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科学家用病人自身细胞订做器官

A First: Organs Tailor-Made With Body’s Own Cells
科学家用病人自身细胞订做器官

STOCKHOLM — Andemariam Beyene sat by the hospital window, the low Arctic sun on his face, and talked about the time he thought he would die.

斯德哥尔摩——安德马里亚姆·贝耶恩(Andemariam Beyen)坐在医院的窗户旁,低斜的极地阳光照映着他的脸,他开始述说那段以为自己就要死去的时光。

Two and a half years ago doctors in Iceland, where Mr. Beyene was studying to be an engineer, discovered a golf-ball-size tumor growing into his windpipe. Despite surgery and radiation, it kept growing. In the spring of 2011, when Mr. Beyene came to Sweden to see another doctor, he was practically out of options. “I was almost dead,” he said. “There was suffering. A lot of suffering.”

两年半前贝耶恩在冰岛学习工程学,正是在那时,医生发现他的气管中长了一个高尔夫球大小的肿瘤。尽管进行了手术和放疗,肿瘤仍然继续进展。在2011年的春天,当贝耶恩来到瑞典再次就医时,他实际上已经没有多少选择了。“那时我就要死了,”他说:“很痛苦,太难受了”。
 

在瑞典的卡罗林斯卡医学院,研究人员洗去了大鼠心脏和肺脏的活性细胞,留下的是细胞外基质。

But the doctor, Paolo Macchiarini, at the Karolinska Institute here, had a radical idea. He wanted to make Mr. Beyene a new windpipe, out of plastic and his own cells.

但是卡罗林斯卡医学院(Karolinska Institute)的保罗·马基亚里尼(Paolo Macchiarini)医生有一个根治该病的想法。他希望通过塑型体和患者自己的细胞给贝耶恩先生构建一个新的气管。

Implanting such a “bioartificial” organ would be a first-of-its-kind procedure for the field of regenerative medicine, which for decades has been promising a future of ready-made replacement organs — livers, kidneys, even hearts — built in the laboratory.

几十年来再生医学的发展预示着未来能在实验室里培养替代器官(包括肝脏、肾脏甚至心脏),植入这样一个人造器官是再生医学界的首例。

For the most part that future has remained a science-fiction fantasy. Now, however, researchers like Dr. Macchiarini are building organs with a different approach, using the body’s cells and letting the body itself do most of the work.

最重要的是,这样的未来一直如同科幻小说里描述的一样。现在像马基亚里尼医生一样的研究者正在用一种特殊的方法构建器官,他们利用人自身的细胞并让躯体本身来完成大部分的工作。

“The human body is so beautiful, I’m convinced we must use it in the most proper way,” said Dr. Macchiarini, a surgeon who runs a laboratory that is a leader in the field, also called tissue engineering.

“人体是如此美妙。我坚信我们必须以最合理的方式利用它,”马基亚里尼医生说。马基亚里尼医生目前负责管理这间组织工程领域领先的实验室。

So far, only a few organs have been made and transplanted, and they are relatively simple, hollow ones — like bladders and Mr. Beyene’s windpipe, which was implanted in June 2011. But scientists around the world are using similar techniques with the goal of building more complex organs. At Wake Forest University in North Carolina, for example, where the bladders were developed, researchers are working on kidneys, livers and more. Labs in China and the Netherlands are among many working on blood vessels.

到目前为止,科学家只能构建并移植少数几种器官,即相对简单的空腔脏器,例如膀胱和贝耶恩的气管。2011年6月,人造气管植入了贝耶恩的体内。全世界的科学家希望通过类似的技术制造更多更复杂的器官。北卡罗来纳州的维克森林大学(Wake Forest University)是人造膀胱的发源地,那里的研究者们正为人造肾脏、肝脏和其他器官而努力。中国和荷兰的一些实验室也在众多研究人造血管的机构之列。

The work of these new body builders is far different from the efforts that produced artificial hearts decades ago. Those devices, which are still used temporarily by some patients awaiting transplants, are sophisticated machines, but in the end they are only that: machines.

制造这些新的人体器官与几十年前制造人工心脏的方式完全不同。那些很成熟的仪器设备到现在还暂时用于正在等候移植治疗的患者,但是归根到底机器还是机器。

Tissue engineers aim to produce something that is more human. They want to make organs with the cells, blood vessels and nerves to become a living, functioning part of the body. Some, like Dr. Macchiarini, want to go even further — to harness the body’s repair mechanisms so that it can remake a damaged organ on its own.

