23andMe, Inc.

Regeneron’s CEO and co-chair said he agreed with President Donald Trump’s view that European nations should pay more for new drugs. Leonard Schleifer’s remarks on Regeneron’s second-quarter earnings call on Friday were some of the first public comments from a pharmaceutical industry executive following Trump’s letters to drugmakers demanding “most favored nation” pricing within 60 days. Regeneron, and Schleifer specifically, were on the receiving end of those letters, which were posted Thursday afternoon. “I have been, and the company has been, outspoken that we agree with the president that the Europeans are not paying their fair share of innovation, and some way that needs to change,” Schleifer said on the earnings call. “It’s complicated and it does have to be done at a trade and policy level, because it can’t be done at an individual company level. It’s very difficult.” He added that “the solution is simply not to lower cost prices in the US without some equilibrating in Europe, because then there’ll be no innovation.” Trump’s letters signaled the latest push to get drugmakers to bring their US prices in line with what they charge in other developed countries. But Schleifer said it raises questions over future partnerships between American and European pharmaceutical companies. “I suspect a lot of new contracts will have to deal with the contingency of what happens if you license something to Europe,” Schleifer said. Regeneron has multiple products approved in other countries and relies on partners to help commercialize them . Schleifer pointed to the company’s blockbuster eye drug Eylea as an example. “We don’t control the pricing of Eylea outside of the United States. That’s controlled by Bayer,” he said. Asked by an analyst if he’d been down to Trump’s Mar-a-Lago “a lot” of times to influence policy, Schleifer replied that he has “not been down there frequently.” The chief executives of Eli Lilly and Pfizer have traveled to Trump’s estate in Florida multiple times, the analyst noted. “The president probably knows Regeneron and my first name given that it was the Regeneron cocktail for Covid that may have saved his life,” Schleifer said. “Beyond that, I don’t have any great insights to the policies.” Elsewhere on the earnings call, Regeneron said it received a complete response letter for a bispecific antibody and that additional approvals of Eylea HD will likely be delayed because of an FDA inspection at a manufacturing site in Indiana. Schleifer and chief scientific officer George Yancopoulos also repeatedly shielded questions about the amount of money that Regeneron spends on R&D, with about $5 billion anticipated to be spent this year. “The excitement or enthusiasm of those” Phase 3 programs and other pipeline assets, “is always being limited by people wanting to know what’s going to happen with Eylea and so forth, so I think our pipeline would be viewed very differently if it was viewed in isolation because of the incredible potential and opportunities,” Yancopoulos said. Schleifer said the company has a broad pipeline of 45 development programs, including work across lymphoma, myeloma, complement-mediated diseases, geographic atrophy, myasthenia gravis and thrombotic diseases. A Phase 2 trial of one of those assets, REGN7257, was discontinued in aplastic anemia. But the asset remains in Regeneron’s pipeline as the drugmaker continues to “evaluate next steps,” a spokesperson said in an emailed statement to Endpoints News . Schleifer asked for more attention on the Regeneron pipeline. “It’s hard for any one analyst, or any one analyst team, to look at 45 programs. If you’ve got 10 different companies, and the other nine have two programs each, you could consume all the time. That’s maybe why it doesn’t get as much attention as we’d like,” Schleifer said. The Regeneron CEO also noted the company has focused historically on internal R&D given its bustling research engine. Regeneron has made relatively few acquisitions compared to its pharmaceutical peers. “We want the best stuff for patients and so we go outside and look and look and look, and occasionally we do find stuff, and if we have to do it, we have a lot of flexibility to do it,” Schleifer said. “But to us, it’s not a lifeline like it is for so many companies.” Regeneron bought a London ocular biotech called Oxular for undisclosed terms in January. It tried buying 23andMe, but was outbid by the genetic testing company’s founder .

