成功将猪肾移植到人体内标志着一个重要的医学里程碑，但专家警告说，解决器官短缺问题仍然是一个遥远的目标。 上周，我们首次听说，美国外科医生将一只经过基因编辑的猪的肾脏移植到了一个活人身上。 新闻报道称，该手术是异种移植的一个突破，即器官、细胞或组织从一个物种移植到另一个物种。 异种移植的拥护者认为这是解决世界各地器官短缺的办法。 2023年12月，澳大利亚有1445人在等待捐赠肾脏的名单上。 在美国，超过89000人正在等待肾脏。 一位生物技术公司首席执行官表示，经过基因编辑的猪有望“获得无限量的可移植器官”。 然而，并不是每个人都相信将动物器官移植到人类体内真的是器官移植的答案，或者即使以这种方式使用其他动物的器官是正确的。 手术成功有两个关键障碍：器官排斥反应和动物病毒传播给接受者。 但在过去的十年里，一种被称为ascrispr/cas9的新平台和技术（通常简称为crispr）承诺会缓解这些问题。 什么是薯片？crispr基因编辑利用了自然界中已经发现的一个系统。 crispr的“基因剪刀”在细菌和其他微生物中进化，帮助它们抵御病毒。 它们的细胞机制使它们能够通过切割病毒dna来整合并最终摧毁病毒dna。 2012年，两组科学家发现了如何利用这种细菌免疫系统。 这是由dna和相关蛋白的重复阵列组成的，称为“cas”（crispr-associated）蛋白。 当他们使用一种特殊的cas蛋白（cas9）和一个由单一分子组成的“引导rna”时，他们发现他们可以编程crispr/cas9复合物，在他们想要的精确位置破坏和修复dna。 该系统甚至可以在修复部位“敲入”新基因。 2020年，领导这些团队的两位科学家因其工作获得了诺贝尔奖。 在最新的异种移植中，crispr技术被用于编辑供体猪中的69个基因，以使病毒基因失活，用人类基因使猪“人性化”，并敲除有害的猪基因。 基因编辑异种移植的繁忙时期尽管crispr编辑为异种移植的可能性带来了新的希望，但即使是最近的试验也表明，仍然需要高度谨慎。 2022年和2023年，两名没有资格接受传统心脏移植的晚期心脏病患者获得了接受基因编辑猪心的监管许可。 这些猪心经过十次基因组编辑，使其更适合移植到人类身上。 然而，两名患者都在手术后几周内死亡。 本月早些时候，我们听说中国的一组外科医生（在征得家人同意的情况下）将一个基因编辑的猪肝移植到一名临床死亡的男子身上。 直到试验的十天结束，肝脏功能都很好。 这个最新的例子有什么不同？经过基因编辑的猪肾脏被移植到一个相对年轻、存活、有法律能力且同意的成年人身上。 对供体猪进行基因编辑的总数非常高。 研究人员报告说，他们进行了69次编辑，使病毒基因失活，用人类基因使猪“人性化”，并敲除有害的猪基因。 很明显，将这些器官转化为可存活的移植产品的竞赛正在加速。 就在几个月前，从生物技术的梦想到临床的现实，crispr基因编辑首次出现在主流医学中。 去年11月，英国和美国的药品监管机构批准了世界上第一种基于crispr的人类基因组编辑疗法，用于治疗危及生命的镰状细胞病。 这种被称为casgevy的治疗方法使用crispr/cas-9来编辑患者自身的血液（骨髓）干细胞。 通过破坏使红细胞呈镰刀状的不健康基因，目的是产生健康的球形红细胞。 crispr技术旨在将患病的红细胞恢复到健康的圆形。 尽管这种治疗使用了患者自身的细胞，但同样的基本原理也适用于最近的临床异种移植：可能会对不合适的细胞材料进行编辑，使其对患者有治疗益处。 我们将更多地讨论基因编辑医学和基因技术监管机构越来越多地被要求批准使用基因编辑和crispr的新实验试验。 然而，无论是异种移植还是这项技术的治疗应用，都不会导致可以遗传的基因组发生变化。 要做到这一点，需要在细胞生命的早期阶段对其进行更清晰的编辑，例如在体外（实验室）对早期胚胎细胞进行编辑。 在澳大利亚，故意对人类基因组进行可遗传的改变属于刑事犯罪，可判处15年监禁。 世界上没有一个司法管辖区的法律明确允许可遗传的人类基因组编辑。 然而，一些国家缺乏关于程序的具体规定。 这是未来吗？然而，即使没有产生可遗传的基因变化，使用crispr的异种移植仍处于起步阶段。 尽管头条新闻充满希望，但目前还没有一个在活体中进行持续7个月以上的稳定异种移植的例子。 虽然美国最近的这种移植是根据所谓的“同情使用”豁免获得授权的，但猪-人异种移植的常规临床试验尚未开始。 但这种试验的前景可能需要对目前的结果进行重大改进，才能在美国或其他地方获得监管部门的批准。 同样，监管部门批准任何“现成”的异种移植器官，包括基因编辑的肾脏，似乎还有一段路要走。 这篇文章最初发表在对话上，标题是：第一个猪肾被移植到了一个活着的人身上。 但我们离解决器官短缺还有很长的路要走。 这是悉尼法学院的克里斯托弗·鲁奇写的。
the successful transplantation of a pig kidney into a human marks a significant medical milestone, but experts caution that solving organ shortages remains a distant goal.in a world first, we heard last week that us surgeons had transplanted a kidney from a gene-edited pig into a living human. news reports said the procedure was a breakthrough in xenotransplantation – when an organ, cells or tissues are transplanted from one species to another.champions of xenotransplantation regard it as the solution to organ shortages across the world. in december 2023, 1,445 people in australia were on the waiting list for donor kidneys. in the united states, more than 89,000 are waiting for kidneys. one biotech ceo says gene-edited pigs promise “an unlimited supply of transplantable organs”.not, everyone, though, is convincedtransplanting animal organs into humans is really the answer to organshortages, or even if it’s right to use organs from other animals thisway.there are two critical barriers to the procedure’s success: organ rejection and the transmission of animal viruses to recipients. but in the past decade, a new platform and technique known ascrispr/cas9 – often shortened to crispr – has promised to mitigate theseissues.what is crispr?crispr gene editing takes advantage of a system already found in nature. crispr’s “genetic scissors” evolved in bacteria and other microbes to help them fend off viruses. their cellular machinery allows them to integrate and ultimately destroy viral dna by cutting it.in 2012, two teams of scientists discovered how to harness this bacterial immune system. this is made up of repeating arrays of dna and associated proteins, known as “cas” (crispr-associated) proteins.when they used a particular cas protein (cas9) with a “guide rna” made up of a singular molecule, they found they could program the crispr/cas9 complex to break and repair dna at precise locations as they desired. the system could even “knock in” new genes at the repair site.in 2020, the two scientists leading these teams were awarded a nobel prize for their