组织工程师们旨在把这一件事变得更人性化。他们希望用细胞、血管和神经制造器官,使其成为身体的一个有活力、有功能的部分。有些专家,比如马基亚里尼医生,希望能做更多——利用机体的修复机制,通过它自己来重建器官。

Researchers are making use of advances in knowledge of stem cells, basic cells that can be transformed into types that are specific to tissues like liver or lung. They are learning more about what they call scaffolds, compounds that act like mortar to hold cells in their proper place and that also play a major role in how cells are recruited for tissue repair.

研究者正在利用干细胞、基底细胞研究的进展,现在他们知道这些细胞能分化成特异的组织,例如肝脏或肺。他们正在了解更多称作“支架”(scaffolds)的复合物的知识,这种复合物能够像水泥一样将细胞支撑在合适的位置,并且也在为组织修复募集细胞方面发挥重要作用。

Tissue engineers caution that the work they are doing is experimental and costly, and that the creation of complex organs is still a long way off. But they are increasingly optimistic about the possibilities.

组织工程师们提醒说,他们所做的工作只是实验性的,并且花费相当高昂,创造复杂器官仍然需要很长的路要走。但是他们对最终实现的可能性越来越乐观。

“Over 27 years, I’ve become more convinced that this is doable,” said Dr. Joseph P. Vacanti, a director of the Laboratory for Tissue Engineering and Organ Fabrication at Massachusetts General Hospital and a pioneer in the field.

“27年来,我越来越坚信这样做是可行的。”麻省总医院(Massachusetts General Hospital)组织工程与器官制造实验室主任、行业先驱约瑟夫·P·瓦坎(Joseph P. Vacanti)医生说道。

In Mr. Beyene’s case, an exact copy of his windpipe was made from a porous, fibrous plastic, which was then seeded with stem cells harvested from his bone marrow. After just a day and a half in a bioreactor — a kind of incubator in which the windpipe was spun, rotisserie-style, in a nutrient solution — the implant was stitched into Mr. Beyene, replacing his cancerous windpipe.

在贝耶恩先生的案例中,多孔的纤维材料上种植了取自骨髓的干细胞,由此制成了人工气管。置入生物反应器中一天半后,移植物即与贝耶恩的身体融为一体,代替了他的长有肿瘤的气管。生物反应器是类似于烤肉架的培养器,气管在当中旋转。

It was such a seemingly wild scheme that Mr. Beyene had his doubts when Dr. Macchiarini first proposed it.

当马基亚里尼医生第一次提出该治疗方案的时候,听来似乎非常不切实际,贝耶恩对此表示怀疑。

“I told him, I prefer to live three years and then die,” he said. “I almost refused. It had only been done in pigs. But he convinced me in a very scientific way.”

“我告诉他,我宁愿再活三年就死,”他说,“我差点就回绝了,这种事情以前只在猪的身上成功过。但是他用一种非常科学的方法让我信服了。”

Now, 15 months after the operation, Mr. Beyene, 39, who is from Eritrea, is tumor-free and breathing normally. He is back in Iceland with his wife and two small children, including a 1-year-old boy whom he had thought he would never get to know. In Stockholm earlier this year for a follow-up visit, he showed the long vertical scar on his chest and spoke quietly in English, the raspiness of his voice a leftover from radiation therapy.

手术后15个月,现年39岁、来自厄立特里亚的贝耶恩没有肿瘤的烦恼,能够正常呼吸。他和妻子及两个孩子回到了冰岛,其中一岁的小儿子是他以为永远也不可能拥有的。在今年早些时候在斯德哥尔摩的随访中,他展示了胸部的长纵行疤痕,他声音嘶哑(放疗相关的后遗症),能够说流利的英语。

His strength was improving every day, he said, and he could even run a little.

他说,自己正逐步恢复元气,有时还甚至能小跑一会儿。

“Things are good,” Mr. Beyene said. “Life is much better.”

“感觉很好,”贝耶恩说:“生活好多了”。

Imitating Nature

模仿自然


To make an organ, it helps to know how nature does it.

制作一个器官,得先知道自然是怎么创造它的。

That is why Philipp Jungebluth, a researcher in Dr. Macchiarini’s lab, had mounted a heart and a pair of lungs inside a glass jar on a workbench and connected them by tubing to another jar containing a detergent-like liquid. The organs, fresh from a sacrificed rat, had slowly turned pale as the detergent dripped through and out of them, carrying away their living cells. After three days the cells were gone, leaving a glistening mass that retained the basic shape of the organs.

