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SCIENCE science.org 6 MAY 2022 • VOL 376 ISSUE 6593 565

F

or 3 decades, biochemist Charles

Serhan at Brigham and Women’s Hos-

pital has been the torch bearer for

“resolution immunology”—a research

field he pioneered after discovering

the first molecules that seem to tamp

down, or resolve, inflammation, the body’s

rapid cellular and chemical response to in-

juries, infections, and even allergens. Ever

since, research on these stop signals, for-

mally known as specialized pro-resolving

mediators (SPMs), has exploded (Science,

2 January 2015, p. 18).

Scientists around the world have im-

plicated multiple classes of these lipid-

based molecules in all manner of diseases.

A search on PubMed for “lipoxin,” the

first SPM identified, turns up more than

2200 papers, and at least three biotech com-

panies are planning clinical trials with syn-

thetic molecules meant to restore or boost

the body’s natural ability to end inflamma-

tion, which can wreak havoc if prolonged.

But what if a large chunk of the research

on SPMs is based on flawed science?

Last month, in a paper in Frontiers in

Pharmacology, an international group of

18 scientists including specialists in lipid

analysis argued that the studies identifying

these molecules in people typically detect

them at levels so low they are unlikely to

play a major role in resolving inflamma-

tion. The critics also found that most stud-

ies of human samples merely correlate

SPM levels with a phase during the arclike

time course of inflammation; data proving

SPMs actually resolve it are weak to non-

existent, the authors argue.

The paper’s authors offered an even

more damning critique: Protocols devel-

oped by Serhan and his collaborators to

detect SPMs in body fluids or tissue sam-

ples don’t conform to accepted standards,

they say. What is provided as proof of SPMs

in many papers should actually be inter-

preted as mere “noise,” they argue. “You

cannot ignore the fact that there is a grow-

ing number of analytical chemists who

cannot detect these things,” says Nils Helge

Schebb, chair of food chemistry at the Uni-

versity of Wuppertal and lead author.

Even some scientists who didn’t join the

broadside have struggled. Immunology re-

searcher Derek Gilroy of University College

London, who has collaborated with Serhan

but is now moving his lab away from SPMs,

tells Science he has had a “very negative

experience working with these things and

seen some data that makes me question

whether these things are real.”

The concerns over the detection methods,

Science has learned from several sources,

have prompted investigations at Harvard

Medical School, the parent organization of

Serhan’s hospital, and at Queen Mary Uni-

versity of London (QMUL), where molecu-

lar pharmacologist Jesmond Dalli, a former

Serhan postdoc, now studies lipid mediators.

Neither university would confirm the

probes to Science. The criticisms in the Fron-

tiers commentary are “not true,” Serhan said

in an email. “Many others have indeed de-

tected SPMs in human samples.” A single

critical paper compared with thousands on

SPMs “is not a valid comparison of the facts.

It’s not clear to me what the goal of their ‘re-

view’ is because it’s totally wrong.”

“I am baffled,” adds QMUL immuno-

pharmacologist Mauro Perretti, who stud-

ies SPMs independently of Dalli but also

collaborates with Serhan. “SPMs exist, they

have been characterized in multiple ways,

they have been synthesized, and they are

active.” SPM proponents also note that ani-

mal studies and one human trial have al-

ready yielded hints that synthetic versions

of the molecules work as advertised.

SEARCHING FOR SIGNALS

Serhan has been studying inflammation

since his postdoc years at the Karolinska

Institute. In 1984, he discovered a novel

fatty acid made by the body. Over time, he

and his collaborators piled up evidence that

the molecule, which they dubbed lipoxin,

could shut down inflammation. At the time

researchers believed inflammation just dis-

sipated, like a crowd after an event. Serhan

argued instead that lipoxin and other mol-

ecules actively end the response, like riot

police arriving to disperse the crowd. Since

then, his lab and others around the world

have found and characterized more than

20 other types of lipid-based biochemicals

that form four SPM classes—lipoxins, re-

solvins, maresins, and protectins.

Schebb began to look for SPMs about

6 years ago but had trouble detecting any

of them in human samples. He visited

Dalli’s lab, looking for advice, but says

“they didn’t teach me anything that

helped.” Schebb soon learned that several

other scientists also had trouble detecting

SPMs, and he became increasingly skepti-

cal of the research.

Enter Valerie O’Donnell, a lipid bio-

chemist at Cardiff University. About

3 years ago, when reviewing papers on

SPMs, O’Donnell noticed a few “strange”

looking figures showing the results of liq-

uid chromatography mass spectrometry

(LCMS), which separates a sample’s mo-

lecular contents into ions with distinct

molecular masses, producing a chart called

a chromatogram. These diagrams are sup-

posed to show a sharp peak representing

a detected molecule. But when O’Donnell

looked at high-resolution images of

By Gunjan Sinha

BIOMEDICINE

Doubt cast on inflammation’s stop signals

Critics challenge data underpinning “resolution immunology,” triggering university probes

Time (minutes)

0

Relative intensity (%)

100

Suggested peak

Disputed lipid detection in sample

Noise

Height of

peak signal

above noise

0

Relative intensity (%)

100

Time (minutes)

Test lipid

Point of contention

To be content a sample contains a molecule such

as a lipid, scientists usually require a sharp peak, far

above the noise, in data from liquid chromatography

mass spectrometry (top). Critics of research on

inflammation-resolving lipids say several chromato-

grams in one paper don’t show a clear peak (bottom).

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