▎藥明康德

編者按：自Donald Ingber博士最初設想建立Wyss研究所（Wyss Institute）至今已近二十年。這一大膽設想源于這樣一個信念：將工程學原理與對生物學的深刻洞見相結合，可以為醫學及其他領域帶來變革性解決方案。如今這一愿景已蓬勃發展成為現實。Wyss研究所已成為轉化科學的典范，不僅開創了器官芯片（organs-on-chips）、仿生材料等突破性技術，更孵化出六十余家初創企業，積極塑造著醫療健康的未來圖景。美國FDA在今年早些時候宣布一項計劃，旨在減少新藥臨床試驗申請中的臨床前安全性研究對動物實驗的依賴。這一監管方向的變化，正體現了像Wyss研究所推動的人體模擬平臺等前沿技術在藥物開發中的重要性和前景。最近，我們與Ingber博士進行了一次對話，探討該研究所的獨特架構如何為學術界的創新引擎提供動力，以傳統學術環境中難于見到的方式加速創新。

Donald E. Ingber博士現任Wyss研究所創始所長，并同時擔任哈佛醫學院血管生物學系Judah Folkman講席教授和哈佛大學John A. Paulson工程與應用科學學院Hansj?rg Wyss講席教授。作為橫跨醫學、工程與基礎科學的跨界科學家，他開創性地研發了器官芯片、靶向血管閉塞部位的剪切力激活納米療法等多項突破性技術，在力學生物學、納米醫學等領域持續引領生物醫學創新。Ingber博士已發表500余篇學術論文，獲得200多項專利，創立8家生物科技公司，其開發的"人體器官芯片"技術被世界經濟論壇評為十大新興技術，并被紐約現代藝術博物館永久收藏。Ingber博士曾兩度入選《自然·生物技術》“全球頂尖轉化研究者TOP20”，并斬獲多項跨領域榮譽。

您好，很高興與您對話。Wyss研究所常被形容為工程學與生物學交匯之地。在您的工作中，您如何定義"轉化"這一概念？

Donald Ingber博士：Wyss研究所成立的初衷是助力構建未來。我們在約20年前開始構思，并于16年前正式創立了研究所。我們堅信，實驗室里的發現如果不能走出實驗室，就難以產生現實影響力。在轉化研究層面，這種設計思維塑造了我們的創新方式。合成生物學是我們工作的主要部分之一——例如利用基因工程等手段對細胞、組織乃至完整生物體進行重編程，或者開發跨越血腦屏障的載體（如工程化蛋白或病毒載體）。我們始終致力于融合生物學與工程學，以構建新一代療法、診斷技術、醫療設備和生物材料。

今年早些時候，美國FDA宣布了一項計劃，旨在減少新藥臨床試驗申請中的臨床前安全性研究對動物實驗的依賴，并將器官芯片技術列為潛在替代方案。作為該領域的先驅，您認為哪些關鍵轉折點推動了這項技術從學術概念轉化為具有現實影響力的解決方案？

Donald Ingber博士：在Wyss研究所創立之初，我的實驗室正好孕育出了器官芯片技術。這項技術最初始于一個博士后項目，其基礎是我們耗費近二十年研發的技術——將計算機微芯片制造方法創新應用于生物活體細胞研究。我們創建了內襯活細胞的設備，其中包含模擬生理功能（例如肺部呼吸運動或腸道的蠕動功能）的空腔通道。但關鍵在于證明這些芯片能真正復現人類器官級別的功能——這要求我們不斷優化生物模型、設計出更好的設備，并開發能進行長期培養與功能維持的配套系統。

然而，降低技術轉化過程中的風險需要做的努力遠不止于科研層面。我們直接與醫藥企業展開合作，這些合作不僅對技術驗證至關重要，更幫助我們精準把握行業真實需求：他們究竟需要實驗室臺式設備還是大型系統？怎樣的用戶界面最理想？這些產業合作有助于我們優化產品與市場的契合度。

在Wyss研究所，我們還組建了約50人的內部團隊，成員均具備深厚的產品開發經驗——其中許多人曾在初創公司或醫藥公司工作過，有些人擁有基于細胞的毒性檢測的技術背景，有些人則擁有生物技術工具商業化的背景。因此，我們不僅降低了技術風險，更系統性地規避了研究成果轉化的全鏈條風險。

這是一個極具代表性的案例。那么，Wyss研究所在推動技術商業化過程中，如何確定優先推進哪些技術？是基于潛在影響力、技術可行性，還是產業界興趣來進行決策的？

Donald Ingber博士：Wyss研究所采用的運營模式可謂獨樹一幟，與我見過的任何機構都截然不同。某種程度上，我們打造了一個“學術界創新工坊”的加強版。我們的教授可以自由使用研究所的核心平臺資源，并獲得內部資金用于支持博士后和學生的研究。更重要的是，他們始終保持著完全的學術自主權。我們不會將學者的實驗室完全遷入研究所內，而是精選每個團隊中具創業精神和技術驅動力的成員。

我們的核心策略之一是鼓勵盡早報告發明成果。研究所內設有戰略知識產權律師團隊——他們的職責不是撰寫專利，而是提供具有可操作性的早期反饋。例如在審閱發明報告時，他們會指出："當前的方案雖然不能申請專利，但若對A、B、C三方面進行調整優化，它可能會變得非常有價值。"這種指導能讓研究人員及時調整方向，確保走在最具轉化潛力的捷徑上。

