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The international journal of science / 23 May 2024

MOMENT

IN THE SUNNear-surface instabilities drive

the solar magnetic dynamo

Under pressure

How can researchers

be protected from

increased harassment?

Missing link

Promethium complex

captured in solution

fills gap in observations

History lesson

Downturns helped

give ancient societies

long-term resilience

Vol. 629, No. 8013

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By Asher Mullard

With obesity drugs now helping

people to slim down, research-

ers are working to capitalize on

their popularity by bulking up

the weight-loss-drug pipeline.

The latest contender takes a Trojan horse

approach — hiding a small molecule in a

gut-hormone-mimicking peptide that is already

used in obesity drugs — to strike a double blow

to the brain cells that control appetite.

The work, which demonstrated the effects

of this drug candidate in mice and rats, was

published on 15 May in Nature1.

“It’s a strong paper,” says Daniel Drucker,

an endocrinologist at Mount Sinai Hospital in

Toronto, Canada, who helped to unravel the

role of gut hormones such as GLP-1 (gluca-

gon-like peptide-1) and GIP (glucose-depend-

ent insulinotropic polypeptide) in obesity. The

blockbuster weight-loss drugs semaglutide

(sold as Wegovy) and tirzepatide (Zepbound)

act by mimicking these hormones, binding to

their receptors on neurons in the brain that

control hunger pangs. These drugs can help

people to lose 15–20% of their body weight.

And it could be possible to eke even more

activity from these hormone mimics by fusing

them with other drugs, the study suggests.

Trojan therapeutics

“Very high marks for the novelty” of the

research, says Drucker, who was not involved

in the study and is a consultant for the phar-

maceutical industry. “Let’s hope that we’ll see

some proof of concept in the clinic”, when the

approach is tested in humans.

The drug contender takes aim at both the

Researchers adapted a peptide similar to the one used in the obesity drug Wegovy
to elicit an even more potent weight-loss response in mice.

LISE AASERUD/NTB/ALAMY

Test of weight-loss candidate in mice shows that there

is still room for improvement in a burgeoning field.

EXPERIMENTAL OBESITY

DRUG PACKS DOUBLE

PUNCH TO REDUCE WEIGHT

Nature | Vol 629 | 23 May 2024 | 733

The world this week

News in focus



GLP-1 receptor and the NMDA receptor, an ion

channel found on brain cells that was linked

to obesity in 2015 (ref. 2). At the time, small

molecules that blocked the NMDA recep-

tor seemed like a non-starter for obesity

drug developers, because this type of com-

pound, which includes the ‘party drug’ and

antidepressant ketamine, is associated with

harmful side effects.

But Christoffer Clemmensen, a metabolism

specialist at the University of Copenhagen,

saw a path forwards. He speculated that

it might be possible to sidestep the safety

risks by fusing an NMDA-receptor blocker to

a gut-hormone mimic that acts only on the

neurons that regulate appetite.

To make this a reality, Clemmensen and his

colleagues attached a peptide that looks like

the GLP-1 hormone to a small molecule, dizo-

cilpine (also called MK-801), that blocks the

NMDA receptor. Dizocilpine was discovered in

the 1980s by researchers at the US pharmaceu-

tical firm Merck, based in Rahway, New Jersey,

but was then abandoned. Clemmensen and the

team saw that, in mice and rats, GLP-1-loving

neurons in the brain took up this peptide–drug

conjugate, and then cut the dizocilpine payload

loose to block the NMDA receptor. (Some mem-

bers of the team work at Novo Nordisk, which

makes semaglutide, although Clemmensen

says this was an academic collaboration and

not a commercial one.)

“This is a really creative way to optimize

for weight loss,” says Darleen Sandoval, a

physiologist at the University of Colorado in

Aurora. “The big picture here is how far we

have come in terms of being able to target

the brain to treat obesity,” adds Sandoval, who

co-authored a commentary that accompanied

the study in Nature3

.

Treating mice with dizocilpine alone caused

side effects such as overheating and excess

movement. The peptide–drug conjugate was

safer, and it offered similar weight-loss bene-

fits to treating mice with semaglutide alone.

