Scientists can now sequence an entire genome overnight.
This technology has been the key tool for identifying and tracking variants of Covid.
Unlock the Covid code
By Jon Gertner
Edward Holmes was in Australia on a Saturday morning in early January 2020, on the phone with a Chinese scientist named Yong-Zhen Zhang, who had just sequenced the genome of a novel pathogen that was infecting people in Wuhan. The two men – old friends – discussed the results. "I knew we were dealing with a respiratory virus," recalls Holmes, a virologist and professor at the University of Sydney. He also knew it looked dangerous.
Could he share the genetic code publicly? Asked Holmes. Zhang was in China, waiting for take-off on a plane. He wanted to think about it for a minute. So Holmes waited. He heard a flight attendant tell Zhang to turn off his phone.
"OK," Zhang finally said. Almost immediately, Holmes posted the sequence on a website called Virological.org; then he linked it on Twitter. Holmes knew that researchers around the world would immediately begin uncoiling the pathogen's code to find ways to defeat it.
From the moment Holmes first published the virus genome, you could find a genetic component in almost every aspect of our public health responses to SARS-CoV-2. For example, a pharmaceutical company typically needs samples of a virus to make a vaccine. But when the sequence was in public space, Moderna, an obscure biotech company in Cambridge, Massachusetts, immediately began working on a plan with the National Institutes of Health. “You never had the virus on site. They really just used the sequence and viewed it as a software problem, "Francis deSouza, the executive director of Illumina, who makes the sequencer Zhang uses, told me last summer, six months before the Moderna vaccine received an emergency approval from Food and Beverage Drug administration. The virus's code also set the testing industry in motion. Only by analyzing characteristic aspects of the virus’s genetic sequence could scientists be able to produce kits for the P.C.R. Machines that have used genetic information for decades to formulate rapid diagnostic tests.
In the meantime, sequencing has been used to track viral mutations – starting with studies published in February 2020 showing the virus is spreading in the United States. This type of work falls under the realm of genomic epidemiology or "Gene Epi" in the field tend to call it. Much of the knowledge comes from the mid-1990s, including a group of researchers in Oxford, England, including Holmes. They found that following evolutionary changes in viruses that have persistent mutations every 10 days (like the flu) or every 20 days (like Ebola) is inherently similar and, as we now know, inherently more useful than – to follow them in animals. where evolution could take place over a million years.
An early hurdle was the boredom of work. The Oxford group had to analyze genetic markers through a slow and deliberate process that could provide insight into a few dozen characteristics of each new variant. It wasn't until the late 2000s that drastic improvements in genetic sequencing devices, aided by huge leaps in computing power, made it easier and faster for researchers to read the full genetic codes of viruses, as well as the genetic blueprint for humans and animals, plants and microbes.
In public health, one of the first major breakthroughs made possible by faster genome sequencing came in 2014 than a team at the Broad Institute of M.I.T. and Harvard began sequencing samples of the Ebola virus from infected victims during an outbreak in Africa. The work showed that contrasting genetic codes could identify and disrupt hidden routes of transmission, with the potential to slow (or even stop) the spread of infection. It was one of the first real applications of what is known as genetic surveillance. A few years later, doctors began using handheld genome sequencers to track down the Zika virus in Central and South America. Sequencers got better, faster, and easier to use.
For many, the most familiar faces of this technology are clinical testing companies that use sequencing machines to read pieces of our genetic code (known as "panels" or "exomes") and examine some key genes, such as those linked to a higher one are breast cancer risk. In recent years, however, more profound promises of genome sequencing have been covertly building up in areas from personal health to cultural anthropology to environmental surveillance. Crispr, a technology that relies on sequencing, offers scientists the potential to repair disease-causing mutations in our genomes. "Liquid biopsies," which test a small amount of blood for DNA markers, offer the prospect of a cancer diagnosis long before symptoms appear. Harvard geneticist George Church told me that one day sensors could “slurp the air” so a genomic app on our phones can tell us if a pathogen is lurking in a room. Sequencing could even make it possible to store any kind of data we want in DNA – such an archiving system would, in theory, be so efficient and dense that it could hold all of the internet's contents in a pillowcase.
