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PNASwww.pnas.org
Submissions are accepted fromresearchers all over the world.Authors do not need to have a connection toan NAS member to publish in PNAS.
PNAS is committed to transparencyin its editorial review process.
FAQs for authors explaining the review process are
available at www.pnas.org/site/authors/authorfaq.xhtml.
All articles are evaluated solelyon their scientific merit by peers—
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Organized by
Previously dismissed as cellular debris, extra-
cellular vesicles are currently seen as ìmes-
sages in a bottle,î rife with RNA and signaling
proteins. These vesicles play key roles in both
development and disease. Now, researchers
are developing new tools and strategies to
study them and to exploit their potential in
both diagnostics and therapeutics.
Membranemessengers:Extracellularvesicles
See the full story on page 1349.
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LIFE SCIENCE TECHNOLOGIES
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1349SCIENCE sciencemag.org/custom-publishing
LIFE SCIENCE TECHNOLOGIES Produced by the Science/AAAS Custom Publishing OfficeEXOSOMES/MICROVESICLES
In 2007, Johan Skog, a new postdoc in Xandra Breake-
GHIJ���I�������������Harvard Medical School, tried to
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ìMessage in a bottleî��J�����H�H���H���I��H���H��HGHIJ���J�/����'�������H���H��
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��H�H���IIHJ�Exosome Diagnostics)����H������������J����
�H��H���������H����I�������%(����J���������I��H������������-
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��H�7H����H����������H��������J�8H�H�������La Trobe
University����9HI����H�������I������H���H��JH���HIH�������H�
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��J�>HII����I���������H�University of Utrecht�������HH����-
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1350 sciencemag.org/custom-publishing SCIENCE
LIFE SCIENCE TECHNOLOGIES
EXOSOMES/MICROVESICLES
Produced by the Science/AAAS Custom Publishing Office
Liquid biopsiesDespite the yawning knowledge gap in
basic vesicle biology, many researchersí
<��?���=?�?��>�?
clinical potential.
Many on the diagnostics front, for instance,
are pursuing so-called ìliquid biopsies.î Rather
than diagnosing, staging, and monitoring disease (especially
cancer) via a solid tumor biopsy or noninvasive imaging,
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1351SCIENCE sciencemag.org/custom-publishing
LIFE SCIENCE TECHNOLOGIES Produced by the Science/AAAS Custom Publishing OfficeEXOSOMES/MICROVESICLES
patient samples to develop a signature that was better able to
detect cancer in dense breast tissue than was mammography.
Similarly, Saugstad has studied the RNA con tent of ce-
-./-0�����������������0��.���������0�.�������������-.�0��
Alzheimerís disease. Starting from a set of 756 known human
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���.����������.�-���0��0--.���.��������.���.��.�� �!.��
that miRNAs are regulatory noncoding molecules, that infor-
mation could identify novel proteins involved in pathophysiol-
ogy, she says.
In Boston, Hakho Lee, director of the Biome dical
Engineering Program at the Center for Systems Biology
���"��������.���� .�.-���#0�������������$�����.����0��.-�
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Lee has developed liquid biopsy analytical tools based on
multiple principles over the years, including electrochemical
detection, magnetics, acoustics, and more. His current state-
of-the-art technology, he says, exploits surface plasmon
-.�0����.��'����
SPR is a mature technology that has been commercialized
/���0�����.����������(���0-.��0����-��0�� )�#.������-.��
to quantify protein-protein and protein-ligand interactions. To
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��0�����-�����+���������������-0������.��-����/0���.��0,����.�
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to the opposite face of the gold sensor, that angle changes
in proportion to the degree of binding, providing a real-time
readout of molecular interaction.
In Leeís version of the technology, antibodies are spotted
on tiny gold sensors in a ìperiodic nanohole array,î which
����--���.�0�������-0����������������!.����.��/����0���.�.�
DOI: 10.1126/science.opms.p1600106
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sensors, their spectral responses change proportionally to
the degree of binding. Best of all, the measured vesicles can
��5�4&�4�����54���3���4��63��6����34����4�4����63��36�4���
analysis.
