Engineering human organs in the laboratory
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Tissue engineering is quicker, compared with using stem cells, at least with some organs
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THE CHALLENGE: While bladder muscle cells grow easily enough in the lab, urothelial cells had challenged scientists for long. — AP
OF ALL the organs, the bladder is the least glamorous in the human body. It is a source of embarrassment, a sleep-spoiler and one that speaks with greater authority than the boss. It does not ask for attention but demands it. All this happens while the bladder is normal and functioning well. When disorder strikes, it can be awful.
Stones form and obstruct the easy passage of urine but the doctor can now do an easy procedure to get rid of them. Infection can set in, and here again aggressive antibacterial drug therapy solves the problem.
It is the other causes — bladder tumours, bladder rupture in injuries and accidents, and disorders due to multiple sclerosis, diabetes or spina bifida (where the spinal cord in the lower end is malformed) — that pose a great problem, often requiring a replacement of the bladder itself. It is these cases that demand approaches and solutions from biomedical research. A promising advance has been made in this area using the method of tissue engineering.
Successful results
Dr. Antony Atala of the Wake Forest Institute for Regenerative Medicine, at Winston-Salem, North Carolina, U.S., has published some successful results of a four-year follow up of seven human patients aged 4-19 (suffering from spina bifida, which harmed their bladders).
The paper published online in the April 4, 2006 issue of The Lancet, illustrates the promise of tissue engineering and the possibility of taking cells from the patient's own bladder to generate healthy, functional bladders that can be put back in the patient.
As an organ, the bladder is far simpler than the heart, kidney or the spleen. It is a hollow vessel with an outer layer of muscle cells and an inner layer of special cells called urothelial cells, which form an impermeable reservoir for urine.
While bladder muscle cells grow easily enough in the lab to make sheets, urothelial cells had challenged scientists for long. It was this difficulty that had made earlier researchers use a variety of substitutes as bags and artificial bladders.
Most popular approach
These were bags made from skin, sheaths of connective tissue, the peritoneum (which is the inner membrane lining of the abdominal cavity), the placental sheet, intestinal bits, and synthetic polymers such as silicone. Of all these, the most popular approach so far among surgeons has been to take out sections of the patient's own intestines, shape them into a substitute bladder and fit this on to the patient by surgery.
This has offered some relief but also an unwelcome side effect. Having come from the intestine, this substitute material remembers its history and starts absorbing, while it should only act as a storage vessel! It was at this stage that Dr. Atala (then at Boston) and Dr. David Mooney (of the University of Michigan) began using a small piece of the bladder itself, and finding ways to expand it into a full-fledged bladder.
The big step forward came in 1998, when they found the right combination of growth factors and nutrient mixtures (the right `soup') that would make both the muscle cells and urothelial cells grow.
Using dogs as the experimental animals, they cut out a postage-stamp size bladder sample and separated the muscle cells and urothelial cells from it.
They then used a biodegradable plastic mould and shaped it into a bladder size shell, and coated the outside with layers of muscle cells and the inside with urothelial cells. The right soup did the trick and the lab-made bladder was ready.
They then went to the dogs, removed most of the bladder and stitched on the lab-made bladder to the remaining part in the dog's body.
Within a month, the implanted organ worked like normal bladder. Within 3 months, the plastic shell had degraded and the transplanted organs were hard to distinguish from natural ones.
What is more, blood vessels grew and nerves formed the proper connections, allowing the dogs to regain normal bladder control. Follow-up for about a year showed no problems and indicated the success of this method of growing an organ in the laboratory.
Their paper "De novo reconstitution of a functional mammalian urinary bladder by tissue engineering" was published in the February 1999 issue of Nature Biotechnology.
Based on this success, Drs. Atala, S.B. Bauer, S. Saken, J.J. Yoo and A.B. Retik now attempted to tissue engineer bladders for needy humans. They took out a tiny portion (1-2 square cm) of the bladder, isolated the muscle and urothelial cells, and cultured them on a scaffold made of collagen and synthetic polyglycolic acid. Starting with about 1 million cells, they grew the bladders (containing 1.5 billion cells) in about seven weeks. The engineered tissue was hooked up in each patient with the remaining bladder.
Significant improvement
After the operation, the patients reported significant improvement. And follow-ups of three years and five in some cases show that tissue engineering or lab-grown organs are a reality in the case of bladders.
Some tissues and organs in the body (skin, muscle, bladder, cornea, liver) are simpler than others (heart, pancreas, spleen, kidney, brain). Transplanting of some of these (heart, liver, kidney, cornea) is already done, but lab-growing them is still a challenge. The present work is a small step but a "really nice clinical milestone" as the tissue-engineer Robert Langer of MIT says.
The discerning reader is sure to ask — why not take the stem cell path to make these organs? Yes, but in some of these cases, tissue engineering is easier and more sure-footed. Tissue engineering involves taking the patient's own cells, cultivating them to grow along a scaffold that gives the needed form, and then re-implanting them where needed.
With stem cells, you need to do the cell engineering first, that is to ask the starter cells to make the various cells types you want in the end, blend them right to make the layers of tissues and connectives, and then the organ. Tissue engineering is thus a can-be-done-sooner approach, at least with some organs.
Another question
Another question is: why can we not do what many other animals do, namely, when an organ (or part of it) is gone, simply rebuild it in situ? Look at lizards and zebra fish, which regrow many lost parts.
The reason that these animals do these with ease appears to be that when wound or disorder recurs, regeneration starts when mature cells at the site start reverting into an immature state and form a blob called the blastema. It appears, as Nicholas Wade writes in the April 11 New York Times, that the blastema perhaps draws into the embryogenesis program to regrow the organs.
What a pity that evolution, while bestowing the blastema to the so called `lower organisms' has dropped us humans from this facility! Evolutionary biologists think that the machinery for regeneration must be a hardwired part of animal genome but has fallen into disuse in many species.
Now, is there a way to switch on these genes — a drug or a method to make blastemas in us, so that we may regenerate our worn out or diseased organs? Here is a new candidate for the Holy Grail of human biology.
D. Balasubramanian
dbala@lvpei.org
D. BALASUBRAMANIAN
dbala@lvpei.org
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