引言当熟悉的旋律响起，我们能毫不费力地跟着节奏拍手；当内心的想法涌现，我们能自然而然地将它们组织成流畅的语言。这两个看似毫不相关的能力，对大多数人来说如同呼吸般自然。然而，对全球数以亿计的口吃 (stuttering) 人群而言，后者却是一场持续的挑战。长期以来，口吃被误解为心理问题、坏习惯，甚至是性格缺陷，给患者带来了沉重的社会污名和心理负担。然而，科学的迷人之处，在于它总能拨开偏见的迷雾，直达问题的本质。7月28日，一项发表于《Nature Genetics》的里程碑式研究“Large-scale genome-wide analyses of stuttering”为我们揭开这个谜团提供了迄今为止最强有力的线索。该研究不仅在基因层面为口吃这一复杂的神经发育障碍提供了坚实的生物学证据，更巧妙地揭示了它与抑郁 (depression)、自闭症谱系障碍 (autism spectrum disorder, ASD) 甚至音乐节拍感知能力之间意想不到的深刻联系。这不仅仅是一次基因的寻宝游戏，更是一次对人类大脑如何协同调控语言、情绪和节律这一基本问题的深刻洞见。百万分之一的“密码”：前所未有的研究尺度我们的基因组是一部由30亿个字母组成的百科全书。要在这部浩瀚的巨著中，找到那些与特定疾病相关的“印刷错误”——也就是致病基因变异——无异于大海捞针。对于像口吃这样复杂的性状，其背后的遗传因素并非由单一“主效”基因决定，而是由成百上千个微效基因共同作用的结果，这使得寻找工作难上加难。过去的家族和双胞胎研究早已证实口吃具有很强的遗传性，遗传度估计在 42%到84% 之间，但要精确定位具体的基因位点，就需要巨大的样本量来提供足够的统计学效力。这项研究的磅礴之处，首先就体现在其惊人的研究尺度上。研究团队利用了23andMe公司庞大的数据库，分析了近 10万名 (99,776人) 自我报告曾有过口吃经历的个体 (病例组)，以及超过 一百万名 (1,023,243人) 从未有过口吃经历的个体 (对照组) 的基因数据。如此庞大的样本，为检测那些效应微弱但真实存在的遗传变异提供了前所未有的能力。然而，仅仅拥有庞大的数据是不够的。人类群体拥有丰富的遗传多样性，不同祖先来源的人群在基因背景上存在差异。如果将所有人群混在一起分析，可能会因为人群结构差异而产生虚假的关联信号。为了解决这个问题，研究人员采取了一种更为精细的策略：他们将样本按照遗传学方法确定的祖源，分为四个主要的群体：欧洲裔 (European, EUR)、非洲裔 (African, AFR)、东亚裔 (East Asian, EAS) 和拉丁/混合美洲裔 (Latino/Admixed American, AMR)。不仅如此，在每个祖源群体内部，他们还进一步按性别进行了分层。这种 “分层分析” 的巧妙设计，如同用不同颜色的滤镜去观察同一幅画作，使得研究人员不仅能够发现普遍适用于所有人群的遗传风险位点，还能捕捉到那些仅在特定性别或特定祖源人群中才显现其影响的“专属”遗传信号。这种精细化的分析策略，对于理解为何口吃在不同人群和性别中患病率存在差异至关重要。拨开迷雾：57个与口吃相关的“新大陆”通过这一系列严谨而复杂的分析，研究人员成功地在这片广阔的遗传海洋中，发现了 57个前所未见的、与口吃风险显著相关的独特基因座 (genetic loci)。这些新发现的“遗传大陆”，为理解口吃的生物学机制开辟了全新的疆域。在针对欧洲裔人群的分析中，研究人员发现了显著的性别差异。在欧洲裔男性中，他们找到了10个与口吃相关的基因座。这些区域附近的候选基因包括 VRK2、CAMTA1 和 CTNND2 等，它们大多参与了神经发育和功能调控。而在欧洲裔女性中，研究人员则发现了9个不同的基因座，包括与金属离子转运相关的 SLC39A8，以及在神经元迁移中扮演重要角色的 DCC 基因等。一个特别有趣的发现是，尽管欧洲裔男性和女性的口吃风险在遗传上高度相关 (遗传相关性系数rg高达 0.8952，P值小于10的-50次方)，但他们在全基因组层面显著的风险位点却几乎没有重叠。这就像两支去往同一个目的地的探险队，他们共享着相同的地图大方向，但最终各自在不同的地点扎下了营寨。这一发现有力地表明，口吃的遗传结构是复杂的，它既包含男女共享的遗传基础，也涉及性别特异的风险因素，这些因素可能共同塑造了最终的表型。这项研究的意义还在于它超越了以往主要集中于欧洲人群的研究局限。在对其他族裔的分析中，同样涌现出新的发现。例如，在非洲裔男性的样本中，研究人员识别出了与 PTPRQ、SHISA2 和 CYTH4 等基因相关的位点；而在拉丁裔女性和男性中，也分别找到了与 SORCS1 和 RGCC 相关的独特风险位点。这些发现在全球范围内扩展了我们对口吃遗传多样性的认知，强调了在遗传学研究中纳入不同祖源人群的重要性，为最终实现跨人群的精准医疗奠定了基础。口吃者的“朋友圈”：意想不到的遗传交集如果我们把一个人的全部遗传信息看作是其独特的身份密码，那么当两种截然不同的性状，其背后的遗传密码出现大量重叠时，这就暗示着它们之间可能存在着某种内在的、共享的生物学联系。研究人员利用 “连锁不平衡分数回归 (LD Score regression, LDSC)” 这一强大的统计工具，探索了口吃在遗传层面的“朋友圈”，结果发现了一系列出人意料的交集。