Why Can’t We Regrow Organs Yet?

The first lab-grown organ was transplanted into a patient in 1999 — but they still aren’t commonly available.

National Journal
Brian Resnick
Nov. 13, 2013, midnight

Play­ing God can take dec­ades.

In 2006, Dr. An­thony Atala of the Wake Forest School of Medi­cine pub­lished a break­through study. In the sev­en years be­fore, he had suc­cess­fully grown and re­placed dis­eased blad­ders in sev­en chil­dren. Grew them, as in he took por­tions of the pa­tients’ ori­gin­al blad­ders, coaxed the cells in­to a re­gen­er­at­ive state, and then mol­ded them on a bio­de­grad­able scaf­fold in­to the shape of a blad­der. The blad­ders were then trans­planted in­to the chil­dren, and after years of ob­ser­va­tions, he called the en­tire op­er­a­tion a suc­cess.

So are lab-grown blad­ders now a com­mon treat­ment for end-stage blad­der dis­ease?

No. That 2006 re­port was just the end of phase one of the four-phase clin­ic­al tri­al pro­cess. Each phase of clin­ic­al tri­als in­creases the size of the sub­ject pools, test­ing safety and long-term out­comes. For phar­ma­ceut­ic­als, the pro­cess can take 15 years. For something more in­vas­ive such as a trans­plant pro­ced­ure, it’s bound to take longer, dec­ades even.

“We didn’t got to phase two un­til sev­er­al years after that,” Atala says of the ini­tial pub­lic­a­tion. “And many people have asked us, ‘Well, why did you wait so long?’ ” Doc­tors had nev­er im­planted a lab-grown blad­der in­to a hu­man pa­tient be­fore. “We really did not know what to ex­pect long term.”

Today, the blad­ders have not moved bey­ond phase two clin­ic­al tri­als, 14 years after they were first im­planted in pa­tients.

Trail­blaz­ing — for all its con­not­at­ive speed — needs to be done slowly.

Ex­plos­ive Growth Meets Slow Mov­ing Reg­u­la­tions

The prom­ise of lab-grown or­gans is enorm­ous. Just in the Unites States, more than 120,000 people are cur­rently on or­gan-trans­plant wait­ing lists, and only 19,000 trans­plants took place in the first eight months of 2013. Since the 1990s, the gulf between the num­ber of trans­plant pa­tients and the num­ber of or­gans has only grown wider.

After a pa­tient is ap­proved for a trans­plant, there are still dangers. Fif­teen to 20 per­cent of kid­ney re­cip­i­ents will face or­gan re­jec­tion with­in five years of im­ple­ment­a­tion. Twenty-five per­cent of heart trans­plant re­cip­i­ents ex­per­i­ence some re­jec­tion in the first year after sur­gery.

Re­gen­er­at­ive medi­cine can help solve these two prob­lems: Grow or­gans on de­mand to in­crease sup­ply, but also grow them from the host’s cells, to mit­ig­ate com­plic­a­tions.

Luck­ily, in­nov­a­tion is ex­plod­ing.

Stem cells are a re­l­at­ively re­cent in­ven­tion, first cul­tiv­ated out­side the body in the 1990s. Since then, the field has grown by leaps and bounds. Now, we can coax an adult cell in­to an em­bryon­ic-like state, or what’s known as a pluri­po­tent state, which means it can trans­form in­to many dif­fer­ent types of cells.

That work won a No­bel Prize in 2012. “Clearly, that’s had a huge im­pact on the field,” says Wil­li­am Wag­n­er, dir­ect­or of re­gen­er­at­ive medi­cine at the Uni­versity of Pitt­s­burgh. “A lot of people are look­ing to those cells as a po­ten­tial source,” as the de­bate around em­bryon­ic stem cells has be­come clin­ic­ally ir­rel­ev­ant. With such tech­no­lo­gies, labs have grown mildly func­tion­ing kid­neys and beat­ing hearts for rats. For hu­mans, lab-grown skin and car­til­age are com­ing in­to main­stream use. We can grow noses on fore­heads.

More than the cells them­selves, the struc­tur­al en­gin­eer­ing sci­ence is also boun­cing ahead. Three-di­men­sion­al print­ers can build bio­lo­gic­al struc­tures one cell at a time, craft­ing the del­ic­ate or­gan struc­tures of the body. One of the more ex­cit­ing de­vel­op­ments is the abil­ity to wash an an­im­al or hu­man or­gan of all its cells to re­veal the un­der­ly­ing struc­ture. Then, re­search­ers re­an­im­ate the or­gan with com­pletely new cells, spe­cif­ic to the host — bring­ing dead tis­sues back to life.

