Trinitrate

▎药明康德编者按：自Donald Ingber博士最初设想建立Wyss研究所（Wyss Institute）至今已近二十年。这一大胆设想源于这样一个信念：将工程学原理与对生物学的深刻洞见相结合，可以为医学及其他领域带来变革性解决方案。如今这一愿景已蓬勃发展成为现实。Wyss研究所已成为转化科学的典范，不仅开创了器官芯片（organs-on-chips）、仿生材料等突破性技术，更孵化出六十余家初创企业，积极塑造着医疗健康的未来图景。美国FDA在今年早些时候宣布一项计划，旨在减少新药临床试验申请中的临床前安全性研究对动物实验的依赖。这一监管方向的变化，正体现了像Wyss研究所推动的人体模拟平台等前沿技术在药物开发中的重要性和前景。最近，我们与Ingber博士进行了一次对话，探讨该研究所的独特架构如何为学术界的创新引擎提供动力，以传统学术环境中难于见到的方式加速创新。Donald E. Ingber博士现任Wyss研究所创始所长，并同时担任哈佛医学院血管生物学系Judah Folkman讲席教授和哈佛大学John A. Paulson工程与应用科学学院Hansjörg Wyss讲席教授。作为横跨医学、工程与基础科学的跨界科学家，他开创性地研发了器官芯片、靶向血管闭塞部位的剪切力激活纳米疗法等多项突破性技术，在力学生物学、纳米医学等领域持续引领生物医学创新。Ingber博士已发表500余篇学术论文，获得200多项专利，创立8家生物科技公司，其开发的"人体器官芯片"技术被世界经济论坛评为十大新兴技术，并被纽约现代艺术博物馆永久收藏。Ingber博士曾两度入选《自然·生物技术》“全球顶尖转化研究者TOP20”，并斩获多项跨领域荣誉。您好，很高兴与您对话。Wyss研究所常被形容为工程学与生物学交汇之地。在您的工作中，您如何定义"转化"这一概念？Donald Ingber博士：Wyss研究所成立的初衷是助力构建未来。我们在约20年前开始构思，并于16年前正式创立了研究所。我们坚信，实验室里的发现如果不能走出实验室，就难以产生现实影响力。在转化研究层面，这种设计思维塑造了我们的创新方式。合成生物学是我们工作的主要部分之一——例如利用基因工程等手段对细胞、组织乃至完整生物体进行重编程，或者开发跨越血脑屏障的载体（如工程化蛋白或病毒载体）。我们始终致力于融合生物学与工程学，以构建新一代疗法、诊断技术、医疗设备和生物材料。今年早些时候，美国FDA宣布了一项计划，旨在减少新药临床试验申请中的临床前安全性研究对动物实验的依赖，并将器官芯片技术列为潜在替代方案。作为该领域的先驱，您认为哪些关键转折点推动了这项技术从学术概念转化为具有现实影响力的解决方案？Donald Ingber博士：在Wyss研究所创立之初，我的实验室正好孕育出了器官芯片技术。这项技术最初始于一个博士后项目，其基础是我们耗费近二十年研发的技术——将计算机微芯片制造方法创新应用于生物活体细胞研究。我们创建了内衬活细胞的设备，其中包含模拟生理功能（例如肺部呼吸运动或肠道的蠕动功能）的空腔通道。但关键在于证明这些芯片能真正复现人类器官级别的功能——这要求我们不断优化生物模型、设计出更好的设备，并开发能进行长期培养与功能维持的配套系统。然而，降低技术转化过程中的风险需要做的努力远不止于科研层面。我们直接与医药企业展开合作，这些合作不仅对技术验证至关重要，更帮助我们精准把握行业真实需求：他们究竟需要实验室台式设备还是大型系统？怎样的用户界面最理想？这些产业合作有助于我们优化产品与市场的契合度。在Wyss研究所，我们还组建了约50人的内部团队，成员均具备深厚的产品开发经验——其中许多人曾在初创公司或医药公司工作过，有些人拥有基于细胞的毒性检测的技术背景，有些人则拥有生物技术工具商业化的背景。因此，我们不仅降低了技术风险，更系统性地规避了研究成果转化的全链条风险。这是一个极具代表性的案例。那么，Wyss研究所在推动技术商业化过程中，如何确定优先推进哪些技术？是基于潜在影响力、技术可行性，还是产业界兴趣来进行决策的？Donald Ingber博士：Wyss研究所采用的运营模式可谓独树一帜，与我见过的任何机构都截然不同。某种程度上，我们打造了一个“学术界创新工坊”的加强版。我们的教授可以自由使用研究所的核心平台资源，并获得内部资金用于支持博士后和学生的研究。更重要的是，他们始终保持着完全的学术自主权。我们不会将学者的实验室完全迁入研究所内，而是精选每个团队中具创业精神和技术驱动力的成员。我们的核心策略之一是鼓励尽早报告发明成果。研究所内设有战略知识产权律师团队——他们的职责不是撰写专利，而是提供具有可操作性的早期反馈。例如在审阅发明报告时，他们会指出："当前的方案虽然不能申请专利，但若对A、B、C三方面进行调整优化，它可能会变得非常有价值。"这种指导能让研究人员及时调整方向，确保走在最具转化潜力的捷径上。在后续阶段，我们设立了称为“验证项目”的内部申请机制。这类项目往往由团队自发组建——通常包括博士后、学生以及具有产业经验的技术人员。他们只需提交约5页的简明提案，阐述初步的高价值应用场景、技术里程碑和1-2年的项目时间线。此时团队已初步具备初创企业特质，我们的业务开发团队和知识产权专家会协助制定上市策略、专利布局和专利的自由实施分析。多数项目最终会孵化成为初创企业，通常是在发表了具有重大影响力的论文并获得了早期投资者的青睐之后。但有时投资者的反馈意见会指出需要进一步降低技术或商业风险。若多位投资者提出相同顾虑，团队可申请作为“研究所项目”以获得支持。这类项目将获得专项资助来解决潜在投资者所发现的具体问题——无论是补充更多临床前数据、降低制造成本、亦或是完善监管策略。我们推动的转化案例跨度极大：从最终授权给医药企业的新型癌症疫苗（我们开展了1期临床试验），到在临床研究中能让老年人的平衡能力恢复到20岁年轻人水平的智能鞋垫（其间我们将生产成本降低了十倍以上）。这些都不是传统学术机构中的常见成果。这也正是Wyss研究所与众不同的地方：我们不仅研发技术，我们还致力于打造让技术产生实际影响力的全流程体系。您能否也分享一些未按计划顺利推进的案例？从这些案例中我们可以汲取哪些教训？Donald Ingber博士：好的。有些创意本身没有问题，但为时尚早。时机往往决定一切。1998年我曾创办一家初创企业，专注于医疗设备及其他材料的3D打印应用。这是正确的方向，但当时的市场远未成熟——我们只是超前了。另一个我曾寄予厚望的案例，是我们2012年发表在《科学》杂志的项目。灵感来源于血小板对血管狭窄处高剪切应力环境的响应机制——这种力学刺激会触发血栓形成。我们设想：能否模拟这一机制，将药物精准递送至心梗、卒中或肺栓塞等血管阻塞部位？这类疾病中，溶栓药物虽能救命，但前提是必须快速给药，而且会带来全身性出血等重大风险。我们采用可规模化的喷雾干燥技术开发出了血小板大小的纳米颗粒聚集体，表面覆盖溶栓药物。在肺栓塞动物模型中，仅需1%常规剂量就能挽救85%的实验动物，效果极其显著。然而随后多重挑战接踵而至，包括药物原材料的供应、对扩大化生产的疑虑、以及中风领域的融资环境。后来我们调整方向，转而使用该技术来递送硝酸甘油——一种血管扩张剂。在缺血性卒中临床前模型中，装载硝酸甘油的微粒可以恢复侧枝血管的血流，减轻神经损伤，且规避了全身性副作用。不久前我们就此提交了一篇论文，时隔十三年终于获得了投资者的关注。虽然这个项目尚未成功，但希望仍在。阻碍它的因素并不在科学层面，而是商业化方面的挑战：时机、风险承受能力、找到关键合作伙伴。根据我的经验，多数“失败”与理念或数据无关，归根结底是两个因素：人与市场时机。最大的教训主要就在此处。展望未来，您认为科学转化流程在未来十年将如何演变？在您看来，下一个前沿领域在哪里？您认为像Wyss这样的机构又该如何发展以迎接这些机遇？Donald Ingber博士：我们已经在探索并实践若干极具前景的新模式。最令人振奋的进展之一是与风险投资机构的早期合作。这些机构现在为我们创新管线的上游环节——我称之为创新漏斗的"左侧"或“创新工坊”阶段，提供不加限定的支持。此外，他们还资助一些验证项目，这些项目往往是初创企业的雏形。这些机构不会被动地等待技术风险降低后再介入，而是从初期阶段就开始参与项目培育——有时甚至组建外部团队与我们内部团队并行开发。这种深度早期合作已经催生多个前景广阔的初创企业。我们开发的另一创新模式是“预竞争联盟（pre-competitive consortium）”，该联盟聚焦神经治疗最大瓶颈——穿越血脑屏障。我们发现几乎所有大型药企都在努力应对这一挑战，尤其是在阿尔茨海默病、肌萎缩侧索硬化（ALS）等疾病的生物制品研发领域，超过95%的候选药物曾经折戟沉沙。在与药企和生物科技公司的对话中，我们捕捉到一个关键信息：企业都对共享药物递送技术持开放态度。