The 'Wondrous Map': Charting of the Human Genome, 20 Years Later

Alicia Ault

December 11, 2020

Twenty years ago, President Bill Clinton announced completion of what was arguably one of the greatest advances of the modern era: the first draft sequence of the human genome.

"Without a doubt, this is the most important, the most wondrous map ever produced by humankind," Clinton said on June 26, 2000 from the White House, predicting that genome science "will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases." In the future, he said, "doctors will increasingly be able to cure diseases like Alzheimer's, Parkinson's, diabetes, and cancer by attacking their genetic roots."

And indeed, the sequencing of the human genome — achieved simultaneously by the Human Genome Project (HGP), an international consortium begun in 1990 and led by Francis Collins, MD, then director of the National Human Genome Research Institute, and by J. Craig Venter, PhD, with his team at the privately held Celera Genomics — has revolutionized the approach to human health.

President Bill Clinton is flanked by Dr J. Craig Venter (left) and Dr Francis Collins announcing the first draft sequence of the human genome in June 2000.

Although the unbridled optimism of 20 years ago has not been matched with success in every quarter, much of the promise has begun to be realized. Scientists have so far identified 5000 rare diseases and 40 to 50 genes that confer cancer risk, developed simple prenatal blood tests to detect chromosomal abnormalities, and generated genetic profiles of tumors to facilitate better-targeted therapies, among other accomplishments. Even the current global fight against COVID-19 is relying on genomics.

"There hasn't been a pharmaceutical developed in last 20 years that hasn't utilized genome information," Venter told Medscape Medical News.

"Not a day goes by in science that we don't see some offshoot of benefit from what happened 20 years ago," said Eric Topol, MD, the chair of innovative medicine at Scripps Research in La Jolla, California, and Editor-in-Chief of Medscape.

Finding the genes was just the beginning though; describing function and using that information therapeutically is still just getting underway in many clinical areas. "We now know that genes are only a small fraction of the complexity of the human genome," says Eric Green, MD, PhD, the current director of the National Human Genome Research Institute (NHGRI).

Big Bang for the Buck

When it started, the sequencing of the human genome did not seem like a value proposition — nor was it expected to be. Congress authorized $3 billion for the HGP in 1990 and set a target completion date of 2005.

The final sequence, a database of some 3 billion DNA base pairs, came in under budget — the NHGRI estimates the cost at $2.7 billion — in 2003, two years ahead of schedule and exactly 50 years after James Watson and Francis Crick first described DNA.

It had been only 15 months since the international consortium of 1000 researchers across six nations began their sequencing effort in earnest, and a scant 9 months from when Venter's team starting sequencing its human genome. Celera Genomics spent just $100 million, Venter estimates.

What seemed like a massive investment at the time now looks like chicken scratch. "It was a bargain," Topol said.

The race to create the map of the human genome would generate goodwill, create strife, elevate egos, and make careers. Much has been written about the clash between Collins and Venter — two polar opposites with different motivations and different approaches.

Collins, a dedicated public servant and man of deep Christian faith, believed in the power of the academic and governmental research enterprise.

Venter, on the other hand, ruffled feathers with his big ideas and generally more capitalistic approach. He began his career at the National Institutes of Health (NIH) in 1984 and created a gene discovery tool called expressed sequence tags (ESTs). That caught the eye of venture capitalists, who lured him out of the agency. They backed Venter's nonprofit, The Institute for Genomic Research (TIGR), to develop the technology.

At TIGR, Venter decoded the genome of Haemophilus influenzae using his whole genome "shotgun" technique. When he applied to the NIH for a grant to support the shotgun method, however, he was rejected. The maker of a DNA sequencing machine, PE Biosystems, then installed Venter as the CEO of the new, private Celera Genomics in 1998.

The NIH-led consortium did not see the value of the shotgun approach and instead relied on a more traditional sequencing method, which was more laborious and time-consuming, Topol recalls. After that NIH rejection, the competition was on, and the rivalry became bitter.

"There was no love lost between these two gentleman," Topol acknowledged. On that day in June 2000 when the announcement was made, "it required Clinton and whoever else to kind of get them to stand together and make nice," added Topol, who was present at the celebration.

A release from the NIH on the commemoration of the 20th anniversary in June of this year describes the situation this way: "The joint presence of these two scientific leaders signified the agreed-upon shared success of the public HGP and private Celera Genomics efforts in generating the first draft sequence of the human genome."

Still, the competition, in retrospect, was a good thing because it accelerated progress, Topol said.