But here’s the key dis­claim­er: “If it can be done in a mouse or a rat, ex­tra­pol­at­ing that to a hu­man, the num­ber of pit­falls, and the num­ber of as­sump­tions that hap­pen in that, par­tic­u­larly in the mouse mod­el, are huge,” Wag­n­er ex­plains. In 2006, Atala’s blad­ders were, in terms of the clin­ic­al-ap­prov­al timeline, worlds bey­ond, let’s say, a lab-grown pan­creas de­rived from testicle cells that could pos­sibly cure dia­betes. Any proof of concept in an an­im­al is dec­ades away from wide­spread use, and that’s as­sum­ing it will be vi­able for hu­mans at all.

Maybe We Can’t Grow a Heart, But Can We Heal One?

In the near fu­ture, we’ll be more likely to see stem-cell-based ther­apies rather than out­right or­gan re­place­ment.

“We’re shoot­ing at the moon in try­ing to make a heart or make a liv­er, and you dis­cov­er so many things along the way that some­times you don’t want to go to the moon after all,” Wag­n­er says.

For in­stance, in­stead of whole­sale or­gan re­place­ment, doc­tors are find­ing that simply in­ject­ing an or­gan with cer­tain stem cells can pro­duce a heal­ing ef­fect. A large num­ber of on­go­ing in­vest­ig­a­tions ex­pect cell ther­apy to even­tu­ally change the treat­ment of any giv­en chron­ic con­di­tion, Wag­n­er says. Maybe in a dec­ade, he says, they will yield ther­apies for con­di­tions such as as heart dis­ease and stroke. And per­haps, later on, for Alzheimer’s and Par­kin­son’s. In 2013, a pub­lished clin­ic­al tri­al that in­volved in­ject­ing cells in­to dis­eased heart tis­sue showed that “every pa­tient in the stem-cell-treat­ment group im­proved.”

“Are they go­ing to be cures? Prob­ably not in a 10-year time frame,” Wag­n­er says. “But they are go­ing to show enough be­ne­fit that they would be ad­op­ted, op­posed to what’s cur­rently done clin­ic­ally.”

And then there are prac­tic­al con­cerns to grow­ing en­tire or­gans. It may not prove to be a vi­able busi­ness mod­el to tail­or-make or­gans for in­di­vidu­al pa­tients. “Private in­dustry is go­ing to have to raise mil­lions and mil­lions of dol­lars not around the sci­ence, but around the prac­tic­al­ity,” Wag­n­er says. “Spe­cific­ally, what pa­tients are you go­ing to treat, how many per year, what’s your re­im­burse­ment rate go­ing to be, how long it’s go­ing to take to get through the FDA. All these prac­tic­al reg­u­lat­ory busi­ness con­cerns — and of­ten that’s what is put­ting a bar­ri­er between an in­ter­est­ing re­port that you read about a study in ro­dents or even in pigs and if it ever gets trans­lated to hu­mans.”

But the Baby Steps Still Mat­ter

If, today, we built a hu­man body us­ing only lab-grown parts, the ana­tomy would be sparse. The body would have a blad­der, a trachea, some blood ves­sels, some muscle fiber, skin, tear ducts, and a ur­ethra — maybe a sphinc­ter.

These are the sim­pler or­gans of the body. There are four levels of or­gan com­plex­ity, the first be­ing flat sur­faces like skin, the second hol­low tubes like trachea, the third hol­low struc­tures, like the blad­der and stom­ach, and the fourth sol­id struc­tures, such as the liv­er and lungs. “Up to this point, we’ve been able to im­plant the first three types in pa­tients,” Atala says, “but we have not yet im­planted sol­id struc­tures in pa­tients. That’s still years away.”

One of the bar­ri­ers to that next step is feed­ing those or­gans. A kid­ney re­quires a lot of ves­sels to keep func­tion­ing. And not just big ar­ter­ies, but tiny ca­pil­lar­ies to feed all the cells. Over the sum­mer, Johns Hop­kins re­search­ers found a way to grow net­works of tiny hu­man blood ves­sels in mice, the type that could someday feed a lab-grown kid­ney or oth­er com­plic­ated or­gan, or to simply re­pair ca­pil­lar­ies dam­aged by dia­betes. “This is why we are very ex­cited about it — be­cause the vas­cu­lature is rel­ev­ant for al­most any tis­sue type,” Shar­on Gerecht, a re­search­ers on the study, says. Still, the field re­mains in in­fancy.

“You have to re­mem­ber, the field star­ted with mouse cells in 2006, so it is pretty young,” she says. “We still don’t know ex­actly how pluri­po­tent they are. Do they re­mem­ber that they were dis­eased and old be­fore? We still don’t know this, and it will take time for re­search to find out.”

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