Nature news: 未來40年,DNA測序將走向何方?

2021-02-15 PaperRSS

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    40年前,Sanger測序技術誕生,讓DNA片段的測序成為現實.自此,DNA測序技術以驚人的速度發展,越過一座又一座的裡程碑.那麼,未來40年,DNA測序又將變成什麼樣?Eric Green、Edward Rubin和Maynard Olson三位科學家本周在《Nature》上發文,展望了這項技術的未來.

Coloured DNA bands.

測序的需求

    技術的改進可能增加需求,也可能減少需求.作者認為,DNA測序將遵循計算和攝影的模式.隨著測序變得更便宜、更方便,應用將會激增,需求將會上漲.當DNA測序突破科研市場,進入臨床、消費者及其他領域,"供應越多意味著需求越多"的規則將愈加明顯.

    上世紀90年代,人類基因組測序的想法讓人覺得不可思議.如今,遺傳學家卻希望對地球上的每個人、每種組織中的每個細胞進行測序.同時,考古學家也希望藉助測序來了解祖先群體的基因流動.生態學家、進化生物學家也試圖分析所有物種的基因組,甚至是整個生態系統.

    當然,目前的瓶頸是分析和解釋所有的DNA序列數據.作者預測,大量的DNA序列數據以及表型信息的結合,將讓研究人員能夠推斷基因組序列所編碼的生物學功能.更重要的是,解釋數據所需的大部分基礎知識已經準備好了.

殺手級應用

    縱觀其他技術,比如智慧型手機、網際網路和數碼攝影,真正的顛覆者都是應用,而不是新技術.作者確信,DNA測序將徹底改變的一個領域將是醫學.

    目前,DNA測序的突破性臨床應用是產前檢測.它通過檢測在母體血液中循環的少量胎兒游離DNA,來檢測染色體的數量異常.據估計,全世界每年大約有400-600萬名孕婦在接受這一檢測,十年內這個數字將超過1500萬.從中也許能推斷出未來應用的一些特徵:非侵入性、易於開展、對核苷酸水平的準確性要求較低.

SOURCE: National Human genome research Institute


    在腫瘤學方面,人們已經投入相當多的資金來開發液體活檢.不難想像,基於序列的癌症檢測將會成為常規的篩查工具,就像巴氏塗片和結腸鏡檢查.隨著癌症治療開始針對特定突變,而不是腫瘤類型,液體活檢最終將指導治療幹預.

    作者也設想了DNA測序在診所之外的各種應用,特別是手持式DNA測序儀.流行病學家可以利用這種裝置來檢測空氣、水、食品、動物和昆蟲載體,當然還有人的咽部標本和體液.DNA測序技術的輕鬆獲取可以促進"全球病毒組計劃"這樣的項目,以了解傳播疾病的各種病毒.此外,這種儀器也可能成為刑偵上的工具.

    最後,文章也提到了測序技術的絆腳石.DNA測序技術也許很快就能納入常規的臨床應用,以分析各種情況下獲得的體液.不過,只有整合數百萬人多年醫療史的數據,才能提供所需的元信息(meta-information),確定何時忽略這些數據,以及何時採取行動.這是一個挑戰

原文標題:The future of DNA sequencing

Nature 550, 179–181 (12 October 2017) doi:10.1038/550179a

    Forty years ago, two papers1, 2 described the first tractable methods for determining the order of the chemical bases in stretches of DNA. Before these 1977 publications, molecular biologists had been able to sequence only snippets.

    The evolution of DNA sequencing from these nascent protocols to today's high-throughput technologies has occurred at a breathtaking pace3. Nearly 30 years of exponential growth in data generation have given way, in the past decade, to super-exponential growth. And the resultant data have spawned transformative applications in basic biology and beyond — from archaeology and criminal investigation to prenatal diagnostics.

What will the next 40 years bring?

    Prognosticators are typically wrong about which technologies — or, more importantly, which applications — will be the most disruptive. In the early days of the Internet, few predicted that e-mail that would achieve staggering popularity. Similarly, traders on Wall Street and investors in Silicon Valley failed to foresee that games, online video streaming and social media would come to dominate the use of today's available processing power and network bandwidth.

    We would probably fare no better in predicting the future of DNA sequencing. So instead, we offer a framework for thinking about it. Our central message is that trends in DNA sequencing will be driven by killer applications, not by killer technologies.

In demand

    Improvements in a technology can either increase or decrease demand. Microsoft co-founder Bill Gates famously cited radial tyres as an example of the latter: because they were more durable than earlier designs, the need for tyres dropped and the tyre industry shrank.