这一洞见促使我们建立预竞争联盟，开发新型血脑屏障穿透载体并将其非独家授权给多家公司。这是一个双赢的局面：企业仍可开发自己的独有药物，而穿透载体技术能更快获得广泛应用。简而言之，在Wyss研究所，我们正在尝试开创一种前所未有的商业化协作模式——这种模式不仅在哈佛大学没有先例，在学术界和产业界也都是前所未见。这种协作模式正是突破下一个前沿领域所需的关键驱动力。感谢您的真知灼见！Turbocharging the Skunkworks of Academia: A Conversation with Dr. Donald Ingber, Founding Director of the Wyss Institute at HarvardEditor’s Note: It’s been nearly two decades since Dr. Donald Ingber first envisioned the Wyss Institute—a bold idea rooted in the belief that engineering principles, when combined with a deep understanding of biology, could unlock transformative solutions in medicine and beyond. Today, that vision is a thriving reality. The Wyss Institute has become a model for translational science, pioneering technologies such as organs-on-chips and bioinspired materials, and launching more than sixty startups that are actively shaping the future of healthcare. We recently sat down with Dr. Ingber to explore how the Institute’s unique structure has “turbocharged the skunkworks of academia,” accelerating innovation in ways rarely seen in traditional academic settings.Don, it’s great to speak with you. The Wyss Institute is often described as a place where engineering and biology truly converge. How do you define "translation" in the context of your work?Donald Ingber: The Wyss Institute was created to help engineer the future. We began thinking about this nearly 20 years ago and officially launched the Institute 16 years ago. We believe that discoveries made at the bench won’t have a real-world impact unless they move beyond the lab. When it comes to translation, this design perspective shapes how we invent. Synthetic biology is a major part of our work—using genetic engineering and other tools to reprogram cells, tissues, and even whole organisms, or to develop shuttles that cross the blood-brain barrier—be it engineered proteins or viral vectors. We’re blending biology and engineering to build the next generation of therapeutics, diagnostics, devices, and biomaterials.Recently, FDA announced a plan to reduce reliance on animal testing in preclinical safety studies included in Investigation New Drug applications, and listed organs-on-chips technologies as a potential alternative. As a pioneer in this field, what were the key inflection points that helped move it from an academic concept to something with real-world impact?Donald Ingber: The organs-on-chips technology emerged from my lab right around the time the Wyss Institute was launching. It started with a postdoc project and was built on techniques we had been developing for almost two decades—adapting methods from computer microchip manufacturing and applying them to biology and living cells. We created devices lined with living cells, containing hollow channels that mimic physiological functions—like breathing motions in the lung or peristaltic movements in the intestine. We had to prove that these chips could truly replicate human organ-level functions. That meant refining the biology, engineering better devices, and developing instruments that could support long-term culture and function.But de-risking went far beyond the science. We engaged directly with pharmaceutical companies—these collaborations were critical not just for validation, but for understanding what industry actually needed. Would they want something that fits on a lab bench or a larger system? What kind of user interface would be ideal? These partnerships helped us refine the product-market fit.At the Wyss Institute, we also built a strong internal team—about 50 people with deep product development experience, including many who had worked in startups or pharma. Some had backgrounds in cell-based toxicity testing, others in commercializing