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Alternatives to animal testing are finally taking off

Changing habits may be the hardest engineering challenge of all.

改变习惯可能是所有工程挑战中最困难的一项。

Lab rats have long been a mainstay of biomedical research and drug development. Now, technologies such as Emulate’s Lung-on-a-Chip aim to model human biology without relying on animals.

长期以来，实验大鼠一直是生物医学研究和药物开发的中流砥柱。如今，诸如 Emulate 公司的“肺芯片”（Lung-on-a-Chip）等技术旨在模拟人体生物学，而无需依赖动物。

Seventeen years ago, cell biologist Donald Ingber and his colleagues at Harvard University’s Wyss Institute for Biologically Inspired Engineering submitted a paper to the journal Science describing their model human lung. It was smaller than a USB stick and made of a clear polymer slab containing narrow channels, which were lined with the type of cells that line a lung’s air sacs and blood vessels. When air was pumped through hollow chambers beside the channels, the device rhythmically expanded and contracted—it “breathed.”

十七年前，细胞生物学家唐纳德·英格伯（Donald Ingber）及其在哈佛大学威斯生物启发工程研究所（Wyss Institute for Biologically Inspired Engineering）的同事向《科学》杂志提交了一篇论文，描述了他们的人体肺模型。它比 U 盘还小，由一块透明的聚合物板制成，内部包含狭窄的通道，通道内壁覆盖着肺气囊和血管内壁的细胞。当空气被泵入通道旁的中空腔室时，该装置会节律性地扩张和收缩——它“呼吸”了。

This lifelike movement was a dramatic change from previous generations of lung models, which typically used static cultures of lung tissue that were unable to simulate the movements essential to lung function. When exposed to inflammatory proteins and bacteria, Ingber’s artificial lung reacted much as living lungs would. And exposure to silica nanoparticles used to model the effects of ultrafine particulates revealed that movement affected how tissues absorbed them.

这种栩栩如生的运动与前几代肺模型相比发生了巨大变化，前几代模型通常使用无法模拟肺功能所需运动的静态肺组织培养物。当暴露于炎症蛋白和细菌时，英格伯的人造肺表现得与活体肺非常相似。而暴露于用于模拟超细颗粒物影响的二氧化硅纳米颗粒实验则表明，运动会影响组织吸收这些颗粒的方式。

Donald Ingber led the team that developed the first human lung-on-a-chip at Harvard University’s Wyss Institute. Sam Ogden

唐纳德·英格伯领导了在哈佛大学威斯研究所开发出首个“人体肺芯片”的团队。（摄影：Sam Ogden）

It was a powerful proof-of-principle demonstration of a system that could be used to test drugs and other chemicals, providing a complement and even an alternative to testing in tissue cultures or in animals. Even so, the editors at Science were hesitant. They rejected the paper and suggested that Ingber’s team also run the tests in mice.

这是一个强有力的原理验证演示，证明了该系统可用于测试药物和其他化学品，为组织培养或动物测试提供了一种补充，甚至是一种替代方案。即便如此，《科学》杂志的编辑们仍持犹豫态度。他们拒绝了这篇论文，并建议英格伯的团队也在小鼠身上进行测试。

It wasn’t an unreasonable request: Harvard’s lung system was new and comparing the results it generated to results from mice would help validate it. Ingber’s team ran the suggested experiments and resubmitted their study a year later, in 2010, at which point it was published. (It has since been cited by nearly 5,400 other papers.) Still, the incident spoke to how animal models have been the default of modern biomedical research.

这并非不合理的要求：哈佛的肺系统是全新的，将其产生的结果与小鼠的结果进行比较有助于验证其有效性。英格伯的团队进行了建议的实验，并在一年后的 2010 年重新提交了研究报告，随后该研究得以发表。（此后，该论文已被近 5400 篇其他论文引用。）尽管如此，这一事件反映出动物模型在现代生物医学研究中一直处于默认地位。

An early lung-on-a-chip developed at Harvard’s Wyss Institute used microfluidic channels lined with human cells to reproduce key features of lung function. Wyss Institute at Harvard University

哈佛大学威斯研究所开发的早期“肺芯片”利用内衬人体细胞的微流控通道，再现了肺功能的关键特征。（图片来源：哈佛大学威斯研究所）

A recent story told by Ilka Maschmeyer, a translational toxicology researcher and executive at the German biotech company TissUse, shows how much things have changed. TissUse specializes in building organ-on-a-chip systems—the conversational name for systems like Ingber’s lung—that are used by pharmaceutical companies for research. A few months ago, says Maschmeyer, a pharmaceutical company approached TissUse after being denied permission by the U.S. Food and Drug Administration to run a clinical trial of a new drug. The problem: It had presented animal data, but the FDA wanted data from organs-on-a-chip or some comparable alternative. The standards had come full circle.