"Prehistoric" Technologies

The draft sequence unveiled in 2000 covered 90% of the genome at an error rate of one in 1000 base pairs, but there were more than 150,000 gaps, and only 28% of the genome had reached true completion. When the final version was made public in 2003, there were less than 400 gaps and 99% of the genome was finished with an accuracy rate of less than one error in every 10,000 base pairs.

Looking back, the technologies used then "now seem almost prehistoric," says NHGRI director Green. "Nothing in the way we sequence DNA is the same now. We can do it in a day or two and it costs less than a thousand dollars." He expects the cost of sequencing a human genome will eventually drop below $100.

The final, almost-complete sequence published in 2003 was "foundational," providing "the alphabet around which everything else has been constructed," said Mark McCarthy, MD, senior director and staff scientist in human genetics at the California-based biotechnology company, Genentech. "It's hard to think of a more concrete example in science other than maybe the periodic table," McCarthy told Medscape Medical News.

Doing genetic research before the full sequence was published, he says, was like being an "explorer in some novel land." Without a clear map of the terrain, researchers used analogue methods to try to determine locations of genes or recombination events, he said. It was frustrating and "a huge impediment to progress." 

Now, scientists can "just click on a mouse and get almost immediately the worlds of data around any genomic regions," he said.

"Most scientists today never had to sequence a gene," Venter points out. "They don't have to, because they just look it up on the internet."

"Graduate students today can't imagine how we ever did any experiments or learned anything without having access to the human genome sequence with a click of a mouse," said Collins, in a video testimonial celebrating the 30th anniversary of the start of the project.  

To Collins, one of the genome project's main goals was to give clinicians better tools to heal their patients. "Together we must develop the advances in medicine, that is the real reason for doing this work," he said in 2000.

If you would have told me that in my professional career I would have seen genomics actually change the practice of medicine in any way, shape, or form, I would have said, 'There's just no way, we're two generations away from that.' Dr Eric Green, director of the National Human Genome Research Institute

But it wasn't until a decade later that genomics was talked about in medicine, said Green. "Now, we have clear examples for genomics being used every day," he said.

"If you would have told me that in my professional career I would have seen genomics actually change the practice of medicine in any way, shape or form, I would have said, 'There's just no way, we're two generations away from that,' " Green said.

Precision Oncology

Perhaps the biggest impact of these advances in genomics to date has been in the practice of oncology.

"Cancer care has been one of the biggest beneficiaries of the genomic revolution," said Frederick M. Schnell, MD, chief medical officer of the Community Oncology Alliance (COA). Schnell points to the work of Brian Druker, MD, who helped discover the mutation that causes chronic myelogenous leukemia and also was instrumental in developing a precision treatment for CML, imatinib (Gleevec).

"That was probably the singular most important development for a particular, albeit not common, but not uncommon disease that had a disgraceful, horrible projected survival and mortality associated with it, and has changed it to a curable disease," Schnell told Medscape.

The HGP led to the Cancer Genome Atlas, a book of some 20,000 cancer genomes and matched normal samples spanning 33 cancer types.

"In order to understand what was going wrong in a cancer, you first had to understand what the genome was supposed to look like in somebody — the cell that was not cancerous," said Richard Schilsky, MD, chief medical officer and executive vice president of the American Society of Clinical Oncology (ASCO).

The comparisons "help us identify mutations that are real drivers of cancer and have opened up the whole field of precision oncology," Schilsky, formerly chief of hematology/oncology and deputy director of the University of Chicago Comprehensive Cancer Center, told Medscape Medical News.

In addition to helping identify cancer susceptibility genes, the genome project also led to variations associated with how drugs are metabolized, Schilsky said.

For instance, it is now known that 10% of the population has a variant of the UGT1A1 gene that leads to poor metabolism of the chemotherapy drug irinotecan (Camptosar), causing worse side effects. The drug's label now notes the availability of a simple lab test to look for the variant.

Schilsky is lead investigator of an ASCO-sponsored trial called TAPUR that aims to match patients with certain tumor variants to therapies that might work, but are not FDA-approved for that particular cancer. Some 2000 individuals have enrolled and received free medications (provided by one of the eight drug companies participating) since the trial began in 2016, said Schilsky.   

One goal is to collect evidence on off-label uses — which might help therapies gain acceptance in clinical practice guidelines and, potentially, reimbursement. TAPUR also aims to help oncologists learn more about genomics.

Precision oncology is still not available to all cancer patients, however. Schnell said the COA is lobbying for better access and insurance coverage.  

