研究人员对导管细胞进行了改造——正如一些先前研究所发现的那样，这些细胞偶尔会自发转化为β细胞。在成年人体内，细胞往往牢固地固定在其特定身份上，这种现象颇为罕见，它向科学家暗示，导管细胞将是一个很好的研究起点。
The researchers engineered ductal cells, which—as some previous studies had found—occasionally transform into beta cells all on their own. This is an unusual phenomenon among cells in adult bodies, which tend to be firmly fixed in their identities, and it hinted to the scientists that these ductal cells would be a good place to start.
领导这项发表于《科学·转化医学》最新研究的哈佛医学院博士后研究员李健（音译）表示，科学家此前完全不知道是什么基因在驱动这种变形。因此，研究人员采用了一种称为基因筛选的方法，即在全基因组范围内打断微小的DNA片段，以观察哪些片段对特定生物学过程至关重要。这有点像在没有示意图的情况下，逐个拆除汽车发动机的零件，看看什么会坏，从而弄清哪些部件参与供油或对转向至关重要。
Scientists previously had no clue what genes were driving this metamorphosis, said Jian Li, a postdoctoral researcher at Harvard Medical School who led the recent study in Science Translational Medicine. The researchers therefore took an approach called a genetic screen, which involves breaking little bits of DNA all across the genome to see which are important for a certain biological process. It’s a bit like individually removing pieces of a car engine without a schematic and seeing what breaks to learn which components are involved in delivering fuel or are essential for steering.
通过这一过程，研究人员发现，敲除一个名为ALDH3B2的基因，能以更高的比率将导管细胞转化为类β细胞。在没有基因改造的情况下，不到1%的导管细胞会自发呈现类β细胞状态，但当ALDH3B2被沉默后，这一比例上升至约8.5%。
Through this process, the researchers found that taking out a gene called ALDH3B2 turned ductal cells into beta-like cells at a higher rate. Without the genetic alteration, fewer than 1 percent of ductal cells spontaneously took on a beta-cell-like state, but when ALDH3B2 was silenced, that proportion increased to about 8.5 percent.
这些初步实验是在培养皿中的人类细胞上进行的，随后研究人员将这些细胞移植到患有糖尿病的小鼠体内。人胰岛素开始在小鼠体内循环，动物的血糖水平降至接近正常水平。这些效果持续了六周。
Those initial experiments were performed on human cells in a dish, which the researchers then transplanted into mice with diabetes. Human insulin began circulating in the mice, and the animals’ glucose levels dropped to near-normal levels. These effects persisted for six weeks.
科学界此前曾探索过一些针对糖尿病的基因疗法，希望能提供长期缓解。例如，今年早些时候启动的一项临床试验采取了一种创新方法，让肌肉细胞携带制造胰岛素的基因指令。其他新兴疗法旨在实验室中生成新的产胰岛素细胞，然后将其移植给患者。
Science has previously explored some gene therapies for diabetes with the hopes of offering long-term relief. For example, a clinical trial launched earlier this year is taking the creative approach of equipping muscle cells with the genetic instructions to make insulin. Other emerging treatments aim to generate new insulin-producing cells in the laboratory and then transplant them into the patient.
这伴随着一些风险，主要是免疫系统的激活。这项新研究指向另一种可能性：利用胰腺中已存在的细胞，通过关闭一些维持其身份的基因开关，使它们改变功能。
This comes with a few risks, namely activation of the immune system. This new study points to another possibility: harnessing the cells that already exist in the pancreas and causing them to change function by turning off some of the genetic switches that maintain their identity.
这种方法也有其自身的障碍，其中最重要的之一是确保只编辑目标细胞。ALDH3B2 被身体中的许多细胞使用，而不仅限于胰腺，因此精准性对于防止不可预见的并发症至关重要。
That method also has its own hurdles, one of the most important of which is ensuring that only the target cells are edited. ALDH3B2 is used by many cells in the body, not just in the pancreas, so precision is important to prevent unforeseen complications.
还有一个主要的悬而未决的问题：这个基因是如何参与将导管细胞转化为 β 细胞的？李说：“这是我们首先需要验证的部分。”然后，“下一步要么是基因疗法，要么是寻找特定的小分子来抑制这个基因，看看我们能否达到类似——甚至更好——的效果。”即使是部分改善，也可能对全球估计 8.3 亿糖尿病患者的生活产生巨大影响，其中包括每年因相关并发症死亡的许多人。
There’s also a major lingering question: How is this gene involved in turning ductal cells into beta cells? “That's the part we need to verify first,” Li said. Then, “the next step is either gene therapy or to find specific small molecules to inhibit this gene to see if we can achieve a similar—or even better—effect.” Even partial improvement could make a massive impact in the lives of the estimated 830 million people who have diabetes worldwide, including many who die each year due to related complications.
本文最初发表于 WIRED en Español，并已从西班牙语翻译而来。
This story originally appeared on WIRED en Español and has been translated from Spanish.