biotech tools. So we didn’t just de-risk the technology—we de-risked the entire translational pathway.That’s a great example. At Wyss Institute, how do you prioritize which technologies to move toward commercialization? Is it based on potential impact, feasibility, or industry interest?Donald Ingber: The Wyss Institute operates under a very unique model—unlike anything I’ve seen elsewhere. In a way, we’ve turbocharged what I call the “skunkworks of academia.” Our faculty have open access to the Institute’s platforms and receive internal funding to support postdocs and students. Importantly, they maintain complete creative freedom. We don’t move in entire faculty labs on site—just the more entrepreneurial, technology-driven people from each group.One of our key strategies is to encourage early reporting of inventions. We have strategic intellectual property attorneys on site—not to write patents, but to offer early, actionable feedback. They’ll look at a report of invention and say, for example, “This isn't patentable as-is, but if you tweak A, B, and C, it could be highly valuable.” That allows researchers to refocus early and be sure that they are on the shortest path to impact.Later in the process, we have an internal application for what we call Validation Projects. These often arise when a team begins to self-assemble—frequently including postdocs, students, along with technical staff who have industry experience. They submit a short proposal—usually about five pages—describing an initial high-value application, technical milestones, and a one to two-year timeline. They essentially begin forming a startup-ready team, pulling in our business development staff and IP experts to build a go-to-market strategy, IP landscape, and freedom-to-operate analysis.Most of these projects spin out as startups, often following a high-impact publication and early investor interest. But sometimes, investor feedback highlights a need for additional technical or commercial de-risking. If multiple investors echo the same concerns, teams can apply for support as an Institute Project. These receive funding to address specific gaps identified by potential investors—whether it’s additional preclinical data, manufacturing cost reduction, or regulatory strategy.We’ve done everything from running a Phase 1 trial for a cancer vaccine later licensed by a pharmaceutical company, to developing a shoe insole that restored balance in a clinical study with elderly to that of 20-year-olds—where we had to reduce manufacturing costs more than tenfold. That’s not the kind of work you typically see in an academic environment. It’s what makes the Wyss Institute truly different: we don’t just develop technology—we build the full pathway to real-world impact.Can you also share examples that didn’t go as planned? What can we learn from that experience?Donald Ingber: Absolutely. Sometimes the idea is right—but it’s just too early. Timing can be everything. Back in 1998, I founded a startup focused on 3D printing of medical devices and other materials for various applications. It was the right idea, but way too early for the market. We were just ahead of our time.Another example—one I thought would be a blockbuster—was a project we published in Science in 2012. The idea was inspired by how platelets respond to narrowing in blood vessels, which creates high shear stress and triggers clot formation. We thought: what if we could mimic that mechanism to deliver drugs specifically to sites of vascular obstruction, like in heart attacks, strokes, or pulmonary embolisms? These are conditions where clot-busting drugs can save lives—but only if administered quickly, and they come with major risks