Some Pancreatic Cells Are Just One Genetic Tweak Away From Treating Diabetes

部分胰腺细胞只需一次基因微调，即可用于治疗糖尿病

A human pancreas typically contains about a billion beta cells, the primary producers of insulin. Among people with diabetes, these cells are either missing or dysfunctional, and thus scientists have been looking for ways to replenish their numbers as a possible long-term treatment or even cure for the condition. A team of researchers recently took a step closer to that reality, genetically altering another type of pancreatic cell to produce and release insulin in response to high blood sugar.

人类胰腺通常含有约十亿个β细胞，它们是胰岛素的主要生产者。在糖尿病患者体内，这些细胞要么缺失，要么功能失调。因此，科学家们一直在寻找补充这些细胞数量的方法，以作为该疾病的长期治疗方案，甚至寻求治愈手段。最近，一个研究团队向这一目标迈进了一步：他们通过基因改造，使另一种胰腺细胞能够响应高血糖并产生和释放胰岛素。

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.

研究人员对导管细胞进行了改造。正如一些先前的研究所发现的那样，这些细胞偶尔会自发转化为β细胞。这在成年人体的细胞中是一种罕见的现象，因为成年细胞的身份通常是固定的。这一发现向科学家暗示，导管细胞将是一个理想的切入点。

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.

哈佛医学院博士后研究员、该项发表在《科学转化医学》杂志上的研究负责人李健（音译）表示，科学家此前并不清楚是什么基因驱动了这种转变。因此，研究人员采用了一种称为“基因筛选”的方法，即通过破坏基因组中各处的微小DNA片段，来观察哪些片段对特定的生物过程至关重要。这有点像在没有图纸的情况下，逐一拆卸汽车引擎的零件，通过观察哪些部位损坏，来了解哪些组件负责输送燃料或对转向至关重要。

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.

通过这一过程，研究人员发现，剔除一个名为ALDH3B2的基因，能以更高的比例将导管细胞转化为类β细胞。在没有进行基因改造的情况下，只有不到1%的导管细胞会自发呈现出类β细胞的状态；但当ALDH3B2基因被沉默后，这一比例上升到了约8.5%。

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.

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了患有糖尿病的小鼠体内。人类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。

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.

科学界此前已探索了一些针对糖尿病的基因疗法，希望能提供长期缓解方案。例如，今年早些时候启动的一项临床试验采取了一种创造性的方法，即为肌肉细胞配备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胰岛素产生细胞，然后将其移植到患者体内。

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.

这些方法伴随着一些风险，主要是免疫系统的激活。这项新研究指出了另一种可能性：利用胰腺中现有的细胞，通过关闭维持其身份的部分基因开关，促使它们改变功能。

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.

这种方法也有其自身的障碍，其中最重要的一点是确保只有目标细胞被编辑。ALDH3B2基因不仅存在于胰腺中，还被体内许多其他细胞使用，因此精确度对于防止不可预见的并发症至关重要。

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.”

还有一个悬而未决的主要问题：这个基因究竟是如何参与将导管细胞转化为β细胞的？李健说：“这是我们首先需要验证的部分。”接着，“下一步要么是进行基因治疗，要么是寻找特定的抑制该基因的小分子，看看能否达到类似甚至更好的效果。”

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.

即使是部分的改善，也可能对全球约8.3亿糖尿病患者的生活产生巨大影响，其中包括许多每年因相关并发症而死亡的患者。