NEWS | IN DEPTH

832 31 AUGUST 2018 • VOL 361 ISSUE 6405 sciencemag.org SCIENCE

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They might have a tougher time with

a compound developed by Astraea Thera-

peutics, a biotech company in Mountain

View, California, that hits two brain mol-

ecules at once. AT-121 stimulates not only

MOR, but also a close cousin known as the

nociceptin opioid receptor (NOR). When

activated in the brain, NOR appears to

counteract MOR. At the same time, it re-

inforces MOR’s pain relieving activity else-

where in the central nervous system, says

Nurulain Zaveri, Astraea’s founder and

chief scientific officer. The drug isn’t the

first to target both receptors—another one

is already in phase III trials for diabetic

nerve pain, among other uses, but that

compound targets other receptors as well,

and animal studies suggest it may have ad-

dictive properties.

In this week’s issue of Science Transla-

tional Medicine, Zaveri and academic col-

leagues in the United States and Japan

report that rhesus monkeys given AT-121

experienced 100-fold greater pain relief

than the same dose of morphine provided.

Yet the drug did not trigger respiratory de-

pression, addictivelike behaviors, or even

tolerance, where more of a compound

is needed over time to produce the same

desirable effects such as pain relief. AT-

121 even appears to counteract addiction

to standard opioids, such as oxycodone,

Zaveri says. Monkeys hooked on oxyco-

done and trained to self-administer the

drug sharply reduced further drug seeking

when given AT-121. “It looks very promis-

ing,” Bohn says of the new compound.

Avoiding opioid receptors altogether is

another appealing strategy for relieving

pain with a reduced risk of addiction, says

Roger Kroes, senior director for discovery

science at Aptinyx, a biotech firm in Evan-

ston, Illinois, who described one of his com-

pany’s compounds at the meeting. Called

NYX-2925, it activates the NMDA receptor,

which helps strengthen neural synapses in-

volved in learning and memory. Although

acute pain doesn’t involve a learned compo-

nent, chronic pain is thought to bring about

long-term neural changes orchestrated, in

part, by NMDA receptors.

Many well-known drugs that block these

receptors—among them ketamine and

methadone—can relieve pain and can be

less addictive than opioids. But these com-

pounds hit other targets as well and have

widespread side effects. NYX-2925, how-

ever, is more selective, data show. At the

meeting, Kroes reported that in preclinical

studies on mice and rats, the compound

reduced pain and led to a remodeling of

synapses involved in learning and memory,

essentially rewiring neural circuitry away

from being habituated to pain.

The results “were pretty exciting,” says

Ben Milgram, a medicinal chemist with Am-

gen in Cambridge, Massachusetts, who at-

tended the meeting. Aptinyx is now testing

NYX-2925 in two phase II clinical studies in

people with diabetic nerve pain and fibro-

myalgia, a disease marked by widespread

muscle and skeletal pain.

Drugs designed to deliver the benefits

of opioids without the deadly risks can

easily falter. At the meeting, researchers

from Genentech, Merck & Co., and Amgen

described compounds designed to tamp

down yet another nonopioid receptor tar-

get, a protein called Nav1.7. Although all

found their target and reduced pain in ani-

mals, they proved weaker on other scores;

for example, some were poorly absorbed in

the blood or blocked other Nav proteins,

causing side effects. Still, with the opioid

crisis taking an ever-larger toll, even pre-

liminary good news is welcome. j

Infecting an estimated 230 million

people, schistosomiasis is the world’s

most widespread parasitic disease after

malaria. But temperate latitudes were

thought to be spared: Schistosome flat-

worms are common only in warm places

in Africa, India, and South America. So

parasitologist Jerome Boissier was surprised

when, in a single week in 2014, physicians

in France and Germany called him to report

that two families who had never left Europe

had developed the disease, which can cause

fever, chills, muscle aches, and bloody urine.

Epidemiologists later traced the cases

to the Cavu River on Corsica, a French is-

land in the Mediterranean Sea, where the

patients had swum during a vacation. Sci-

entists found that a local freshwater snail

was serving as the intermediate host that’s

essential to the flatworms’ complicated life

cycle. The river is still infested: At least

120 people have become infected. And the

disease is turning up elsewhere on Corsica.

In earlier work, Boissier, who’s at the Uni-

versity of Perpignan Via Domitia in France,

had shown that the culprit is no ordinary

schistosome parasite, but rather a hybrid of

two species. Now, his team has uncovered

the hybrid’s advantage: It appears to be bet-

ter than the parent species at infecting both

the snails and its unfortunate mammalian

hosts. Such hybrids, discovered in other

parasitic species as well, could widen a para-

site’s range of host mammals, complicating

efforts to control it. Presented here last week

at the Second Joint Congress on Evolution-

ary Biology by Boissier’s grad student Julien

Kincaid-Smith, the work “is changing the way

we think about disease transmission,” says

Christina Faust, a disease ecologist at the Uni-

versity of Glasgow in the United Kingdom.

