Where Are All the AI Drugs?
In an industry where 90 percent of drug candidates fail before reaching the market, a handful of startups are betting everything on AI to beat the odds.
AI药物都去哪了?
在一个90%的药物候选者在进入市场前就宣告失败的行业里,少数初创公司正押上一切,用AI来挑战这一概率。
Peter Ray knows that. Born in what is now Zimbabwe, the child of a mechanic and a radiology technician, Ray fled with his family to South Africa during the Zimbabwean War of Liberation. He remembers the journey there in 1980 in a convoy of armored cars. As the sun blazed down, a soldier taught 8-year-old Ray how to fire a machine gun. But his mother kept having to stop. She didn’t feel well.
Doctors in Cape Town diagnosed her with cancer. Ray remembers going to her radiation treatments with her, the hospital rooms, the colostomy bags. She loved the beach, loved to walk along the line where the water met the land. But it got harder for her to go. Sometimes she came home from the hospital for a while and it seemed like things would get better. Ray got his hopes up. Then things would fall apart again. Surgery, radiation, chemotherapy—the treatments that were on the table in the 1980s—were soon exhausted. As she lay dying, he promised her he was going to make a difference, somehow. He was 13 years old.
彼得·雷深知这一点。雷出生在如今的津巴布韦,父亲是机械师,母亲是放射科技师。在津巴布韦解放战争期间,他随家人逃往南非。他记得1980年那次旅程,他们乘坐装甲车车队。烈日炎炎下,一名士兵教会了8岁的雷如何操作机枪。但他的母亲不得不一次次停下来。她感觉很不舒服。
开普敦的医生诊断她患有癌症。雷记得陪她去接受放射治疗,那些病房,那些结肠造口袋。她热爱海滩,喜欢沿着水陆交界线散步。但她越来越难以前往。有时她从医院回家待一阵子,情况似乎会好转。雷燃起了希望。然后情况又会再次恶化。手术、放疗、化疗——这些80年代的治疗手段很快就被用尽了。在她弥留之际,雷向她承诺,无论如何,他要做出改变。那年他13岁。
【单词解析】
beat the odds:克服困难,战胜不利条件或低概率,取得出乎意料的成功。odds: 名词,复数形式。原指“不平等”,后引申为赌博或事件中的“概率,可能性”,尤指不利的概率。短语 the odds 特指“成功或失败的可能性”。
radiology technician:/ˌreɪdiˈɒlədʒi tekˈnɪʃ(ə)n/。放射科技师。
convoy:/ˈkɒnvɔɪ/。名词,文中意:(用于保护平民的)装甲车队。原意:一支由车辆(或船只)组成的队伍,通常为了安全或效率而在护送下集体行进。动词: 护送,为一组车辆或船只护航。
armored:/ˈɑːməd/。形容词,装甲的,带有防护装甲的。
colostomy bags:/kəˈlɒstəmi bæɡz/。结肠造口袋。colostomy: 名词。colo-(词根,指“结肠”)+ -stomy(后缀,源自希腊语“stoma”,意为“开口”)。指在腹部为结肠开一个口的手术。
be on the table:字面意: 在桌子上。比喻意: (尤指建议、计划、选项等)被正式提出供讨论、考虑或谈判。
Ray studied to become a medicinal chemist, first in South Africa, taking out loans to fund his studies, then at the University of Liverpool. He worked at drug companies across the UK, on numerous projects. Now, at 53, he is one of the lead drug designers at a pharmaceutical company called Recursion. He thinks about that promise to his mom a lot. “It’s lived with me my whole life,” he says. “I need to get drugs on the market that impact cancer.”
The desire to stop your own tragedies from happening to someone else may be a strong motivator. But the process of drug discovery has always been grindingly,gruelingly slow. First, chemists like Ray zero in on their target—usually a protein, a long string of amino acids coiled and folded upon itself. They call up a model of it on their computer screen and watch it turn in a black void. They note the curves and declivities in its surface, places where a molecule, sailing through the darkness like a spaceship, could dock. Then, atom by atom, they try to build the spaceship.
雷努力学习成为一名药物化学家,先是在南非,靠贷款完成学业,然后去了利物浦大学。他在英国各地的制药公司工作,参与过众多项目。如今,53岁的他是Recursion制药公司的一名首席药物设计师。他常常想起对母亲的那个承诺。"它伴随了我一生,"他说,"我需要让能够影响癌症的药物上市。"
阻止自己的悲剧在他人身上重演,这或许是一个强大的动力。但药物发现的过程始终是缓慢而磨人的。首先,像雷这样的化学家要锁定他们的目标——通常是一种蛋白质,一条长长的、自身盘绕折叠的氨基酸链。他们在电脑屏幕上调出它的模型,看着它在黑色的虚空中旋转。他们记下其表面的曲线和凹陷,那是分子——像飞船一样在黑暗中航行——可以停靠的地方。然后,他们原子接原子地,尝试建造这艘飞船。
【单词解析】
taking out loans:从银行或其他金融机构正式办理并取得贷款。take out: 核心动词短语,意为“办理,取得(正式文件、服务、产品)”,如 take out insurance (购买保险),take out a mortgage (办理抵押贷款)。
pharmaceutical:/ˌfɑːməˈsuːtɪk(ə)l/。形容词 (也可作名词),制药的,医药的。
grindingly:/ˈɡraɪndɪŋli/。副词,以令人精疲力竭、单调乏味且似乎永无止境的方式。grind (研磨;艰苦地做) + -ing (构成形容词) + -ly (构成副词)。
gruelingly:/ˈɡruːəlɪŋli/。副词,极其艰苦、费力、让人筋疲力尽地。gruel (名词,稀粥),grueling (形容词,源于比喻“像只喝稀粥一样耗尽体力”),gruelingly (副词)。
zero in:军事/技术: (用武器或仪器) 调整瞄准点以对准目标。引申义: 将注意力、努力等集中到某个特定事物上。
coil:/kɔɪl/。动词: 将(绳子、线等)卷成环状或螺旋状;自身盘绕。名词: 一卷(绳子、线等);螺旋或环状物。
call up:召唤: 召集,征召(入伍),打电话给。计算/记忆: 从计算机存储器中检索(数据);在脑海中唤起(记忆)。
declivity:/dɪˈklɪvɪti/。名词,斜坡、凹陷处(是分子可能的结合位点)。
dock:/dɒk/。动词:(航海): (使船) 进入船坞停靠。(航天): (使航天器) 对接。(生物/化学): (分子) 与另一个分子(如受体)特异性结合。名词: 码头,船坞;被告席。
When the new molecule is ready, the chemists pass it along to the biologists, who test it on living cells in warm rooms. More tragedy: Many cells die, for reasons that are not always clear. Biology is complex, and the new drug doesn’t work as expected. The chemists will have to create another, and another, tweaking, adjusting, often for years. One biologist, Keith Mikule of Insilico Medicine, told me of his experience at a different drug company. After five years of work, their best molecule had unforeseen,dangerous side effects that meant they could take it no further. “There was a large team of chemists, a large team of biologists, thousands of molecules made, and no real progress,” he said.
