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在体内培养替代器官

One Day, Growing Spare Parts Inside the Body
在体内培养替代器官

LOS ANGELES — Dr. Tracy Grikscheit held a length of intestine in her gloved hands, examining it inch by inch as if she were checking a bicycle tube for leaks.

洛杉矶——特蕾西·格里克施特医生(Tracy Gritscht)戴手套的手中持有一段小肠,她一段一段地仔细检查,如同在检查一个漏气的自行车轮胎一样。

The intestine was still attached, at one end, to Mark Barfknecht, a 1-year-old whose pink cheeks belied the reason he was lying on an operating table at Children’s Hospital Los Angeles. Born three months premature, Mark had developed a disorder that affects up to 10 percent of babies who weigh about 3 pounds or less at birth, causing some of their intestinal tissue to die. Mark’s case was so severe that most of his intestines had been removed.

这段小肠的一端仍连接在一岁小男孩马克·巴夫克内施特(Mark Barfknecht)的体内。他的小脸红扑扑的,这掩盖了他正躺在洛杉矶儿童医院的手术台上的原因。马克早产三个月,在出生时体重不足3磅(合1.36公斤)的婴儿中,有多达10%的婴儿会罹患一种疾病,导致部分患儿的肠组织坏死,马克就遇到了这种情况。他的病情很严重,大部分的小肠都已被切除。

Now Dr. Grikscheit, a surgeon, was trying to determine how much of the rest she could save.

现在外科医生格里克施特正在思量着,考虑她能挽救多少剩余的小肠。
 

马克·巴夫克内施特坏死的小肠被切除,他的医生目前正在寻找再生替代器官的方法,不过研究仍处在早期阶段。

Dr. Grikscheit is renowned for her skill in treating infants like Mark, whose only way to survive may be as what she calls a “short gut kid” — left with too little intestine to absorb food normally and forced to get nutrition through a needle into the bloodstream.

格里克施特医生以擅长治疗像马克这样的“短肠综合征”患儿而著名,这些患儿只有很少的小肠能正常吸收食物,因此不得不通过静脉途径获得营养。

But devoted as she is to saving children in the operating room, Dr. Grikscheit is equally determined to find a better solution than the intravenous feeding, possibly for life, that such patients face. Much of her time is spent in her laboratory across the street, at the hospital’s Saban Research Institute, where she is working with her research team to find a way to make replacement intestines for infants like Mark, using the body itself to nourish and push the engineered tissue to grow.

格里克施特医生一面在手术室努力拯救患儿,一面还在决意找到一种比静脉营养更好的解决方法,否则这类患者有可能终身离不开静脉滴注营养液。大部分时间,她都泡在医院对面的沙班研究中心(Saban Research Institute)实验室里,和她的研究团队一起为像马克这样的患儿寻找构建替代小肠的方法,他们要通过利用机体本身去为组织提供营养,并促进其生长。

Dr. Grikscheit’s work is at the forefront of efforts in laboratories around the world to build replacement organs and tissues. Although the long-sought goal of creating complex organs like hearts and livers to ease transplant shortages remains a long way off, researchers are having success making simpler structures like bladders and windpipes, thanks to advances in understanding stem cells — basic cells that can be transformed into other types within the body — and to the development of innovative techniques.

在全世界各地构建替代器官组织和器官的实验室里,格里克施特医生所做出的工作处于领先地位。虽然构建像心脏和肝脏这样的复杂器官和组织以弥补移植的缺陷,这仍然还有一段很长的路要走,但是目前研究者们已经成功地构建了像膀胱和气管这种较简单的器官,这得益于在认识干细胞(能够在体内转变为其他类型细胞的基础细胞)方面的进展,以及创新技术的发展。

So far Dr. Grikscheit has concentrated on growing rat, mouse and pig intestinal tissue in laboratory animals. But she has recently had success in growing human intestinal tissue, using donor cells, and is beginning to study how to develop the technique for human patients. There are many hurdles, and human testing is still years away, but she has a surgeon’s confidence that the technique will work.

目前格里克施特医生致力于在试验动物身上培养家鼠、实验鼠和猪的小肠组织。但是她最近利用供者细胞成功地培养出了人类的小肠组织,并开始研究如何开发这项技术为患者服务。此过程困难重重,人体试验仍然需要好几年才能实现,但是作为一个外科大夫,她深信这项技术会成功。

“We have a huge problem that if we solve it, it will change the future for a lot of children,” she said.