like systemic bleeding. So, we developed nanoparticle aggregates—about the size of a platelet—using a scalable spray-drying technique. We coated them with clot-busting drugs, and in animal models of pulmonary embolism, we saved 85% of the animals using just 1% of the typical drug dose. It was incredibly promising. But then came the hurdles. We couldn’t get access to tissue plasminogen activator (tPA), and no one wanted to license it for this use because the stroke market had a history of failure. Venture capitalists wouldn’t take the risk. Others raised concerns about manufacturing scale-up.We later pivoted and used this technology to deliver nitroglycerin instead—a widely available, low-cost vasodilator. We’ve now shown in preclinical models of ischemic stroke that nitroglycerin-loaded particles restore blood flow through collateral vessels, reduce neurological damage, and avoid the usual systemic side effects. We just submitted a paper on it and are finally getting serious investor interest—13 years later.So while it hasn’t succeeded yet, it might still. What’s held it back hasn’t been the science—it’s been the commercial barriers: timing, risk tolerance, access to key partners. In my experience, most failures aren’t about the idea or the data. They come down to two things: people and timing. Either the team dynamics break down, or the commercial ecosystem just isn’t ready for the leap. That’s where the biggest lessons often lie.Looking ahead, how do you see the process of translation evolving over the next decade? Where do you think the next frontier lies, and how do you see institutions like yours evolving to meet those opportunities?Donald Ingber: We've already begun exploring and implementing new models that are showing real promise. One of the most exciting developments is our early-stage collaboration with venture capital firms. These firms are now providing unrestricted support for the early part of our innovation pipeline—what I call the "left side" of our innovation funnel, or the skunkworks. In addition, they are then funding some of our Validation Projects, which are often the seeds of startups. Instead of waiting for de-risked technologies to emerge, they’re helping to shape and support them from the ground up—sometimes even assembling external teams to work in parallel with our internal ones. This type of deep, early collaboration is already producing some very promising startups.Another promising model we’ve developed is a pre-competitive consortium focused on solving one of the biggest bottlenecks in neurotherapeutics: crossing the blood-brain barrier. We saw that nearly every major company struggles with this challenge—especially with biologics for diseases like Alzheimer’s and ALS, where over 95% of drug candidates fail. In conversations with pharma and biotech companies, we realized something important: they all want to protect their own drugs, but they’re open to sharing delivery technologies. That insight led us to launch a pre-competitive consortium where we develop and license novel BBB shuttles non-exclusively to multiple companies. It’s a win-win: companies retain their proprietary drugs, and the shuttles get broadly adopted faster. So, if I had to sum it up: at the Wyss Institute, we experiment with commercial collaboration types, things that Harvard's never done before, we've never done before, companies have never done before. And that’s exactly what’s needed to unlock the next frontier.Thank you for your insights!参考资料：[1] Donald E. Ingber, M.D., Ph.D.FOUNDING DIRECTOR AND CORE FACULTY Retrieved June 19, 2025, from https://wyss.harvard.edu/team/core-faculty/donald-ingber/免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。