If a team is very lucky, they get a molecule that, in mice, does what it’s supposed to.They get a chance to give it to a small group of healthy human volunteers, a phase I trial. If the volunteers stay healthy, then they give it to more people, including those with the disease in question, in a phase II. If the sick people don’t get sicker, they get a chance—phase III—to give it to more sick people, as many as they can find, as diverse a group as possible.
当新的分子准备就绪,化学家会把它交给生物学家,后者在温暖的房间里对活细胞进行测试。更多的悲剧发生了:许多细胞死亡,原因往往不明确。生物学极其复杂,新药并不按预期工作。化学家们将不得不再次、再次地创造新分子,不断调整,往往持续数年。Insilico Medicine的生物学家基思·米库尔向我讲述了他在另一家制药公司的经历。经过五年的工作,他们最好的分子出现了不可预见且危险的副作用,这意味着他们无法再推进。"那是一支庞大的化学家团队,一支庞大的生物学家团队,合成了数千个分子,却没有真正的进展,"他说。
如果一个团队非常幸运,他们得到了一个在小鼠身上能起作用的分子。他们有机会将其给一小群健康的人类志愿者服用,这是一期临床试验。如果志愿者保持健康,那么他们会在二期试验中将其给更多人服用,包括患有相关疾病的患者。如果患者没有病情加重,他们将有机会进入三期试验——将其给尽可能多的、尽可能多样化的患者群体服用。
【单词解析】
tweak:/twiːk/。文中意,(化学家们) 对(药物分子)进行微调、细微调整。原意,动词:拧,捏(用手指突然地扭或捏(尤指鼻子或耳朵));微调,精细调整:对某物(如系统、计划、设计、设置)做小幅度的改进或调整以优化其性能或状态;名词:拧,捏的动作。小的调整,微调。
At each stage, for reasons few people understand and fewer can predict, great rafts of drugs drop out. More than 90 percent of hopefuls fail along the way. When you meet drug hunters, you might ask them, cautiously, tenderly, if they’ve ever had a drug make it. “It’s very rare,” says Mikule, who has one drug (niraparib, for ovarian cancer) to his name. “We’re unicorns.”
But Mikule, Ray, and other chemists and biologists are trying a new approach. When I talk to Ray, he’s excited to show me a molecule he and his colleagues at Recursion have been working on. It’s a so-called MALT1 inhibitor, designed to interfere with the growth of blood cancer cells. On his screen, REC-3565 is a series of rings and lines,another skeletal spaceship floating in the void. But it exists in the real world too: Just a few weeks before my chat with Ray, the first phase I volunteers swallowed it in a little pill. What’s special about this molecule, Ray says, isn’t just that it has survived the gauntlet thus far. It’s that REC-3565 “wouldn’t have come by human design.”Ray’s team, he believes, would not have made the logical leaps required to reach this point without using artificial intelligence.
在每个阶段,由于鲜为人知、更难预测的原因,大量药物会中途退出。超过90%的候选药物在此过程中失败。当你遇到药物研发者时,你可能会谨慎、温和地问他们,是否有药物真的成功上市。"非常罕见,"米库尔说,他名下有一种药物(用于治疗卵巢癌的尼拉帕利)。"我们就像独角兽。"
但是,米库尔、雷以及其他化学家和生物学家正在尝试一种新方法。当我与雷交谈时,他兴奋地向我展示他和Recursion的同事们一直在研究的一个分子。这是一种所谓的MALT1抑制剂,旨在干扰血癌细胞的生长。在他的屏幕上,REC-3565是一系列环和线构成的又一个骨架般的飞船,漂浮在虚空中。但它也存在于现实世界中:就在我与雷聊天的几周前,首批一期临床试验的志愿者吞下了一颗小药丸。雷说,这个分子的特别之处,不仅在于它迄今为止经受住了重重考验。还在于REC-3565"不会是靠人类设计出来的"。他相信,如果没有使用人工智能,他的团队不可能做出达到此点所需的逻辑飞跃。
【单词解析】
raft:/ræft/。名词,大量,许多(尤指问题、文件、事情等);木筏,筏子。
drop out:退出活动、比赛、组织等: 停止参与;辍学: 特指在未完成学业的情况下离开学校;脱离主流社会,追求另类生活方式。
unicorn:/ˈjuːnɪkɔːn/。名词,独角兽,独角兽公司;罕见、独特、近乎完美的事物。
skeletal:/ˈskelətl/。形容词,骨骼的,与骨骼有关的;极瘦的,瘦骨嶙峋的;(结构) 框架的,纲要的,最基本的。
gauntlet:/ˈɡɑːntlət/。名词,文中意: 严酷的考验,重重难关。原意:run the gauntlet: (习语) 字面指古代一种刑罚,受刑者从两排人中间跑过并遭受殴打;比喻经历一连串的批评、攻击或困难。
As the world’s pharma giants get caught up on AI, Recursion is among a group of startups betting everything on the technology. Founded 12 years ago by academics in Utah, the company made its name by taking snapshots of cells under various conditions, creating a vast database of pictures, and turning AI on them to identify potential new targets. Last year, Recursion acquired another decade-old startup—Ray’s former employer, Exscientia—which pioneered the use of AI to design small molecules. There are others, including Mikule’s employer Insilico, which was founded in 2014. Just last year, Xaira Therapeutics launched with $1 billion in venture capital—the biggest biotech funding round in years. (The only other new startup that pulled in as much in 2024 was Safe Superintelligence, cofounded by a former top OpenAI researcher.)
