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The Decade in Genomics: CRISPR, Single Cells, Long Reads, Clinical and Consumer Applications

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NEW YORK – Genomics has made a big leap forward over the past decade, both in terms of new technologies and clinical applications. While the first decade of the century was marked by the completion of the Human Genome Project and the advent of next-generation sequencing, the second decade saw new developments, including CRISPR genome editing and single-cell genomics, as well as the launch of population-based genome projects, the introduction of genomics into clinical care — particularly for inherited disease diagnostics and oncology — and the boom of consumer genetic testing, which also enabled novel applications in forensics.

To get a better idea of the most significant developments, in February GenomeWeb asked a number of prominent researchers in the field via email about their top picks for notable developments or achievements in genomics during the 2010s. Maybe unsurprisingly, their answers were colored by their own areas of study, reflecting the deep reach of genomics into many branches of research. However, several themes emerged from their responses.

CRISPR

One of the most frequent answers, even from those not directly involved in developing or advancing the technique, was CRISPR genome editing. Many thought of this as an "obvious" choice that needs no further explanation, given how pervasive the method has become in life science research. Designated as "breakthrough of the year" by Science in 2015, CRISPR "opened up new fields of precise gene editing, ultra-rapid diagnostics, and targeted therapeutics," said Charles Chiu, professor in the Division of Infectious Diseases at the University of California, San Francisco.

Moreover, CRISPR enabled "new genome-wide functional genome screens and the construction of genetic cellular and animal models of disease at scales previously entirely out of reach," said David Goldstein, director of the Institute for Genomic Medicine at Columbia University.

"Nowadays, it is hard to imagine a grant application or major research paper and molecular biology not applying this technique, or methodologies derived from this technique, at some stage," said Jan Korbel, group leader and senior scientist at the European Molecular Biology Laboratory (EMBL) in Heidelberg.

Mike Zody, senior director of computational biology at the New York Genome Center, agreed. "Aside from the fact that being able to relatively easily engineer DNA changes has opened up a wide range of functional assays that were theoretically possible but exceedingly tedious before, just the number of times I’ve been in a meeting and heard some variant of 'Did you CRISPR it?' makes me think this has to be the most significant development of the last decade," he said.

But while the significance of CRISPR and its myriad applications remain undisputed, "we have yet to understand its true impact," said Rick Wilson, executive director of the Institute for Genomic Medicine at Nationwide Children's Hospital, and "the politics of the IP fight are depressing," said Paul Flicek, associate director of services at EMBL's European Bioinformatics Institute.

Single-Cell Genomics

Another top choice for notable developments was single-cell genomics. "Single-cell genomics has changed everything!" said Eric Lander, president of the Broad Institute, without elaborating.

"Of course one could say CRISPR was a bigger deal (in many ways true), but in the end, I think the shift to single cell will be more profound," said David Haussler, scientific director of the University of California, Santa Cruz Genomics Institute. "The single cell is the most meaningful unit in biology. It is at the center of everything."

"Single-cell genomics has empowered us to measure molecular profiles in individual cells, at massive scale (looking at each of hundreds of thousands of single cells in one “go”)," said Aviv Regev, professor of biology at the Massachusetts Institute of Technology and faculty chair at the Broad Institute. "This has opened the way to re-examine the fundamentals of biology — including cell types, states, development, responses, locations, and interactions — in homeostasis and disease, and across species, providing a new conceptual appreciation of both phenotypes and mechanisms," she said.

"In particular, it opened the way to build a Human Cell Atlas, comprehensive reference maps of all human cells — the fundamental units of life — as a basis for both understanding human health and diagnosing, monitoring, and treating disease."

Others also mentioned the HCA as an important initiative. "My prediction is that the HCA project will have as fundamental an impact on future biology and medicine as the Human Genome Project has had today," said Mats Nilsson, scientific director of the Science for Life Laboratory and a professor at Stockholm University in Sweden.

"It's still early days, but I believe that these technologies have the potential to fundamentally advance our understanding of human and model organism biology," said Jay Shendure, professor of genome sciences at the University of Washington, about single-cell genomics, his top pick.

Those views were echoed by Dennis Lo, professor of chemical pathology at the Chinese University of Hong Kong. "I think that the ability to study genomics, transcriptomics, and epigenomics on a single-cell level has revolutionized our understanding of biology, giving us a resolution that was not previously possible," he said. "We can now start to understand the heterogeneity of cells and how such cells interact with one another. Such developments have created new avenues for research, particularly in neuroscience and in oncology. With the reduction in costs of such technologies, it is likely that [they will] make an increasing impact diagnostically."

