科學家用病人自身細胞訂做器官

科學家用病人自身細胞訂做器官

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.

斯德哥爾摩——安德馬里亞姆·貝耶恩(Andemariam Beyen)坐在醫(yī)院的窗戶旁，低斜的極地陽光照映著他的臉，他開始述說那段以為自己就要死去的時光。

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.”

兩年半前貝耶恩在冰島學習工程學，正是在那時，醫(yī)生發(fā)現(xiàn)他的氣管中長了一個高爾夫球大小的腫瘤。盡管進行了手術(shù)和放療，腫瘤仍然繼續(xù)進展。在2011年的春天，當貝耶恩來到瑞典再次就醫(yī)時，他實際上已經(jīng)沒有多少選擇了。“那時我就要死了，”他說：“很痛苦，太難受了”。

 

在瑞典的卡羅林斯卡醫(yī)學院，研究人員洗去了大鼠心臟和肺臟的活性細胞，留下的是細胞外基質(zhì)。

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.

但是卡羅林斯卡醫(yī)學院(Karolinska Institute)的保羅·馬基亞里尼(Paolo Macchiarini)醫(yī)生有一個根治該病的想法。他希望通過塑型體和患者自己的細胞給貝耶恩先生構(gòu)建一個新的氣管。

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.

幾十年來再生醫(yī)學的發(fā)展預示著未來能在實驗室里培養(yǎng)替代器官(包括肝臟、腎臟甚至心臟)，植入這樣一個人造器官是再生醫(yī)學界的首例。

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，這樣的未來一直如同科幻小說里描述的一樣。現(xiàn)在像馬基亞里尼醫(yī)生一樣的研究者正在用一種特殊的方法構(gòu)建器官，他們利用人自身的細胞并讓軀體本身來完成大部分的工作。

“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.

“人體是如此美妙。我堅信我們必須以最合理的方式利用它，”馬基亞里尼醫(yī)生說。馬基亞里尼醫(yī)生目前負責管理這間組織工程領(lǐng)域領(lǐng)先的實驗室。

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.

到目前為止，科學家只能構(gòu)建并移植少數(shù)幾種器官，即相對簡單的空腔臟器，例如膀胱和貝耶恩的氣管。2011年6月，人造氣管植入了貝耶恩的體內(nèi)。全世界的科學家希望通過類似的技術(shù)制造更多更復雜的器官。北卡羅來納州的維克森林大學(Wake Forest University)是人造膀胱的發(fā)源地，那里的研究者們正為人造腎臟、肝臟和其他器官而努力。中國和荷蘭的一些實驗室也在眾多研究人造血管的機構(gòu)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.

制造這些新的人體器官與幾十年前制造人工心臟的方式完全不同。那些很成熟的儀器設(shè)備到現(xiàn)在還暫時用于正在等候移植治療的患者，但是歸根到底機器還是機器。

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.

組織工程師們旨在把這一件事變得更人性化。他們希望用細胞、血管和神經(jīng)制造器官，使其成為身體的一個有活力、有功能的部分。有些專家，比如馬基亞里尼醫(yī)生，希望能做更多——利用機體的修復機制，通過它自己來重建器官。

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.

研究者正在利用干細胞、基底細胞研究的進展，現(xiàn)在他們知道這些細胞能分化成特異的組織，例如肝臟或肺。他們正在了解更多稱作“支架”(scaffolds)的復合物的知識，這種復合物能夠像水泥一樣將細胞支撐在合適的位置，并且也在為組織修復募集細胞方面發(fā)揮重要作用。

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.

組織工程師們提醒說，他們所做的工作只是實驗性的，并且花費相當高昂，創(chuàng)造復雜器官仍然需要很長的路要走。但是他們對最終實現(xiàn)的可能性越來越樂觀。

“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年來，我越來越堅信這樣做是可行的。”麻省總醫(yī)院(Massachusetts General Hospital)組織工程與器官制造實驗室主任、行業(yè)先驅(qū)約瑟夫·P·瓦坎(Joseph P. Vacanti)醫(yī)生說道。

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.

在貝耶恩先生的案例中，多孔的纖維材料上種植了取自骨髓的干細胞，由此制成了人工氣管。置入生物反應器中一天半后，移植物即與貝耶恩的身體融為一體，代替了他的長有腫瘤的氣管。生物反應器是類似于烤肉架的培養(yǎng)器，氣管在當中旋轉(zhuǎn)。

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

當馬基亞里尼醫(yī)生第一次提出該治療方案的時候，聽來似乎非常不切實際，貝耶恩對此表示懷疑。

“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.”

“我告訴他，我寧愿再活三年就死，”他說，“我差點就回絕了，這種事情以前只在豬的身上成功過。但是他用一種非?？茖W的方法讓我信服了。”

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.