随着全球制药巨头纷纷涉足人工智能,Recursion属于那群将所有赌注都押在这项技术上的初创公司之一。该公司由犹他州的学者于12年前创立,其成名之道是在各种条件下对细胞进行快照成像,创建庞大的图像数据库,然后运用人工智能进行分析以识别潜在的新靶点。去年,Recursion收购了另一家已有十年历史的初创公司——雷的前雇主Exscientia,该公司率先使用人工智能设计小分子。还有其他公司,包括米库尔所在的Insilico,成立于2014年。就在去年,Xaira Therapeutics带着10亿美元的风险资本启动,这是多年来生物科技领域最大的一轮融资。(2024年另一家获得同样高额融资的新初创公司是由前OpenAI顶尖研究员共同创立的Safe Superintelligence。)
【单词解析】
get caught up:文中意:(世界制药巨头) 开始涉足、卷入、参与(AI浪潮);原意:被卷入,陷入(某种活动、情绪或境地);赶上,补上(进度、工作、新闻等):与 on 或 in 连用;(在交谈或思考中) 全神贯注,沉迷于。
make one's name:成名,出名,树立名声。
There are no drugs on the market designed using AI. But both Recursion and Insilico have gotten candidates through phase II clinical trials, which means they’re safe in patients. REC-994 is for cerebral cavernous malformation, a disease that causes brain lesions, and ISM001-055 is for idiopathic pulmonary fibrosis, a progressive, fatal lung condition. More AI-linked drug candidates are in development, from Insilico, Recursion, and other companies, including the one Ray showed me.
All of these molecules, right now, are like cards lying face down on the table. Can AI help make drugs that actually work, faster and cheaper than usual, or are the drug hunters about to be dealt another losing hand?
目前市场上还没有使用AI设计的药物。但Recursion和Insilico都已让候选药物通过了二期临床试验,这意味着它们对患者是安全的。REC-994用于治疗脑海绵状血管畸形,这是一种导致脑部病变的疾病;ISM001-055用于治疗特发性肺纤维化,这是一种进行性、致命的肺部疾病。更多与AI相关的候选药物正在研发中,来自Insilico、Recursion和其他公司,包括雷向我展示的那一种。
所有这些分子,此刻都像面朝下扣在桌子上的纸牌。AI能帮助制造出真正有效的药物吗,比通常更快、更便宜?还是药物猎手们即将拿到一手烂牌?
【单词解析】
cerebral cavernous malformation:/ˈserɪbrəl ˈkævənəs ˌmælfəˈmeɪʃ(ə)n/。脑海绵状血管畸形。
lesion:/ˈliːʒ(ə)n/。名词,病灶,损伤。
idiopathic pulmonary fibrosis:/ˌɪdiəˈpæθɪk ˈpʌlmənəri faɪˈbrəʊsɪs/。特发性肺纤维化。
fatal:/ˈfeɪt(ə)l/。致命的,致死的。
deal someone a losing hand:被给予/面临一个注定失败的局面或劣势条件。losing hand 指一手没有赢面的牌。
In the summer of 1981, a headline on the cover of Fortune magazine proclaimed that the age of digital drug discovery was at hand. The story explored how scientists were using computer visualization to select the best molecules to try in cells, hoping to break through the gridlock. Derek Lowe, a medicinal chemist who writes the long-running blog In the Pipeline, recalls that the Fortune article made some drug hunters at the time nervous. At the pharmaceutical company Schering-Plough, where he worked, there was a room labeled “Computer-Aided Drug Discovery (CADD),” packed with expensive equipment. “The medicinal chemists across the hall didn’t think too much of that,” Lowe told me, “so they put a sign over their door that said ‘BADD:Brain-Assisted Drug Discovery.’”
Computers did revolutionize everything. But the hard problems of drug discovery didn’t evaporate with the touch of a cursor. Seasoned drug hunters refer in a jaundiced tone to combinatorial chemistry, an attempt to stumble across new kinds of drugs by assembling molecular pieces in random order. (It didn’t work, in part because the costs of such a wildly democratic approach were crippling.) Computational chemistry, which allows scientists to simulate how a target and a molecule will interact, gained grudging acceptance—but its success depends on accurate models of the target and the candidates, and for that you need old-fashioned elbow grease in the lab.
1981年夏天,《财富》杂志封面的一则头条宣称,数字药物发现的时代即将到来。这篇报道探讨了科学家如何利用计算机可视化技术来选择在细胞中进行测试的最佳分子,希望突破僵局。一位撰写长期博客《In the Pipeline》的药物化学家德里克·洛回忆说,当时《财富》的文章让一些药物猎手感到紧张。在他工作的先灵葆雅制药公司,有一个房间标着"计算机辅助药物发现(CADD)",里面堆满了昂贵的设备。"走廊对面的药物化学家们对此不以为然,"洛告诉我,"所以他们也在自己门上挂了个牌子,写着'BADD:大脑辅助药物发现'。"
计算机确实彻底改变了一切。但药物发现的难题并未随着光标的一点就烟消云散。经验丰富的药物猎手们以一种带着怀疑的口吻提及组合化学——试图通过随机顺序组装分子片段来偶然发现新药。(它没有成功,部分原因是这种极度民主式的做法成本过高。)计算化学能让科学家模拟靶点和分子如何相互作用,逐渐获得了勉强接受——但其成功取决于对靶点和候选分子模型的准确性,而这需要实验室里老式的辛勤工作。
【单词解析】
be at hand:近在手边,在附近 (空间上)。即将发生,临近 (时间上)。随时可用,方便获得。
gridlock:/ˈɡrɪdlɒk/。名词,(政治、谈判、进程中的) 僵局,停滞;交通全面堵塞,路网瘫痪。
evaporate:/ɪˈvæpəreɪt/。动词,(液体) 蒸发,挥发;(比喻) 消失,不复存在 (尤指突然或逐渐地)。
cursor:/ˈkɜːsə(r)/。名词,(计算机) 光标。
seasoned:/ˈsiːz(ə)nd/。形容词,经验丰富的,久经沙场的 (指人);调过味的,加了佐料的 (指食物);(木材)经过干燥处理的,可用的。
jaundiced:/ˈdʒɔːndɪst/。形容词,有偏见的,嫉妒的,愤世嫉俗的;患黄疸病的 (医学)。因疾病使人眼白和皮肤发黄,引申为“用黄色的、不健康的眼光看待事物”,即带着偏见、怀疑或嫉妒。
stumble:/ˈstʌmbl/。动词,(比喻)偶然发现,碰巧遇到:常与across, on, upon连用;结结巴巴地说;绊脚,绊倒。
crippling:/ˈkrɪplɪŋ/。形容词,造成严重损害的,使瘫痪的,难以承受的;使严重残疾的,致残的(医学)。
grudging:/ˈɡrʌdʒɪŋ/。形容词,不情愿的,勉强的,吝啬的 (指给予认可、赞美、尊重等)。
elbow grease:/ˈelbəʊ ɡriːs/。艰苦的体力劳动,费力的工作 (尤指实验室里传统、费时的人工劳动)。
If anything, the hard problems have grown harder as the full complexity of biology has come into focus. “We have more things to worry about than we used to,” says Lowe. Cancers with different mutations driving them respond to different therapies. Drugs that attached to a certain receptor were linked to heart problems, and thus any new drug candidate, no matter how promising, must be removed from the running if it shows affinity for that receptor.