分析显示，口吃的遗传风险与多种健康状况和行为特征存在显著的相关性。其中，最引人注意的是口吃与 抑郁症 之间的紧密联系。无论是在欧洲裔男性还是女性中，导致口吃风险增加的遗传变异，同样也显著增加了患上抑郁症的风险 (男女性P值均极显著)。这一发现为临床上观察到的口吃患者常伴有更高水平抑郁症状的现象，提供了深刻的遗传学解释。它告诉我们，这种共病现象可能不仅仅是长期口吃带来的心理压力所致，其背后或许还埋藏着共同的神经生物学根源。更有趣的是，在欧洲裔女性群体中，口吃的遗传关联网络显得更为广泛和复杂。研究人员发现，女性的口吃遗传风险与多种看似风马牛不相及的特质紧密相连，包括存在显著正相关的 听力损失 (Hearing loss) (P = 6.50 × 10⁻⁹)，提示听觉处理通路的异常可能在口吃中扮演某种角色；同样呈现正相关的 哮喘 (Asthma) (P = 2.91 × 10⁻⁸)；还有指向执行功能和注意力控制网络可能存在共同脆弱性的 注意力缺陷多动障碍 (ADHD) (P = 4.66 × 10⁻⁶)；以及呈现强烈正相关的 体重指数 (Body mass index, BMI) (P = 4.08 × 10⁻¹⁷)。与此同时，研究还发现了一些负相关关系，即增加口吃风险的遗传因素，反而会降低某些行为的频率，例如 饮酒频率 (frequency of alcohol consumption) (P = 5.0 × 10⁻⁸) 和 步行速度 (walking pace) (P = 8.81 × 10⁻¹¹) 。这些发现如同打开了一个潘多拉魔盒，揭示了口吃的遗传影响远远超出了言语系统本身。它不再是一个孤立的言语流畅性问题，而是嵌入在一个由情绪、代谢、注意力和运动协调等多种生理功能交织而成的复杂网络之中。节拍、自闭与抑郁：是谁在“导演”口吃？相关性不等于因果性，这是科学研究的基本准则。找到了口吃与抑郁、自闭症等疾病的遗传重叠，我们仍需回答一个更深层次的问题：它们之间究竟是谁“导致”了谁？是口吃引起了抑郁，还是抑郁导致了口吃，亦或是存在某个“幕后黑手”同时导演了这两场大戏？为了解开这个因果之谜，研究人员动用了 “孟德尔随机化, MR)” 分析。MR分析的原理十分巧妙。它利用了这样一个事实：我们的基因是在出生时随机分配的，就像一场天然的、终身不变的随机对照试验。通过分析那些与“暴露”因素 (如自闭症遗传风险) 强相关的基因变异，是否也同样影响“结局” (如口吃)，研究人员可以在很大程度上排除后天环境混杂因素的干扰，从而推断出两者之间是否存在因果关系。这次的MR分析结果，为我们描绘了一幅清晰而深刻的因果关系图景：首先是 节拍感知与口吃的双向奔赴。一个最为振奋人心的发现，是口吃与 节拍同步能力 (beat synchronization) 之间存在显著的双向因果关系。研究发现，天生节拍感较差的遗传倾向，会显著增加患口吃的风险。反过来，口吃的遗传倾向也会导致节拍同步能力的受损。这一发现为长期以来悬而未决的“非典型节律风险假说 (Atypical Rhythm Risk Hypothesis)” 提供了首个强有力的遗传学证据。该假说认为，大脑处理节律和时间信息的核心能力受损，是导致发育性言语和语言障碍 (包括口吃) 的一个关键风险因素。其次是 抑郁与口吃的双向纠缠。MR分析证实了口吃与抑郁症之间的双向因果关系。这意味着，口吃本身会增加患上抑郁症的风险，但同时，遗传上易患抑郁症的倾向，也会反过来增加口吃的风险。这提示两者可能共享着更为底层的神经生物学通路。再者是 自闭症对口吃的单向影响。研究还发现，自闭症谱系障碍 (ASD) 的遗传风险对口吃存在单向的因果效应。也就是说，携带更多ASD遗传风险的个体，也更容易患上口吃。这支持了口吃和自闭症这两种神经发育障碍在病理机制上的重叠。此外，研究还在欧洲裔女性中观察到，口吃的遗传倾向会增加患上ADHD的风险，而较慢的步行速度和较高的BMI也对女性口吃有因果效应。这些发现共同编织了一张复杂的因果网络，将口吃牢牢地定位为一个核心的神经发育问题，其影响远远超出了嘴唇和舌头的运动。神经元的“交响乐”：口吃基因在大脑中的“回响”找到了与口吃相关的基因位点，并厘清了其与其它疾病的因果关系后，下一个合乎逻辑的问题是：这些基因究竟是如何在大脑中发挥作用，最终影响到我们说话的流畅性的？为了回答这个问题，研究团队进行了 “分区遗传度 (Partitioned heritability)” 分析，旨在探究口吃相关的遗传变异，是否优先富集在特定类型或特定区域的脑细胞中。分析结果将矛头指向了大脑的指挥官—— 神经元 (neurons)。研究发现，与口吃相关的遗传信号，在那些主要在神经元中表达的基因组区域表现出显著的富集。这说明，口吃的遗传基础主要作用于神经元的功能，而非其他脑细胞（如星形胶质细胞或少突胶质细胞）。更进一步的组织特异性分析，则为我们勾勒出了一幅“口吃大脑”的功能地图。