这就是马基亚里尼医生实验室的研究员菲利普·荣格布鲁斯 (Philipp Jungebluth)做了以下工作的原因:他将一只心脏和一对肺脏装在了工作台的一只玻璃瓶中,并且连接上另一个装有清洗剂样液体的玻璃瓶。当清洗剂流过这些从实验鼠身上取出来的器官,带走其中有活性的细胞时,器官逐渐变得苍白。三天后细胞消失了,剩下一团闪亮的组织保有了器官的基本形状。

These were the heart and lungs’ natural scaffolds, or extracellular matrix — intricate three-dimensional webs of fibrous proteins and other compounds that keep the various kinds of cells in their proper positions and help them communicate.

这些便是心脏和肺脏的天然支架复合体,即细胞外基质——由纤维蛋白和其它复合物构成错综复杂的三维网状物质,能够将各种细胞保持在恰当的位置并帮助细胞间的信号传递。

Labs around the world are now experimenting with scaffolds. In some cases the goal is to use the natural scaffolds themselves to build new organs — to take a donor lung, for example, strip all its cells and reseed it with a patient’s own cells. Why not use what nature has perfected, this line of thinking goes, rather than try to replicate it in a synthetic scaffold?

全世界许多实验室现在都在进行支架复合体的相关实验。在一些病例中目标是利用天然支架复合体本身组建新器官,譬如说,取一个供者的肺,去掉所有的细胞,将患者自己的细胞“种植”于其中。这一想法认为,相比于一个人工合成的支架复合体,还不如充分利用人体本身的支架复合体复制器官。

Dr. Macchiarini and his team tried this beginning in 2008, successfully implanting reseeded windpipes from cadavers in about a dozen patients, most of whom are now living normal lives. Because the donor’s own cells are removed, this approach all but eliminates a major problem of transplants: the risk that foreign tissue will be rejected by the recipient. But it does not solve several other problems that may be just as troublesome. A donated windpipe may not be the right size; it has to be stripped of its cells and reseeded while the recipient waits; and the procedure still requires donor organs, which are in short supply.

马基亚里尼医生和他的团队在2008年开始尝试,成功地将再生气管植入了12名患者的体内,他们中的大多数现在过上了正常的生活。因为供者自身的细胞已经移除,这个方法消除了移植的一个最主要的问题:异体组织被受体排斥的风险。但是这并没有解决一些同样很棘手的其他问题,例如:供者的气管可能大小不合适、受者必须等待去除供者气管并再植细胞的这段时间、需要的供者器官非常稀缺等等。

So for Mr. Beyene, the decision was made to produce a scaffold out of plastic. But all the work with natural windpipes proved useful. “We learned so much, starting from zero,” Dr. Macchiarini said. “We could have never done the artificial transplant without the past experience.”

因此针对贝耶恩的病例,研究者决定制作一个塑型支架复合体,但是所有关于自体气管的工作都是有帮助的。“我们从零开始,学到了如此多的东西,”马基亚里尼医生说,“如果没有以往的经验,我们也许就无法做人工移植。”

Made to Order

量身定制


Mr. Beyene’s synthetic scaffold was fabricated by scientists at University College London, using scans of his natural windpipe as a template. It was an exquisite piece of polymer engineering, tailor-made to fit his chest.

贝耶恩的合成支架复合体由伦敦大学学院(University College London)的科学家们构建的,利用他自己的气管作为模板。这是一个为其胸廓“量身定制”的高分子材料工程的精细作品。

But it was still just a lifeless piece of porous plastic. To become a working organ, the tiny spaces in the plastic needed to be filled with cells that would eventually function together as tissue. Not just any cells would do; Dr. Macchiarini and his team would start with stem cells.

但如果仅仅这样,它还仅是一个没有生命的多孔塑形体。为了成为能够工作的气管,这个塑形体之间的小缝隙需要填满那些最终能形成组织并有功能的细胞。并不是所有的细胞都能完成这项任务,马基亚里尼医生和他的团队从干细胞开始着手。

To ensure that the organ would not be rejected, the cells had to come from Mr. Beyene himself, which also bypasses the kind of ethical issues that have arisen over the use of embryonic stem cells. Mr. Beyene’s stem cells were obtained from his bone marrow. The cells were placed in nutrient solution and then dripped by pipette over the scaffold. It was like basting a turkey.