Karen Billeci, a principal biologist at Recursion, still remembers one of the first times she heard a drug hunter mention artificial intelligence. One dawn in 1993, Billeci was walking across her company’s parking lot on the edge of the San Francisco Bay with a couple of other employees. They worked at a scrappy startup called Genentech (later acquired by Roche for $47 billion). Billeci’s programmer friends were exploring whether neural networks—a form of machine learning—could be used to find patterns in patient information and help reveal why some responded to a drug and others didn’t. “These great drugs would go into humans, and they would fail,” Billeci says. They talked in the parking lot about whether, someday, there would be software that could learn to see patterns they couldn’t. “We didn’t say ‘train,’” Billeci recalls. “We didn’t have the words for that yet.”
如果说有什么不同的话,那就是随着生物学全部复杂性的清晰显现,这些难题变得愈发棘手。"我们要担心的事情比以前更多了,"洛说。由不同突变驱动的癌症对不同的疗法有反应。附着在某种受体上的药物与心脏问题相关联,因此任何新的候选药物,无论前景多么广阔,只要显示出对该受体的亲和力,就必须被排除在外。
Recursion的首席生物学家卡伦·比莱西仍然记得她第一次听到药物猎手提及人工智能的情景。1993年的一个黎明,比莱西和另外几名员工一起,穿过公司位于旧金山湾边缘的停车场。他们当时在一家名为基因泰克(后来被罗氏以470亿美元收购)的顽强初创公司工作。比莱西的程序员朋友们正在探索神经网络(一种机器学习形式)能否用于发现患者信息中的模式,帮助揭示为什么有些人对药物有反应而有些人没有。"这些好药进入人体后,却会失败,"比莱西说。他们在停车场讨论,有朝一日是否会有软件能够学会发现他们无法看到的模式。"我们那时没说'训练',"比莱西回忆道。"我们还没有那个词。"
【单词解析】
remove someone/something from the running:使退出竞赛(或竞选、角逐),使失去资格。the running 指“参赛行列”。
affinity:/əˈfɪnəti/。名词,(化学/生物学中的) 亲和力,吸引力;(天生的)喜好,喜爱,亲近感;密切关系,相似性。
scrappy:/ˈskræpi/。形容词,(尤指在不利条件下)顽强的,不屈不挠的,有拼搏精神的;好斗的,爱吵架的;由碎片拼凑的,不连贯的。
It gradually became clear, over the next several decades, that AI might do more than pick out patterns in patient data. In 2020, something happened that crystallized what might be possible. In a global competition that fall, an AI built by Alphabet’s DeepMind showed it could correctly predict how a protein would fold up into its final form—a canonical hard problem in biology and a key task for drug hunters. DeepMind’s AI easily beat out all the other contestants. David Baker, a biochemist at the University of Washington, was inspired to dig deeper into using AI to design new drug proteins, work that later won him the 2024 Nobel Prize for Chemistry. “It didn’t take us long to develop methods that surpassed the ones we had been developing before,” he says. (Baker is one of the founders of Xaira.)
After that, what else might be possible with AI? What if it were shown all the drugs that have ever existed, with all the data about how they work, and then set loose on a database of untried molecules to identify others to explore? What if—and this is where the discussion around machine learning has gotten to now, in 2025—the software could take in a decent chunk of all the information about biology generated by humankind and, in an act both spooky and profound, suggest entirely new things?
在接下来的几十年里,人们逐渐清楚,AI可能不仅仅能识别患者数据中的模式。2020年,发生了一件事,使得可能实现的愿景变得清晰起来。在那年秋季的一场全球竞赛中,Alphabet旗下DeepMind构建的AI展示出它能够准确预测蛋白质如何折叠成最终形态——这是一个生物学上的经典难题,也是药物猎手的一项关键任务。DeepMind的AI轻松击败了所有其他参赛者。华盛顿大学的生物化学家大卫·贝克深受启发,深入研究利用AI设计新的药物蛋白质,这项工作后来为他赢得了2024年诺贝尔化学奖。"我们没花多长时间就开发出了超越之前已有方法的新方法,"他说。(贝克是Xaira的创始人之一。)
在那之后,AI还可能做到什么?如果让它了解所有曾经存在过的药物及其作用机制的所有数据,然后将其释放到一个未经试验的分子数据库中,去识别其他有待探索的分子呢?如果——这正是2025年围绕机器学习的讨论现状——软件能够摄入人类产生的关于生物学的相当一部分信息,并以一种既令人惊异又深刻的方式,提出全新的东西呢?