In addition, single-cell genomic techniques can provide insights into the 3D architecture of the genome, which "critically determines cell functions," said Sunney Xie, director of the Beijing Advanced Innovation Center for Genomics at Peking University.

Long-read sequencing

A third frequently mentioned development of the past decade was the rise of long-read single-molecule sequencing from Pacific Biosciences and Oxford Nanopore Technologies.

"After a very boring decade of resequencing people and mice with short reads, we are now finally on the precipice of the real potential of genomics," said Gene Myers, a director at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany. "I've become completely psyched about our ability to produce nearly perfect, certainly reference-quality, genomes de novo with long-read sequencing and scaffolding technologies such as Hi-C, 10X read clouds, and Bionano [Genomics] restriction maps. The price point for all of this will soon be very affordable and the world will enter an era of exploring all the genomes of the natural world."

And while "factory-scale sequencing is still short reads," said Matt Loose, professor of genomics and cell and developmental biology at the University of Nottingham in the UK, "I believe the last decade will be remembered as the transition from short- to long-read sequencing."

"That this technology can be pocket-sized enables much of the innovative field-based sequencing we have seen in the last decade, with notable studies including that on the Ebola outbreak and countless examples of deployed sequencers since," he added.

According to Richard Durbin, an investigator at the Wellcome Sanger Institute and professor of genetics at the University of Cambridge, long-read techniques "are just at the edge of coming into their own now" and are enabling the complete assembly of chromosomes from end to end, as well as full-length transcript sequencing.

"PacBio enabled high-quality de novo assemblies including complete microbial genomes, and nanopore [sequencing] is democratizing sequencing away from large centralized centers and into the hands of individual scientists," said Adam Phillippy, head of the genome informatics section at the National Human Genome Research Institute.

"These technologies make it possible to quickly and affordably develop reference-quality genomes in virtual any species," said Michael Schatz, a professor of computational biology and oncology at Johns Hopkins University. "Now for a few thousand dollars, we can sequence and assemble a human genome to a level of contiguity and accuracy that surpasses the reference human genome. Within human genomics, this has been especially important for finding structural variants and other complex variants that cannot be found using short-read sequencing, including finding the genetic origins of many diseases that were previously missed."

EBI's Flicek agreed that the ability to create cost-effective, highly complete, high-quality genome assemblies from all species, and the launch of serious efforts to do so, will have a big effect. "This will lead to genomics impacting a far greater swath of biology than it currently does," he said.

Another breakthrough over the last decade has been the development of functional genomics assays, according to Stephen Montgomery, professor of pathology and genetics at Stanford University. "[T]he past decade has ushered in numerous impactful studies that are using functional genomics to explore the impact of genetics and the environment (GxE)," he said. "This is providing novel insights into how genetics shapes our response to the environment and together impacts human disease."

Research applications

While many scientists picked specific technological advances, others pointed more generally to the type of research next-gen sequencing has enabled over the past decade. "Although we could trace [next-gen sequencing/whole-genome sequencing] back to 2005, it became scalable to many humans in 2010, then in 2015 broke $1,000 for a clinical-grade genome," said George Church, professor of genetics at Harvard Medical School.

Sequencing has been "even more significant than [gene] editing" during the past decade, he argued, since it is needed to determine what to edit, and to check edits. In addition, "variations on NGS are also revolutionizing microscopy, including in situ RNA, super-resolution imaging of genome folding and even proteins," he said.

"The ability to easily and cheaply sequence DNA or RNA anywhere has revolutionized how we can see the molecular dynamics in clinical contexts … but it has also done much more," said Chris Mason, professor of physiology and biophysics at Weill Cornell Medicine. For example, he said, it has enabled the creation of "genetic maps of cancers, subways, space stations, and synthetic genomes, but also led to unexpected mergers of previously disparate fields, like microbiology and cancer."

Hand in hand with high-throughput sequencing goes the ability to interpret and integrate large amounts of genomic data. According to Richard Gibbs, director of the Human Genome Sequencing Center at Baylor College of Medicine, the last decade has seen "spectacular advances in data integration and processing. Through cloud computing and advances in data sharing, genome analyses are possible at scale."

