你想过小白鼠的性别吗？

   五年前，马里兰大学的研究人员Alisa Morss Clyne在实验室培养的人类细胞中研究肺动脉高压(一种影响肺部动脉的高血压)。但她所看到的结果并不相符。“误差很大，数据没有任何意义，”她说，“让我们看一看男性和女性的对比图表——我们的发现非常有趣。”

The blood vessels in the lungs of people with pulmonary hypertension take up more glucose, and she found the female cells metabolized the glucose in way that changed a protein that was critical to blood vessel function. In other words, the sex of the cells became an important variable that affected the outcome of the research.

肺动脉高压患者肺部的血管吸收葡萄糖更多，她还发现女性细胞通过改变葡萄糖代谢的方式改变了一种对血管功能至关重要的蛋白质。换句话说，细胞的性别成为了影响研究结果的一个重要变量。

Concern has been growing in recent years that ignoring or downplaying differences in sex as a biological variable -- whether in cells under a microscope or in lab animals -- is undermining biomedical research at the earliest stages.

近年来，人们越来越担心，忽视或淡化性别差异作为一种生物学变量正在破坏早期阶段的生物医学研究——无论是在显微镜下的细胞中，还是在实验室动物中。

This matters because many diseases -- including Covid-19 -- affect men and women differently, and missing sex-based differences can make misdiagnosis and mistreatment more likely.

这很重要，因为包括新冠在内的许多疾病对男性和女性的影响是不同的，忽视基于性别的差异更可能会产生误诊和误治。

While it's often unclear what sex the cells used in lab research are, and to what degree female cells are underrepresented, the default lab rat has long been male.

虽然人们通常不清楚实验室研究中使用的细胞是什么性别，雌性细胞代表性缺失程度有多大，但长期以来，默认的小白鼠一直是雄性。

One study from 2011 found that in neuroscience research, male animals were used six times more often than females, and figures from a more recent analysis in 2017 suggest they have only improved marginally.

2011年的一项研究发现，在神经科学研究中，雄性动物被使用的频率是雌性动物的6倍；而2017年的一项最新分析数据显示，这些数据只做了微小的改善。

Women have been routinely included in clinical trials since the 1990s, but "integrating female animals into basic and preclinical research -- which is the key building block for studies in humans -- has been much slower," said Hunter.

自上世纪90年代以来，女性一直被纳入临床试验，但“将雌性动物纳入基础和临床前研究也是人类研究的关键组成部分，但它的速度要慢得多。” 美国国家卫生研究院妇女健康研究办公室基础和转化研究副主任Chyren Hunter说。

Women are more likely to be misdiagnosed than men when it comes to a wide range of conditions, including heart attacks and ADHD. And women typically experience more -- and more intense -- side effects from pharmacological drugs. Some drugs are more effective in men than women, including common over the counter ones such as ibuprofen and naproxen -- both forms of nonsteroidal anti-inflammatory drugs (NSAID).

在很多情况下，女性比男性更容易被误诊，包括心脏病和多动症，而且女性通常会经受药理学药物更严重的副作用。有些药物对男性更有效，包括常见的非处方药，如布洛芬和萘普生——这两种形式的非甾体抗炎药。

And it goes both ways: Alosetron, a drug approved to treat severe irritable bowel syndrome, is only approved for treatment in women as it is largely ineffective in men."We're saying here that not all researchers need to study sex differences. But all researchers really should consider how biological sex can impact the questions that they're studying," Hunter said.

当然影响是双向的：阿洛司琼是一种被批准用于治疗严重肠易激综合征的药物，它只被批准用于女性，因为对男性基本上无效。“我们的意思是，并不是所有的研究人员都需要研究性别差异。但所有的研究人员都应该考虑生理性别对他们手头的研究问题有什么影响。” Hunter说。

In the case of research into Covid-19, it's not clear that sex as a biological variable is consistently being taken into account even though men are three times more likely than women to be admitted to the ICU.

在对新冠的研究中，我们尚不清楚性别作为一种生物学变量是否一直被考虑在内，尽管男性入住ICU的可能性是女性的三倍。

   科学研究的主要资助方——包括每年处理8万笔拨款的美国国立卫生研究院（NIH）—— 已经开始要求他们资助的研究将性别作为一个生物学变量考虑在内。2016年起，NIH的拨款申请必须在设计研究和分析结果时包含雄性和雌性动物或细胞，或者为只研究一种性别提供强有力的理由。

The NIH doesn't have any mechanism to ensure the funded research adheres to what was set out in the grant application, and some feel the efforts made in grant applications are only lip service.

但NIH没有任何机制来确保被资助的研究遵循拨款申请中的规定，一些人认为在拨款申请中所做的努力只是嘴上说的好听。

"It's been nearly six years, and we haven't seen the needle move in any considerable direction in terms of even understanding what the sex differences are at baseline level in between males and females," said Aditi Bhargava, a professor in the Department of Ob/Gyn and the Center for Reproductive Sciences at the University of California San Francisco.