work.in the case of the latest xenotransplantation, crispr technology was used to edit 69 genes in the donor pig to inactivate viral genes, “humanise” the pig with human genes, and knock out harmful pig genes.a busy time for gene-edited xenotransplantationwhile crispr editing has brought new hope to the possibility of xenotransplantation, even recent trials show great caution is still warranted.in 2022 and 2023, two patients with terminal heart diseases, who were ineligible for traditional heart transplants, were granted regulatory permission to receive a gene-edited pig heart. these pig hearts had ten genome edits to make them more suitable for transplanting into humans. however, both patients died within several weeks of the procedures.earlier this month, we heard a team of surgeons in china transplanted a gene-edited pig liver into a clinically dead man (with family consent). the liver functioned well up until the ten-day limit of the trial.how is this latest example different?the gene-edited pig kidney was transplanted into a relatively young, living, legally competent and consenting adult.the total number of gene edits edits made to the donor pig is very high. the researchers report making 69 edits to inactivate viral genes, “humanise” the pig with human genes, and to knockout harmful pig genes.clearly, the race to transform these organs into viable products for transplantation is ramping up.from biotech dream to clinical realityonly a few months ago, crispr gene editing made its debut in mainstream medicine.in november, drug regulators in the united kingdom and us approved the world’s first crispr-based genome-editing therapy for human use – a treatment for life-threatening forms of sickle-cell disease.the treatment, known as casgevy, uses crispr/cas-9 to edit the patient’s own blood (bone-marrow) stem cells. by disrupting the unhealthy gene that gives red blood cells their “sickle” shape, the aim is to produce red blood cells with a healthy spherical shape.crispr technology is aiming to restore diseased red blood cells to their healthy round shape. although the treatment uses the patient’s own cells, the same underlying principle applies to recent clinical xenotransplants: unsuitable cellular materials may be edited to make them therapeutically beneficial in the patient.we’ll be talking more about gene-editingmedicine and gene technology regulators are increasingly asked to approve new experimental trials using gene editing and crispr.however, neither xenotransplantation nor the therapeutic applications of this technology lead to changes to the genome that can be inherited.for this to occur, crispr edits would need to be applied to the cells at the earliest stages of their life, such as to early-stage embryonic cells in vitro (in the lab).in australia, intentionally creating heritable alterations to the human genome is a criminal offence carrying 15 years’ imprisonment.no jurisdiction in the world has laws that expressly permits heritable human genome editing. however, some countries lack specific regulations about the procedure.is this the future?even without creating inheritable gene changes, however, xenotransplantation using crispr is in its infancy.for all the promise of the headlines, there is not yet one example of a stable xenotransplantation in a living human lasting beyond seven months.while authorisation for this recent us transplant has been granted under the so-called “compassionate use” exemption, conventional clinical trials of pig-human xenotransplantation have yet to commence.but the prospect of such trials would likely require significant improvements in current outcomes to gain regulatory approval in the us or elsewhere.by the same token, regulatory approval of any “off-the-shelf” xenotransplantation organs, including gene-edited kidneys, would seem some way off.this article was originally published on the conversation as: the first pig kidney has been transplanted into a living person. but we’re still a long way from solving organ shortages. it was written by christopher rudge from the sydney law school.