Another important advance in genomics over the past decade has been the development of standards to ensure reproducibility of results. "It may seem prosaic, but the most important contribution our field has made is to show that biology can be 'industrialized,' said Carlos Bustamante, a population geneticist and professor at Stanford University.

Developing personalized treatments can only happen if human genomes can be analyzed at scale, he said, which is what the past decade has been about. "Now in the roaring '20s, we're on to the next phase of engineering biology and boy will we be happy that we took the time to develop reproducibility as a key concept so we can chase the best leads for the fastest translation of basic science into medicines and other vehicles for improving human health and wellbeing," he added.

Among the most important genomics projects started or completed during the last decade, researchers cited the 1000 Genomes Project, the UK Biobank resource, the Cancer Genome Atlas, and various population genomics projects, including the National Institutes of Health's All of Us research study.

According to EMBL's Korbel, the impact of the 1000 Genomes Project on genomic medicine is immense. "Key sequence and variant formats; alignment algorithms; and single nucleotide polymorphism, indel, and structural variation algorithms used across all fields of genomics nowadays were developed in this context, and studies from cancer genomic projects to rare disease research have since used 1000 Genomes data as a reference benchmark," he said.

Columbia's Goldstein said that population-scale sequencing will allow for "the development of datasets that show us what does and does not normally happen in the human genome in the general population, leading to unimagined accuracy in the genetic diagnosis of more simple genetic diseases using whole-exome sequencing and allowing for comprehensive evaluation of phenotypic consequences of genetic variation using growing population-scale resources like UK Biobank and eventually the [All of Us] research program."

For David Reich, a geneticist and professor at Harvard University, the landmark development in genomics over the past decade is the ability to generate whole-genome data from ancient human samples. "In this period, the number of ancient individuals with whole-genome data has gone from 0 to more than 10,000, and analysis of the data has revolutionized our understanding of the deep past and upended many previously established ideas about the way our species evolved," he said.

According to the Sanger Institute's Durbin, sequencing Neanderthal, Denisovan, and other ancient genomes "has changed (and is continuing to change) our understanding of what it is to be human."

But for Stephan Schuster, professor of biological sciences at Nanyang Technological University Singapore, another breakthrough has been the increased understanding of human history not from ancient DNA but from the analysis of large numbers of modern genomes from population genomics projects. "This allows to unravel human history and ancient migration with unprecedented precision," he said. "Human history will eventually be rewritten because of this."

Clinical applications

For clinical researchers, the most important breakthrough of the past decade was the application of genomics in medicine, particularly in diagnostics.

"For me, the most significant development has been the advent of clinical sequencing, whether exome or genome," said Bruce Korf, professor of medical genetics at the University of Alabama at Birmingham School of Medicine. "We are solving diagnoses that had been elusive for years, if not decades. Also, a high proportion of these diagnoses would never have been made prior to the advent of genome sequencing. This is providing peace of mind to families, knowledge of recurrence risks and natural history, and, in a few cases, has even revealed potential new approaches to treatment."

Wendy Chung, a clinical geneticist and professor at Columbia University, specifically mentioned the recent advances in early spinal muscular atrophy (SMA) diagnosis and treatment, which "have been transformative and will serve as a model for rare diseases in the future."

Sharon Plon, a geneticist and professor at Baylor College of Medicine, pointed to the use of clinical exome and genome sequencing not only for research but to diagnose patients with extremely rare disorders. "Prior to that, most genomics research involved accumulating very large number of individuals with the same disorder and performing discovery research that was not disclosed to a patient/treating physician," she said.

Clinical sequencing has also provided new insights into inherited diseases. "Most striking has been that neurodevelopmental disorders such as intellectual disability, autism, and to a lesser extent schizophrenia all have a considerable burden of new mutations," said Han Brunner, a geneticist and professor at Radboud University in the Netherlands. Another finding is that many genes are shared between intellectual disability, autism, epilepsy, and schizophrenia. "Human neurodevelopmental disorders clearly represent a clinical continuum," he said.

Another important breakthrough has been the launch of clinically useful public gene variant databases, according to Heidi Rehm, chief genomics officer at Massachusetts General Hospital. These include population databases such as ExAC and gnomAD, which houses data from nearly 200,000 individuals, and resources like ClinVar and ClinGen, which contain clinically interpreted variants submitted by thousands of labs around the world. "These resources have dramatically improved our ability to return accurate and clinically meaningful answers to patients with suspected genetic disorders," she said.