“我们目前面临一个很大的难题,一旦能解决这个难题,将会改变很多儿童的未来,”她说。

In her lab, her team is currently working with mice. They first remove good intestine from the animals, cut it up and treat it with enzymes and other compounds to form clusters of mixed cells, including stem cells that are found in the absorptive lining of the intestine and others that make up the tougher connective tissue.

在她的实验室中,她的团队正在用老鼠做实验。他们先将正常小肠从动物体内取出、切断,用酶和其他复合物处理,使其成为一团混合细胞,包括一些在小肠内发现的干细胞和组成强韧结缔组织的细胞。

The clusters are then placed on a piece of porous biodegradable plastic, about the size and shape of the eraser on a pencil. The plastic serves as a scaffold, supporting the cells and orienting them, which has the effect of making the lining grow inward while the connective tissue grows on the outside.

这一团细胞放在一块带孔的可生物降解的塑料板上,大小和形状类似于铅笔上的橡皮。这块塑料板充当支架的作用,支持并引导细胞生长,使得细胞在内面生长,结缔组织在外面生长。

This kind of seeding of scaffolds with cells is a common approach in the field of regenerative medicine, also known as tissue engineering. But in most cases, the goal is to swap the bad organ — a windpipe, for example — with the engineered replacement, where it can grow into its permanent position in the body.

在再生医学(或组织工程)领域,将细胞种植于支架上是最常用的方法。但是在大多数的情况下,目标是用新的再生器官去替代坏的器官(例如一个气管),在原位长出新的永久组织。

Dr. Grikscheit has had success in the lab with a different method, using another part of the body to nourish the replacement as it grows.

格里克施特医生在实验室中成功发明了一种新方法:当替代器官生长时,用身体另外一部分去为它提供营养。

She and her team sew the bundle of cells into the mouse’s omentum, a membranous fold inside the abdomen. There, the bundle is surrounded by blood vessels that supply nutrients, helping it to grow. The plastic eventually dissolves as the bundle grows into a hollow ball of tissue. A few weeks later, Dr. Grikscheit and her researchers remove the ball from the omentum — for study, to better understand how the regenerative growth occurs. The tissue has all the components of intestines, including the lining, muscles, nerves and blood vessels.

她和她的团队将一团细胞植入老鼠的大网膜(腹腔内的一个折叠起的膜状物)。在大网膜中,这团细胞被提供营养帮助生长的血管包围。当这团细胞长成一个空球组织的时候,塑料板最终被降解。几周之后,格里克施特医生和她的研究员们将组织球从大网膜中分离出来,用于更好地研究再生组织是如何生长的。这团组织包含小肠的所有成分,包括内皮细胞、肌肉、神经和血管。

In earlier studies in rats, Dr. Grikscheit went a step further, splicing the tissue into the digestive tract of animals that had had much of their intestines removed. Rats with the engineered intestine recovered more quickly than those without it.

在早期的老鼠实验中,格里克施特医生更进一步,她将组织拼接到大部分小肠被切除的动物的消化系统中。拥有再生小肠的老鼠比没有的老鼠恢复得更快。

By combining this kind of lab work with her surgical practice, Dr. Grikscheit is doing what she has always thought surgeons should do. “You move medicine ahead,” she said.

通过将实验室工作和手术实践结合起来,格里克施特医生做到了她认为一名外科医生应该做的事。“你推动了医学的发展,”她说。

Dr. Grikscheit, 40, who is intense and energetic and easy to spot in the hospital in her strawberry-print surgical cap, says she always knew she was going to be a surgeon — she told her great-grandmother as much when she was 6, growing up outside Salt Lake City. During her training she gravitated toward pediatric surgery. Compared with adults, children were works in progress — sometimes imperfect ones.

今年40岁的格里克施特医生非常热情,充满活力,在医院中很容易认出戴着印有草莓图案手术帽的她。她在盐湖城郊外长大,一直希望自己将会成为一名外科医生——6岁那年,她就对曾祖母讲述了自己的这个理想。在医师训练过程中,她受到小儿外科的吸引,从而选择以此为终身职业。与成人相比,儿童是正在逐步完善的作品——有时候这件作品并不会那么尽善尽美。

“The really fascinating thing is how to put something together that came out wrong and make it as right as possible,” she said.

