Science - USA (2022-02-11)

item and order information during a work-
ing memory delay ( 33 – 35 ). Our data support
such a sustained activity mechanism because
the geometry of disentangled representations
was stable during the delay period (Fig. 3B).
Our results suggest that the brain transforms
time into space by converting temporally seg-
regated sensory inputs into spatially overlap-
ping sustained brain activity patterns. They do
not, however, exclude the simultaneous pres-
ence, at a finer time scale, of a temporal code
involving phase synchrony or replay.
Seven decades ago, Karl Lashley ( 36 ) pos-
tulated that serial order is processed by cre-
ating and manipulating a spatial pattern of
neural activity. He speculated that to control
sequential actions, our brain needed to trans-
form temporally segregated sensory experi-
ences into a sustained spatial pattern of brain
activity. In agreement with this early intui-
tion, the simple geometrical organization of
SWM that we uncovered may provide a fun-
damental neural mechanism to bridge our
understanding of neural circuits and their
computational functions.

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    ACKNOWLEDGMENTS
    We thank W. Fang for data analysis, Y. Li and H. Jiang for animal
    surgery, and Peking University Laboratory Animal Center for animal
    care.Funding:This study was supported by National Science
    and Technology Innovation 2030 Major Program 2021ZD0204102
    (L.W. and B.M.), Shanghai Municipal Science and Technology
    Major Project 2021SHZDZX and 2018SHZDZX05 (L.W.), Strategic
    Priority Research Programs XDB32070201 (L.W.), Natural Science
    Foundation of China 11901557 (B.M.), and Natural Science
    Foundation of China 31730109 and U1909205 (S.T.).Author
    contributions:Conceptualization: Y.X., P.H., X.-J.W., T.Y., S.D., S.T.,

B.M., and L.W. Methodology: Y.X., P.H., J.L., X.-J.W., T.Y., S.D., B.M.,

and L.W. Investigation: Y.X., W.S., J.C., and S.T. Visualization:

Y.X. and P.H. Funding acquisition: S.T. and L.W. Project

administration: S.T. and L.W. Supervision: S.T., B.M., and L.W.

Writing–original draft: B.M., S.D., and L.W. Writing–review and

editing: Y.X., P.H., X.-J.W., T.Y., B.M., S.D., and L.W.Competing

interests:The authors declare that they have no competing

interests.Data and materials availability:All data and code used

in this study are available on Zenodo ( 37 , 38 ).

SUPPLEMENTARY MATERIALS

science.org/doi/10.1126/science.abm0204

Materials and Methods

Figs. S1 to S12

Tables S1 to S5

References ( 39 – 46 )

MDAR Reproducibility Checklist

24 August 2021; accepted 12 January 2022

10.1126/science.abm0204

BIOMEDICINE

An autonomously swimming biohybrid fish designed

with human cardiac biophysics

Keel Yong Lee^1 †, Sung-Jin Park1,2†, David G. Matthews^3 , Sean L. Kim^1 , Carlos Antonio Marquez^1 ,

John F. Zimmerman^1 , Herdeline Ann M. Ardoña^1 ‡§, Andre G. Kleber^4 ,

George V. Lauder^3 , Kevin Kit Parker1,5,6*

Biohybrid systems have been developed to better understand the design principles and coordination

mechanisms of biological systems. We consider whether two functional regulatory features of the

heart—mechanoelectrical signaling and automaticity—could be transferred to a synthetic analog of

another fluid transport system: a swimming fish. By leveraging cardiac mechanoelectrical signaling, we

recreated reciprocal contraction and relaxation in a muscular bilayer construct where each contraction

occurs automatically as a response to the stretching of an antagonistic muscle pair. Further, to

entrain this closed-loop actuation cycle, we engineered an electrically autonomous pacing node, which

enhanced spontaneous contraction. The biohybrid fish equipped with intrinsic control strategies

demonstrated self-sustained body–caudal fin swimming, highlighting the role of feedback mechanisms

in muscular pumps such as the heart and muscles.

C

irculatory systems in living organisms

are intricately designed to transport

blood throughout the body. Their most

basic function is fluid transport, and a

diversity of similar fluid pumping mech-

anisms and designs are found throughout

nature ( 1 ). Fluid pumps in vertebrates, con-

sidered broadly, range from a human circula-

tory system with closed vessels within which

fluid moves, to oscillatory fluid mechanisms in

aquatic species in which fluid is transported

along the body to generate propulsive thrust.

Inspired by these distinct but similar natural

processes, we and others have developed bio-

hybrid analogs of an external fluid pump ca-

pable of mimicking the locomotion of aquatic

species ( 2 – 4 ). The underlying motivation for

developing biohybrid systems capable of repro-

ducing biological behaviors is to better under-

stand the design principles and coordination

mechanisms of biological systems, although

the performance of these systems has been

lacking in comparison to natural fluid transport

pumps ( 4 ).

A key feature of aquatic species is closed-

loop actuation of antagonistic musculature that

provides control over the direction of momen-

tum transfer from the body muscles to the

SCIENCEscience.org 11 FEBRUARY 2022•VOL 375 ISSUE 6581 639

(^1) Disease Biophysics Group, John A. Paulson School of
Engineering and Applied Sciences, Harvard University,
Boston, MA 02134, USA.^2 Biohybrid Systems Group, Coulter
Department of Biomedical Engineering, Georgia Institute of
Technology and Emory University School of Medicine,
Atlanta, GA 30322, USA.^3 Museum of Comparative Zoology,
Harvard University, Cambridge, MA 02138, USA.^4 Beth Israel
Deaconess Medical Center, Harvard Medical School, Boston,
MA 02115, USA.^5 Wyss Institute for Biologically Inspired
Engineering, Harvard University, Boston, MA 02115, USA.
(^6) Harvard Stem Cell Institute, Harvard University, Cambridge,
MA 02138, USA.
*Corresponding author. Email: [email protected]
†These authors contributed equally to this work.
‡Present address: Department of Chemical and Biomolecular
Engineering, Henry Samueli School of Engineering, University of
California Irvine, CA 92697, USA.
§Present address: Sue and Bill Gross Stem Cell Research Center,
University of California, Irvine CA 92697, USA.
RESEARCH | RESEARCH ARTICLES