结果显示，口吃相关的遗传变异显著富集于那些在特定脑区高度表达的基因上，而这些脑区早已在过去的神经影像学研究中被发现与口吃密切相关：额叶皮层 (Frontal cortex) 和 前扣带皮层 (Anterior cingulate cortex)，大脑的“总指挥部”；基底节 (Basal ganglia)，包括 尾状核 (caudate) 和 黑质 (substantia nigra)，大脑的“运动调度中心”；以及 小脑 (Cerebellum)，运动协调和时间感知的中枢。这些发现将宏观的神经影像学观察与微观的遗传学证据连接了起来。它告诉我们，携带口吃遗传风险的个体，其大脑在负责语言规划、运动执行和节律感知的核心网络上，可能天生就存在着某种脆弱性。当这些基因在大脑中“奏响”时，它们共同谱写了一曲不太和谐的“神经元交响乐”，最终导致了言语输出的“卡顿”。是“男”“女”有别，还是“持续”与“自愈”之分？在口吃的世界里，性别差异是一个长期存在且令人困惑的现象。儿童早期，男女患病比例接近，但进入青春期和成年后，男性患者的数量可达女性的4倍之多。这种差异背后，究竟是单纯的生理性别差异，还是隐藏着更复杂的生物学故事？这项研究通过构建 多基因风险评分 (Polygenic Risk Score, PRS)，为我们提供了新的思考角度。PRS就像一个遗传风险的“计分卡”，它将成千上万个与疾病相关的微效基因变异累加起来，计算出个体患某种疾病的综合遗传风险。研究人员分别利用欧洲裔男性和女性的GWAS数据，构建了两种性別特异性的PRS模型，并在两个独立的、经过临床诊断的口吃患者队列中进行了验证。验证结果出人意料：由 男性数据构建的PRS模型，在预测男性和女性的口吃状态时都表现出色。在一个由临床医生严格诊断的、持续性口吃患者占多数的国际口吃项目 (International Stuttering Project, ISP) 队列中，男性模型的预测准确性 (AUC为 0.6108) 显著高于女性模型。相比之下，由女性数据构建的PRS模型，其预测能力则相对较弱，仅在女性群体中显示出一定的预测价值。这一不对称的结果引发了深刻的思考。为什么男性的遗传风险模型能更好地概括口吃的普遍风险？研究人员提出了几种可能的解释，其中最值得关注的是 “持续”与“自愈”的遗传差异。我们知道，大约80%的口吃儿童会自然恢复，而女性的自愈比例远高于男性。因此，在成年女性样本中，可能包含了大量已经自愈但仍报告“曾有过口吃”的个体。相比之下，成年男性样本则更富集那些持续性口吃的患者。这或许意味着，男性GWAS数据捕获到的，更多是导致口吃“持续不愈”的遗传信号；而女性GWAS数据则混合了“持续”和“自愈”两种不同结局的遗传信号，从而削弱了其预测能力。这个发现为未来的研究指明了一个激动人心的方向：区分持续性口吃和自愈性口吃的遗传基础，将是彻底解开这个古老谜题的关键一步。新发现的启示这项规模空前的研究，其意义远不止于在基因组上标注出57个新的位点。它从根本上重塑了我们对口吃的认知，并为未来的干预和治疗点亮了新的路径。首先，这项研究为口吃“去污名化”提供了迄今最坚实的科学武器。它用海量的数据证明，口吃是一种具有复杂遗传基础的神经发育障碍，而非心理脆弱、缺乏意志力或家庭教育不当的产物。将口吃的根源牢牢地锚定在生物学之上，有助于消除长期以来围绕在口吃患者身上的误解和偏见，促进社会对他们的理解和接纳。其次，研究揭示的口吃与抑郁、自闭症和节律感知障碍之间的遗传和因果联系，为临床实践提供了重要的启示。这意味着对口吃患者的评估和干预，不应局限于言语本身。关注他们的心理健康状况，评估其在注意力、社交和节律处理方面可能存在的潜在困难，并提供一个整合了言语治疗、心理支持和认知训练的“全人”治疗方案，可能会取得更好的效果。最后，这项研究无疑为口吃领域的 精准医疗 拉开了序幕。尽管目前的研究成果还不能直接用于临床诊断或基因治疗，但它为未来的发展铺平了道路。通过识别特定的生物学通路，研究人员可以着手筛选和开发针对这些通路的新型药物或干预手段。而随着对不同遗传亚群的理解不断深入，我们有理由期待，未来能够根据每个患者独特的遗传背景，为他们量身定制最有效的个性化治疗方案。从一个令人困扰的言语现象，到大脑中特定脑区的异常活动，再到基因组上一个个具体的编码位点，科学正带领我们一步步深入口吃的核心。对于全球数以亿计的口吃患者而言，这无疑是迈向更好理解和更有效支持的关键一步。参考文献Polikowsky, H.G., Scartozzi, A.C., Shaw, D.M. et al. Large-scale genome-wide analyses of stuttering. Nat Genet (2025). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41588-025-02267-2声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！往期热文：Nature Genetics | 解码自闭症“千人千面”：从“一体”到“四型”，我们离个性化干预又近了一步Nature Methods | 里程碑突破！研究人员将百万碱基人类DNA植入小鼠胚胎，现场直播生命“开机”过程Science | 重启大脑“免疫系统”！革命性疗法为致命脑白质病带来新生曙光Science | 百年进化之谜终结？一个理论统一性别、物种与生命禁区Nature | 4亿年的精雕细琢：代谢如何一步步塑造了酶的“容貌”？Nature Medicine | 你的器官几岁了？一管血揭示11个器官的“真实年龄”，大脑和免疫系统或是长寿的关键密钥