Though exome sequencing remains cheaper, clinical whole-genome sequencing has been driven forward by decreasing sequencing costs, increased ease of use and robustness, automated protocols, and maturing bioinformatics data analysis tools, according to Edwin Cuppen, professor of human genetics at UMC Utrecht in the Netherlands. "This has now resulted in routine clinical implementation of [whole-genome sequencing] for congenital disease diagnostics in many places, increasing both speed and yield of diagnostics," he said.

"Furthermore, the same technology is now being implemented clinically for cancer precision medicine, where an increasing number of reports show the patients benefit from this approach," Cuppen said. Besides benefitting patients, this provides important new insights into the biology underlying disease development and treatment response, he added.

Indeed, cancer diagnostics is another field that has been transformed by genomics over the last decade.

According to Bert Vogelstein, professor of oncology at the Ludwig Center at Johns Hopkins, the most significant development has been technologies for the early detection of cancer. "Though the development of new therapeutics is critical, I believe that earlier detection will be the key to reducing morbidity and mortality from these diseases in the future," he said. "[N]ew therapeutics will unequivocally be more successful in treating patients with lower burdens of disease, so early detection will synergize with new therapeutic development. There are many technological advances that have contributed to this field, but those that allow the detection of rare tumor-derived alterations in DNA are probably the most important."

Rossa Chiu, professor of clinical pathology at the Chinese University of Hong Kong, pointed to targeted therapies for cancers with specific mutations, such as tyrosine kinase inhibitors for non-small cell lung cancers with sensitizing EGFR mutations, as another breakthrough development this past decade. "Targeted therapy is a prime example of how genomic knowledge of diseased cells could be turned into therapeutic action," she said.

Her colleague Lo picked liquid biopsy as the most important genomics development of the last decade for clinical applications. Not only may it allow for earlier cancer detection, but it also has applications in other areas, such as noninvasive prenatal testing (NIPT) and transplantation monitoring. While NIPT has already created "a paradigm shift in prenatal medicine," he said, cancer liquid biopsy has made an impact in therapy selection, treatment monitoring, prognostication, and cancer screening, and the use of plasma DNA markers for transplantation monitoring has affected both the clinic and research.

NIPT in particular, which first became commercially available in 2011, was "the first widely used clinical application based on whole-genome massively parallel sequencing," said Chiu. "Its clinical demand drove the need for rapid upscaling of clinical testing laboratories both for NGS and for bioinformatics, which were skill sets concentrated mainly in research laboratories at the time."

Preimplantation genetic testing for monogenic diseases is another area where genomics has made a big impact over the last decade, according to Peking University's Xie. "Thanks to the accuracy of single-cell whole-genome amplification and NGS, to date more than 1,000 families with monogenic diseases around the world have successfully prevented the passing of parents' genetic disorders to their newborns," he said.

But genomics is poised to fuel the development of personalized therapies even more going forward. According to Eric Schadt, professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, "[a]t the tail end of the decade, we witnessed astonishing (in my view!) proofs of concept around the treatment of the most catastrophic disorders, given the convergence of genomic understanding and biological programming technology." These ranged from individualized cancer vaccines to the reprogramming of cells to fix defects in proteins involved in disorders such as sickle cell disease.

Consumer genomics and forensics

Last but not least, a few researchers picked the rise of consumer genomics and its use in forensics as their top genomic development of the decade.

"I am biased but I think that the consumer genomics revolution was one of the main highlights of the decade," said Yaniv Erlich, chief science officer at MyHeritage, a genetic genealogy company.

More than 30 million people now have access to their genomic information, and researchers analyzing their data, and how they use it, have learned a lot. "We learned that people don't care that much about medical insights in their genome as they care about their origin," Erlich said. "We abolished the idea that family secrets can stay a secret and that there is something like anonymous sperm donation. During this process, we let hundreds of thousands of people find their birth families and connect with them. We also challenged the views of white supremacists about race and identity. Finally, we created population-scale genetic surveillance that allowed solving crimes with unprecedented power."

According to Ed Green, professor of biomolecular engineering at the University of California, Santa Cruz, it is now possible to identify many individuals using DNA and open databases. "This is now being applied in law enforcement. But it may soon be applied in other domains like intelligence work or corporate intelligence gathering," he said. "Coupled with advances in extracting and sequencing tiny amounts of DNA, it seems like the age of GATTACA is here. 1990s science fiction is today's reality."

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