她说:“真正让人着迷的地方在于,如何将一些看来是错误的事情放在一起,并使其产生尽可能正确的结果。”

She envisions a day when her approach moves beyond the lab to the operating room. Future operations to remove dead intestine from a baby — or from other patients with severe intestinal damage — would include an additional step: a little bit of good intestine would be sent to a table nearby, where technicians would quickly prepare a bundle for immediate implantation in the patient’s omentum.

她设想有一天她的技术能够不仅限于实验室,更能走进手术室。在将来,对于小肠坏死的婴儿或是其他小肠严重损伤的患者,手术除了切除小肠,还会增加另外一步:将一截健康的小肠送到旁边的桌上,技术人员能快速准备好一团细胞立刻移植到患者的大网膜上。

The patient might have to be on intravenous nutrition for a month or so while the intestine grows, but eventually could be weaned off it after the new tissue was harvested and sewn in.

当小肠细胞生长的时候,患者可能需要一个月左右的静脉营养。但是当新组织生长好并成功植入的时候,最终就不需要静脉营养了。

Not much new intestine would be required. “You only need to engineer an organ up to the point where you fix the missing function,” Dr. Grikscheit said. Even a couple of inches might be enough. “That will tip them back over into having enough absorptive function to get off of I.V. nutrition and live a full life.”

这一过程并不需要太多新的小肠。“你只需要构建一个能够弥补缺失的功能的器官,”格里克施特医生说。几英寸也许就足够了,“这会使其拥有足够的吸收功能,从而摆脱静脉营养,过上正常的生活。”

Such a remedy is still too far off for Mark Barfknecht.

但是这样的治疗方法对马克而言仍然太过遥远。

Back in the operating room on that day earlier this year, Dr. Grikscheit and a fellow surgeon, Dr. Demetri Merianos, continued to examine Mark’s intestines. Without the ability — yet — to regenerate the child’s intestinal tissue, they were focused on keeping as much of the damaged organ as possible.

让我们再回到今年早些时候的那一天,在手术室,格里克施特医生和手术助理迪米特利·梅里亚诺斯(Demitri Merianos)医生继续检查马克的小肠。那时还没有再生小儿小肠组织的技术,他们集中精力保留尽可能多的损坏的器官。

“This is coming down to something narrow,” Dr. Grikscheit said as she felt the tissue, which she and Dr. Merianos had spent the better part of two hours delicately freeing from Mark’s abdominal cavity, smoke rising from the cauterizing blade as they cut through places where it had adhered to the liver after an earlier surgery.

“现在到了狭窄的地方了,”格里克施特医生说道,她摸到了那段组织,这正是她和梅里亚诺斯医生花了近2小时仔细地从马克的腹腔里分离下来的组织。当他们切下原本连接在肝脏上的组织的时候,一缕烟从烧灼的电刀上升起。

To ensure that they could properly reconnect Mark’s digestive tract at the end of the four-hour procedure, they tagged the open ends of the intestines with surgical thread and clamps of different kinds, and jotted notes on the paper surgical drapes about which end went where.

为了保证在4个小时的手术结束时,他们能够将马克的肠管重新恰当地连接起来,他们用手术缝线和不同的夹子标记了小肠的开放末端,并在手术铺巾上做了笔记。

“I don’t care for this,” Dr. Grikscheit said, frowning. She and Dr. Merianos agreed that a 3-inch length of intestine would probably have to be cut out.

“这段(小肠)不行。”格里克施特医生皱了皱眉。她和梅里亚诺斯医生一致认为这段3英寸长的小肠必须被切除。

For a baby who had about only 15 inches of small intestine remaining, that was not good news.

对于一个只剩15英寸长小肠的婴儿来说,这不是个好消息。

But Mark, his mother says, is a survivor.

但是如同他母亲所说,马克是一个幸存者。

“Oh yeah, he’s been through it,” Karen Barfknecht said a few hours before the surgery, after his father, Michael, had detailed all the procedures their son had endured. “He has a cry that just makes you feel so bad,” Ms. Barfknecht said. “You’ll do absolutely anything for him.”

“是的,他已经受了很多苦了,”在手术的几个小时前,马克的父亲迈克尔(Michael)详述了这个孩子经受的各种磨难,他的妈妈凯伦这样说。“他哭一声,都会让人难受极了。你愿意为他付出一切。”

No one knows precisely what triggers the disorder, but prematurity plays a role.