加州大学旧金山分校妇产科和生殖科学中心的教授Aditi Bhargava表示:“近6年来，就了解男性和女性在基线水平上的性别差异而言，我们还没有看到任何重大进展。”

Rebecca Shansky, an associate professor in the Department of Psychology at Northeastern University in Boston, wrote in Nature Neuroscience in March that considering sex as a biological variable "will require a global shift in science culture."

波士顿东北大学心理学系副教授Rebecca Shansky在3月份的《自然神经科学》杂志上写道，将性别视为生物变量“将需要全球科学文化的转变”。

For a long time, female lab animals were thought too hormonal and messy for science, said Shansky, and one of the main reasons given for not using female mice was that they made data more "variable" as a result of the female reproductive cycle. But this is a myth, she said. Hormones aren't a uniquely female problem. The testosterone levels of male mice can also vary widely.

Shansky说，在很长一段时间里，实验室里的雌性动物被认为激素过多，会使得实验混乱，而不使用雌性老鼠的主要原因之一是，由于雌性生殖周期的缘故，它们使数据更加“多变”。但这只是一种缺乏根据的说法，她说。荷尔蒙并不是女性独有的问题。雄性小鼠的睾丸激素水平也有很大的差异。

A study published last year in the journal Science found that over 13,000 genes are expressed differently between the sexes; the researchers also identified sex-biased patterns of gene regulation that were linked to over 50 bodily traits and functions. These differences don't always matter and shouldn't be exaggerated.

去年发表在《科学》杂志上的一项研究表明，超过13000个基因在性别之间表达不同；研究人员还确定了与50多个身体特征和功能相关的基因调控的性别偏见形式。这些差异并不总是重要的，也不应该被夸大。

For example, the popular sleep medication zolpidem, better known as Ambien, lingers longer in the blood of women than of men, causing drowsiness, cognitive impairment and increased traffic accidents. For these reasons, the FDA in 2013 halved the recommended dosage prescribed to women. One subsequent study into the drug after the FDA changed its recommendations suggested that it was body weight, not sex, that was the key biological variable.

例如，流行的睡眠药物唑吡坦(俗称安必恩)在女性血液中停留的时间比男性长，导致嗜睡、认知障碍和交通事故的概率增加。出于这些原因，美国食品及药物管理局（FDA）在2013年将建议给女性的处方剂量减半。但在FDA提出该建议后，一项后续研究表明，体重而不是性别，是关键的生物变量。

However, many researchers agree it should be taken into account. Bhargava said disease should be thought of as a destination, and researchers needed to pay more attention to the journey at the biochemical and cellular level. "I want to come to London. If I'm coming from San Francisco, I could take a nonstop flight, or I could come via Washington DC and Paris," she said. "The outcome is that we've all reached London, but the paths were divergent.

然而，许多研究人员认为应该将其考虑在内。Bhargava称，应该将疾病视为一个目的地，研究人员需要在生物化学和细胞水平上更加关注这一过程。“我想去伦敦。如果我从旧金山来，我可以坐直飞航班，也可以经停华盛顿特区和巴黎，”她说。“结果是我们都到达了伦敦，但路径不同。”

"Men and women can take different paths, and they may cross and intersect, to reach the same destination -- or in this case, in disease -- but that doesn't mean that they started off in a same way, or that every single step that they took to reach that destination was identical."

“男人和女人可以采取不同的路径，他们可能十字相交, 到达相同的目的地，在这种情况下，也就是在疾病中，这并不意味着他们以相同的方式开始，踩着完全相同的每一步才能达到目的地。”

For Clyne at the University of Maryland, the realization that the cells she worked on differed by sex has completely reshaped how she and her lab work."I had never thought about the sex of my cells before," she said. "I just thought you take cells out of a person, and you get rid of the physical and biochemical differences that happen in the blood vessels of men and women, and we should all be the same."

马里兰大学的Clyne意识到，她所研究的细胞因性别而异而完全改变了她和实验室的工作方式。“我以前从来没有想过细胞的性别，”她说，“我只是认为，从一个人体内取出细胞，就可以消除男人和女人血管中发生的生理和生化差异，我们应该是一样的。”

Information on where the cells comes from isn't routinely available, and she now spends time tracking down the details. She also has twice as many samples in each experiment, which adds up in terms of cost and time.

关于细胞来源的信息并不常见，她现在正在花时间追踪细节。她在每个实验中还拥有两倍的样本，这就增加了成本和时间。

Plus, it can be hard to confident about the sex effects in experiments. "We have been asked how many cell donors we need to be sure that an effect is sex rather than donor related. We don't yet know the answer to that question," Clyne said. But even with these challenges, she thinks the effort is crucial. "People think that if you take the cells out of the living being and put them in a dish, there's no difference anymore. A lot of thoughts about male and female differences are based around estrogen and sex hormones, but it's more fundamental than that."

此外，在实验中很难确定性别产生的影响。“我们曾被问及需要多少细胞供体，才能确定一种效应与性别有关，而不是与供体有关。我们还不知道这个问题的答案，”Clyne说。但即使面临这些挑战，她仍认为这项工作至关重要。“人们认为，如果将细胞从生物体中取出来并放入盘中，就不再有区别了。很多关于男性和女性差异的想法都是基于雌激素和性激素，但其实存在更根本的差异。”