《科学》2021年度十大科学突破揭晓

（English version below）

北京时间17日，《科学》网站公布了2021年度十大科学突破评选结果。让我们一起来看看今年科学界都有哪些重大成果。

1. 人工智能预测蛋白质结构

今年7月，世界知名人工智能团队深度思维宣布，已经利用AI智能软件程序——阿尔法折叠预测了人类表达的几乎所有蛋白质的结构，以及其他20种生物几乎完整的蛋白质组。AI预测蛋白质结构将实现广泛应用，提供对基础生物学的见解并揭示潜在的药物靶点。

8月，中国研究人员使用阿尔法折叠2绘制了近200种与DNA结合的蛋白质结构图。11月，德国和美国的研究人员利用阿尔法折叠2和冷冻电镜绘制了核孔复合物的结构图。现在，科学家正使用阿尔法折叠2来模拟奥密克戎变体刺突蛋白突变的影响。通过在蛋白质中插入更大的氨基酸，突变改变了它的形状——也许足以阻止抗体与其结合并中和病毒。

2. 解锁古老泥土DNA宝库

最近，科学家们从洞穴地面的土壤中解锁了一个更大的古代DNA宝库。研究人员使用这种“泥土DNA”来重建世界各地穴居人的身份。

在西班牙的Estatuas洞穴，核DNA揭示了8万至11.3万年前生活在那里的人类的遗传特征和性别，并表明尼安德特人的一个谱系在10万年前结束的冰川期之后取代了其他几个谱系。在美国佐治亚州Satsurblia洞穴有2.5万年历史的土壤中，科学家们发现了来自以前未知的尼安德特人系的女性人类基因组，以及野牛和现已灭绝的狼的遗传痕迹。通过将墨西哥奇基维特洞穴中1.2万年前的黑熊DNA与现代熊DNA进行比较，科学家们发现，在最后一个冰河时代之后，洞中黑熊的后代向北迁徙至阿拉斯加。

3. 实现历史性核聚变突破

8月，美国国家点火装置 (NIF) 产生了一种聚变反应，这种反应产生的能量比点燃它所需的激光能量更多。NIF使用来自世界上最高能量激光的脉冲来压缩胡椒粒大小的氢同位素氘和氚胶囊。这种方法每次发射产生170千焦的聚变能量——远低于1.9兆焦的激光输入。但在8月8日记录显示，该能量飙升至1.35兆焦耳。研究人员认为这是燃烧等离子体的结果，这意味着聚变反应产生了足够的热量，可以像火焰一样通过压缩燃料传播。

4. 抗新冠强效药出现

数据显示，美国默克公司的抗病毒药物莫奈拉韦可将未接种疫苗的高危人群的住院或死亡风险降低30%；而辉瑞公司的抗病毒药物PF-07321332，如果在出现症状的3天内开始服用，则可使住院率降低89%。科学家们强调，抗病毒药物不能取代疫苗接种，但它们仍然至关重要。如果新的奥密克戎变体导致突破性感染激增，它们的重要性将更加突出。

5. “摇头丸”可治疗创伤后应激障碍

一项多中心、随机、对照试验发现，3,4-亚甲基二氧基甲基苯丙胺(MDMA) ，也就是我们常说的“摇头丸”的主要成分，显著减轻了创伤后应激障碍(PTSD)患者的症状。76名受试者，部分接受了3次MDMA治疗，部分接受了安慰剂指导治疗课程。2个月后，67%的接受MDMA治疗的患者不再有PTSD症状，而安慰剂组则仅有32%。

6. 单克隆抗体治疗传染性疾病

今年单克隆抗体 (mAb)开始在对抗新冠病毒和其他威胁生命的病原体，包括呼吸道合胞病毒 (RSV)、HIV 和疟疾寄生虫等方面显现出效果。到今年年底，已有3种用于治疗新冠病毒的单克隆抗体获得FDA紧急使用授权。科学家还正在开发针对流感、寨卡病毒和巨细胞病毒的单克隆抗体。两个旨在预防所有婴儿呼吸道合体病毒(RSV)的候选药物被寄予厚望。单克隆抗体或将成为传染病武器库中的“标配”。