Science historians sometimes talk about new paradigms or new ways of thinking that are changing our collective thinking about what is true or possible. But paradigms often evolve not only when new ideas displace existing ones, but when new tools enable us to do – or see things – that would previously have been impossible to consider. The advent of commercial genome sequencing has recently and credibly been likened to the invention of the microscope, an assertion that led me to wonder whether this new, still relatively obscure technology, disseminated in well-equipped laboratories around the world, would prove itself to be the most important innovation of the 21st century. According to Church estimates, sequencing is 10 million times cheaper and 100,000 times better than it was just a few years ago. When a new technological paradigm emerges, with a future in which we constantly monitor the genetics of our bodies and everything around us, these sequencers – simple, fast, ubiquitous – will be the machines that will lead us into this realm.
And unexpectedly, Covid-19 proved to be a catalyst. "The pandemic has accelerated the adoption of infectious disease genomics by several years," said deSouza, Illumina CEO. He also told me that he believes the pandemic has accelerated the adoption of genomics into society in a broader sense – suggesting that in the midst of chaos and global catastrophe, the age of cheap, faster sequencing has quietly dawned.
Last one morning On August 6th, after the first wave of the East Coast pandemic subsided, I visited the New York Genome Center in Lower Manhattan to observe the genetic sequencing process. That day, lab technicians were working on a series of SARS-CoV-2 samples taken from patients at Hackensack University Medical Center in New Jersey. Dina Manaa, a laboratory manager at the center, gave me a blue lab coat when I arrived. "I'll walk you through the whole process," Manaa said and for the next 20 minutes we walked up and down the hall of the laboratory while she explained the work.
Sequencing a virus is tedious, much like sequencing human DNA from a cheek swab or a drop of blood. Samples are moved along what is essentially an assembled line: “weighed” on exquisitely sensitive “scales” to check the mass of the sample; bathed in chemical solutions known as reagents; marked with a "barcode" made of genetic material so that each sample can be tracked individually. Most preparations, Manaa explained, involve checking the quality of the virus sample and then amplifying its genetic material. A tiny and invisible amount of the coronavirus extracted from a swab is converted into large amounts of DNA, everything is read and analyzed in preparation by a device that was built precisely for this purpose.
In another lab, Manaa stopped by a series of five sleek and identical new machines, the Illumina NovaSeq 6000 – or "Nova-Seek" as they are called. These were similar to the machines that were used to sequence the virus for the first time in China six months earlier. The NovaSeqs are about the size of an office copier and have few distinguishing features besides a large touchscreen surface and a ventilation pipe that extends from the back of the device to the ceiling. Each machine costs approximately $ 1 million. There are currently around 1,000 of them worldwide. On a nearby lab bench, a technician named Berrin Baysa pipetted tiny amounts of clear, virus-laden solutions from one tube to another and moved their mixtures into small, spinning centrifuges. After almost two days of preparation, these were the last steps for the Hackensack rehearsals. Finally, Baysa combined the tiny cocktails she had made by pouring them together into what is known as a flow cell, a flat glass cartridge the size of an iPhone with four hollow chambers. Then she carefully inserted the flow cell into a drawer slot on a NovaSeq 6000.
In the midst of chaos and global catastrophe, the age of cheaper, faster sequencing has quietly dawned.
"OK, keep your fingers crossed," she said after typing some instructions on a touchscreen and then tapping "GO". She raised both hands and crossed her fingers.
For this particular task, it would take the machine two days to complete the readings, she said – meaning by that time the full genetic sequences of the virus would be ready for the "bioinformaticians" who would look for patterns and variations in the examples .
The NovaSeqs are the culmination of about two decades of technological development, largely beginning with the Human Genome Project, which was completed in 2003 and funded primarily by the National Institutes of Health. The project showed that the human genome – "Nature's complete genetic blueprint for building a human", as the N.I.H. describes it – consists of a sequence of about three billion "base pairs". These are bound chemicals encoded as A, C, G, and T, where A is adenine, C is cytosine, G is guanine, and T is thymine. The chemical pairs are often grouped together on our chromosomes in around 30,000 information-dense strings or clumps. The lumps are our genes.