为了确保器官不会被排斥,细胞必须来自贝耶恩的自体,这同样也能避免那些使用胚胎干细胞会涉及到的一些伦理问题。贝耶恩的干细胞取自他的骨髓。这些细胞保存在营养液中,然后用移液管将细胞从支架复合体中剥离下来,就像给火鸡剥皮一样。

Human stem cells are part of the body’s system for building and repairing itself. They begin as a blank slate, but are able to become specialized cells specific to particular tissues or organs like the windpipe. In recent years, scientists have made great advances in understanding how stem cells can differentiate in this way.

干细胞是机体用来组建和自身修复的一部分。它们一开始像一块空白的石板,但是能够分化成对特定组织或器官(例如气管)特异的细胞。近几年来,科学家在认识干细胞如何分化方面取得了巨大的进展。

The Stockholm team was hoping that with the help of stem-cell-stimulating drugs, the marrow cells placed on the windpipe would start to become the right kinds of cells on both the inside and outside of the organ. But Dr. Macchiarini does not think the process worked quite as planned. “I’m convinced that the cells we are putting in the bioreactor after two or three days are gone,” he said. But as they die they release chemicals that signal the body to send more stem cells from the bone marrow through the bloodstream to the site, aiding the regenerative process.

这个斯德哥尔摩的团队希望在刺激干细胞生长药物的帮助下,种植在气管内的骨髓细胞能分化成器官内部及外部的相应细胞。但是马基亚里尼医生认为这个过程并没有如想象中那样进行。“我相信,细胞在放入了生物反应器两三天后就凋亡了,”他说,但是细胞在凋亡的时候释放出了化学物质,向机体发送信号,使得更多的细胞从骨髓通过血液循环到达了目的地,促进了整个修复过程。

Or at least that is what Dr. Macchiarini thinks happened. “We are far away from understanding this process,” he said. “Far, far away.”

至少这是马基亚里尼医生对这个过程的解释,“我们远没有理解整个过程,”他说,“差的远着呢。”

‘If It Bleeds, It Lives’

“如果它流血了,说明它成活了”


If you cannot cough, you’re dead.

如果你不能咳嗽,你就死了。

That sums up one of the important functions of the windpipe: keeping bacteria and other particles in the air out of the lungs, where they could cause potentially fatal infections. A normal windpipe is lined with specialized cells, including some that produce mucus that can trap the particles. Coughing then brings the mucus up and out.

这总结了气管的重要功能之一:将可能引起潜在致病感染的细菌和其他空气中的微粒阻挡在肺脏以外。一个正常的气管由特异性分化的细胞组成,包括那些能够产生黏液捕获微粒的细胞。而咳嗽能将黏液及微粒带出。

So one test of a tissue-engineered windpipe is whether it contains these specialized cells. In Dr. Macchiarini’s earlier work involving donor windpipes, he had seeded the inside with similar cells taken from the recipient’s nose. But with Mr. Beyene, Dr. Macchiarini was counting on stem cells to differentiate into these other kinds of cells, generating a lining for the windpipe.

因此是否含有这些特化细胞成为检验这些组织工程制造出来的气管的方法之一。马基亚里尼医生早期在进行关于供体气管的研究时,将类似的来源于受者鼻腔的细胞种植于供者气管内。但是对于贝耶恩这个案例,马基亚里尼寄希望于干细胞分化成其他种类的细胞,从而布满气管的内部。

In November, five months after the surgery, Mr. Beyene’s windpipe was found to be partly lined with the specialized cells. And in the later follow-up visit, Dr. Macchiarini noted that the lining was still thriving, with no sign of infection. “And he is able to cough,” Dr. Macchiarini said.

在手术五个月之后的2011年11月,贝耶恩的气管内部分长出了特化细胞。在之后的随访中,马基亚里尼医生注意到这一生长过程仍然非常活跃,并且没有感染的迹象。“而且他已经能够咳嗽了,”马基亚里尼说。

If the cells are surviving, that means the windpipe is developing a complex network of tiny blood vessels through the same regenerative process that produced the specialized cells. All tissues must have such a network so that every cell can get oxygen and nutrients. But developing one — or ensuring that one develops — is an enormous challenge for tissue engineers.

如果细胞存活下来,这意味着气管通过与产生特化细胞一样的方式生长出了由小血管组成的复杂网络。所有的组织都必须有这样的网络,这样每个细胞才能得到氧和营养。但是对于组织工程师们而言,生长出一个网络,或者说确保这个网络能继续生长,是一个巨大的挑战。

“From the beginning, our view was that the principal barrier to this was going to be the blood supply,” said Dr. Vacanti, whose laboratory has long worked on developing a tissue-engineered liver, among other organs.

