ILLUSTRATION: V. ALTOUNIAN/SCIENCE566 6 MAY 2022 • VOL 376 ISSUE 6593 science.org SCIENCENEWS | IN DEPTHchromatograms said to show SPMs, the fig-
ures didn’t look like “real data,” she says.
She consulted Ian Blair and Garret
FitzGerald, both at the University of Penn-
sylvania, and Robert Murphy at the Uni-
versity of Colorado, Denver, who also study
lipids, and together they analyzed other
published SPM papers. They found at least
70 papers between the Serhan and Dalli
research groups with chromatograms that
they considered suspicious.
They took some of their criticism public
last year. In a preprint posted on 8 Decem-
ber 2021, the same group together with
other specialists in lipid analysis high-
lighted a paper published by Dalli’s group
in 2020 that identified a lipoxin, a resolvin,
and a maresin in the serum of people with
early rheumatoid arthritis. The paper went
on to suggest the SPMs could be used as
biomarkers to assess patients’ response to
medications. But the critics said Dalli wasnot setting a limit of detection—a value
representing the lowest measurable con-
centration that provides high confidence a
molecule exists. Instead, they say, he used
a different method that did not comply
with accepted standards for detecting bio-
molecules. When O’Donnell and colleagues
applied the criteria described in the paper
to inert methanol and buffer fluid, they
found it indicated the presence of lipids
where clearly none existed.
O’Donnell and her colleagues concluded
that Serhan and Dalli often appeared to
quantify lipids by integrating what the
critics would consider “noise.” “We had
never seen mass spectrometry quantita-
tion performed this way before,” Blair says.
In a rebuttal posted this week as a preprinton bioRxiv, Dalli, Serhan, and a colleague de-
fend their methods by reanalyzing some of
their LCMS data using the limit-of-detection
criteria suggested in the preprint. The out-
come confirms his group’s original results,
Dalli says. Dalli also notes that an analysis
of blank samples on his lab’s mass spectro-
metry instruments did not yield false signs
of SPMs. Dalli canceled an interview after
Science contacted QMUL about the dispute
but answered questions by email, calling
the conclusions of the preprint “incorrect.”
He added: “I really cannot understand why
someone would feel they need to go to these
lengths to attack me and my colleagues.”NO RESOLUTION
With the Frontiers paper, the critics have
now broadened their case against the SPM
work. But if they are right about the flaws
in the analyses, how did these papers pass
peer review and get published? FitzGeraldsays there are very few experts in mass
spectrometry of low abundance lipids.
Consequently, submitted papers about
SPMs are usually sent just to experts in the
particular disease being studied, who do
not necessarily understand the intricacies
of mass spectrometry. The critics also note
that journals prefer to publish positive re-
sults, not negative detections.
Hardly any of the positive results come
from labs without a tie to Serhan, FitzGerald
says, and only a handful of labs, including
Serhan’s, are responsible for the analytical
chemistry. “We are motivated to get the lit-
erature corrected,” says FitzGerald, whose
own doubts about SPMs date back to 2015,
when his group found no relationship be-
tween inflammation and the formation ofSPMs in the urine or plasma of healthy
volunteers. “I had satisfied myself that
there was nothing to this story, so we just
stopped working on it,” he says.
FitzGerald and the other authors on the
Frontiers paper aren’t arguing that lipoxins,
resolvins, and other putative SPMs don’t
exist at all. Some researchers have detected
them in people suffering from COVID-19
or septic shock, for example. But they
don’t find the signals in “most biological
samples,” Schebb says, or see compelling
evidence they resolve inflammation.
Serhan counters that just because other
scientists have trouble detecting the bio-
chemicals in human samples doesn’t make
them irrelevant. “These mediators are made
in the local environment and by the time they
get out in the blood or urine they are on their
way out.” There is no reason why they would
exist in such samples at high levels, he says.
It is not just an academic debate. Ani-
mal studies that indicate SPMs can calm
inflammation are paving the way toward
clinical tests in people. A phase 1 trial of
a lipoxin-based mouthwash published last
year indicated the drug was safe in people
with periodontal disease and also showed
some hints of efficacy. Thetis Pharma-
ceuticals is planning trials of a synthetic
resolvin for cases of inflammatory bowel
disease and cancer. Two other biotech-
nology companies, OSE Therapeutics and
ResoTher Pharma, have SPM-based drugs
in their pipelines. (Several of the sources
quoted in this article, including Serhan,
Dalli, and the critics, are involved with the
commercial development of SPMs or re-
ceive funding from companies developing
other types of anti-inflammatory lipids.)
A single phase 1 trial designed to show
safety doesn’t prove anything about ef-
ficacy, FitzGerald says. But, he concedes,
“It is possible that these chemical entities
given at high concentrations can modulate
the inflammatory response.” Even if SPMs
don’t naturally resolve inflammation, it
may not matter for drug developers if syn-
thetic versions still do so.
Serhan is sticking to his guns: “I have
had independent confirmation of all the
work. People can buy synthetic SPMs from
several companies, they can use them for
detection or functional studies. That’s why
there are thousands of publications. If I
was trying to pull the wool over people’s
eyes, I don’t think you’d see positive results
come out of a clinical trial.”
Scientists from both camps are sched-
uled to give talks at a workshop in late
June. But no one expects an easy resolu-
tion to this highly inflamed dispute. jGunjan Sinha is a science journalist in Berlin.In this artist’s concept, a dying neutrophil (purple) releases putative inflammation-resolving lipids such as
lipoxin (yellow) as a macrophage (blue) starts to clear its remains.0506NewsInDepth_15558970.indd 566 5/3/22 5:45 PM