The human genome project took 13 years of work and cost more than $ 3 billion. Jeffery Schloss, who for many years oversaw technology grants at the National Human Genome Research Institute, a division of the N.I.H., told me that he attended a meeting in 2002 to plan the future of sequencing. “It was a tremendous effort to sequence the human genome,” recalls Schloss, “but we knew this was just the beginning of what we had to do, which meant the sequencing had to change dramatically. And in the course of that meeting, some people got this crazy idea: what if you could sequence a large genome for a thousand dollars? What would that make possible? "
Most of the scholars in Schloss & # 39; Kreis believed this could lead to profound revelations. By studying the genomes of a large population of, for example, Alzheimer's patients, researchers could find out how certain genes or combinations of genes make someone more likely to get sick. In an even longer period of time, they may gain insight into the health or disease markers of entire populations or countries. Sequencing could find uses beyond basic research – for example, routine clinical scans for prenatal tests or for genes known to increase the likelihood of certain types of cancer.
The Schloss office invested $ 220 million in various startups and ideas over a period of approximately 15 years. The ultimate goal was to reduce the cost of sequencing the entire genome and increase the speed. Even if the $ 1,000 genome remained inaccessible, a new generation of machines could potentially be approaching. “It was really unclear how long it would be before any of them got into commercialization,” recalls Schloss. “They had to be commercially successful. It was all pretty insecure. "Indeed, many of the sequencing startups from the early 2000s ultimately failed in the marketplace. However, some were incorporated into the core technology of other companies. For example, a company called Solexa came up with brilliant ideas known as 'sequencing by synthesis'. , where genetic samples were optically measured with fluorescent dyes that illuminated elements of DNA in the samples.This company was eventually bought by another company – Illumina, which quickly became an industry leader.
As the machines improved, the effects were mainly felt in university laboratories, which relied on a process called Sanger sequencing, developed by Nobel Prize winner Frederick Sanger in the mid-1970s. This laborious technique, in which DNA samples were passed through baths with electrically charged gels, was what the scientists at Oxford had relied on in the mid-1990s. It was also what Dave O'Connor, a virologist at the University of Wisconsin, Madison, used in the early 2000s when he and his lab partner Tom Friedrich were tracking virus mutations. "The H.I.V. The genome is about 10,000 letters," O’Connor said, which makes it easier than the human genome (at three billion letters) or the SARS-CoV-2 genome (at around 30,000). "In an H.I.V. Genome, when we started doing this, we could look at a few hundred letters at a time. “But O'Connor says his job has changed with the advent of new sequencing machines. Until around 2010, he and Friedrich were able to decrypt 500,000 letters a day. A few years later it was five million.
Up until 2015 the pace of improvement was breathtaking. "As a postdoctoral fellow, I actually worked in Fred Sanger's lab," said Tom Maniatis, director of the New York Genome Center. “I had to sequence a piece of DNA that was around 35 base pairs, and it took me a year to do that. And now you can create a three billion base pair genome overnight. “The decrease in costs was also astonishing. Illumina hit the $ 1,000 genome in 2014. Last summer, the company announced that its NovaSeq 6000 could sequence an entire human genome for $ 600. At the time, deSouza, Illumina's chief executive officer, told me that his company's path to a $ 100 genome would not be a breakthrough, only incremental technical improvements. "No miracle is required at this point," he said. Several of Illumina's competitors – including BGI, a Chinese genomics company – have said they will soon hit a $ 100 genome as well. Those in the industry I spoke to predicted it could only be a year or two more.
These numbers don't fully explain what faster speeds and affordability could mean. In healthcare, the prospect of a cheap whole genome test, possibly from birth, signals a significant step closer to realizing personalized medications and lifestyle plans tailored to our genetic strengths and weaknesses. "When that happens, this will likely be the most powerful and valuable clinical test you could have as it's a lifelong record," said Maniatis. Your entire genome won't change in the course of your life, so it only needs to be sequenced once. And Maniatis envisions that as new information is gathered through clinical trials, your re-researched doctor could re-examine your genome and find, for example, by age 35 that you have a mutation that is a problem if you are 50. "Really, this isn't science fiction," he says. "That said, personally, I'm sure it will happen."
