Podcasts 科学播客 | 「CRISPR基因编辑疗法：道阻且长」

基因编辑是一种精确修改基因组序列以诱导基因组插入、删除或碱基替换的技术。许多疾病都伴随着体内基因表达的变化，尤其是一些由单个基因突变引起的遗传疾病，而基因编辑技术有望在基因水平控制疾病的发生。CRISPR基因编辑技术是目前最热门的生物工具之一，该技术在治疗癌症、心血管疾病、镰状细胞性贫血和神经退行性疾病方面具有令人瞩目的潜力。然而，研究人员在使用CRISPR技术编辑基因时也会遇到意想不到的挑战。

印度一组研究人员试图开发基于CRISPR的基因编辑疗法挽救一位患有罕见神经退行性疾病的年轻女性的生命。尽管他们付出了极大的努力，但由于研究进展过于缓慢，最终未能及时挽回她的生命。虽然许多人坚信基因编辑疗法能为那些罹患被忽视遗传疾病的患者带来希望，但要开发出能迅速定制个性化治疗方案的技术，可能还需要面临数年的挑战和努力。

When researcher Arkasubhra Ghosh finally met Uditi Saraf, he hoped that there was still a chance to save her.

当研究员Arkasubhra Ghosh终于见到Uditi Saraf时，他仍然希望她有机会被挽救。

Ghosh and his collaborators were racing to design a one-off treatment that would edit the DNA in the 20-year-old woman’s brain cells and get them to stop producing toxic proteins. It was an approach that had never been tried before, with a long list of reasons for why it might not work.

Ghosh和他的团队正全力设计一种个性化治疗，旨在编辑这位20岁女性大脑细胞中的DNA，阻止其继续产生有毒蛋白质。这是一种前所未有的治疗方法，尽管存在许多可能导致失败的原因。

But the team was making swift progress. The researchers were maybe six months away from being ready to give Uditi the therapy, Ghosh told her parents over breakfast at their home outside New Delhi last June. Even so, Uditi’s mother was not satisfied. Work faster, she urged him.

但团队的进展十分迅速。Ghosh在去年六月与Uditi的父母一起在他们位于新德里郊外的家中共进早餐时告诉他们，研究人员或许只需六个月便能准备好为Uditi提供治疗。尽管如此，Uditi的母亲仍不满足，催促加快进度。

Then, Uditi was carried to the breakfast table, and Ghosh understood her urgency. Once a gregarious and energetic child and teenager, with a quick laugh and a mischievous streak, Uditi was now unable to walk or feed herself. She had become nearly blind and deaf. Her family tried to talk to her: “These are the people who are making a therapy for you,” they said loudly.

随后，Uditi被抬到餐桌前，Ghosh才真正体会到她的迫切。曾经是一个开朗活泼、充满精力的孩子和青少年，Uditi总是笑声爽朗、调皮捣蛋，而现在她已无法走路，也不能自己进食，几乎失明且失聪。她的家人试图与她交谈：“这些人正在为你开发治疗方法，”他们大声说道。

Shaken, Ghosh returned to his gene-therapy laboratory at Narayana Nethralaya Eye Hospital in Bengaluru, India, and got to work. “If you need to put up tents in the lab, then we can do so,” he told his students. “I’m not going to sleep.”

Ghosh深受触动，回到了位于印度班加罗尔Narayana Nethralaya眼科医院的基因治疗实验室，开始了紧张的工作。他对学生们说：“如果需要在实验室搭帐篷，我们就搭。我不打算睡觉。”

Four months later, Uditi was gone.

The first therapy using CRISPR genome editing was approved in late 2023 to treat blood disorders that affect thousands of people worldwide. But the approach is also a source of hope to many people who have extremely rare genetic conditions, like the one Uditi had. Genome editing could one day become a radical way to address the diseases that are overlooked by pharmaceutical companies. “Patients are waiting, families are waiting,” says Jennifer Doudna, a molecular biologist at the University of California, Berkeley. “So we need to get on with it.”

四个月后，Uditi去世了。

2023年底，首个使用CRISPR基因编辑的疗法获得批准，用于治疗影响全球成千上万人的血液疾病。但这种方法也为许多患有极为罕见遗传病的人们带来了希望，正如Uditi所患的那种疾病一样。基因编辑有一天或许能成为一种突破性的方式，用于治疗那些被制药公司忽视的疾病。加利福尼亚大学伯克利分校的分子生物学家Jennifer Doudna说道：“患者在等待，家庭在等待。我们必须继续前进。”

Researchers are still laying the groundwork for this future. They are working out how best to design and manufacture the treatments, and how to deliver them to precise locations in the body. The cost is also a problem: the price of genome-editing therapy threatens to put it out of reach for many. Ghosh wants to bring those barriers down, and he’s convinced that India will eventually be the country to do it.

研究人员仍在为这一未来奠定基础。他们正在努力探索如何最好地设计和制造治疗方案，并如何将其准确地送达身体的特定部位。成本问题也是一个挑战：基因编辑治疗的价格可能会使许多人无法承受。Ghosh希望能够降低这些障碍，他深信印度最终将成为实现这一目标的国家。

But Uditi’s family could not wait — the pace of scientific research was too slow. They needed a sprint, and a team of researchers willing to take on not only the scientific challenge, but also the emotional heft and high risk of failure involved in attempting something that had never been done. “What we were trying to do was really almost in the realms of science fiction,” Ghosh says.

