Genes undergo routine clinical scans.

In about 15 years, Schloss’s organization has invested $220 million in various start-ups and ideas. Its ultimate goal is to help reduce the cost of whole-genome sequencing and increase sequencing speed. Even if $1,000 to complete genome sequencing is still out of reach, a new generation of machines may also be available soon. Schloss recalled: “It is not clear how long it will take for any of them to be commercialized. But they must be commercially successful. Everything is still uncertain.” Indeed, the establishment of a sequencing startup in the early 2000s Many aspects of marketization ultimately failed. However, there are also a few companies that have been incorporated into the core technologies of other companies. For example, the company Solexa has put forward some original ideas, which are so-called “sequencing by synthesis”, which uses optical methods to measure genetic samples, that is, fluorescent dyes are used to highlight the DNA elements of the samples. ??????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? The company was eventually acquired by Illumina, which soon became a leader in this industry.

The improvement of equipment is mainly due to the university laboratory that relied on the Sanger sequencing process invented by Nobel Laureate Frederick Sanger in the 1970s. The impact of this has been felt. Sanger sequencing is a laborious technique that involves separating DNA samples using gel electrophoresis. In the 1990s, scientists at Oxford University also relied on this technology to conduct research. In the early 2000s, Dave O’Connor, a virologist at the University of Wisconsin-Madison, also used this technique. At the time, he was tracking viral mutations with his lab partner Tom Friedrich. O’Connor said: “The HIV genome has about 10,000 characters.” In other words, it is simpler than the human genome (about 3 billion characters) or the SARS-CoV-2 genome (about 30,000). “When we first started sequencing the HIV genome, we could hold on to a few hundred characters at a time.” But O’Connor said that with the advent of the new sequencer, his work has changed. By around 2010, he and Friedrich could decode 500,000 characters in a day. A few years later, this number became five million.

By 2015, the pace of improvement has reached a breathtaking level. Tom Maniatis, head of the New York Genome Center, said: “When my child was still a postdoctoral researcher, I was working in Sanger’s laboratory. I had to sequence about 35 base pairs of DNA, and it cost me A year’s time. Now, you can sequence a 3 billion base pair genome overnight.”In addition, the cost reduction is also surprising. Illumina achieved $1,000 in genome sequencing in 2014. Last summer, the company announced that its NovaSeq 6000 could sequence the entire human genome for only $600. At the time, Illumina CEO deSouza told me that the company does not need a breakthrough to achieve $100 genome sequencing, only incremental technological improvements. He said: “At this point, we don’t need miracles.” Several of Illumina’s competitors, including BGI, said that they will soon achieve genome sequencing for $100. Industry insiders I have spoken to predict that this may only take a year or two.

These numbers do not fully explain what it might mean to be faster and more affordable. But in the field of healthcare, the development prospects of cheap whole-genome testing (perhaps from birth) indicate that we will move towards achieving personalized medicine and lifestyle tailored to individual genetic strengths and weaknesses An important step is planned. Maniatis said: “Once you take that step, it will be the most powerful and valuable clinical test you can have, because this is your lifetime record.” Your complete genome will not change in your lifetime. , So you only need to sequence once. And Maniatis believes that as clinical research continues to accumulate new information, doctors who receive new research results can re-evaluate your genome. Maybe they will find that, for example, your gene mutation at the age of 35 will become a problem by the age of 50. . He said: “Really, that’s not science fiction. I am personally very sure that this will happen soon.”

In some ways, this matter has already begun, even in the midst of a public health crisis. In January of this year, the New York Genome Center began to establish a partnership with Weill Cornell Medical Center and New York Presbyterian Hospital to perform whole-genome sequencing on thousands of patients. Olivier Elemento, project leader at Weill Cornell Medical Center, told me that the goal is to understand how the full sequence of the genome (rather than just identifying a few genetic features) can provide a basis for diagnosis and treatment. Based on the patient’s genome, what is the best drug? What is the ideal dose? Elemento explained: “We are trying to solve a very important question, a question that has never been answered on this scale. What is the use of whole-genome sequencing?” He said that he believes that within a year or two, this A study will give the answer.

The price of sequencing has been 10 million times cheaper, and the quality has increased by 100,000 times.