WASHINGTON — US lawmakers are slowly coalescing around biotech as a national security imperative, building off a report released earlier this year that industry has touted as a blueprint for future investments and a way to stay ahead of China. The BIOTech Caucus , launched last month by Reps. Chrissy Houlahan (D-PA) and Stephanie Bice (R-OK), is a bipartisan effort to fortify US biomanufacturing and biosecurity. They both spoke with Endpoints News about their effort, and how they plan to inform and generate support among their colleagues. “This might be an opportunity, if we’re aggressive enough about this, to actually think about this issue and legislate for this issue on time, rather than a decade late,” Houlahan said in an interview this week. Combating China’s rising influence and prowess in biotech has been brewing for years. The House passed the Biosecure Act last year to disincentivize US companies from using China-based manufacturers like WuXi AppTec and WuXi Biologics, though the bill died in the Senate. Meanwhile, China’s rapidly growing R&D efforts have made it a tantalizing location for pharmas and venture capitalists to scout new drugs. Houlahan acknowledged that caucuses alone are not an indication of legislative momentum, but said this one has the opportunity to tackle an issue before the US falls behind its allies and adversaries abroad. The first step is to educate members on the urgency, and next is finding legislative paths for new money, she said. The caucus and its focus are based on findings from the National Security Commission on Emerging Biotechnology, a congressional commission on which Bice serves. The commission’s report released in April called for a $15 billion infusion into the sector and specifically highlighted China’s ascent. Trade groups like BIO have also shifted their rhetoric in recent years to elevate biotech as a national security issue. Bice and Houlahan have worked together before on paid family leave legislation earlier this year. The two lawmakers, along with their four vice-chairs — two Democrats and two Republicans — are looking to rally other members behind the sector. Bice