德国生物技术公司 TissUse 的转化毒理学研究员兼高管伊尔卡·马施迈耶（Ilka Maschmeyer）最近讲述的一个故事，展示了情况发生了多大的变化。TissUse 专门构建“器官芯片”系统——这是对英格伯肺模型这类系统的通俗称呼——供制药公司用于研究。马施迈耶说，几个月前，一家制药公司在被美国食品药品监督管理局（FDA）拒绝批准进行新药临床试验后，找到了 TissUse。问题在于：该公司提交了动物数据，但 FDA 要求提供来自器官芯片或类似替代方案的数据。标准已经完成了一个轮回。

The lung chip re-creates the interface between an air sac and a blood vessel, with human lung and endothelial cells growing on opposite sides of a porous membrane. Vacuum channels rhythmically stretch and relax the tissue to mimic breathing, reproducing mechanical forces that can affect how lung cells respond to substances they encounter. In one experiment, researchers added bacteria to the air channel and white blood cells to the blood channel; the immune cells crossed the membrane and engulfed the bacteria, reproducing an inflammatory response.

肺芯片再现了气囊与血管之间的界面，人体肺细胞和内皮细胞在多孔膜的两侧生长。真空通道节律性地拉伸和放松组织以模拟呼吸，再现了可能影响肺细胞对所遇物质反应的机械力。在一次实验中，研究人员在空气通道中加入了细菌，在血液通道中加入了白细胞；免疫细胞穿过膜并吞噬了细菌，再现了炎症反应。

The moment spoke to a trend, perhaps even the early days of a fundamental shift, away from the use of animals in toxicology and drug development. “It’s rare still,” says Maschmeyer, “but I think it’s going to be more and more frequent.”

这一时刻反映出一种趋势，甚至可能是一个根本性转变的初期，即在毒理学和药物开发中减少对动物的使用。“这种情况仍然很少见，”马施迈耶说，“但我认为它会变得越来越频繁。”

A host of these kinds of alternatives to experiments on animals have been developed over the years. Collectively they’re known as NAMs, an acronym that stands, depending on whom you’re talking to, for new approach methodologies, novel alternative methods, or nonanimal methods. Most NAMs have yet to be rigorously tested, but early studies suggest their potential.

多年来，人们开发了许多此类动物实验的替代方案。它们统称为 NAMs，这个缩写根据交流对象的不同，分别代表“新方法论”（new approach methodologies）、“新型替代方法”（novel alternative methods）或“非动物方法”（nonanimal methods）。大多数 NAMs 尚未经过严格测试，但早期研究表明了它们的潜力。

As NAMs have become more sophisticated, the question of how they will be implemented has become less about their technical qualities and more about the practical next steps needed to realize their potential. Validating NAMs—standardizing the systems, conducting head-to-head comparisons with animal experiments—is an enormous challenge. Moreover, simply outperforming animal models is necessary but not sufficient. The adoption of NAMs will require changes in policy, training, and culture.

随着 NAMs 变得越来越复杂，如何实施它们的问题已不再仅仅关乎其技术质量，更多地在于实现其潜力所需的实际后续步骤。验证 NAMs——即标准化系统、与动物实验进行直接对比——是一项巨大的挑战。此外，仅仅优于动物模型是必要条件，但还不够。采用 NAMs 将需要政策、培训和文化方面的变革。

“This transition process is much more complicated than you would think,” says Thomas Hartung, a toxicologist and director of the Center for Alternatives to Animal Testing at Johns Hopkins University. “It is more about change management than it is about the technology.”

“这个转型过程比你想象的要复杂得多，”约翰霍普金斯大学毒理学家兼动物测试替代中心主任托马斯·哈通（Thomas Hartung）表示，“这更多是关于变革管理，而不是技术本身。”

For decades, animal advocates and many scientists have criticized both the morality and usefulness of experimenting on animals. An estimated 92 percent of all drugs that enter U.S. clinical trials fail to reach the market, sometimes for business reasons but often because the drugs prove ineffective or unsafe in ways that were not predicted by animal experiments. Failure rates are even higher in drugs for heart disease, cancer, and diseases of the brain.

几十年来，动物权益倡导者和许多科学家一直批评动物实验的道德性和有效性。据估计，进入美国临床试验的所有药物中，有 92% 未能上市，有时是出于商业原因，但通常是因为药物被证明无效或不安全，而这些问题在动物实验中并未被预测到。心脏病、癌症和脑部疾病药物的失败率甚至更高。

These statistics don’t automatically mean that a reliance on animals is to blame. Flawed study designs are a problem too, and also the sheer confounding complexity of disease. But there’s little question that animals have made poor surrogates for many conditions. And just as animal experiments may mistakenly suggest efficacy or fail to predict harm in humans, they might also erroneously suggest that drugs are ineffective or harmful when they could actually work in humans. Some researchers argue that if aspirin or acetaminophen had been discovered after the advent of modern testing re

这些统计数据并不自动意味着对动物的依赖是罪魁祸首。有缺陷的研究设计也是一个问题，疾病本身的复杂性也是如此。但毫无疑问，动物在许多疾病状况下并不是理想的替代品。正如动物实验可能错误地暗示疗效或未能预测对人类的伤害一样，它们也可能错误地暗示药物无效或有害，而这些药物实际上可能对人类有效。一些研究人员认为，如果阿司匹林或对乙酰氨基酚是在现代测试方法出现之后才被发现的……