Where the conjugate shone was in mice pre-

dosed with semaglutide: once the animals

reached a weight-loss plateau with that drug,

giving them the conjugate as an add-on treat-

ment drove their body mass down further.

“It is competitive with the current best

therapies on the market,” says Clemmensen.

“Possibly, we can outperform these.”

To the clinic

As a next step, Clemmensen and some col-

leagues have co-founded Ousia Pharma, based

in Copenhagen, to advance a related drug can-

didate into clinical trials. This potential ther-

apeutic, called OP-216, has the added benefit

of also mimicking GIP in addition to GLP-1,

Clemmensen says. “We could be in the clinic

in 2025,” he adds.

The success of the current crop of obesity

drugs has set a high bar for next-generation

therapeutics. But “there’s definitely room for

more drugs and targets”, says Ruth Loos, an

obesity geneticist at the University of Copen-

hagen who co-led the 2015 genetics study that

linked the NMDA receptor to obesity 2 . Not

everyone sheds weight using the currently

available options. And gut-hormone mimics

need to be taken continuously to maintain

their effect.

Loos, who has also consulted for the phar-

maceutical industry, was not involved in devel-

oping the latest peptide–drug conjugate, but

hopes it will encourage others to look for inno-

vative ways to treat obesity. Dozens of weight-

loss drugs — many targeting GLP-1 and GIP

— are already in the clinic, and drug developers

are on the lookout for up-and-coming agents.

The weight-loss drug market is forecast to be

worth up to US$100 billion by 2030.

It’s predicted that by 2035, more than half

of adults worldwide will be obese. Treating

them with obesity drugs could confer wider

health advantages, such as cardiovascular and

anti-inflammatory benefits. Trials of these

drugs are also under way to treat kidney dis-

ease, Parkinson’s and Alzheimer’s diseases,

and addiction-related behaviours such as

drinking and smoking.

“Not all these trials are going to be success-

ful,” Drucker says. But enough might pan out

to reshape the therapeutic landscape, he adds.

“It’s going to be fascinating to watch.”

“When I started working on obesity in 2013,

there was no interest in it,” Clemmensen says.

Right now, he adds, all the activity is a bit wild.

1. Petersen, J. et al. Nature https://doi.org/10.1038/s41586-

024-07419-8 (2024).

2. Locke, A. E. et al. Nature 518, 197–206 (2015).

3. Cook, T. M. & Sandoval, D. Nature https://doi.org/10.1038/

d41586-024-01352-6 (2024).

By Davide Castelvecchi

Three separate research groups have

demonstrated quantum entangle-

ment — in which two or more objects

are linked so that they contain the same

information even if they are far apart

— over several kilometres of existing optical

fibres in real urban areas. The feat is a key step

towards a future quantum internet, a network

that could allow information to be exchanged

while encoded in quantum states.

Together, the experiments are “the most

advanced demonstrations so far” of the

technology needed for a quantum internet,

says physicist Tracy Northup at the Univer-

sity of Innsbruck in Austria. Each of the three

research teams — based in the United States,

China and the Netherlands — was able to

connect parts of a network using photons in

the optical-fibre-friendly infrared part of the

spectrum, which is a “major milestone”, says

fellow Innsbruck physicist Simon Baier.

A quantum internet could enable any two

users to establish almost unbreakable crypto-

graphic keys to protect sensitive information.

But full use of entanglement could do much

more, such as connecting separate quantum

computers into one larger, more powerful

machine. The technology could also enable

certain types of scientific experiment, for

example by creating networks of optical tele-

scopes that have the resolution of a single dish

hundreds of kilometres wide.

Two of the studies 1,2 were published in

Nature on 15 May. The third was described last

month in a preprint posted on arXiv 3

, which

has not yet been peer reviewed.

Impractical environment

Many of the technical steps for building a

quantum internet have been demonstrated in

the laboratory over the past decade or so. And

researchers have shown that they can produce

entangled photons using lasers in direct line of

sight of each other, either in separate ground

locations or on the ground and in space.

But going from the lab to a city environment

is “a different beast”, says Ronald Hanson, a

physicist who led the Dutch experiment 3 at

the Delft University of Technology. To build

a large-scale network, researchers agree that

Experiments mark progress towards networks

that could have revolutionary applications.