said she’s spoken with Rep. Mike Rogers (R-AL), who chairs the House Armed Services Committee, about including some of the caucus’ goals in the National Defense Authorization Act, which guides national defense policy. Bice also sits on the House Appropriations Committee and would look to find new money to include in the defense budget to pay for those policies. An alternative to more money, Bice added, could be a US partnership with ally nations to share rare earth minerals or active pharmaceutical ingredients to fortify the US supply chain. Pharma products are currently under a Commerce Department investigation as the White House mulls placing tariffs on the industry to incentivize onshoring. The administration has said that such tariffs could arrive as soon as the end of the month. While the focus on national security and supply chain resilience is bipartisan, stemming the cuts to the US’ federal science infrastructure is less so. Houlahan lamented the administration’s cut-and-ask-questions-later mentality, especially for the science agencies . Those cuts threaten to put a damper on biotech innovation and development, she said. “In the case of something like basic science and the National Science Foundation and the NIH, we can’t afford to be lighting things on fire and hosing them down right now,” she said. Houlahan has spoken to universities in Pennsylvania where scientists have already been poached as a result of a lack of funding, highlighting Singapore and Europe as destinations. Bice suggested that NIH funding was slightly out of the purview of the commission and of her focus, saying the agency’s research homes in on health, not national security. “This is a little bit different in that we’re looking at it from a national security perspective,” she said. Bice referenced 23andMe’s recent bankruptcy as an example of how biotech and national security overlap, claiming that the company’s trove of genetic data could have been exploited and capitalized on by China. Co-founder and former CEO Anne Wojcicki ultimately bought 23andMe through her nonprofit. But Bice hopes the US will use it as a lesson and invest in protecting biodata. “We want to see legislative wins,” she said.