    We think that DNA sequencing will follow the pattern of computing and photography, not of tyres. As it becomes cheaper and more convenient, applications will proliferate, and demand will rise (see 'Better, cheaper, faster'). As DNA sequencing breaks out of the research market and into clinical, consumer and other domains, the rule of 'more supply means more demand' will hold ever more strongly.

    Researchers have an insatiable appetite for DNA-sequence data. In the 1990s, the idea of sequencing a human genome seemed daunting. Now, geneticists would like to have DNA sequences for everyone on Earth, and from every cell in every tissue at every developmental stage (including epigenetic modifications), in health and in disease. They would also like to get comprehensive gene-expression patterns by sequencing the complementary DNA copies of messenger RNA molecules. Meanwhile, archaeologists are beginning to reconstruct the flow of genes through ancestral populations, just as they previously deduced the flow of languages, cultural practices and material objects. And taxonomists, ecologists, microbiologists and evolutionary biologists are seeking to analyse the genomes of all living (and extinct) species — and even whole ecosystems.

    Obviously, a sustained demand for data would require that the vast cataloguing efforts proffer actual understanding. At present, the bottleneck is analysing and interpreting all the DNA-sequence data. But just as new informatics approaches and massive data sets have dramatically improved language translation and image recognition, we predict that massive DNA-sequence data sets coupled with phenotypic information will enable researchers to deduce the biological functions encoded within genome sequences.

    What's more, much of the basic science needed to interpret the data is already in place for a growing repertoire of practical applications (such as high-quality reference sequences of bacterial genomes, or the rules by which certain gene networks operate in healthy people). These range from recognizing microbial DNA sequences in unbiased surveys of environmental or clinical samples to identifying genome changes associated with known biological consequences.

Killer applications

    Over the years, the platforms for DNA sequencing have changed dramatically (see 'Many ways to sequence DNA'). Yet the trajectories of other technologies for which there is a seemingly insatiable demand — smartphones, the Internet, digital photography — suggest that the real disrupters will be the resulting applications, not the new technologies.

Many ways to sequence DNA

Over the past 40 years, the platforms for DNA sequencing have repeatedly been replaced.

    By 1985, almost all DNA sequencing was performed with the Sanger or dideoxy chain-termination method2; reaction products were labelled with radionucleotides, separated on acrylamide slab gels, and detected with autoradiography (the use of X-ray or photographic film to detect radioactively labelled samples). By 2000, the four-colour-fluorescence method reigned supreme; reaction products were labelled with chain-terminating nucleotide analogues, separated electrophoretically in capillaries filled with a jelly-like media, and detected with energy-transfer fluorescent dyes. By 2010, the techniques had diversified. The dominant instruments were based on massively parallel analyses of DNA 'polonies' (clonal amplifications of a single DNA molecule) and on sequencing-by-synthesis chemistries (these rely on reversible chain-terminators).

    From now on, the requirements for each DNA-sequencing platform will depend on what it is to be used for. In oncology and medical genetics, the goal will often be to identify every base correctly and to define every variant of genomic segments that exist in multiple copies. By contrast, when a yes or no 'match' is required — for instance, in species identification — the ability to run tests quickly and easily in the field may be more important than accuracy.

    Another factor that will probably change is the relative need for centralized versus decentralized DNA sequencing. An epidemiologist trying to assess in real time what virus has affected a particular village in Sierra Leone might need cheap, portable devices. But for those generating massive data sets, it might be more efficient and cost effective to ship samples to centralized commercial operations, especially when the laboratories are required to meet exacting standards for quality control and sample tracking, as in clinical applications.

    Today's 'breakout' clinical application of DNA sequencing — in terms of the sheer number of tests conducted — is prenatal testing for the presence of an abnormal number of chromosomes, such as trisomy 21, which causes Down's syndrome. This test now relies on detecting the small amount of cell-free fetal DNA that circulates in maternal blood. Not even imagined at the end of the Human Genome Project, it has been described as 「the fastest growing genetic test in medical history」4. In fact, experts in the field estimate that some 4 million to 6 million pregnant women are now receiving this test each year worldwide, and that the number will surpass 15 million within a decade (D. Bianchi, D. Lo and D. Zhou, personal communication). Some of the hallmarks of the test seem likely to characterize many future applications of DNA sequencing in primary care: it is non-invasive, easy to perform and has low requirements for nucleotide-level accuracy (chromosomes can be counted without assessing sequence variation).