手術(shù)后15個月，現(xiàn)年39歲、來自厄立特里亞的貝耶恩沒有腫瘤的煩惱，能夠正常呼吸。他和妻子及兩個孩子回到了冰島，其中一歲的小兒子是他以為永遠也不可能擁有的。在今年早些時候在斯德哥爾摩的隨訪中，他展示了胸部的長縱行疤痕，他聲音嘶啞(放療相關(guān)的后遺癥)，能夠說流利的英語。

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

他說，自己正逐步恢復元氣，有時還甚至能小跑一會兒。

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

“感覺很好，”貝耶恩說：“生活好多了”。

Imitating Nature

模仿自然

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

制作一個器官，得先知道自然是怎么創(chuàng)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.

這就是馬基亞里尼醫(yī)生實驗室的研究員菲利普·榮格布魯斯 (Philipp Jungebluth)做了以下工作的原因：他將一只心臟和一對肺臟裝在了工作臺的一只玻璃瓶中，并且連接上另一個裝有清洗劑樣液體的玻璃瓶。當清洗劑流過這些從實驗鼠身上取出來的器官，帶走其中有活性的細胞時，器官逐漸變得蒼白。三天后細胞消失了，剩下一團閃亮的組織保有了器官的基本形狀。

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.

這些便是心臟和肺臟的天然支架復合體，即細胞外基質(zhì)——由纖維蛋白和其它復合物構(gòu)成錯綜復雜的三維網(wǎng)狀物質(zhì)，能夠?qū)⒏鞣N細胞保持在恰當?shù)奈恢貌椭毎g的信號傳遞。

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?

全世界許多實驗室現(xiàn)在都在進行支架復合體的相關(guān)實驗。在一些病例中目標是利用天然支架復合體本身組建新器官，譬如說，取一個供者的肺，去掉所有的細胞，將患者自己的細胞“種植”于其中。這一想法認為，相比于一個人工合成的支架復合體，還不如充分利用人體本身的支架復合體復制器官。

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.

馬基亞里尼醫(yī)生和他的團隊在2008年開始嘗試，成功地將再生氣管植入了12名患者的體內(nèi)，他們中的大多數(shù)現(xiàn)在過上了正常的生活。因為供者自身的細胞已經(jīng)移除，這個方法消除了移植的一個最主要的問題：異體組織被受體排斥的風險。但是這并沒有解決一些同樣很棘手的其他問題，例如：供者的氣管可能大小不合適、受者必須等待去除供者氣管并再植細胞的這段時間、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.”

因此針對貝耶恩的病例，研究者決定制作一個塑型支架復合體，但是所有關(guān)于自體氣管的工作都是有幫助的。“我們從零開始，學到了如此多的東西，”馬基亞里尼醫(yī)生說，“如果沒有以往的經(jīng)驗，我們也許就無法做人工移植。”

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.

貝耶恩的合成支架復合體由倫敦大學學院(University College London)的科學家們構(gòu)建的，利用他自己的氣管作為模板。這是一個為其胸廓“量身定制”的高分子材料工程的精細作品。

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.

但如果僅僅這樣，它還僅是一個沒有生命的多孔塑形體。為了成為能夠工作的氣管，這個塑形體之間的小縫隙需要填滿那些最終能形成組織并有功能的細胞。并不是所有的細胞都能完成這項任務，馬基亞里尼醫(yī)生和他的團隊從干細胞開始著手。

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.

為了確保器官不會被排斥，細胞必須來自貝耶恩的自體，這同樣也能避免那些使用胚胎干細胞會涉及到的一些倫理問題。貝耶恩的干細胞取自他的骨髓。這些細胞保存在營養(yǎng)液中，然后用移液管將細胞從支架復合體中剝離下來，就像給火雞剝皮一樣。

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.

干細胞是機體用來組建和自身修復的一部分。它們一開始像一塊空白的石板，但是能夠分化成對特定組織或器官(例如氣管)特異的細胞。近幾年來，科學家在認識干細胞如何分化方面取得了巨大的進展。

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.

這個斯德哥爾摩的團隊希望在刺激干細胞生長藥物的幫助下，種植在氣管內(nèi)的骨髓細胞能分化成器官內(nèi)部及外部的相應細胞。但是馬基亞里尼醫(yī)生認為這個過程并沒有如想象中那樣進行。“我相信，細胞在放入了生物反應器兩三天后就凋亡了，”他說，但是細胞在凋亡的時候釋放出了化學物質(zhì)，向機體發(fā)送信號，使得更多的細胞從骨髓通過血液循環(huán)到達了目的地，促進了整個修復過程。

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

至少這是馬基亞里尼醫(yī)生對這個過程的解釋，“我們遠沒有理解整個過程，”他說，“差的遠著呢。”

‘If It Bleeds, It Lives’

“如果它流血了，說明它成活了”

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.