In some ways it has already started, even in the midst of a public health crisis. In January, the New York Genome Center partnered with Weill-Cornell and New York-Presbyterian Hospitals to perform entire genome sequences on thousands of patients. Olivier Elemento, a doctor who leads the initiative at Weill-Cornell, told me the goal is to find out how a sequence of the entire genome – not just identifying a few genetic traits – can affect diagnosis and treatment. What is the best drug based on a patient's genome? What is the ideal dosage? "We are trying to answer a very important question that has never been answered on this scale," Elemento explained: "What is the benefit of sequencing the entire genome?" He said he believed the study would lead to an answer within a year or two.
"Sequencing is 10 million times cheaper and 100,000 times more expensive than it was a few years ago."
Some of the The greatest hopes for sequencing have sprung from the idea that our genes are deterministic – and that by understanding the code of our DNA we could limit our fate. When early reading of the human genome was revealed in 2000, President Bill Clinton noted that we were given a glimpse of "one of the most important and wondrous maps humanity has ever made." But the map has often proven difficult to read and its routes are unclear. The last 20 years have shown that inherited genes are just one aspect of a confusing system that is not easy to interpret. For example, advances in the use of gene therapy to treat disease have stalled. It was only last year that doctors had resounding success treating multiple patients with heritable genes for sickle cell anemia. In the meantime, scientists have recognized something else: A complex superposition of environmental and lifestyle factors as well as our microbiomes appear to have interrelated effects on health, development and behavior.
Yet over the past year some of the extraordinary hopes for genomic sequencing have been fulfilled, but for an unexpected reason. I spoke frequently with executives at Illumina and UK competitor Oxford Nanopore during the summer and fall. It was clear that the pandemic was a startling disruption to their business, but at every company top executives saw the situation as an opportunity – the first pandemic in history where genome sequencing would affect our decisions and actions in real time.
From the beginning, it was clear to the Gen-Epi community that the SARS-CoV-2 virus would form new variants every few weeks as it multiplied and spread. It soon became clear that it could develop one or more changes (or mutations) simultaneously in the 30,000 base letters of the genome. Based on this finding, on January 19, 2020, just over a week after the virus code was published, scientists were able to examine 12 complete virus genomes from China and conclude that these were almost identical at around the same time, 12 people had been infected and became infected with almost certainly each other. "That was something where genomic epidemiology could help us say out loud that human transmission was widespread when it wasn't really recognized as it should have been," said Trevor Bedford, a researcher at Fred Hutchinson Cancer Research Center. told me.
When Bedford's Seattle lab began studying viral genomes, he was able to go one step further. In late February, he concluded that new cases he was seeing weren't just imported into the US from China. Based on observations of local mutations – two strains six weeks apart looked too similar to be a coincidence – community transmission took place here. On February 29, Bedford published a Twitter post in which he horrifyingly stated, "I believe we are facing an already significant outbreak in Washington state that has not yet been detected." His proof was in the code.
Bedford's laboratory was one of many around the world that began tracking the development of the virus and sharing it in global databases. Meanwhile, Gen Epi researchers were also using sequencing for local experiments. In the spring of 2020, a team of British scientists compared virus sequences taken from sick patients in a single hospital to see if their infections were from each other or from a different location. "We were able to generate data that was useful in real time," said Esteé Torok, an academic doctor at Cambridge University who led the research. "And in an ideal world, you could do that every day." In other words, sequencing was so advanced from a few years ago when scientists might have published papers a year after an outbreak that genetic epidemiologists could compare mutations in a given location to raise alarms! Send patients in floor 3 to floor 5! – and act immediately.
Observing the pandemic from the perspective of those working in the genomics field has meant both the amazing power of new sequencing tools and the catastrophic failure of the American health system to take full advantage of them. In late July, the National Academy of Sciences released a report that found that advances in genome sequencing could allow us "to interrupt or delay virus transmission to reduce morbidity and mortality". However, the report snappy pointed out that sequencing efforts for the coronavirus were "patchy, typically passive, reactive, uncoordinated and underfunded". Every scientist I've spoken to understands that the virus can develop into dangerous new variants. It took many months for a specific one known as B.1.1.7 to show up and show that it was more transmissible and, most likely, more fatal. Researchers were similarly concerned that our sequencing efforts to track the routes of infection were faltering, unlike more serious and government-sponsored efforts in the UK or Australia.