【单词解析】
crystallize:/ˈkrɪstəlaɪz/。动词,(使) 变得具体明确;(使) 成形;(使) 结晶。
canonical:/kəˈnɒnɪk(ə)l/。形容词,经典的,标准的,规范的。
contestant:/kənˈtestənt/。名词,参赛者,竞争者。
spooky:/ˈspuːki/。形容词,令人不安的,诡异的,不可思议的。
Sometimes, humanity is learning, AI produces things that look good at first glance but turn out to be whimsical potpourris of words or thoughts, mere nothingburgers. The fact that drug discovery involves extensive real-life testing makes it unlikely that such suggestions would survive the process. The biggest risk of AI hallucinations might be wasted time and resources. But the failure rate of new drugs is already so high that scientists at these startups think the risk is worth taking.
Peter Ray looks at the MALT1 inhibitor floating in the void. “If I get a drug to market,I would feel I had fulfilled my promise,” he says. He points out where the AI revealed a way to remove a section of the molecule that could cause toxicity. It was a reaction that had not occurred to any of the humans involved.
有时,人类意识到,AI产生的东西乍看之下不错,但结果却是异想天开的文字或思想大杂烩,纯属虚妄。药物发现涉及广泛的现实测试,这一事实使得此类建议不太可能通过这一过程。AI幻觉的最大风险可能只是浪费时间和资源。但新药的失败率已经如此之高,以至于这些初创公司的科学家认为值得冒这个险。
彼得·雷看着漂浮在虚空中的MALT1抑制剂。"如果我能让一种药物上市,我会觉得我兑现了我的承诺,"他说。他指出AI如何揭示了一种移除分子中可能导致毒性的部分的方法。这是一种所有相关人员都未曾想到的反应。
【单词解析】
whimsical potpourris:/ˈwɪmzɪk(ə)l ˌpəʊpʊˈriːz/。whimsical: 形容词。异想天开的,古怪有趣的,随心所欲的。potpourri: 名词。原指“百花香”(一种干花和香料的混合物);引申为“大杂烩,混合物”(尤指五花八门、成分繁杂的集合)。
nothingburger:/ˈnʌθɪŋˌbɜːɡər/。名词,没有实质内容或重要性的事物;令人失望或空洞的结果。形象地比喻一个没有肉饼的汉堡,外表是汉堡,里面却什么都没有。
hallucination:/həˌluːsɪˈneɪʃ(ə)n/。名词,医学/心理学)幻觉;(AI领域专有术语)幻觉:模型生成看似可信但事实上不正确或无法验证的信息。
The real question is whether molecules designed using AI are any better at getting to market. The last few stages of the process are the most expensive, the most unpredictable. In any clinical trial, it’s hard to find the right people, says Carol Satler, the vice president of clinical development at Insilico. It’s slow. She worries about it—hopes she has made the right choices, contacted the right doctors, excluded the people who would not benefit, included those who might, to see what the drug can do. By the time a drug reaches trials, it represents a billion dollars and a decade in the lives of hundreds, if not thousands, of scientists. One patient signs up. Then two. Months pass. Time crawls. “The meter is always running,” Satler says. “It’s so expensive.”
Late last year, soon after Recursion finalized its acquisition of Exscientia, 300-odd drug hunters from both companies converged on an event space in London.
真正的问题是,使用AI设计的分子是否更有可能成功上市。这个过程的最后几个阶段是最昂贵、最不可预测的。Insilico负责临床开发的副总裁卡罗尔·萨特勒说,在任何临床试验中,找到合适的人都很难。过程很缓慢。她为此忧心忡忡——希望自己做出了正确的选择,联系了正确的医生,排除了那些不会受益的人,纳入了那些可能受益的人,以观察药物的效果。当一种药物进入试验阶段时,它代表了数十亿美元的资金,以及数百名(如果不是数千名)科学家十年的人生。一个患者报名了。然后两个。几个月过去了。时间缓缓流逝。"计量器一直在走,"萨特勒说。"成本太高了。"
去年年底,就在Recursion完成对Exscientia的收购后不久,两家公司的300多名药物猎手聚集在伦敦的一个活动场所。
【单词解析】
crawl:/krɔːl/。(时间) 缓慢地流逝,拖得很慢。
converge:/kənˈvɜːdʒ/。动词,(线条、道路、人群等)向一点会合,聚集;(观点、思想等)趋同,达成一致。
The pink-lit conference hall buzzed with news of an announcement made just days before by Recursion’s chief scientific officer. Molecule REC-617, developed by Exscientia, had been given to 18 patients whose terminal cancers had stopped responding to other treatments. The phase I clinical trial was designed to see both whether patients could tolerate the drug candidate and whether it had any effect. One patient—a woman with ovarian cancer that had come back three times—surprised everyone: She lived. She was still alive after six months of the treatment. Because the trial is blinded, no one at Recursion or Exscientia has any idea who this woman is and whether she is still alive today. But in that room, she seemed to radiate with life.
The announcement contained another noteworthy detail. Because Exscientia used AI to narrow down the number of candidate molecules before any of them were made, it was not thousands but a mere 136 that were finally manufactured and tested in cells. (Ray’s MALT1 inhibitor involved making only 344, also a tiny fraction of what would have happened in a traditional setting.) Chris Gibson, Recursion’s cofounder and CEO, underscored that number in his talk to the assembled crowd, emphasizing the savings in time and resources. By failing faster, goes the logic—by using AI not only to invent new molecules but also to rule most of them out in advance—it might be possible to bring down the cost of the first stages of this extremely costly process.