    In high-income countries, genome sequencing is already used routinely to evaluate children with ill-defined congenital conditions. Analyses of the resulting sequences can reveal the disease-causing mutations in around 30% of such cases5, 6 — a figure that will only rise as the ability to interpret the data matures. In some instances, the resulting diagnoses have led to dramatic improvements in clinical management7,8. More typically, they benefit both families and physicians by ending a diagnostic odyssey and providing clinical clarity.

    In oncology, considerable investments are being poured into the development of liquid biopsies9. It is easy to imagine such a sequence-based cancer test becoming a routine screening tool, used much like Pap smears and colonoscopies. With the advent of cancer treatments that target specific mutations, rather than tumour types10, liquid biopsies could ultimately guide therapeutic interventions even when tumours are known to exist only from DNA-sequence signatures present in blood samples.

    Various applications can be envisioned outside the clinic, too, particularly for hand-held DNA sequencers. Epidemiologists and even caregivers working in rural areas could use such devices to test air, water, food, and animal and insect vectors, not to mention human throat swabs and body fluids. In fact, easy access to DNA-sequencing technologies in low- and middle-income countries is already facilitating projects such as the Global Virome Project. This aims to sequence numerous samples of wildlife DNA to identify a significant fraction of the viruses that can be transmitted into humans and cause disease.

    Meanwhile, public-health specialists are starting to discuss how they might sequence the DNA of all the microorganisms in the waste-water outlets of entire cities to speed up the recognition of disease outbreaks. And marine biologists are exploring ways to monitor the health of the oceans through systematic metagenomic studies.

    On the street, portable instruments could bring DNA analysis out of the crime lab and make it a front-line policing tool. Police might be able to 'read' people's DNA, much as they currently check car number plates or identification documents. In fact, the degree to which cheap and easy DNA sequencing opens up possibilities for mass surveillance has recently sparked concern among human-rights groups.

    In the home, DNA-sequencing appliances could become the next 'smart' or 'connected' devices, after smoke alarms and thermostats. One commentator even identified the toilet as the ideal place to monitor family health through real-time DNA sequencing11.

Hitting limits

What are the stumbling blocks?

    In a mere 40 years, the central goal of putting molecular data about cells to practical use has changed from an informational challenge to a meta-informational one.

    「DNA-sequencing appliances could become the next 'smart' or 'connected' devices.」

    Take clinical applications of genome-sequence data. It may soon be possible to use DNA sequencing routinely to analyse body fluids obtained for any clinical purpose. But only a vast amount of well-organized data about the multi-year medical histories of millions of people will provide the meta-information needed to establish when to ignore such data and when to act on them.

    With respect to medicine, we echo the recommendations of advisory groups such as the US National Research Council's Precision Medicine Committee12 on the need to create a vast 「information commons」. This would overlay molecular and clinical data onto the germ-line genome sequences of millions of individuals. Several such population-scale efforts are under way, including the UK Biobank resource and the US All of Us Research Program.

    Here we have laid out our best guesses. Surprises are a certainty. In fact, it is possible that decades from now, much of the world's data (now residing on hard drives or in the cloud) will be stored in DNA, and that the main driver of DNA sequencing will be not our quest to tackle disease, but our insatiable appetite for data storage.

參考文獻

1 Maxam, A. M. & Gilbert, W. Proc. Natl Acad. Sci. USA 74, 560–564 (1977).

2 Sanger, F., Nicklen, S. & Coulson, A. R. Proc. Natl Acad. Sci. USA 74, 5463–5467 (1977).

3 Shendure, J. et al. Nature http://dx.doi.org/10.1038/nature24286 (2017).

4 Paxton, A. CAP Today (March 2017); available at go.nature.com/2hoipsp.

5 Bick, D. et al. J. Pediatr. Genet. 6, 61–76 (2017).

6 Eldomery, M. K. et al. Genome Med. 9, 26 (2017).

7 Worthey, E. A. et al. Genet. Med. 13, 255–262 (2011).

8 Bainbridge, M. N. et al. Sci. Transl. Med. 3, 87re3 (2011).

9 Alix-Panabières, C. & Pantel, K. Cancer Discov. 6, 479–491 (2016).

10 Garber, K. Science 356, 1111–1112 (2017).

11 Erlich, Y. Genome Res. 25, 1411–1416 (2015).

12 National Research Council. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease (National Academies Press, 2011); available at go.nature.com/2fmz99


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