One of the Biden government's approaches to slowing the pandemic was to invest $ 200 million in sequencing virus samples from people who tested positive. The recent approval of the US $ 1.9 trillion rescue plan will allocate an additional $ 1.75 billion to the Centers for Disease Control and Prevention to aid in genome sequencing and disease surveillance.
At the end of January, the C.D.C. started paying money to public health laboratories across the country to support the sequencing work already being done in academic laboratories. However, efforts assumed a low baseline. A calculation in the Washington Post found the United States ranked 38th in the world in terms of sequencing during the pandemic. In mid-February, the US was still trying to catch up with many European and Asian countries. And that's why you can't say that new or dangerous variants did not land on our shores or reappear here. What could be said is that we couldn't know.
One day sensors could slurp the air so that a genomic app on our cell phones can tell us if a pathogen is lurking in a room.
One day at At the New York Genome Center, a researcher named Neville Sanjana told me that he didn't see genetic sequencers as a typical invention, but rather as a kind of “platform technology”. The sentence resonates with those who study innovation. Such technological leaps are rare. They represent breakthroughs that lead to “platforms” – cell phones or web browsers, for example – that over time revolutionize markets and society.
The immense value of a platform innovation relates to how it can be customized for a range of uses that were initially unforeseen. It can be like a toolbox waiting in the back of a closet. A good example is what happened to sequencing during the pandemic. Another reason is Sanjana's work on new Crispr technologies, which he uses to modify or repair strings of DNA to better understand the genetic basis of human disease. Twenty years ago when officers from the N.I.H. Investing in the future of sequencing and regularly changing the human, plant, or animal genome wasn't something they could have predicted. However, Crispr requires Sanjana to keep evaluating his edit by using sequencers – usually a desktop Illumina model in his case – to verify the results. "It would be impossible to do these experiments any other way," he says.
In the past, platform innovations didn't just create new applications. They create new industries. And while countless genomics companies have sprung up, only four companies currently do the most sequencing analysis in the world. These are Illumina and Pacific Biosciences, based in the United States. Oxford Nanopore Technologies based in the UK; and China's BGI group.
According to the Federal Trade Commission, Illumina controls approximately 90 percent of the sequencing machine market in the United States and, according to the company's own estimates, compiles 80 percent of the genomic information available worldwide in a given year. It is sometimes referred to as the Google of the Genomics business, not only because of its huge market share, but also because of the ability of its products to "search" all of our genetic makeup. In short, it dominates the business. Last year the company had sales of over $ 3 billion and net income of approximately $ 650 million. In its hunger for expansion, the company recently made a number of acquisitions. In late September, for example, Illumina announced that it intended to acquire a $ 8 billion biotech company called Grail, which has created a genome test that runs on an Illumina sequencer, and that an early study suggests more As 50 types can be successfully identified from cancers from a small blood sample. DeSouza recently called Grail and Cancer Detection "by far the largest clinical application of genomics that we are likely to see in the next decade or two" on a corporate earnings call.
As the pandemic unfolded, I often spoke to genomics executives about what industries their technologies could transform and how their machines would be used in the years to come. A model for the future has been built around Illumina's strengths – large machines like the NovaSeq with exceptional sequencing capacity, housed in central test labs (as they are now) and operated by specialists. A very different set of ideas, however, emerges from one of Illumina's main competitors, Oxford Nanopore. Oxford sequencers are a technology that is more electronic than optical. Es basiert auf dem Konzept, eine DNA-Probe durch winzige Löcher – Nanoporen – in einer Membran zu bewegen. Das Gerät misst, wie genetisches Material (beispielsweise aus einer Blutprobe entnommen) während des Prozesses auf elektrischen Strom reagiert, und registriert die Buchstabenfolge – A, G, C, T – entsprechend. Ein charakteristisches Merkmal ist, dass ein Nanoporengerät längere DNA-Fäden lesen kann als ein Illumina-Gerät, was für einige Anwendungen hilfreich sein kann. Es kann auch Anzeigen in Echtzeit geben.