粉色灯光映照的会议厅里,人们热议着几天前Recursion首席科学官宣布的一条消息。由Exscientia开发的分子REC-617已给18名对其他治疗停止反应的晚期癌症患者服用。一期临床试验旨在观察患者是否能耐受该候选药物以及它是否有效果。其中一位患者——一位卵巢癌三次复发的女性——让所有人感到惊讶:她活了下来。在接受治疗六个月后,她仍然活着。由于试验是双盲的,Recursion或Exscientia没有人知道这位女性是谁,也不知道她今天是否还活着。但在那个房间里,她仿佛散发着生命的光芒。
这则公告还包含了另一个值得注意的细节。因为Exscientia在制造任何候选分子之前就使用AI来缩小候选分子数量,最终制造并在细胞中测试的分子不是数千个,而只有136个。(雷的MALT1抑制剂也只制造了344个,也远低于传统情况下的数量。)Recursion的联合创始人兼首席执行官克里斯·吉布森在向聚集的人群讲话时强调了那个数字,强调节省的时间和资源。其逻辑是:通过更快地失败——不仅使用AI来发明新分子,还预先排除大部分分子——或许有可能降低这个极其昂贵过程的初始阶段的成本。
【单词解析】
radiate:/ˈreɪdieɪt/。动词:(热、光、能量等)辐射,发散 (物理);(从中心)向外伸展,呈辐射状散开;(比喻)流露,显示,焕发 (情感、品质、活力等);形容词 (radiant): 容光焕发的,喜气洋洋的;光芒四射的。
In the center’s lobby, a breakout group with David Mauro, Recursion’s chief medical officer, Jakub Flug, an Exscientia medicinal chemist, and a handful of others stood in a circle. The employees were having what amounted to an enormous blind date. They were meeting people they’d never seen in person, telling their stories, trying to see how they would all fit together. They took turns introducing themselves and saying why they had chosen to join these companies. One person said: I’m here to have fun. Another said: I’m here because I was tired of doing something that I didn’t believe in anymore. Another: I am here because I want to actually release a drug onto the market. Everyone nodded at this one.
Downstairs, in a basement room, Gibson was thinking about the future too. His hope is that Recursion is laying the groundwork for what drug discovery will someday be like across the industry, starting with the eight drugs that have advanced to clinical trials and the handful behind them, in the preclinical stage. “If we’re doing this right, if we’re building a learning system, the next 10 drugs after that have a higher probability of success. Next 10 drugs after that, higher probability of success. We keep refining this thing,” he said.
在中心的大厅里,一个小组围成一圈,包括Recursion的首席医疗官大卫·毛罗、Exscientia的药物化学家雅各布·弗拉格等几人。员工们正在进行一场相当于大型相亲会的活动。他们见到了从未见过面的人,讲述自己的故事,试图看看如何融合在一起。他们轮流自我介绍,说明为何选择加入这些公司。一个人说:我来这里是为了乐趣。另一个人说:我在这里是因为厌倦了做不再相信的事情。又一个人说:我在这里是因为我想真正推出一款药物上市。听到这一句,每个人都点头表示赞同。
楼下的一间地下室里,吉布森也在思考未来。他希望Recursion正在为未来整个行业的药物发现方式奠定基础,从已进入临床试验的8种药物和其后处于临床前阶段的几种药物开始。"如果我们做得对,如果我们正在构建一个学习系统,那么接下来的10种药物会有更高的成功概率。再接下来的10种,成功概率更高。我们不断优化这个东西,"他说。
【单词解析】
breakout:/ˈbreɪkaʊt/。形容词,(会议)分组的,分会的;突然成功的,脱颖而出的。名词,爆发,突发;越狱。
refine:/rɪˈfaɪn/。动词,改进,完善,使更文雅(方法、设计、想法、品味等);提炼,精炼;使纯化。
I asked him about his claim, last summer, that there would soon be information about 10 or so different candidates. This critical mass, with information going public in a large bolus, is a calculated goal, he said: If around 90 percent of drugs fail, then Recursion needs to show results of about 10 different programs just to see if they are doing what they hope. “At the end of the day, it’ll be fair to judge us by the first 10,” Gibson says. “That’s enough of an n.” Enough of a sample size, in other words, to see what this approach can do.
One cold morning late last year, I went to see one of Recursion’s discovery engines. Patrick Collins, the director of automation, and Su Jerwood, a principal scientist in pharmacology, showed me into a room the size of a small supermarket with aisles of machines in plate-glass cases. White lamps like halos hung above them. “We’ve got biology on one side, chemistry on the other,” Collins said. A magnetic railway threaded through the machines, connecting pipetting robots to incubator chambers. “It’s about design, make, test, learning, loop,” Collins said. He indicated cases of bottles and powders, “all the building blocks, reagents and things.” Humans keep the machines topped up.
我问他关于去年夏天他声称很快会有大约10种不同候选药物信息的说法。他表示,这个关键数量,即大量信息同时公开,是一个经过计算的目标:如果大约90%的药物失败,那么Recursion需要展示大约10个不同项目的结果,才能看看他们是否达到了预期。"归根结底,根据前10个(的结果)来评判我们是公平的,"吉布森说。"那足够构成一个'n'。"换句话说,足够大的样本量,来看看这种方法能做什么。
去年年底一个寒冷的早晨,我去参观了Recursion的一个"发现引擎"。自动化总监帕特里克·柯林斯和药理学首席科学家苏·杰伍德带我进入了一个如小型超市大小的房间,里面排列着玻璃柜中的机器设备。白色灯管像光环一样悬挂在它们上方。"我们这边是生物学,那边是化学,"柯林斯说。一条磁力轨道穿梭于机器之间,将移液机器人与培养箱连接起来。"这是关于设计、制造、测试、学习、循环的过程,"柯林斯说。他指着柜子里的一瓶瓶试剂和粉末,"所有的基础构件、试剂等等。"由人类负责给机器补充物料。
【单词解析】
bolus:/ˈbəʊləs/。名词,文中意,一次性的、大量的信息发布;原意:(比喻)一团,一块;(医学)团,丸;(兽医学)大丸药。
aisle:/aɪl/。名词,通道,过道。
pipetting:/pɪˈpetɪŋ/。动名词,移液操作。
incubator chamber:/ˈɪŋkjubeɪtə(r) ˈtʃeɪmbə(r)/。培养箱,恒温箱。
powder:/ˈpaʊdə(r)/。名词: 粉末,细粉;(化妆用) 粉;动词: 在…上搽粉;使成粉末。
building block:基础材料,构成要素;积木。
top up:加满,添满;补充,充值;(英式) 为(饮料)续杯。
These machines, Jerwood explained, dispense molecules created from raw atoms, molecules that AI systems have already tested and explored in virtual spaces. The candidate drugs drip onto trays of cells, and the system evaluates their effects. It’s new, and there are kinks to be worked out. Some parts of the automated process still need humans to move them along, Collins said, and Recursion is figuring out how to streamline the flow of information to and from the AI. But when it works, scientists will have the results of thousands of tests glowing on their screens. The automated system has been up and running for about a year, so it wasn’t involved in making the candidates currently in clinical trials. But it is helping to make future drugs.
