Health Sciences Report Summer 2003

The Mystery of Regeneration
By Phil Sahm

Losing one's head is a matter of grave prospect to most earthly creatures.

Not so for the planarian.

The planarian, a quarter-inch long worm that lives in oceans, freshwater, and soil, has the enviable capacity to grow a new head in the event its old one becomes separated from its body.

While that no doubt comes in handy in an accident, this peculiar ability plays an even more important role: losing its head is one way the planarian propagates its species.

Some planarians, also called flatworms, are hermaphrodites, meaning they possess both male and female sexual characteristics, and copulate all by their lonesome to reproduce sexually.

Other flatworms carry out their biological duties in an equally curious fashion: they stretch until their bodies separate into two parts. The part with the head sprouts a new body, while the other part grows a new head. Not the most romantic way to make a new worm, but it has gotten the job done for millions of years.

The ability to regrow entire animals from mere fragments, called regeneration, has captivated scientists for 300 years, according to Alejandro Sanchez Alvarado, Ph.D., associate professor of neurobiology and anatomy at the University of Utah School of Medicine. Sanchez Alvarado, a native Venezuelan who came to America at 17 to attend Vanderbilt University, counts himself among the fascinated.

"It's all a mystery," he says.

And it's a mystery that intrigues him enough that five years ago, while at the Carnegie Institution in Washington, D.C., Sanchez Alvarado dedicated his research to identifying the genes and molecules that allow planarians to regenerate. Sanchez Alvarado, who received his Ph.D. in pharmacology and cell biophysics from the University of Cincinnati Medical School, has continued his quest since coming to Utah nearly two years ago.

In one sense that appears to be a modest goal: he and his 10-member lab want only to understand the basic processes of regeneration. But in science, understanding elemental processes often is a huge job, and researching planarian regeneration could keep Sanchez Alvarado, 38, busy the rest of his career.

Planarians and humans are not close cousins on the evolutionary scale, but flatworms could provide insight into human cellular processes and our potential for regeneration: 70 percent of the 4,500 genes researchers have looked at in planarians are found in people, too, according to Sanchez Alvarado.

He cites four main reasons for studying planarians:

  • They regenerate exceptionally well.
  • The genes in planarians regulate a remarkable amount of developmental plasticity.
  • They reproduce both sexually and asexually.
  • Planarians carry many stem cells.

In addition, planarians are one of the simplest animals in which regeneration can be studied in the extant organism, providing a living laboratory.

Planarians are not the only metazoans, (animals that originate from a single cell and grow into complex organisms with cells arranged into different organs) that regenerate. Salamanders grow new limbs and eyes. People regenerate organs, such as the liver, and our blood and skin cells are replaced by the billions every day.

But planarians regenerate better than most animals. A tissue fragment as small as 1/279th of a planarian, taken from almost any part of its body, can regenerate an entire worm, according to Sanchez Alvarado. How they accomplish this is the heart of the mystery.

Planarians contain cells called neoblasts (stem cells) throughout their bodies. Neoblasts are capable of differentiating into all planarian tissue types, depending on what is needed. In one context, a neoblast might give rise to neurons, while in another it may form muscle cells.

Scientists do not know the exact number of neoblasts required for a planarian to regenerate an entire organism. But, theoretically, it's possible for a planarian to regenerate an entire worm from a single neoblast. "In principle, they are immortal," Sanchez Alvarado said.

Scientists can only speculate why metazoans developed the ability to regenerate.

It's possible regeneration evolved as a way for primitive species to propagate. Life was not easy in the primordial soup, and species survived any way they could. But, for reasons unknown, as many species evolved over hundreds of millions of years, they lost the ability to regenerate to the extent of planarians.

Why this would happen presents a challenging question.

One explanation, according to Sanchez Alvarado, is that evolution actually selected against regeneration in some species. It sounds counterintuitive that animals would devolve something as apparently advantageous as regeneration. But regeneration may have been selected against, because it was inimical to the long-term survival of any given species.

Regeneration depends on neoblasts, which have the potential to turn into many different cells. But, if production of those cells goes uncontrolled, it could result, for example, in the unregulated formation of tumors that eventually kill the host organism. That would provide powerful incentive for a species to eliminate the ability to regenerate.

It's also possible that the ability to regenerate was neither selected for nor against in any species and disappeared for other reasons.

As he investigates how and why regeneration evolved in metazoans, Sanchez Alvarado wants to understand the molecular processes driving it. That, ultimately, may provide knowledge that helps people.

Using microarray techniques, which give researchers the ability to examine many bits of genetic information at the same time, Sanchez Alvarado's lab has begun to delineate the behavior of more than 4,000 planarian DNA clones. By examining these clones, he can monitor gene expression in regenerating tissue to learn the molecular routines that planarians employ to regenerate.

He also uses knockout techniques to learn a gene's function in regeneration. He and his lab associates found that double-stranded RNA silences gene expression in planarians. In a pilot screen at the U of U, Sanchez Alvarado has detected functional defects in 63 percent of all genes examined, and many of these may play some role in regeneration. Sanchez Alvarado doesn't know whether those roles are a cause or effect of regeneration, but finding the answer would be an important step in understanding the whole process.

"This may help us identify the genes that allow regeneration to take place," he said.

In a third area, Sanchez Alvarado is exploring stem cells to understand regeneration in the normal replacement of cells and when cells are injured.

He hopes to apply the insights gained from his research to higher organisms. He suspects the basic pathways and processes that allow planarians to regenerate are preserved in other species, too--maybe even people.

His research comes, Sanchez Alvarado said, just as biology has entered its "golden age" with the mapping of the human genome. What the periodic table did for chemistry, the human genome will do for biology: knowing how many elements one has to work with transforms a problem with infinite outcomes to one with finite outcomes. Knowing the total number of genes in an organism limits the possible number of combinations in which these genes can interact with one another.

Does all this mean people will grow new heads one day?

Doubtful.

Even the prospect of human regeneration of limbs seems unlikely, if not impossible, today.

But the humble flatworm may provide information that one day brings discoveries to help people with degenerative diseases, spinal cord injuries, and the like.

As a first step, Sanchez Alvarado expects that, in his lifetime, it may be possible to regenerate specific cell types, such as neurons and muscles.

"I see no reason why it would not be possible to regenerate cells," he said. "The processes of cell determination and fate restriction are things we are really beginning to understand."

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