7. “洞察”号首次揭示火星内部结构

自“扎根”火星以来，美国国家航空航天局（NASA）的“洞察”号火星探测器在其着陆点测量了大约733次地震。科学家基于其中35次地震的数据，揭示了火星的内部结构，估计了火星地核的大小、地幔的结构和地壳的厚度。这也是科学家第一次使用地震数据来探测地球以外行星的内部，这是了解火星形成和热演化的重要一步。

8. 粒子物理学的标准模型出现“裂缝”

4月7日，美国费米国家加速器实验室进行的缪子反常磁矩实验显示，缪子的行为与标准模型理论预测不相符。研究报告称，巨大的、不稳定的类电子粒子——缪子，比最初预测的更具磁性。此外，费米实验室里的质子加速器也可以大量制造缪子。研究人员现在正在仔细检查今年的计算结果，如果成立，并且理论和实验结果之间的差异持续存在，可能将标志着有50年历史的粒子物理标准模型的预言失败，或打开物理学变革之门。

9. CRISPR基因编辑疗法对人类疗效首次证明

基因编辑工具CRISPR于2020年首次显现出或可治愈镰状细胞病和β—地中海贫血患者的功能。今年，科学家们更进一步，直接在人体内部署CRISPR-Cas9。在小型研究中，该策略减少了一种有毒的肝脏蛋白质，并适度改善了遗传性失明患者的视力。6月26日，美国Intellia医药公司和再生元公司科学家在6名患有一种名为转甲状腺素淀粉样变性病的罕见疾病的患者身上测试了他们的治疗方法。结果显示，所有参与者的畸形蛋白质水平均下降，其中两名接受高剂量注射的人的蛋白质水平平均下降了87%。

10. 体外胚胎培养为早期发育研究打开新窗户

通常，老鼠胚胎在母鼠体外生长的时间为3到4天。但在3月，一个团队报告了一个将这一期限延长到11天的方案。该研究进展有望为子宫外孕育人类铺平道路。此外，还有科学家设计了被称为“胚泡”的关键胚胎阶段的替代品。一个研究小组从人类胚胎干细胞中复制了胚泡，并诱导了多能干细胞(IPS)。另一项研究发现，转化为诱导性多能性细胞的皮肤细胞会产生囊胚状结构。这些人造胚泡并不是真正的胚胎，但其中一些可作为某些研究的替代方案以减少伦理争议。5月，国际干细胞学会宣布放宽人类胚胎培养“14天规则”，进一步提振了该领域的研究。

2021 BREAKTHROUGH OF THE YEAR

On the 17th, the "Science" website announced the results of the 2021 top ten scientific breakthroughs. Let us take a look at the major achievements of the scientific community this year.

1. Protein structures for all

This year, AI predictions shifted into overdrive. In mid-July, Baker and his colleagues reported that their AI program RoseTTAFold had solved the structures of hundreds of proteins, all from a class of common drug targets. A week later, DeepMind scientists reported they had done the same for 350,000 proteins found in the human body—44% of all known human proteins. In coming months, they expect their database will grow to 100 million proteins across all species, nearly half the total number believed to exist.

Code for AlphaFold2 and RoseTTAFold is now publicly available, helping other scientists jump into the game. In November, researchers in Germany and the United States used AlphaFold2 and cryo-EM to map the structure of the nuclear pore complex, an assembly of 30 different proteins that controls access to the cell nucleus. In August, Chinese researchers used AlphaFold2 to map the structures for nearly 200 proteins that bind to DNA, which could be involved in everything from DNA repair to gene expression. Last month, Google’s parent company, Alphabet, launched a new venture that will use predicted protein structures to design new drug candidates. And Baker’s team is using its software to dream up novel protein sequences that will fold into stable structures, an advance that could lead to new antivirals and catalysts.

2. Ancient soil DNA comes of age

Recently, scientists unlocked a much larger trove of ancient DNA: from the soil of cave floors. This year, for the first time, cave dirt yielded DNA once housed in the nucleus of human cells, and researchers used such “dirt DNA” to reconstruct the identity of cave dwellers around the world.