As I examined the machines in their pristine chambers, I wondered about what it means, now, to be the kind of human who loves to think about molecules, loves to make them, whose joy comes from understanding how they work. I asked Collins this. He thought back to the moment when he first crystallized a protein by hand, first saw a drug molecule clasped against it. “I was hooked for life,” he said. Those traditional tools still have their place. But perhaps it is not here, where the focus is getting something to the clinic as fast as possible, something that works. “We’re all trying to think about patients,” Collins said.
这些机器,杰伍德解释道,会分配由原始原子合成的分子,这些分子是AI系统已经在虚拟空间中测试和探索过的。候选药物滴到装有细胞的托盘上,系统评估它们的效果。这是新事物,尚有一些问题需要解决。自动化过程的某些部分仍然需要人工推动,柯林斯说,Recursion正在研究如何简化与AI之间的信息流。但当它正常工作时,科学家将在他们的屏幕上看到成千上万次测试的结果。这套自动化系统已启动运行了大约一年,所以目前进入临床试验的候选药物并非由它参与制造。但它正在帮助制造未来的药物。
当我审视那些在洁净无尘的柜室中的机器时,我思考着,对于那种热爱思考分子、热爱制造分子、其乐趣来自于理解分子如何工作的人来说,这意味着什么。我问了柯林斯这个问题。他回想起自己第一次亲手结晶蛋白质,第一次看到一个药物分子与之结合的时刻。"我从此着迷一生,"他说。那些传统工具仍有其用武之地。但也许不在这里,因为这里的重点是尽快得到某种有效的东西进入临床。"我们都在努力为患者着想,"柯林斯说。
【单词解析】
dispense:/dɪˈspens/。动词,分配,分发;配(药),发(药);实施,执行(法律、正义等) (正式用语)。
streamline:/ˈstriːmlaɪn/。动词,精简,使(系统、流程)更高效;使成流线型。
pristine:/ˈprɪstiːn/。形容词,原始的,未受破坏的;崭新的,洁净的;纯正的,最初的。
crystallize:/ˈkrɪstəlaɪz/。动词,(使) 形成晶体,结晶;(使想法、计划等) 变得具体明确。
clasp against:紧紧地扣住/贴合在…上。
hook:/hʊk/。动词,使着迷,吸引住;钩住,挂;成功连接到(电话、网络等)。
Jerwood gave her answer: “I am so hungry for something new all the time.” Standing there, above the automated lab, she imagined the regions of chemistry where no one has yet gone, structures and reactions that lie on the far side of unknown processes. The sun was just pulling itself over the horizon. She thought of all the things the machines might do, all the things that she will do no longer. “It’s down to the untouched space, yeah? Because then I will have time to look into that space,” she said. “I will have time to take that risk.”
For some pharmaceutical researchers, though, the promise of AI goes beyond pushing scientific boundaries or even treating disease. Alex Zhavoronkov, the CEO and cofounder of Insilico, says the company favors targets that are implicated in both illness and aging. Its drug candidate for idiopathic pulmonary fibrosis, for example, is designed to prevent scarring of the lungs by dampening certain biological pathways, but it also may slow the aging of healthy cells. Zhavoronkov hopes to bring new drugs to the clinic, perhaps faster and cheaper, even as he uncovers new treatments for aging-related disease and decline.
杰伍德给出了她的答案:"我永远渴望新事物。"站在自动化的实验室上方,她想象着化学领域中尚未涉足的区域,那些位于未知过程彼岸的结构和反应。太阳正从地平线升起。她想到机器可能做的所有事情,想到所有她将不再需要做的事情。"(把那些事交给机器)就能专注于未触及的空间,对吧?因为那样我将有时间去探索那个空间,"她说。"我将有时间去冒那个险。"
然而,对于一些制药研究人员来说,AI的承诺超越了推动科学边界,甚至超越了治疗疾病。Insilico的联合创始人兼首席执行官亚历克斯·扎沃隆科夫表示,公司青睐那些与疾病和衰老都相关的靶点。例如,其针对特发性肺纤维化的候选药物旨在通过抑制某些生物通路来防止肺部瘢痕形成,但也可能减缓健康细胞的衰老。扎沃隆科夫希望将新药更快、更便宜地推进临床,同时也在探索与衰老相关疾病和衰退的新疗法。
【单词解析】
dampen:/ˈdæmpən/。动词,抑制,减弱,降低;使微湿,弄潮。
When I speak with Zhavoronkov, he’s at a company-wide retreat in Chongqing, China. “In 20 years, I’m going to be 66,” he says. “I saw my dad when he was 66, and it’s not pretty.” He is frank about having high expectations, about his desire for speed in an industry where speed isn’t always readily available. He shows me a video of an automated lab in Suzhou, China. “We built it during Covid,” he says, explaining that some of the laboratory scientists on the project worked around the clock, sleeping in the facility, to get it up and running.
There is something vaguely science-fictional about the setup, and about Zhavoronkov’s particular form of pragmatism. Zhavoronkov has scars on his arm where he’s had skin removed to make induced pluripotent stem cells, which can be reprogrammed to grow into many types of tissue. “If you want to buy my IPSC, give us a call. We’ll ship it to you,” he says. “The more data there is about you in the public domain, the higher chances you have to get a real good treatment when you get sick, especially with cancer.”
我与扎沃隆科夫交谈时,他正在中国重庆参加公司的全员务虚会。"20年后,我就66岁了,"他说。"我看到我父亲66岁时的样子,那并不美好。"他坦言抱有很高的期望,渴望在一个并非总能轻易提速的行业里加快速度。他给我看了一段位于中国苏州的自动化实验室的视频。"我们在新冠疫情期间建成的,"他说,并解释该项目的部分实验室科学家曾昼夜不停地工作,睡在设施里,才使其得以启动运行。
这种设置以及扎沃隆科夫那种特有的实用主义,都带有某种模糊的科幻色彩。扎沃隆科夫手臂上有疤痕,那是他为了制造诱导多能干细胞(iPSC)而取皮留下的,这种细胞可以被重新编程发育成多种类型的组织。"如果你想购买我的iPSC,给我们打电话。我们会寄给你,"他说。"你在公共领域的数据越多,当你生病(尤其是癌症)时,获得真正良好治疗的机会就越高。"
【单词解析】
retreat:/rɪˈtriːt/。名词,务虚会,集体静修活动;撤退,退却;隐居处,静养所。动词,撤退,退避。
vaguely:/ˈveɪɡli/。副词,略微,有点儿;模糊地,不明确地;心不在焉地,茫然地。
pragmatism:/ˈpræɡmətɪzəm/。名词,实用主义,务实作风。
pluripotent stem cells:/ˌplʊərɪˈpəʊt(ə)nt stem selz/。多能干细胞。
In the lab video, the camera glides through a black hallway, then through an anteroom, past a wall of glass. The glass can be dimmed, if the work going on behind it is confidential. Behind the wall are machines loaded with trays of reagents and cells, with arms that swivel as they move components around. Humans are rarely needed.