在后續階段，我們設立了稱為“驗證項目”的內部申請機制。這類項目往往由團隊自發組建——通常包括博士后、學生以及具有產業經驗的技術人員。他們只需提交約5頁的簡明提案，闡述初步的高價值應用場景、技術里程碑和1-2年的項目時間線。此時團隊已初步具備初創企業特質，我們的業務開發團隊和知識產權專家會協助制定上市策略、專利布局和專利的自由實施分析。

多數項目最終會孵化成為初創企業，通常是在發表了具有重大影響力的論文并獲得了早期投資者的青睞之后。但有時投資者的反饋意見會指出需要進一步降低技術或商業風險。若多位投資者提出相同顧慮，團隊可申請作為“研究所項目”以獲得支持。這類項目將獲得專項資助來解決潛在投資者所發現的具體問題——無論是補充更多臨床前數據、降低制造成本、亦或是完善監管策略。

我們推動的轉化案例跨度極大：從最終授權給醫藥企業的新型癌癥疫苗（我們開展了1期臨床試驗），到在臨床研究中能讓老年人的平衡能力恢復到20歲年輕人水平的智能鞋墊（其間我們將生產成本降低了十倍以上）。這些都不是傳統學術機構中的常見成果。這也正是Wyss研究所與眾不同的地方：我們不僅研發技術，我們還致力于打造讓技術產生實際影響力的全流程體系。

您能否也分享一些未按計劃順利推進的案例？從這些案例中我們可以汲取哪些教訓？

Donald Ingber博士：好的。有些創意本身沒有問題，但為時尚早。時機往往決定一切。1998年我曾創辦一家初創企業，專注于醫療設備及其他材料的3D打印應用。這是正確的方向，但當時的市場遠未成熟——我們只是超前了。

另一個我曾寄予厚望的案例，是我們2012年發表在《科學》雜志的項目。靈感來源于血小板對血管狹窄處高剪切應力環境的響應機制——這種力學刺激會觸發血栓形成。我們設想：能否模擬這一機制，將藥物精準遞送至心梗、卒中或肺栓塞等血管阻塞部位？這類疾病中，溶栓藥物雖能救命，但前提是必須快速給藥，而且會帶來全身性出血等重大風險。我們采用可規模化的噴霧干燥技術開發出了血小板大小的納米顆粒聚集體，表面覆蓋溶栓藥物。在肺栓塞動物模型中，僅需1%常規劑量就能挽救85%的實驗動物，效果極其顯著。

然而隨后多重挑戰接踵而至，包括藥物原材料的供應、對擴大化生產的疑慮、以及中風領域的融資環境。

后來我們調整方向，轉而使用該技術來遞送硝酸甘油——一種血管擴張劑。在缺血性卒中臨床前模型中，裝載硝酸甘油的微粒可以恢復側枝血管的血流，減輕神經損傷，且規避了全身性副作用。不久前我們就此提交了一篇論文，時隔十三年終于獲得了投資者的關注。

雖然這個項目尚未成功，但希望仍在。阻礙它的因素并不在科學層面，而是商業化方面的挑戰：時機、風險承受能力、找到關鍵合作伙伴。根據我的經驗，多數“失敗”與理念或數據無關，歸根結底是兩個因素：人與市場時機。最大的教訓主要就在此處。

展望未來，您認為科學轉化流程在未來十年將如何演變？在您看來，下一個前沿領域在哪里？您認為像Wyss這樣的機構又該如何發展以迎接這些機遇？

Donald Ingber博士：我們已經在探索并實踐若干極具前景的新模式。最令人振奮的進展之一是與風險投資機構的早期合作。這些機構現在為我們創新管線的上游環節——我稱之為創新漏斗的"左側"或“創新工坊”階段，提供不加限定的支持。此外，他們還資助一些驗證項目，這些項目往往是初創企業的雛形。這些機構不會被動地等待技術風險降低后再介入，而是從初期階段就開始參與項目培育——有時甚至組建外部團隊與我們內部團隊并行開發。這種深度早期合作已經催生多個前景廣闊的初創企業。

我們開發的另一創新模式是“預競爭聯盟（pre-competitive consortium）”，該聯盟聚焦神經治療最大瓶頸——穿越血腦屏障。我們發現幾乎所有大型藥企都在努力應對這一挑戰，尤其是在阿爾茨海默病、肌萎縮側索硬化（ALS）等疾病的生物制品研發領域，超過95%的候選藥物曾經折戟沉沙。在與藥企和生物科技公司的對話中，我們捕捉到一個關鍵信息：企業都對共享藥物遞送技術持開放態度。這一洞見促使我們建立預競爭聯盟，開發新型血腦屏障穿透載體并將其非獨家授權給多家公司。這是一個雙贏的局面：企業仍可開發自己的獨有藥物，而穿透載體技術能更快獲得廣泛應用。

簡而言之，在Wyss研究所，我們正在嘗試開創一種前所未有的商業化協作模式——這種模式不僅在哈佛大學沒有先例，在學術界和產業界也都是前所未見。這種協作模式正是突破下一個前沿領域所需的關鍵驅動力。

感謝您的真知灼見！

Turbocharging the Skunkworks of Academia: A Conversation with Dr. Donald Ingber, Founding Director of the Wyss Institute at Harvard

Editor’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 listedorgans-on-chipstechnologies 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!

參考資料：

[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/

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