomedical research,” said Rood and Regev.

Flashback to the 1990s. Pulp Fiction played in theaters, Michael Jordan owned the NBA, and an international team decided to crack the base code of human life.

The study arose from years of frustration that genetic mapping tools needed better resolution. Scientists could roughly track down a gene related to certain types of genetic disorders, like Huntington’s disease, which is due to a single gene mutation. But it soon became clear that most of our toughest medical foes, such as cancer, often have multiple genetic hiccups. With the tools that were available at the time, solving these disorders was similar to debugging thousands of lines of code through a fogged-up lens.

Ultimately, the pioneers realized we needed an “infinitely dense” map of the genome to really begin decoding, said the authors. Meaning, we needed a whole picture of the human genome, at high resolution, and the tools to get it. Before the HGP, we were peeking at our genome through consumer binoculars. After it, we got the James Webb space telescope to look into our inner genetic universe.

The result was a human “reference genome,” a mold that nearly all biomedical studies map onto, from synthetic biology to chasing disease-causing mutants to the creation of CRISPR. Massive global consortiums, including the 1000 Genomes Project, the Cancer Genome Atlas, the BRAIN Initiative, and the Human Cell Atlas have all followed in HGP’s steps. As a first big data approach to medicine, before the internet was ubiquitous, HGP laid out a new vision for collaborative science by openly sharing data from labs across the globe—something Covid-19 vaccines have benefited from.

Yet as with AOL, CDs, and Microsoft FrontPage, HGP may be a legacy product from a bygone era.

The Next Generation

The first relatively finished reference genome was published in 2003. Yet two core questions at the heart of the HGP remain. One, what exactly should be considered a “complete reference”? Two, how can it be decoded to benefit humans?

“Reference” is an ambiguous idea in the age of increasingly cheaper genome sequencing. The original reference was what science considered an “average” human. It wasn’t, but the reference genome did focus on mapping the most common variants in a gene. Yet it’s increasingly obvious that humans are wildly diverse in our genetic differences, which could—for example—have a say in our longevity.

“Capturing the ever-growing genetic diversity of humans requires profiling a more diverse set of genomes,” said the authors. “Ultimately, although highly useful, a single reference genome is inherently biased.” Your genealogy results from consumer kits, for example, could be on point or off base, depending on your race and the genetic background of their reference samples. For now, it’s mostly people with European ancestry.

“The HGP and its legacy must serve humanity as a whole, not neglecting those who are currently underrepresented in biological research,” the team said.

Then there’s making sense of it. The HGP itself decoded the genome but didn’t provide an understanding of it—such as what genetic elements actually do, how they work together, and how they contribute to health and disease.

We’re getting there, but slowly. We’ve found genes that protect against Alzheimer’s, and genes that contribute to cancer and muscle disorders. Using a popular method called GWAS (genome-wide association study), scientists are increasingly capable of fishing out gene variants—often hundreds at a time—that play a role in more complex disorders such as autism. But teasing out how bucketloads of genes affect any disease remains difficult. With the rise of machine learning and AI, however, the authors said, we have a powerful tool to begin “unpacking its secrets to affect health.”

What’s next? Thanks to ongoing massive whole genome sequencing projects, we could be shedding the veil of HGP’s “average” human and entering a new era of multiple reference genomes—or even personalized ones. With this would come massive concerns around privacy. The Golden State Killer case, though it had a “happy” ending in that it was ultimately solved, relied on a free and public genealogy database that people may not have knowingly agreed to partake in. Unexpected findings related to long-lost relatives, a high risk of serious diseases, or our own heritage, especially if shared with third parties, could damage relationships or even overthrow our sense of self.

From the idea of a reference genome to a smorgasbord of genetic tools, HGP’s legacy is here to stay. As we move towards a more “snowflake” era of genomics—one that stresses individuality either for mixed-and-matched groups or individuals—the original goal remains the same.

The project left us with a major mission, still relevant even 20 years later, the authors said. We need to better understand how to wield our genetic blueprints, both common and rare, to “promote human health and treat disease”—for all of humanity.


Image Credit: Thor Deichmann from Pixabay

Author:

Shelly Xuelai Fan is a neuroscientist-turned-science writer. She completed her PhD in neuroscience at the University of British Columbia, where she developed novel treatments for neurodegeneration. While studying biological brains, she became fascinated with AI and all things biotech. Following graduation, she moved to UCSF to study blood-based factors that rejuvenate aged brains. She is the… Learn More

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