12.2019 | THE SCIENTIST 49ARIEL SILBER; COLE TRAPNELL, UNIVERSITY OF WASHINGTON
PARASITE OVERLOAD: An Alzheimer’s drug reduces infection in murine
macrophages infected with Trypanosoma cruzi (blue dots).DISEASE & MEDICINEStopping Chagas Parasites
THE PAPER
H.F. Santos Souza et al., “The effect of memantine, an antagonist
of the NMDA glutamate receptor, in in vitro and in vivo infections
by Trypanosoma cruzi,” PLOS Negl Tro p Dis, 13: e0007226, 2019.In 2014, researchers led by Ariel Mariano Silber at the
University of São Paulo in Brazil showed that the Alzheimer’s drug
memantine killed Trypanosoma cruzi, the parasite that causes
Chagas disease, in vitro. Now, Silber and his colleagues report
evidence that the treatment can reduce T. cruzi infection in mice
and in cultured murine macrophages, suggesting it might be a
viable option for patients in parts of Central and South America
where Chagas is widespread.
The two drugs currently used to treat Chagas disease,
nifurtimox and benznidazole, are most effective early on, often
before patients realize they are infected. “Most of the time,
patients assume that [the disease] is something else, like
the flu, so they don’t go to the doctor for a diagnosis,” Silber
tells The Scientist. By the time the disease progresses, he says,
the drugs are less effective, and patients can develop severe
cardiomyopathy. The drugs also have significant side effects.
In the new study, the researchers treated T. cruzi–infected mice
with memantine and found that the mice had fewer parasites in
their blood and hearts, fewer inflammatory cells involved in the
immune system’s infection response, and an increased survival
rate compared with untreated mice. In vitro experiments showed
the drug was clearing the parasite from infected macrophages.
Silber hopes to set up clinical trials of the drug, which has few side
effects in humans, in the future.
Bianca Silvana Zingales, a biochemist at the University of São Paulo
who has collaborated with Silber in the past but was not involved with
the current study, says that while “memantine represents a promising
candidate for Chagas disease,” the current study focused on just one
strain of the parasite, and future work should include other strains. “T.
cruzi strains have extensive genetic and biological diff erences, including
diff erent susceptibilities to drugs,” she says.
—Emily MakowskiCELL BY CELL: Each cell in the C. elegans embryo arranged by transcriptome
similarity and color coded for when in development they are present.DEVELOPMENTAL BIOLOGYWorm Embryos in High Res
THE PAPER
J.S. Packer et al., “A lineage-resolved molecular atlas ofC. elegans
embryogenesis at single-cell resolution,” Science, 365:eaax1971,
2019.Since the late Sydney Brenner first slid a C. elegans under the
microscope more than a half century ago, scientists have used
the species in one of the most exhaustive investigations of any
animal—one that continues to this day. They have tracked each
of the nematode’s cells as it blinks in and out of existence during
development, sequenced the animal’s genome, and cataloged
the transcriptome of the whole organism or the occasional tissue
or cell. Now, Junhyong Kim, a developmental biologist at the
University of Pennsylvania, and his colleagues have traced the
gene expression in nearly every cell, one by one, in developing
worms, from fertilization to hatching.
“For every gene, you see where and when it’s expressed,”
says Itai Yanai, a computational biologist at New York
University’s School of Medicine who was not involved in the
study. “That’s a tremendous step forward.”
By the time an individual C. elegans reaches adulthood it has
had just 1,341 cells, although they don’t all exist in the animal’s
body at the same time. Kim and his team gathered embryos from
various stages of development and isolated individual cells by
centrifugation or filtration, collecting more than 86,000 cells in
total. Using marker genes whose expression Kim’s colleagues
had previously traced to certain cells at certain times, along with
developmental stage and other identifiers, the team was able to
categorize each cell into one of 502 cell types and use RNA-seq
analyses to index its transcriptome.
The team found that cells in different lineages can have similar
gene expression profiles, a pattern that occurs in mice as well,
suggesting this is a common feature of animal development. Kim
likens this to a tree—while the branches might be different, the
leaves on one side are quite similar to those on the other side.
“They converge to the same kind of cell identity,” he says.
—Kerry Grens