Der größte Unterschied kann jedoch die Portabilität sein. Im Jahr 2015 begann Oxford Nanopore mit dem Verkauf eines Sampling- und Sequenzierungs-Gadgets namens Minion (ausgesprochen MIN-eye-on) für 1.000 US-Dollar. Es ist kleiner als ein kleines iPhone. Der Geschäftsführer von Oxford Nanopore, Gordon Sanghera, sagte mir, er sehe das Werkzeug seines Unternehmens als eine Zukunft, in der in jeder Minute eines jeden Tages Erkenntnisse über die Sequenzierung gewonnen werden können. Inspektionsbeamte, die in Fleischverpackungsbetrieben arbeiten, würden innerhalb von Minuten Ergebnisse über pathogene Infektionen erhalten. Vermessungsingenieure, die Umweltüberwachung oder Abwasseranalyse durchführen, können dies bereits tun. Ihr Zahnarzt könnte eines Tages während eines regelmäßigen Besuchs eine Überprüfung Ihres oralen Mikrobioms durchführen, oder Ihr Onkologe könnte Ihr Blut einmal im Monat sequenzieren, um festzustellen, ob Sie sich noch in Remission befinden. Ein Transplantationsspezialist kann sogar vor Ort die genomische Verträglichkeit einer Organspende überprüfen. "Das Unternehmensethos", sagt Sanghera, "ist die Analyse von allem, von jedem, überall." Tatsächlich befindet sich gerade ein Diener auf der Internationalen Raumstation.
Die Technologie wird im Vergleich zu der von Illumina von den meisten Wissenschaftlern, mit denen ich gesprochen habe, als weniger genau angesehen, hat jedoch Vorteile, die über die von Sanghera erwähnten hinausgehen. Es war der Minion, der es Wissenschaftlern ermöglichte, auf Krankheiten wie Zika zu testen, ohne dass eine Infrastruktur außerhalb eines Laptops vorhanden war. In jüngerer Zeit konnten Esteé Torok und andere Forscher in Großbritannien virale Mutationen in Echtzeit in einem Krankenhaus verfolgen. "Diese Fähigkeit zur Sequenzierung vor Ort, selbst im ländlichen Afrika, hat Möglichkeiten eröffnet, die bisher noch nie in Betracht gezogen wurden", sagte mir Eric Green, der das National Human Genome Research Institute, Teil des N.I.H., leitet, kürzlich.
Das Äquivalent eines iPhones in die Genomik zu bringen, kann möglicherweise nicht über Nacht eine Revolution bewirken. Sanghera glaubt nicht, dass große zentrale Testlabors oder Illumina bald verschwinden könnten. In der Tat vermarktet sein eigenes Unternehmen auch eine Reihe großer Sequenzer für große Labore. Und natürlich können verwandte Technologien koexistieren, ähnlich wie Cloud Computing und Desktop Computing, insbesondere wenn sie unterschiedliche Probleme lösen. Derzeit betrachtet Sanghera das Coronavirus und die Überwachungsbemühungen in Großbritannien und den USA, die die Nachfrage nach Produkten seines Unternehmens erhöhen, als Beschleunigung des genomischen Übergangs der Kultur. Er sagte, er sehe in naher Zukunft kein Hindernis für eine 100-Dollar-Sequenz des gesamten menschlichen Genoms. Seine Firma, sagte er mir, arbeitet auch mit einem neuen Chip, der die Kosten möglicherweise auf 10 US-Dollar senken könnte.
Es scheint jenseits Debatte, dass die Pandemie gezeigt hat, dass wir von genomischen Sequenzen profitieren können, noch bevor wir alle ihre Geheimnisse vollständig enträtseln. Wir können sie beispielsweise als eine Art globales Alarmsystem verwenden, so wie sie von Eddie Holmes und Yong-Zhen Zhang verwendet wurden, als sie im Januar 2020 die SARS-CoV-2-Sequenz gemeinsam nutzten. Zufällig gibt es eine Vielzahl von verschiedenen laufenden Überwachungsbemühungen, von denen einige von Gesundheitsbehörden und andere von Wissenschaftlern betrieben werden, die viel weiter gehen würden, als nur eine Sequenz auf einer Website zu veröffentlichen – Bemühungen, die wichtige Informationen zur öffentlichen Gesundheit schneller und allgemeiner austauschen könnten, könnten für andere nützlich sein neues Coronavirus, ein tödlicher Influenza-Stamm oder sogar ein Bioterror-Angriff.
