In a landmark achievement in the science of tissue regeneration, scientists in the lab create a rat's beating heart

FOCUS / SCIENCE : STEM CELLS AND TISSUE ENGINEERING

New heartbeat hails Year of the Rat

In a landmark achievement in the science of tissue regeneration, scientists in the lab create a rat's beating heart

By LAWRENCE K ALTMAN

Medicine's dream of growing new human hearts and other organs to repair or replace damaged ones received a significant boost on Sunday, when University of Minnesota researchers reported success in creating a beating rat heart in a laboratory. Experts not involved in the Minnesota work called it ''a landmark achievement'' and ''a stunning'' development. But they and the Minnesota researchers cautioned that the dream, if it is ever realised, was still at least 10 years away.

Dr Doris A Taylor, the head of the team that created the rat heart, said she followed a guiding principle of her laboratory: ''Give nature the tools, and get out of the way.''

''We just took nature's own building blocks to build a new organ,'' Dr Taylor said of her team's report in the journal Nature Medicine.

The researchers removed all the cells from a dead rat heart, leaving the valves and outer structure as scaffolding for new heart cells injected from newborn rats. Within two weeks, the cells formed a new beating heart that conducted electrical impulses and pumped a small amount of blood.

With modifications, scientists should be able to grow a human heart by taking stem cells from a patient's bone marrow and placing them in a cadaver heart that has been prepared as a scaffold, Dr Taylor said. The early success ''opens the door to this notion that you can make any organ: kidney, liver, lung, pancreas _ you name it and we hope we can make it''.

Todd N McAllister of Cytograft Tissue Engineering in Novato, California, said, ''Doris Taylor's work is one of those maddeningly simple ideas that you knock yourself on the head, saying: Why didn't I think of that?''

Mr McAllister's team has used a snippet of a patient's skin to grow blood vessels in a laboratory, and then implanted them to restore blood flow around a patient's damaged arteries and veins.

The science of tissue engineering has been growing rapidly. For many years, doctors have used engineered skin for burn patients. Engineered cartilage is used for joint repairs. Researchers are investigating the use of stem cells to repair cardiac muscle damaged by heart attacks. Also, new bladders grown from a patient's own cells are being tested in the same patients.

Dr Taylor is a newcomer to tissue regeneration. She began her professional career at the Albert Einstein College of Medicine in the Bronx investigating gene therapy and then cell therapy. She said she switched to tissue regeneration when she realised the limiting step in trying to generate an organ was not the number of cells needed, but the complexity of creating a three-dimensional structure.

''The heart is a beautiful organ,'' Dr Taylor said, ''and it's not one that I thought I'd ever be able to build in a dish.''

Her view changed about three years ago when she recalled that cells were removed from human and pig heart valves before they were used to replace damaged human ones. As she contemplated replacing the old rat cells with new ones, Dr Taylor followed another of her mantras: ''Trust your crazy ideas.''

Progress came in fits and starts. ''We made every mistake known, did every experiment wrong and had to go back and do them right,'' Dr Taylor said.

She poured detergents like those in shampoos in the rat's arteries to wash out the heart cells and then injected neonatal cardiac cells. The first two detergents she tested failed. But a third concoction led to a clear, translucent scaffold that retained the heart's architecture.

After injecting the young rat heart cells into a scaffold, she stimulated them electrically and created an artificial circulation as the equivalent of blood pressure to make the heart pump and produce a pulse. The steps also helped the cells mature. Examining slices of the heart under a microscope showed they were living cells.

To test the biological compatibility of the new hearts, the team transplanted them into the abdomens of unrelated live rats. The hearts were not immediately rejected. A blood supply developed. The hearts beat regularly. And cells from the host rats moved in and began to reline the blood vessels, even growing in the wall of the hearts.

Dr Taylor is conducting similar experiments on pigs as a step toward human work. ''Working out the details in a pig heart made a lot more sense'' because the anatomy of the porcine heart is the closest to humans and pigs are plentiful, she said.

''The next goal will be to see if we can get the heart to pump strongly enough and become mature enough that we can use it to keep an animal alive'' in a replacement transplant, Dr Taylor said.

As for human hearts, the best-case situation would be to obtain them from cadavers, remove their cells to make a scaffold and then inject bone marrow, muscle or young cardiac cells from a patient. The process of repopulating the scaffold with new cells would take a few months, she said.

The body replaces its proteins every few months, so the hope is that the body will create a matrix that it recognises as its own.

One potential problem is that anti-rejection drugs might be required to prevent adverse immune reactions from the scaffold. In that case, Dr Taylor hopes such therapy would be needed only temporarily.

Many things that work in experiments on animals fail in humans because of the species barrier. Mr McAllister said that in Dr Taylor's case ''the principal problem in escalating it to humans is one of scale, not of cell biology, and that is an easier problem to solve potentially''.

Dr Taylor said, ''If it works, it means that there will be many more organs available for transplants.''

Because the components of the biologic matrix differ for every organ, Dr Taylor expects that tests will answer two fundamental questions: Can a stem cell be placed anywhere in the body and still produce a heart, kidney or other organ? Or must a stem cell be placed in its anatomic position to do so?

Such tests might include taking stem cells from one organ, for example a kidney, and putting them in a kidney, liver or heart to begin to understand if the stem cells are innately committed to produce kidneys or whether they will convert to produce livers or hearts. AP