‘QUANTUM INTERNET’

DEMO IN CITIES IS

MOST ADVANCED YET

“The step has now

really been made

out of the lab and

into the field.”

734 | Nature | Vol 629 | 23 May 2024

News in focus



it will probably be necessary to use existing

optical-fibre technology. The trouble is, quan-

tum information is fragile and cannot be cop-

ied; it is often carried by individual photons,

rather than by laser pulses that can be detected

and then amplified and emitted again. This lim-

its the entangled photons to travelling a few

tens of kilometres before losses make the whole

thing impractical. “They also are affected by

temperature changes throughout the day —

and even by wind, if they’re above ground,” says

Northup. “That’s why generating entanglement

across an actual city is a big deal.”

The three demonstrations each used differ-

ent kinds of ‘quantum memory’ device to store

a qubit, a physical system such as a photon or

atom that can be in one of two states — akin to

the ‘1’ or ‘0’ of ordinary computer bits — or in a

combination, or ‘quantum superposition’, of

the two possibilities.

In one of the Nature studies, led by quantum

physicist Pan Jian-Wei at the University of Sci-

ence and Technology of China (USTC) in Hefei,

qubits were encoded in the collective states of

clouds of rubidium atoms 1 . The qubits’ quan-

tum states can be set using a single photon, or

can be read out by ‘tickling’ the atomic cloud to

emit a photon. Pan’s team had such quantum

memories set up in three separate labs in the

Hefei area. Each lab was connected by optical

fibres to a central ‘photonic server’ around

10 kilometres away. Any two of these nodes

could be put in an entangled state if the pho-

tons from the two atom clouds arrived at the

server at exactly the same time.

By contrast, Hanson and his team estab-

lished a link between individual nitrogen

atoms embedded in small diamond crystals,

with qubits encoded in the electron states of

the nitrogen and in the nuclear states of nearby

carbon atoms 3

. Their optical fibre went from

the university in Delft through a tortuous

25-kilometre path across the suburbs of The

Hague to reach a second laboratory in the city.

Photon marathon

In the US experiment, Mikhail Lukin, a phys-

icist at Harvard University in Cambridge,

Massachusetts, and his collaborators also

used diamond-based devices, but with sili-

con atoms instead of nitrogen, making use of

the quantum states of both an electron and

a silicon nucleus 2 . Single atoms are less effi-

cient than atomic ensembles at emitting pho-

tons on demand, but they are more versatile,

because they can perform rudimentary quan-

tum computations. “Basically, we entangled

two small quantum computers,” says Lukin.

The two diamond-based devices were in the

same building at Harvard, but to mimic the

conditions of a metropolitan network, the

researchers used an optical fibre that snaked

around the local Boston area. “It crosses the

Charles River six times,” Lukin says.

The entanglement procedure used by

the Chinese and the Dutch teams required

photons to arrive at a central server with exqui-

site timing precision, which was one of the

main challenges in the experiments. Lukin’s

team used a protocol that does not require

such fine-tuning: instead of entangling the

qubits by getting them to emit photons, the

researchers sent one photon to entangle itself

with the silicon atom at the first node. The

same photon then went around the fibre-optic

loop and came back to graze the second silicon

atom, thereby entangling it with the first.

Pan has calculated that, at the current pace

of advance, by the end of the decade his team

should be able to establish entanglement over

1,000 kilometres of optical fibres using ten

or so intermediate nodes, with a procedure

called entanglement swapping. “The step has

now really been made out of the lab and into

the field,” says Hanson. “It doesn’t mean it’s

commercially useful yet, but it’s a big step.”

1. Knaut, C. M. et al. Nature 629, 573–578 (2024).

2. Liu, J.-L. et al. Nature 629, 579–585 (2024).

3. Stolk, A. J. et al. Preprint at arXiv https://doi.org/10.48550/

arXiv.2404.03723 (2024).

A quantum network node at Delft University of Technology in the Netherlands.

MARIEKE DE LORIJN FOR QUTECH

Nature | Vol 629 | 23 May 2024 | 735


























































































































































































































































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