The greatest hope of sequencing partly comes from the fact that our genes are deterministic, and by understanding our DNA code, we may be able to portray our own destiny. In 2000, when an early interpretation of the human genome was published, President Bill Clinton pointed out that we were glimpsing “one of the most important and wonderful maps ever made by humans.” But this map often proves to be difficult. Interpretation, its route is unclear. The past 20 years have proven that genetics are just one aspect of a confusing and inexplicable system. For example, the use of gene therapy to treat diseases has been stagnant. It was not until last year that doctors successfully treated several patients with hereditary sickle cell anemia genes. At the same time, scientists realized that there are other factors: the complex stacking of environmental and lifestyle factors, and our microbiota, seem to have interrelated effects on health, development, and behavior.

Nevertheless, in the past year, some special expectations for genome sequencing have indeed come true, but for reasons other than those expected. Last summer and autumn, I had many opportunities to talk to the executives of Illumina and its British competitor Oxford Nanopore. Obviously, the epidemic means that their business will suffer a major interruption, but the executives of these companies see this situation as their own opportunity. Genome sequencing can provide information in real-time for our decision-making and actions in dealing with the epidemic, this is the first time in history.

From the very beginning, the “gen epi” community has known that as the SARS-CoV-2 virus replicates and spreads, this virus will form new variants every few weeks; One thing quickly became clear, that is, the 30,000 base pair letters of its genome can produce one or more changes (or mutations) at a time. Based on this insight, on January 19, 2020, just one week after the virus code was released to the world, scientists can see the 12 complete virus genomes shared by China and conclude that they are almost identical. This means that 12 people were infected at about the same time, and it was almost certainly transmitted from person to person.

When Bedford’s laboratory began to study viral genomes in Seattle, he could take it a step further. By late February, he concluded that the new cases he saw were not just imported cases. Based on observations of local mutations—the two strains discovered one after another (at an interval of six weeks) look too similar to the point where it cannot be a coincidence—it shows that there has been community transmission in the local area. On February 29, Bedford posted a chilling post on Twitter: “I think there has been a large-scale outbreak in Washington State, but it has not been detected until now.” His evidence is in the genetic code.

Many around the world began to track thisThe evolution of this virus is placed in a laboratory shared by a global database, and Bedford’s laboratory is one of them. At the same time, genomic epidemiology researchers are also using sequencing to conduct local experiments. In the spring of 2020, a team of British scientists compared virus sequences sampled from patients in a hospital to see if the infection came from each other or elsewhere. Esteé Torok, an academic doctor at the University of Cambridge, who led the research, said: “We can generate useful data in real time. In an ideal world, you can do this every day.” In other words, sequencing technology is comparable. It has developed more than a few years. At that time, scientists may not be able to publish papers until a year after the outbreak, but now genetic epidemiologists can compare mutations in specific locations and then issue alarms—there has been Community spread! The patient on the third floor is infecting the fifth floor! -And take immediate action.

Looking at the outbreak of the epidemic from the perspective of work in the field of genomics not only made people see the amazing power of new sequencing tools, but also made people see the catastrophic failure of the U.S. public health system to make full use of them. At the end of July last year, the National Academy of Sciences issued a report stating that advances in genome sequencing can provide us with the ability to “interrupt or delay the spread of the virus, thereby reducing morbidity and mortality.” But the report also sternly pointed out that the sequencing of the new coronavirus is “very unsatisfactory, often passive, reactive, lacking coordination and insufficient funding.” Every scientist I have spoken to knows this. This kind of virus may evolve into dangerous new variants. At that time, there were still several months before the emergence of the more transmissible and lethal B.1.1.7 variant of the new coronavirus. Researchers have expressed similar concerns regarding the failure of the United States’ sequencing efforts to track infection pathways.

One of the ways the Biden administration has delayed the epidemic is to invest $200 million in sequencing virus samples from people who have tested positive. After the US$1.9 trillion “American Rescue Plan” was recently approved, US$1.75 billion will be allocated to the US Centers for Disease Control and Prevention to support genome sequencing and disease surveillance.

In late January this year, the Centers for Disease Control and Prevention (CDC) began to provide funds to public health laboratories across the country to support sequencing work already carried out in academic laboratories. However, the benchmark for the start of this work is very low. According to calculations by the “Washington Post”, in terms of the adoption of sequencing during the epidemic, the United States ranked 38th in the world. As of mid-February, the United States was still trying to catch up with many European and Asian countries. Therefore, it cannot be said that there are no new or dangerous mutations in the United States. It can only be said that we don’t know.

Translator: boxi