Pardis Sabeti, eine Genetikerin in Harvard, erzählte mir, dass sie im vergangenen Mai ein philanthropisches Stipendium erhalten habe, um bei der Entwicklung und Bereitstellung eines pandemischen „Präventions“ -Netzwerks namens Sentinel zu helfen. “We’ve always aimed for that ability to do surveillance,” she told me, adding that the goal of Sentinel would be to use genomic technologies everywhere — in rural clinics in Europe, villages in Africa, cities in China — to detect familiar pathogens within a single day of their appearance and novel pathogens within a week. The system would then race to share the data, via mobile networks, with health workers and communities so as to elicit a rapid response: travel restrictions, quarantines, medicine. Anything necessary to break chains of transmission. With a virus that spreads exponentially, a day could matter. A week could mean the difference between a small but deadly outbreak and a global cataclysm. (The time between the first case of Covid-19 and the release of the sequence of the virus was most likely about two months.)
As successive waves of the pandemic washed over the world, I noticed that the buzzword at the sequencing companies also became “surveillance.” For the most part, it meant tracking new variants and using sequencing codes to help reveal paths and patterns of transmission. Yet surveillance sometimes seemed a flexible concept, given that Illumina and Oxford Nanopore were selling flexible machines. Surveillance could mean the search for the next novel virus in Asia or even early cancer detection in our bodies. And it sometimes meant mass testing too. Last year, both deSouza and Sanghera successfully adapted their companies’ machines to do clinical diagnostic tests for the coronavirus; the goal was to step in and help increase global testing capacity at a moment when many medical facilities were overwhelmed by the demand.
In many respects, a genetic sequencer is over-engineered for the task of simply testing for a virus. A P.C.R. machine is faster, cheaper and less complex. And yet there are potential advantages to the sequencer. Illumina eventually won emergency approval from the Food and Drug Administration for a diagnostic test for the NovaSeq that can run about 3,000 swab samples, simultaneously, over the course of 12 hours. Thus, a single machine could do 6,000 coronavirus tests per day. Two hundred NovaSeqs could do more than a million. In addition to this immense capacity, it’s viable to test for the virus and sequence the virus at the same time: An analysis run on a sequencer could inform patients whether they have the virus, and the anonymized sequencing data on positive samples could give public-health agencies a huge amount of epidemiology data for use in tracking variants. “I can envision a world where diagnosis and sequencing are kind of one and the same,” Bronwyn MacInnis, who directs pathogen genomic surveillance at the Broad Institute, told me. “We’re not there yet, but we’re not a million miles off, either.”
Last summer, a few big clinical laboratories, notably Ginkgo Bioworks in Boston, began plans to roll out tests for Illumina sequencers, pending authorization from the F.D.A. Ginkgo, with help from investments from Illumina, as well as a grant from the N.I.H., began building a huge new laboratory next to its current one, where the company would install 10 NovaSeqs. “After we get the big facility built, that’s when we’d be trying to hit 100,000 tests a day,” Jason Kelly, Ginkgo’s chief executive, told me at the time. It was technically possible to sequence many of the positive coronavirus samples, too, he said.
When I asked Kelly what he would do if his capacity goes unused, he didn’t seem concerned. He doubted his sequencers would be idle. “By betting on sequencers as our Covid response,” he remarked, “we get flexibility for what you can use this for later.” After the pandemic, in other words, there will still be new strains of flu and other viruses to code. There will be a backlog of sequencing work for cancer and prenatal health and rare genetic diseases. There will be an ongoing surveillance effort for SARS-CoV-2 variants. An even bigger job, moreover, involves a continuing project to sequence untold strains of microbes, a project that Ginkgo has been involved with in search of new pharmaceuticals. “I think of this as like building fiber in the late 1990s, for the internet,” Kelly said. “Back then, we laid down huge amounts of fiber, then everything crashed.”
But it turned out that a decade after the dot-com crash, optical fiber was essential for the expanding traffic of the web. And what Kelly seemed to be saying, I later realized, was that he would expand his lab because sequencing had to be the future, in all kinds of different ways. There was no going back.
Opening illustration includes a portion of the SARS-CoV-2 genome released to the public in 2020.
Jon Gertner is a contributing writer for the magazine and the author of “The Ice at the End of the World.” He writes frequently about science and technology, including features on Tesla and Climeworks, a Swiss company that is removing carbon dioxide from the atmosphere.