Humans and other mammals infected

with schistosomiasis shed eggs in their feces

Hybridization may give some parasites a leg upGenomic study helps explain how schistosomiasis gained a foothold in Europe

INFECTIOUS DISEASES

By Elizabeth Pennisi, in Montpellier, France

Synthetic opioids, such as this fentanyl captured in a drug raid, have caused an alarming rise in overdose deaths.

Published by AAAS

Corrected 29 August 2018. See full text.

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or urine, which hatch if they reach fresh-

water in time. The hatchlings then take up

residence in snails, where they mature and

reproduce asexually, yielding tiny larvae

that exit the snail. If those larvae encoun-

ter another swimming or wading mam-

mal, they burrow into its skin and settle in

blood vessels, completing the life cycle. Five

species infect humans; the most common

one, Schistosoma haematobium, causes uro-

genital schistosomiasis. It often resides in

veins in the bladder wall or the reproduc-

tive tract and can damage organs or impair

fertility. Although the antiparasitic drug pra-

ziquantel is effective, patients in developed

countries can go undiagnosed for years.

S. haematobium probably reached Europe

after a patient infected elsewhere traveled

to Corsica and urinated in the Cavu River,

Boissier says. An intermediate host was wait-

ing: The river is home to the snail Bulinus

truncatus—one of a few Bulinus species that

can support schistosomes—which also occurs

in some African and Middle Eastern coun-

tries. The outbreak “is a wake-up call that this

disease can establish itself wherever the right

[conditions] exist,” says immunologist Daniel

Colley of the University of Georgia in Athens,

who notes that global travel makes such in-

troductions more likely.

Two years ago, Boissier’s team reported

that DNA tests on the parasite eggs suggested

the new arrival was a hybrid of S. haemato-

bium and S. bovis, a schistosome species that

infects livestock; on the basis of the hybrid’s

DNA, Senegal was the most likely source.

The hybrids themselves were not news;

Tine Huyse, a parasitologist at the Catholic

University of Leuven in Belgium, and a col-

league had found them in Senegal in 2008.

But Kincaid-Smith traveled to Senegal and

Cameroon to collect the parent strains, and

the team bred them in the lab to re-create the

hybrid. The researchers then tested the abil-

ity of the parents and hybrid to infect snails

and—as a stand-in for humans—hamsters.

The human parasites found in Africa didn’t

infect the Corsican snails, Boissier reported.

S. bovis, the animal variety, did infect the

snails, but the hybrid did so even more read-

ily, and it thrived not only in Corsican snails

but also in B. truncatus snails from Spain

and a related snail species from Portugal. The

hybrid also developed faster in hamsters and

made them sicker.

Hybrids have emerged in other parasites,

including the agents that cause malaria,

leishmaniasis, and Chagas disease. Just how

important they are in epidemiology is still un-

clear, but their existence is worrisome, Huyse

says, and they seem set to become more com-

mon as travel and migration expand. Hybrids

are more likely to infect multiple hosts, al-

lowing some of them to “hide” in nonhuman

animals, out of reach of the drugs given to

people. And combining two genomes gives a

parasite more genetic variation with which

to adapt to new places and hosts, Faust says.

When Kincaid-Smith and his colleagues

teamed up with the Wellcome Sanger In-

stitute in Hinxton, U.K., to fully sequence

the hybrid, they found that three-quarters

of its DNA came from the human parasite

and the rest from S. bovis. That mixture

may boost the ability of the hybrid to infect

the Corsican snail, but with a quarter of the

genes from S. haematobium missing, “it’s

a wonder how the parasite can still infect

humans,” said Kincaid-Smith, who with his

colleagues posted a preprint about the ge-

nome study on bioRxiv on 11 August. The

fact that DNA from the two parent species

was quite mixed up—sections of S. bovis

chromosomes appeared at various places

along the S. haematobium chromosomes—

indicates that hybrids have been around

long enough to mate with parents and with

each other over multiple generations.

“The level of genomic information [in the

study] is impressive,” Colley says. But he’s

cautious about extrapolating the findings

about the infectious superpowers of the

labmade hybrid to what happens in nature.

“We do not know how it will play out in the

long run in terms of worsening the spread

of or impeding the control of schistosomia-

sis,” he says.

Schistosomiasis seems set to stay on Cor-

sica. Although no human cases occurred

in 2017—after a total of seven cases in the

two preceding years—the worms still occur

in snails in the Cavu River; they also have

surfaced in the nearby Solenzara River,

Boissier says. Whether they overwinter in

snails or take refuge in rodents or some

other mammalian host isn’t clear, Kincaid-

Smith told the meeting: “That’s also some-

thing that needs to be investigated.” j

At least 120 people contracted schistosomiasis in the Cavu River; another river nearby has become infested as well.

0 400

Km

Mediterranean Sea

GERMANY

ALGERIA

AUSTRIA

CROATIA

TUNISIA

FRANCE

ITALY

Sardinia

RomeCorsica

A European foothold Schistosomiasis was discovered on the French

island of Corsica in 2014; a DNA analysis suggests

it originated in Senegal.

Published by AAAS

Corrected 29 August 2018. See full text.

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Hybridization may give some parasites a leg upElizabeth Pennisi

DOI: 10.1126/science.361.6405.832 (6405), 832-833.361Science 

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