這總結(jié)了氣管的重要功能之一：將可能引起潛在致病感染的細菌和其他空氣中的微粒阻擋在肺臟以外。一個正常的氣管由特異性分化的細胞組成，包括那些能夠產(chǎn)生黏液捕獲微粒的細胞。而咳嗽能將黏液及微粒帶出。

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.

因此是否含有這些特化細胞成為檢驗這些組織工程制造出來的氣管的方法之一。馬基亞里尼醫(yī)生早期在進行關(guān)于供體氣管的研究時，將類似的來源于受者鼻腔的細胞種植于供者氣管內(nèi)。但是對于貝耶恩這個案例，馬基亞里尼寄希望于干細胞分化成其他種類的細胞，從而布滿氣管的內(nèi)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.

在手術(shù)五個月之后的2011年11月，貝耶恩的氣管內(nèi)部分長出了特化細胞。在之后的隨訪中，馬基亞里尼醫(yī)生注意到這一生長過程仍然非?；钴S，并且沒有感染的跡象。“而且他已經(jīng)能夠咳嗽了，”馬基亞里尼說。

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.

如果細胞存活下來，這意味著氣管通過與產(chǎn)生特化細胞一樣的方式生長出了由小血管組成的復雜網(wǎng)絡。所有的組織都必須有這樣的網(wǎng)絡，這樣每個細胞才能得到氧和營養(yǎng)。但是對于組織工程師們而言，生長出一個網(wǎng)絡，或者說確保這個網(wǎng)絡能繼續(xù)生長，是一個巨大的挑戰(zhàn)。

“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.

“一開始，我們認為最主要的障礙是供血問題，”瓦坎蒂醫(yī)生說。瓦坎蒂醫(yī)生的實驗室一直致力于通過組織工程制造肝臟和其他器官。

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.

貝耶恩的醫(yī)生們有一個方法，可以來確定他的氣管是否長出了血管網(wǎng)絡系統(tǒng)。作為隨訪試驗的一部分，他們故意輕微破壞了氣管的內(nèi)面。

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

“如果流血了，它便成活了，”馬基亞里尼醫(yī)生說。

Mr. Beyene’s windpipe bled.

貝耶恩的氣管果真流血了。

A Quest Continues

下一個目標

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.

貝耶恩先生希望有朝一日回到厄立特里亞，成為一名地熱工程師。但是現(xiàn)在為了規(guī)律隨訪，他一直呆在離斯德哥爾摩很近的冰島。

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.

氣管只含有他自己的細胞，因此他不需要吃藥抑制自身免疫系統(tǒng)以防止排異反應。但是合成的支架復合體如同任何異物一樣會讓機體產(chǎn)生疤痕組織，而疤痕組織必須移除。雖然這并不是問題，但是貝耶恩并不知道何時他才能回家，或是他究竟能不能回家。“只有當他們告訴我，‘一切都很完美，你不需要進一步的治療了’，我才能回家，”他說。

“Nobody knows. This is the first case.”

“沒有人知道。我這是第一例。”

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，也就是貝耶恩先生手術(shù)后五個月，馬基亞里尼醫(yī)生在另一個腫瘤病人克里斯托弗·萊爾斯(Christopher Lyles)體內(nèi)植入了一個人造氣管。他使用了一個改良的由更細的纖維組成的塑料支架復合體。萊爾斯在今年一月回到了美國馬里蘭州，三月份去世。他的家屬并沒有公布死因，但是馬基亞里尼說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.

盡管遇到挫折，馬基亞里尼醫(yī)生還是在今年六月為俄羅斯的兩名患者進行了類似的手術(shù)。他說，這兩名患者都順利出院了，現(xiàn)在情況良好。

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.

馬基亞里尼醫(yī)生正在籌備進行更多的手術(shù)。但是他說，這種手術(shù)需要花費近50萬美元，大家得找到更簡便易行的方案。

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.

因為這類手術(shù)的潛在需求量很大，“我們不能裝模作樣，假裝我們已經(jīng)能夠離體種植這些特化細胞了，”他說。相反，他設(shè)想開發(fā)出更好的支架系統(tǒng)，不需要細胞就能植入體內(nèi)，靠藥物刺激機體將細胞運送到特定部位。

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

他的終極夢想是淘汰合成支架復合體，讓藥物使機體重建自身的支架復合體。

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

“不在患者身上大動干戈，”馬基亞里尼醫(yī)生說：“只是利用他的身體去創(chuàng)造自己的器官，這樣就太棒了。”