13 MARCH 2015 • VOL 347 ISSUE 6227 1201 SCIENCE sciencemag.org
temperature, because all lower-lying energy
levels are already occupied and thus further occupation is forbidden. For a measurement of position correlations, the
antisymmetry of the wave function results
in an apparent antibunching, where fermions seem to avoid each other. Bosons,
in contrast, experience an increase in the
probability of reaching a state already occupied by other bosons. That is, bosons tend
to bunch together. For small systems of particles, the consequences of quantum statistics were exploited in fermionic (4) as well
as bosonic (5) systems. Preiss et al. observe
this effect of bunching in the position correlations of two identical atoms undergoing
a quantum walk.
Surprisingly, although this behavior due
to quantum statistics seems to be fundamentally fixed, interactions between particles can in fact turn bosonic bunching into
fermionic antibunching and vice versa. This
has been seen, for example, by association
of two fermionic atoms to a bosonic molecule that can undergo Bose-Einstein condensation (6), or pairing of fermions in a
many-body system showing superfluid behavior similar to Cooper pairs in a superconductor (7). Preiss et al. go the other way:
By increasing repulsive interaction more
and more, the bosonic atoms under investigation start to mimic the behavior of weakly
interacting fermions, as was observed in
one-dimensional Bose gases in the so-called
Tonks-Girardeau regime (8, 9). With their
superb position resolution, Preiss et al. can
track the crossover from the quantum statistics–dominated bosonic bunching to the
interaction-dominated antibunching, again
extracting position correlations of two atoms doing a quantum walk.
The system presented by Preiss et al. allows the study of the interplay of all these
aforementioned aspects in a rather simple,
paradigmatic system comprising all these
effects: two identical, interacting atoms.
Beyond the illustration of quantum physics,
their system can serve as a basic building
block for a bottom-up approach to engineering of complex quantum states atom by
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3. M. Karski et al ., Science 325, 174 (2009).
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5. A. M. Kaufman et al ., Science345, 306 (2014).
6. M. Greiner, C. A. Regal, D. S. Jin,Nature 426, 537 (2003).
7. M. W.Zwierlein,J.R.Abo-Shaeer, A.Schirotzek,C.H.
Schunck, W. Ketterle, Nature 435, 1047 (2005).
8. T.Kinoshita, T. Wenger,D.S. Weiss, Science 305,1125
9. B. Paredes et al ., Nature 429, 277 (2004).
Sepsis—a complication of infection—is a factor in at least a third of all hos- pital deaths—a sobering statistic (1). Patients with sepsis frequently pres- ent with fever, shock, and multior- gan failure. Because of this dramatic
clinical scenario, investigators have generally assumed that sepsis mortality is due
to unbridled inflammation (2). Research
in animal models, in which administration
of the cytokines tumor necrosis factor–α
(TNF-α) and interleukin-1 (IL-1) reproduced
many features of sepsis, supported that assertion. Yet, over 40 clinical trials of agents
that block cytokines, pathogen recognition,
or inflammation-signaling pathways have
universally failed (3, 4). However, on page
1260 of this issue, Weber et al. (5) show that
blocking a cytokine—specifically, IL-3—can
indeed be protective against sepsis.
IL-3 is a pleiotropic cytokine that induces
proliferation, differentiation, and enhanced
function of a broad range of hemopoietic
cells (blood cells derived from the bone
marrow). Using a mouse abdominal sepsis model, Weber et al. identified IL-3 as a
critical driving force of sepsis. The authors
observed that the cytokine caused proliferation and mobilization of myeloid cells
that generated excessive proinflammatory
cytokines, thereby fueling systemic inflammation, organ injury, and death. Blocking
IL-3 (by treating wild-type mice with an antibody that blocks the receptor for IL-3 or
using IL-3–deficient mice) prevented sepsis-induced increases in the number of circulating neutrophils and inflammatory monocytes
and decreased the amount of circulating
inflammatory cytokines, thus ameliorating
organ injury and improving survival. Additionally, the authors showed a correlation
between mortality in septic patients and elevated blood IL-3 concentrations.
The findings of Weber et al. are mecha-
nistically analogous to that of another study
in which intravenous injection of mesen-
chymal stem cells (also known as bone
marrow stromal cells) into a mouse model
of sepsis led to reprogramming of immune
cells toward a less inflammatory phenotype,
thereby decreasing organ injury and mortal-
ity (6). In this scenario, mesenchymal stem
cells released factors that reprogrammed
monocytes and macrophages; the down-
stream effect was to prevent a damaging,
unrestrained immune response. Thus, IL-3
blockade and mesenchymal stem cell–based
therapy represent potential approaches for
sepsis treatment because of their ability to
broadly reshape early immune responses
from a proinflammatory, damaging reaction
to a more balanced and effective one.
However, a few cautionary caveats should
be considered before adopting this approach. A phase II clinical trial of granulocyte-macrophage colony-stimulating factor
(GM-CSF), a cytokine that increases production, maturation, and function of monocytes,
macrophages, and neutrophils, thereby
mimicking selected properties of IL-3, was
efficacious in treating sepsis and, indeed, a
large multicenter trial of GM-CSF in sepsis
is under way (7). This is contrary to the findings of Weber et al. that blocking IL-3 can
ameliorate sepsis. Two other highly promising agents that are likely to enter clinical
trials in sepsis are IL-7 (which promotes
CD4+ and CD8+ T lymphocyte proliferation
and maturation) and an antibody to programmed death–ligand 1 [(PD-L1), an immunosuppressive protein] (8, 9). Both IL-7 and
anti-PD-L1 antibody are immunostimulatory
agents that reverse key immunologic defects
in lymphocytes and monocytes from septic
patients ex vivo and are highly effective in
multiple animal models of sepsis (9). Emerging evidence shows correlations between
lymphopenia (decrease in lymphocytes)
and impaired leukocyte functions with late
mortality in patients with sepsis (8, 9). Thus,
there is rationale for using approaches that
selectively enhance antimicrobial immunity
Getting sepsis therapy right
By Richard S. Hotchkiss1
and Edward R. Sherwood2
Is decreasing inflammation or increasing the host immune
response the better approach?
1Department of Anesthesiology, Medicine, and Surgery,
Washington University School of Medicine, St. Louis,
MO, USA. 2Department of Anesthesiology and Pathology,
Microbiology and Immunology. Vanderbilt University School
of Medicine, Nashville, TN, USA. E-mail: email@example.com;
“Which approach to sepsis…
is correct? …there are several