“一开始,我们认为最主要的障碍是供血问题,”瓦坎蒂医生说。瓦坎蒂医生的实验室一直致力于通过组织工程制造肝脏和其他器官。

Mr. Beyene’s doctors had one way to be certain that his windpipe was developing a blood vessel network. As part of their follow-up exam, they purposely injured the internal lining slightly.

贝耶恩的医生们有一个方法,可以来确定他的气管是否长出了血管网络系统。作为随访试验的一部分,他们故意轻微破坏了气管的内面。

“If it bleeds, it lives,” Dr. Macchiarini said.

“如果流血了,它便成活了,”马基亚里尼医生说。

Mr. Beyene’s windpipe bled.

贝耶恩的气管果真流血了。

A Quest Continues

下一个目标


Mr. Beyene hopes to return someday to Eritrea and work as a geothermal engineer. But for now he remains in Iceland, to be close to Stockholm for regular follow-up visits.

贝耶恩先生希望有朝一日回到厄立特里亚,成为一名地热工程师。但是现在为了规律随访,他一直呆在离斯德哥尔摩很近的冰岛。

The windpipe contains only his own cells, so he does not need to take drugs to suppress his immune system to ward off rejection. But the synthetic scaffold, like any foreign material, caused the body to produce scar tissue, which had to be removed. While that is no longer a problem, Mr. Beyene does not know when, or if, he will be able to return home. “They have to say, ‘Things are perfect; you don’t need any more care,’ ” he said.

气管只含有他自己的细胞,因此他不需要吃药抑制自身免疫系统以防止排异反应。但是合成的支架复合体如同任何异物一样会让机体产生疤痕组织,而疤痕组织必须移除。虽然这并不是问题,但是贝耶恩并不知道何时他才能回家,或是他究竟能不能回家。“只有当他们告诉我,‘一切都很完美,你不需要进一步的治疗了’,我才能回家,”他说。

“Nobody knows. This is the first case.”

“没有人知道。我这是第一例。”

Last November, five months after Mr. Beyene’s surgery, Dr. Macchiarini implanted a bioartificial windpipe in another cancer patient, Christopher Lyles. He used an improved plastic scaffold, made up of even smaller fibers for the cells to be embedded in. Mr. Lyles returned home to Maryland in January but died in March. The family did not release the cause of death, but Dr. Macchiarini said that the implant had been functioning well.

去年11月,也就是贝耶恩先生手术后五个月,马基亚里尼医生在另一个肿瘤病人克里斯托弗·莱尔斯(Christopher Lyles)体内植入了一个人造气管。他使用了一个改良的由更细的纤维组成的塑料支架复合体。莱尔斯在今年一月回到了美国马里兰州,三月份去世。他的家属并没有公布死因,但是马基亚里尼说移植物一直工作正常。

Despite that setback, in June Dr. Macchiarini performed similar operations on two patients in Russia. Both have been discharged from the hospital and are doing well, he said.

尽管遇到挫折,马基亚里尼医生还是在今年六月为俄罗斯的两名患者进行了类似的手术。他说,这两名患者都顺利出院了,现在情况良好。

Dr. Macchiarini is planning even more operations. But there needs to be a less complex and cumbersome solution, he said, beyond procedures that can cost up to half a million dollars.

马基亚里尼医生正在筹备进行更多的手术。但是他说,这种手术需要花费近50万美元,大家得找到更简便易行的方案。

Because the need for this kind of work is potentially so enormous, “we cannot pretend that we can reseed with the specific cells outside the body,” he said. Instead, he envisions developing even better scaffolds and implanting them without cells, relying on drugs to stimulate the body to send cells to the site.

因为这类手术的潜在需求量很大,“我们不能装模作样,假装我们已经能够离体种植这些特化细胞了,”他说。相反,他设想开发出更好的支架系统,不需要细胞就能植入体内,靠药物刺激机体将细胞运送到特定部位。

His ultimate dream is to eliminate even the synthetic scaffold. Instead, drugs would enable the body to rebuild its own scaffold.

他的终极梦想是淘汰合成支架复合体,让药物使机体重建自身的支架复合体。

“Don’t touch the patient,” Dr. Macchiarini said. “Just use his body to recreate his own organ. It would be fantastic.”

“不在患者身上大动干戈,”马基亚里尼医生说:“只是利用他的身体去创造自己的器官,这样就太棒了。”
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