And he remains convinced that, despite Uditi’s tragic death, the lessons learnt will help others on a similar path. “It truly is a story of hope.”

但Uditi的家人无法等待——科学研究的进展太慢了。他们需要的是一次冲刺，需要一支愿意接受不仅是科学挑战，还包括尝试从未做过的事所带来的情感压力和高失败风险的研究团队。“我们所尝试做的几乎可以说是科幻领域的事情，”Ghosh说道。尽管Uditi的去世令人悲痛，Ghosh依然相信，所学到的经验教训将帮助其他面临类似困境的人。“这确实是一个充满希望的故事。”

Ghosh thought immediately of the two little boys with Duchenne muscular dystrophy: “What if I’m too late for them, too?”

Ghosh立刻想到了那两个患有杜氏肌营养不良症的小男孩：“如果我也太迟了，来不及救他们怎么办？”

Others in the lab also took the news hard. “For clinicians, perhaps they become hardened,” says Chakraborty. “We don’t have that experience. We were feeling agony.”

实验室的其他成员也深受打击。“对于临床医生来说，也许他们变得更加坚韧，”Chakraborty说道。“但我们没有那种经历。我们感受到的是痛苦。”

Ten days after learning that Uditi died, Chakraborty presented the lab’s efforts at a local conference and finished his talk with a picture of Uditi, smiling. In the audience, Riya Patra, a graduate student in Ghosh’s lab, began to cry. It was the first time she’d let herself see a picture of the young woman she’d tried so hard to save. “Before, I had thought that if I saw her, maybe I would cry,” she says. “And I wouldn’t be able to work anymore.”

在得知Uditi去世的十天后，Chakraborty在一次地方会议上展示了实验室的努力，并以Uditi微笑的照片结束了他的演讲。在场的Ghosh实验室研究生Riya Patra忍不住哭了出来。这是她第一次让自己看Uditi的照片，那位她曾努力挽救的年轻女性。“以前，我一直认为如果看到她的照片，我可能会哭出来，”她说道，“然后我就没办法再工作了。”

An estimated 100 million people in India have a rare disease. For decades, people affected by such conditions have cycled through hope and disappointment as researchers have inched closer to developing therapies that can help them at a genetic level. After a series of sporadic starts and failures, gene therapy has finally begun to find its footing. This has set the stage for CRISPR-based genome editing to rocket to the clinic.

估计有1亿人受到罕见病的影响。在过去几十年里，患有这些疾病的人们经历了希望与失望的反复交替，随着研究人员逐步接近开发能够在基因层面提供帮助的治疗方法。经过一系列的断断续续和失败后，基因疗法终于开始站稳脚跟。这为基于CRISPR的基因编辑技术进入临床应用铺平了道路。

When nine-year-old Uditi first dropped her camera, CRISPR was just an oddity — a strange assembly of sequences found in microbial genomes, only studied by a few die-hard microbiologists. Four years before she was diagnosed with FENIB, researchers showed for the first time that a CRISPR-based system could cut DNA in human cells grown in the lab. And the first CRISPR-based genome-editing therapy was approved in the United Kingdom to treat sickle-cell disease the month after Uditi died.

当九岁的Uditi第一次弄坏她的相机时，CRISPR还只是一个新奇的概念——它是微生物基因组中发现的一种奇特序列，只有少数顽固的微生物学家在研究。就在她被诊断为FENIB的四年前，研究人员首次展示了CRISPR系统能够在实验室培养的人类细胞中切割DNA。而在Uditi去世的下一个月，首个基于CRISPR的基因编辑疗法在英国获批，用于治疗镰状细胞贫血。

In theory, many people with a genetic condition, no matter how rare, could benefit from these technologies. But the reality is harsher. It will take years to establish the techniques needed to create rapid, on-demand, bespoke CRISPR therapies. Most people with these conditions don’t have that kind of time.

从理论上讲，许多遗传性疾病患者，无论其多么罕见，都可能从这些技术中受益。但现实却更加严峻。要建立出能够快速、按需、量身定制的CRISPR疗法所需的技术，可能还需要数年的时间。而大多数患有这些疾病的人，时间并不充裕。

But researchers are working to streamline the process. Doudna’s institute, for example, is working to standardize some aspects of genome-editing therapies, in part to make it cheaper and easier to develop such treatments for people with rare conditions. And the US National Institutes of Health has been trying to develop similar pipelines for gene therapies — an effort that could help to inform genome-editing efforts. “It’s been really hard,” says Doudna. “But what we’re doing is going to have long-term impact.”

然而，研究人员正致力于简化这一过程。例如，Doudna的研究所正在努力标准化一些基因编辑疗法的环节，部分目的是为了降低成本，让罕见病患者能够更容易获得此类治疗。美国国立卫生研究院（NIH）也在尝试开发类似的基因疗法流程，这项努力可能为基因编辑技术的发展提供指导。“这真的非常困难，”Doudna说道。“但我们正在做的事情将产生长期的影响。”