Sooner or later, in some form, AI tools will be standard in drug discovery, suspects Derek Lowe, the medicinal chemist and blogger. He calls himself a short-term pessimist, long-term optimist about these things. It’s happened again and again in the industry: New strategies arrive, ride a wave of hype, crash and burn. Then some of them, in some form, rise again and quietly become part of what’s normal. Already, big pharmaceutical companies—the behemoths of drug discovery—are starting their own AI-related research groups. Recursion, meanwhile, is exploring the use of AI not only to dream up and test new molecules but also to find trial participants, speeding along those last, costliest steps to market.
在实验室视频中,摄像机滑过一条黑色走廊,然后穿过一个前厅,经过一堵玻璃墙。如果后面的工作涉及保密,玻璃可以调暗。玻璃墙后面是装载着试剂和细胞托盘的机器,机械臂在移动组件时旋转。几乎不需要人类。
药物化学家兼博主德里克·洛推测,迟早,AI工具将以某种形式成为药物发现的标准配置。他自称在这些事情上是短期悲观主义者、长期乐观主义者。这种情况在行业内一再发生:新策略出现,掀起炒作浪潮,然后失败。接着,其中一些策略以某种形式重新崛起,悄然成为常态的一部分。大型制药公司——药物发现的巨头——已经开始建立自己的AI相关研究小组。与此同时,Recursion不仅在探索使用AI构思和测试新分子,还在寻找试验参与者,以加快进入市场的最后、最昂贵的步骤。
【单词解析】
confidential:/ˌkɒnfɪˈdenʃ(ə)l/。形容词,秘密的,机密的;受信任的,心腹的。
swivel:/ˈswɪv(ə)l/。动词,(使) 旋转,转动;名词,转环,旋轴。
ride a wave of hype:乘着…的浪潮;因一时的热潮而受益或流行。Hype,(俚语,炒作)。
behemoth:/bɪˈhiːmɒθ/。名词,巨头,巨兽。
costliest:/ˈkɒstliɪst/。costly的最高级形式,花钱最多的,代价最大的。
The transformation isn’t going to be without casualties. “These techniques, both the automation part and the software, are going to make more and more things slide into that ‘humans don’t do that kind of grunt work’ category,” Lowe says. Large numbers of jobs held by human chemists will wink out of existence. Those “who know how to use the machines are going to replace the ones who don’t,” Lowe says. Even Peter Ray no longer feels it’s accurate to describe him as a medicinal chemist. “I’m something else,” he muses. “I don’t know what to call it, to be honest.”
In the months since the blind date in London, Recursion has announced two drug candidates entering clinical trials, the MALT1 inhibitor and a molecule for lung cancer. A drug for a digestive disease is already in trials. Insilico is in the process of trying to advance to a phase III trial for its idiopathic pulmonary fibrosis drug, with Carol Satler on the phone to doctors. The cards are being turned over, one by one. Ray goes running sometimes, through his neighborhood near Dundee, Scotland, and thinks of his mother.
Gibson reflected on the long game he sees Recursion playing. The way it’s tinged with urgency. Yes, they want to change the world. And personally, he thinks it’s been too long in coming. “There’s a lot of people here who have lost a loved one or multiple loved ones to a specific disease,” he said. “They’re pissed off. They’re here because they want to get revenge on the lack of opportunity that that family member,or friend, or child, had.” The meter is ticking, numbering the days, as drugs move through trials and everyone waits to see what happens.
Time is the thing we are all running out of. Some of us faster than others.
这一转型并非没有代价。"这些技术,无论是自动化部分还是软件,将使越来越多的事情滑入'人类不再做那种繁琐工作'的范畴,"洛说。大量由人类化学家担任的岗位将消失。"那些知道如何使用机器的人将取代那些不知道的人,"洛说。即使是彼得·雷也不再觉得称自己为药物化学家是准确的。"我是别的什么,"他沉思道。"老实说,我不知道该怎么称呼它。"
自从伦敦的"相亲会"之后的几个月里,Recursion宣布有两种候选药物进入临床试验:MALT1抑制剂和一种针对肺癌的分子。一种用于消化系统疾病的药物已在试验中。Insilico正致力于推进其特发性肺纤维化药物的三期试验,卡罗尔·萨特勒正忙于与医生们电话沟通。纸牌正在一张张被翻开。雷有时会跑步,穿过他在苏格兰邓迪附近的社区,想起他的母亲。
吉布森反思了他所看到的Recursion正在进行的长期博弈。其中蕴含的紧迫感。是的,他们想改变世界。就个人而言,他认为这已经等待太久了。"这里有很多人因为某种特定疾病失去了一位或多位亲人,"他说。"他们很愤怒。他们来到这里,是想为那位家人、朋友或孩子所缺少的机会复仇。"随着药物通过试验,每个人都在等待结果,计量器滴答作响,数算着日子。
时间是我们所有人都在消耗殆尽的资源。有些人比其他人更快。
【单词解析】
casualties:/ˈkæʒuəltiz/。名词(复数),受害者,牺牲品;(战争、事故中的)伤亡人员;急诊室。
grunt work:繁重、枯燥的基础性工作,苦差事。
wink out:突然熄灭,消失。
muses:/ˈmjuːzɪz/。动词(第三人称单数),沉思,冥想 (常与 on, over, about 连用);若有所思地说。
reflect on:思考,反思,回顾。
tinge with:带有…的色彩,夹杂着…的意味。
piss off:(粗俗俚语) 非常生气的,恼火的。