This year, scientists used nuclear DNA to chart the human and animal occupation of three caves. In Spain’s Estatuas Cave, nuclear DNA revealed the genetic identity and sex of humans who lived there 80,000 to 113,000 years ago, and suggested one lineage of Neanderthals replaced several others after a glacial period that ended 100,000 years ago. In 25,000-year-old soil from Georgia’s Satsurblia Cave, scientists found a female human genome from a previously unknown line of Neanderthals, along with the genetic traces of a bison and a now-extinct wolf. And by comparing 12,000-year-old black bear DNA from Mexico’s Chiquihuite Cave with that of modern bears, scientists discovered that after the last ice age, the cave bears’ descendants migrated as far north as Alaska.

3. Fusion’s day in the Sun?

In an August result that surprised the researchers themselves, the U.S. National Ignition Facility (NIF) produced a fusion reaction that came tantalizingly close to reaching official “breakeven,” the point at which a reaction produces more energy than the laser energy needed to kindle it.

But in an 8 August shot, that yield surged to 1.35 megajoules. Researchers think it’s the result of a burning plasma, meaning the fusion reaction generated enough heat to spread through the compressed fuel like a flame. The result has not been scrutinized by a peer-reviewed journal, but it was presented at the American Physical Society’s Division of Plasma Physics conference in November.

4. Potent pills boost COVID-19 arsenal

Vaccines have had a starring role in the fight against COVID-19, but a new player is joining them on stage: antiviral pills that prevent symptoms and death if taken early in infection.

In the fall, drugmakers Pfizer and Merck & Co. touted positive clinical trial results via press release. More antivirals are in trials, and existing generic drugs—including the obsessive-compulsive disorder treatment fluvoxamine—may also prove useful. Merck’s antiviral, molnupiravir, reduces the risk of hospitalization or death by 30% in high-risk, unvaccinated individuals, according to final data submitted to regulators. (That figure is lower than the 50% from an interim analysis.) Pfizer’s antiviral, PF-07321332, reduces hospitalization by 89% if started within 3 days of symptoms. The United Kingdom approved molnupiravir in November, and an advisory body to the U.S. Food and Drug Administration has narrowly endorsed it; regulators are also considering Pfizer’s treatment.

5. A psychedelic PTSD remedy

The mind-altering power of psychedelic drugs has raised hopes that they can ease psychiatric disease, but few large, rigorous trials have shown they’re effective. This year brought a big win for the field: A multicenter, randomized, controlled trial found that 3,4-methylenedioxymethamphetamine (MDMA), popularly called ecstasy, significantly reduced symptoms in patients with post-traumatic stress disorder (PTSD).

The study, published in Nature Medicine in May, tested an intensive combination of talk therapy and MDMA, which can create a sense of well-being and empathy that may help people process traumatic experiences. The trial’s 76 participants had three 8-hour guided therapy sessions with either the drug or a placebo, plus a set of shorter “preparatory” and “integration” sessions with therapists before and after treatment. After 2 months, 67% of those who got MDMA no longer met the diagnostic criteria for PTSD, versus 32% in the placebo group.

6. Artificial antibodies tame infectious diseases

Labmade antibodies called monoclonals have revolutionized the treatment of some cancers and autoimmune diseases, but they’ve had limited success against infectious diseases. That changed this year, as monoclonal antibodies (mAbs) made inroads against SARS-CoV-2 and other life-threatening pathogens, including respiratory syncytial virus (RSV), HIV, and malaria parasites.

With advances in cloning, animal models, and x-ray crystallography, researchers can now make and screen more mAbs than ever before, simplifying their search. SARS-CoV-2 mAbs showed promising results in clinical trials in 2020, and by late this year, the U.S. Food and Drug Administration had granted emergency use authorization to three to treat COVID-19 and, in some cases, prevent infection.

Monoclonals are also being developed against influenza, Zika, and cytomegalovirus. High hopes surround two candidates designed to prevent RSV in all infants. And in one HIV prevention study that failed overall, the candidate worked well against some strains.

7. NASA lander uncovers the Red Planet’s core

The interior of a rocky planet is a kind of time machine: Its dense core, viscous mantle, and hardened crust can reveal how it coalesced, churned, and settled into what it is today. Until this year, scientists have had access to just two such time capsules: Earth and, briefly during the Apollo missions, the Moon. Now, for the first time, instruments aboard NASA’s InSight lander are bringing Mars’s planetary core into focus.

