Laboratory studies of planarians' reproductive cycles suggest new strategies for treating infections that affect hundreds of millions worldwide.

Intact planarianAfter years of studying a flatworm that infects hundreds of millions of people each year, scientists have turned to an evolutionary “cousin” of the worm for help. By exploring a related flatworm with similar characteristics and biology, they have generated a new approach for studying these worms in the lab and identified a reproductive hormone that might be the worm’s Achilles’ heel.

Flatworms thrive in diverse environments worldwide and infect most vertebrate species, including humans. Their success is due in part to their ability to adapt their reproductive cycles—switching between sexual and asexual reproduction, for example—in response to changing environmental conditions. Scientists have struggled for years to identify effective ways to keep these flatworms from infecting humans. Now, a new study shows that blocking a hormone that helps the flatworm’s nervous system communicate with its reproductive system forces the worms to regress in their sexual development. Targeting such factors in parasitic flatworms could be an effective way to block reproduction in the worms and offer and important new treatment strategy for curtailing infection.

“Flatworms cause important neglected tropical diseases, and understanding the mechanisms that coordinate the reproduction of both free-living and parasitic members of the phylum is important,” says Phillip A. Newmark, a Howard Hughes Medical Institute investigator who led the study. Newmark and colleagues from the University of Illinois at Urbana-Champaign published their study October 12, 2010, in PLoS Biology.

In tropical and sub-tropical communities that lack access to safe drinking water, the flatworm Schistosoma is a problematic parasite. The World Health Organization reports that approximately 200 million people worldwide are infected with schistosomes, which lodge in host tissues for years and lay thousands of inflammation-triggering eggs each day. That inflammation can cause extensive organ damage.

Schistosomes have been difficult to study in the lab because the parasites cannot be propagated outside a host. Newmark recognized that planarians, an organism that is considered to be a “cousin” to schistosomes, might be a viable model organism in which to study basic elements of flatworm biology. Newmark was quite familiar with planarians because he has been instrumental in establishing them as a model system for studying tissue regeneration.

Both types of flatworms have complicated sex lives. Female schistosomes require the presence of males to develop ovaries and accessory reproductive organs. When deprived of their male counterpart, reproductive organs of mature females regress, but can regrow when a female is once again paired with a male. Planarians can reproduce sexually or asexually, and some even switch between modes of reproduction. In times of starvation, planarians resorb their whole reproductive tract and then regrow ovaries, testes, sperm, and eggs when food is plentiful again.

In the lab, planarians are most commonly studied because they have an amazing capacity to regenerate: cut a single worm into a hundred pieces, and each piece will transform into a complete worm. In the course of studying regeneration, researchers had observed that when a planarian’s head is cut off, its sexual organs regress to pre-adolescence until the head regenerates. That suggested that some crucial signal for maintaining the reproductive system could come from the worm’s brain.

In vertebrates, signaling between the central nervous system and the gonads is carried out by small molecules called neuropeptides. So Newmark and post-doctoral fellow Jim Collins began to investigate the possible biological functions of neuropeptides in planarians. In vertebrates, hundreds of neuropeptides are responsible for many kinds of cell-to-cell signaling, but only a few neuropeptide-encoding genes had so far been confirmed in flatworms. Such genes are difficult to find, because the signaling molecules are cleaved from longer molecules called prohormones, and the neuropeptides themselves are only a few amino acids long.

Newmark and his colleagues knew that every peptide hormone is the product of an enzyme called a convertase that acts on a prohormone. Using that information, they started their experiments by eliminating a convertase called pc2 in sexual planarians. Without the enzyme, the worm’s sexual reproduction tissues reverted to a more primitive state.

“The testes completely regressed, you lose all the differentiating cells in the testes and all you are left with essentially is a bag of spermatogonial stem cells [precursors to sperm],” says Newmark. “What’s cool about this finding is that not only does this happen when you knock pc2 down, this also happens to be what germ cells in asexual planarians look like—and what it looks like if you cut the head off a sexual planarian,” he says.

The dramatic impact of the pc2 enzyme on the planarian’s reproductive system also inspired Newmark and his team to delve deeper into possibilities of neuropeptide signaling in flatworms. When they carefully searched the planarian genome, they found 51 genes that they suspected might encode more than 200 neuropeptides. In collaboration with Jonathan Sweedler’s laboratory at the University of Illinois, they used mass spectrometry and biochemical analysis to determine the biochemical properties of 142 of them.

One of these newly identified flatworm hormones was expressed in the nervous system of sexually reproducing planarians, but not in asexual planarians. Disrupting function of the gene encoding this hormone resulted in the loss of reproductive organs resembling that seen after knocking down the convertase. Thus, the hormone appears to be the major peptide responsible for maintaining reproductive maturity.

Newmark’s team has already begun investigating how relevant their planarian findings might be for infectious schistosomes. By comparing the worms’ genomes, they have been able to identify new schistosome hormones that likely give rise to the same peptides as in planarians. The findings show that targeting these hormones could be one way to knock down the schistosome’s ability to reproduce.

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