He believes that genomics could be used as a replacement for screening tests such as mammograms and colonoscopies. "This is going to be a big application point for the genomic revolution as it continues," he said.

Topol agrees that genomics could create a tailored approach to prevention. "Why does every woman need a mammogram when only 12% will ever develop breast cancer?" he says.

Key Weapon Against COVID-19

The progress made to date in understanding the human genome is also proving to be a key weapon as scientists fight the important current threat of the COVID-19 pandemic.

China made the first genetic sequence of the SARS-CoV-2 virus available on January 12, 2020, just weeks after the nation reported the initial cluster of cases.

Researchers have since uploaded 245,000 genomic sequences of the SARS-CoV-2 virus to the World Health Organization's Global Initiative on Sharing All Influenza Data (GISAID) portal. The speedy sequencing and widespread sharing of data led to quick development of molecular diagnostics and identification of potential targets for vaccines and therapeutics.

The NHGRI, among others, is supporting genomic studies around the world that aim to understand the differences between those who become severely ill and those "who barely seem to notice they have the disease," NHGRI director Green told Medscape Medical News. "There is no question there is going to be some genomic basis for the severity of the disease,"

He also expects genomics to be used in vaccine trials to separate responders from nonresponders.

Chronic Disease Puzzle

While rare monogenic diseases were a relative cinch, common illnesses like hypertension, diabetes, and Alzheimer's disease have turned out to be more complicated.

It wasn't until the mid-2000s, when genome-wide association studies (which look for small variations that occur more frequently in people with disease) came into greater use, that scientists began to get a clearer picture, said Genentech's McCarthy.

It turns out that "hundreds, if not thousands of genetic variations and genetic regions" seem to predispose someone to a common disease, he said. He's applying genome-wide approaches in type 2 diabetes, but it requires datasets of a million or more people to get a robust result, McCarthy said.

Even then, "it just gives you a bunch of sign posts around the genome and then you have to work out what they do and how they influence predisposition in a given individual," he said. Researchers have begun to understand "the range of pathways and networks that are involved in the genetic predisposition to type 2 diabetes," which in turn is giving information on potential therapeutic targets. 

The obstacle is not having enough genome-wide genetic data, which may change as more countries find ways to collect more genetic data, McCarthy said.

"We're not getting complete comprehensive views of all the genes involved and all the genomic variants that confer risk," for chronic diseases, agreed Green. "That's the big challenge for the next decade."

Another challenge that NHGRI has outlined in its strategic plan, released in October, is broadening human genome reference databases to include a wider representation of humanity. "Much like all other scientific disciplines, genomics is reckoning with systematic injustice and biases of the past," the agency said in a press release. The plan also addresses data control, privacy, genome editing, and barriers to a thriving genomics enterprise.

Venter believes that getting to the root of chronic diseases means combining the phenotype with the genotype. In 2013, he started Human Longevity, a company that offers sequencing, imaging, and a host of diagnostics to those who can afford the service, to give a complete picture.

"Without extensive phenotype information, the genome isn't highly useful on its own," said Venter, who feels the combination could be a true preventive medicine platform.

Limited Keys to the Treasure Chest

As much as the sequencing of the genome has brought to medicine, "I think the greatest promise of the genome remains to be realized," said Venter.

The initial focus was on genes. Humans, it turns out, have only 20,000 genes, not that many more than worms or fruit flies. But there's more to life outside of those genes, said Green.  

The human genome "is a treasure chest, but we have only gotten a limited number of the keys so far," said Topol. "It is not nearly as informative as it could be."  

And genomics still has the potential to do harm — an issue that gets periodic scrutiny by commissions and the public. On that day in 2000 at the White House, Venter noted that a just-released poll had reported that 46% of Americans believed that "the impact of the Human Genome Project will be negative."

Privacy of genetic information is a perennial concern, and technologies — such as gene editing, which allows scientists to alter DNA — have brought up new ethical challenges.  

On the other hand, the public has been mesmerized by genetic genealogy technologies that allow them to determine their own ancestry or disease risk, and that have more recently helped law enforcement solve crimes, some of them longstanding cold cases.

Twenty years ago, Venter predicted that the wonders would continue unabated. "The complexities and wonder of how the inanimate chemicals that are our genetic code give rise to the imponderables of the human spirit should keep poets and philosophers inspired for the millenniums," he said in 2000.

His view is more tempered today. "I'm optimistic about the future," says Venter now. "I'm pessimistic about how soon it will get here."

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