没有人确切地知道是什么导致疾病产生,但是早产是其中的一个因素。

Called necrotizing enterocolitis, the disorder can crop up suddenly in the weeks after birth. In about a quarter of cases, the death of intestinal tissue ultimately proves fatal. For many of the rest, emergency surgery to resect, or remove, dead tissue creates new problems.

这种叫做坏死性肠炎的疾病,能够在婴儿出生后的数周迅速地毁坏小肠。在大约四分之一的病例中,小肠组织的坏死是致命的。其他许多病例也需要接受急诊手术切除坏死组织,而这又带来了新的问题。

“When I look at their intestine, I already know that to save their life I’m going to resect more than they can manage,” Dr. Grikscheit said. If the amount of dead tissue exceeds 75 percent of the total, the child will almost certainly be forced to get nutrition intravenously, which over the long term can damage the liver. Other operations, up to and including an intestinal transplant, may be needed, which bring other risks.

“当我看到他们的小肠时,就知道为了挽救他们的生命需要切除更多的小肠组织,”格里克施特医生说。如果坏死组织超过总量的75%,婴儿将几乎肯定需要通过静脉获得营养,长此以往,将会损伤肝脏。所以需要其他包括小肠移植在内的手术,然而这又会带来新的问题。

Mark is near that 75 percent threshold, so doctors at another hospital closer to his home in Indio, Calif., had put him on the special intravenous feeding, called total parenteral nutrition, or T.P.N., months before; now his liver is starting to suffer.

马克很靠近75%的阈值,因此在这次手术几周前,他被送去一家离加州印第奥市他的家较近的另外一家医院,医生让他接受特殊静脉营养,也称作全肠外营养(total parental nutrition, 简称TPN)。现在他的肝脏已经开始受到损伤。

He has required such a high level of care that Mr. Barfknecht quit his job as a mechanic. Still, Mark has been in either a hospital or a convalescent facility almost all his short life; his big sister has hardly spent any time with him.

他需要加强护理,为此巴夫克内施特先生辞去了机械师的工作。尽管这样,马克可能要么在医院、要么在疗养院度过他短暂的一生。他的姐姐几乎没机会和他在一起。

“We want him home,” his mother said. “We just want him home.”

“我们希望他回家,”他的母亲说:“我们只希望他能回家。”

That is Dr. Grikscheit’s goal, too. But before she and Dr. Merianos could determine whether Mark had enough good intestine to be weaned off the intravenous feeding eventually, they had to assess the narrow, diseased section they had found earlier. They looked at it again, weighing the options. They checked and rechecked their notes scribbled on the drapes.

这也是格里克施特医生的目标。但是当她和梅里亚诺斯医生在确定马克是否有足够的小肠最终摆脱静脉营养时,他们必须评估已经发现的狭窄、坏死的部分。他们再次检查了一下,权衡了一下选择。他们多次查看了在手术铺单上的笔记。

“Unfortunately, sayonara,” she said, directing Dr. Merianos to begin cutting.

“真不幸,再见吧,”她说,并指导梅里亚诺斯医生开始切除坏死小肠。

But that was the last piece of bad news for Mark. As the doctors continued to look at the remaining intestine, they grew increasingly optimistic that he would have enough. If so, they would stitch the remaining pieces together and reconnect everything from the stomach to the colon. Mark will have to continue the intravenous nutrition for some time, but eventually he should be able to eat normally.

但是对马克而言,这就是最后一个坏消息了。当医生继续查看残留的小肠时,他们更加乐观地认为留下的这部分已经足够了。这样一来,他们会将剩下的肠管缝合起来,将腹腔内所有内容和结肠重新连接。马克在一段时间内仍需要继续使用静脉营养,但是最终他能够正常饮食。

“I think we’ll make it off T.P.N. and get him home,” Dr. Grikscheit said.

“我认为我们能够让他摆脱全肠外营养,然后他便可以回家了,”格里克施特医生说。

It is the infants who are not so fortunate — for whom surgery could not do enough — who motivate Dr. Grikscheit to keep working on a way to make new tissue.

有些手术不能给患儿留下足够的肠管,正是这些不那么幸运的婴儿,激发格里克施特医生不断为构建新组织而努力。

“You keep finding these kids, in my case, who die,” she said. “I think it would be very frustrating to keep beating your head on the same problem and saying, ‘Well, that’s too bad.’ ”

“在我的工作中,会不断发现有婴儿死去,”她说:“我想,因为同一个问题不停敲打自己脑袋,念叨着‘这太糟糕了’,是一件很让人郁闷的事情。”
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