But within 1 year, InSight picked up a handful of moderate quakes, including several stemming from Cerberus Fossae, a fissured region 1600 kilometers away. When combined with estimates of the interior’s composition, those readings helped chart the planet’s depths. Offsets in the quakes’ seismic waves revealed that the martian crust is layered and less than 40 kilometers thick—thinner than Earth’s continental crust. That thin shell would have let Mars quickly shed its early internal heat.

Looking deeper, InSight found the martian mantle lacked the insulating lower layer seen in Earth’s. The mantle was also shallow, squeezed between the crust and an unusually large, liquid core that occupies more than half of Mars’s width. Given the planet’s mass, scientists concluded that the core’s density is low, and that a mixture of light elements such as sulfur likely keep its iron and nickel liquid, despite the planet’s rapid heat loss—much as salt prevents icing. The researchers published their findings in Science this year.

8. At last, a crack in particle physics’ standard model?

It may be a sign of particle physicists’ desperation for something new that the biggest result in years confirms an oddity first observed 2 decades ago. A particle called the muon—a heavier, unstable cousin of the electron—is slightly more magnetic than physicists’ prevailing theory of fundamental particles and forces predicts. Reported in April, the 2.5-parts-per-billion discrepancy could signal new particles lurking just over the high energy horizon.

But a proper comparison depends on the precision of the standard model prediction. On the same day experimenters released their result, one team of theorists published a calculationthat, they argued, increases the standard model prediction and closes the observed gap. Other physicists say the theoretical consensus still indicates that the muon is extra magnetic.

Now, the question is why. Other searches for tiny discrepancies from the standard model’s predictions could yield more clues to the hoped-for new physics. Or, if physicists are lucky, the world’s biggest atom smasher, Europe’s Large Hadron Collider, will blast some new particle into plain view when it comes back online next spring after 3 years of upgrades.

9. CRISPR fixes genes inside the body

The gene-editing tool CRISPR had its first clinical victory in 2020, when it appeared to cure people with two inherited blood disorders, sickle cell disease and beta-thalassemia. Those treatments took place in a lab dish: Scientists removed defective blood stem cells from patients, edited them, and reinfused the cells into patients. This year, scientists took things one step further, deploying CRISPR directly in the body. In small studies, the strategy reduced a toxic liver protein and modestly improved vision in people with inherited blindness.

To fight hereditary transthyretin (TTR) amyloidosis, a disease in which a misfolded TTR protein builds up and damages nerves and the heart, researchers at Intellia Therapeutics and Regeneron Pharmaceuticals gave six patients an infusion of tiny fat balls encasing a guide RNA and the RNA instructions for CRISPR’s genome-snipping enzyme. The team hoped the patients’ own liver cells would take up the particles and make the CRISPR components, which would snip both strands of DNA at the TTR gene. The cell’s repair system would mend the cuts imperfectly, leaving the gene disabled. It worked: After 4 weeks, average blood levels of TTR dropped 52% or 87% depending on the dose, researchers reported in June in The New England Journal of Medicine.

10. Embryo ‘husbandry’ opens windows into early development

Insights into early embryonic development can help scientists understand miscarriages and birth defects—and hone in vitro fertilization (IVF) protocols. But legal, practical, and ethical limitations constrain studies with human embryos. This year, scientists unveiled potential stand-ins: mouse embryos reared far longer than before, and embryo replicas made from human stem cells or reprogrammed adult cells.

Scientists have struggled to grow mouse embryos outside a mother mouse’s body for much longer than 3 or 4 days. But in March, one team reported a recipe for stretching that to 11 days. A key step, they found, was rotating the jars containing the embryos on a device that resembles a miniature Ferris wheel. It continually mixes the nutrient broth that bathes the embryos and ensures that oxygen levels and atmospheric pressure are congenial. The embryos underwent a key stage of cellular reorganization, grew organs, and sprouted hind legs.

The field received another boost in May. The international organization that sets stem cell research guidelines relaxed its long-standing prohibition on growing human embryos in the lab for more than 14 days, allowing scientists to probe embryonic events that occur after that time.

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