According to Lee, the system is highly scalable. In a proof
of principle study, for instance, his lab developed a ìnano-
�����6����4�6�6�4'���#!(���4��63������)�*+,��4�4���6�����4���
36�����66��6�-)��36�4����4��34��4��6��6��3��������43��4���
���4�����4����4�����4������6��36�4���4�6�6�����������34��������4��
subsequently applied to 20 cancer and 10 control subjects.
.�����������34��3���4���34���4���34��6��4������4���#!(��������
Lee notes, with the marker expression dropping in responding
patients but increasing in nonresponders.
Therapeutic exosomes Researchers are also investigating exosomes as vehicles
for delivering therapeutics. EVs, says Joshua Leonard,
associate professor of Chemical and Biological Engineering
at Northwestern University, seem to exhibit some of the
propertiesóespecially low toxicityóthat researchers have been
struggling to achieve with synthetic vesicles.
63��������4��34�4�3��43�������6���!/���������4��������3�6�
using electroporation, or by expressing nucleic acids in EV-
producing cells. In 2011, Matthew Wood and colleagues at the
University of Oxford used both approaches to show that they
could use exosomes to downregulate neuronal gene expression
in the mouse brain by loading the exosomes with a neuron-
��3�4������4����4�������4��������63�����4343����������.����
result, Leonard says, suggests EVs can overcome at least three
��������������3��4����36��������4�5�66��53����5�33�43���4������
���4�������4����������5���4�36������������4��������4���43����
content inside the cells.
More recently, Leonardís team, led by graduate student
Michelle Hung, has begun teasing apart the rules governing
RNA-loading in EVs. The team fused an exosomal protein to
a bacteriophage protein normally involved in loading nucleic
acids into viruses, coupled that proteinís signal sequence
���3�����6������6���$�434����4������������6���634�������
RNAs ended up in the resulting particles. All RNAs could be
loaded, they found, though longer sequences and messenger
������4��4���6��6����4���4"����4������014��3�4���6��6�4����
���������3�������������&����������4�����6���4�3��4��63��6������
EVs,î he explains.
%����������4��6����43�5�4�4$�63���6��6��43���������65�43����6���
into clinical realities, of course. But given the engagement
of the research community, expect those advances sooner
rather than later. ìThereís probably a language here, and weíre
[only] at the level of knowing something about the alphabet,î
�6��4�4�� 34��4��4����014��6�2����6����4��3����3���4��6�2��
��6����62�����������6���6���63���4���63������ ����4234�����3�
ing it out.î
La Trobe Universitywww.latrobe.edu.au
Northwestern Universitywww.northwestern.edu
Oregon Health and Science Universitywww.ohsu.edu
Qiagenwww.qiagen.com
Scintillon Institutewww.scintillon.org
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�����
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University of Texas MD Anderson Cancer Centerwww.mdanderson.org
University of Utrechtwww.uu.nl
BD Bioscienceswww.bdbiosciences.com
Beckman Coulterwww.beckmancoulter.com
Caris Life Scienceswww.carislifesciences.com
Center for Systems Biologycsb.mgh.harvard.edu
Exosome Diagnosticswww.exosomedx.com
Exosome Scienceswww.exosomesciences.com
Harvard Medical Schoolhms.harvard.edu
Insermenglish.inserm.fr
Institut Curiewww.institut-curie.org
Learn more about new methods for detecting EVs
in our recent webinar
bit.ly/imagef ow
FEATURED PARTICIPANTS
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Electronically submit your new product description or product literature information! Go to www.sciencemag.org/about/new-products-section for more information.
Large Capacity Bioprocessing
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increased capacity of up to 16 L of cell
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Exosome Research Products
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exosome isolation from small volumes of
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addition, AMSBIO has introduced new
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calibration standards for quantitation of
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analysis; validated exosomal monoclonal/
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lated from stem cells for cell culture. To
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marker analysis in a number of pathological
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and neurodegenerative diseases, a new
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BIOís new expanded suite will facilitate researchersí understanding
of exosomes.
AMS Biotechnology
For info: +44-(0)-1235-828200
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HiCen GT Centrifuge
The HiCen GT Centrifuge has impressive
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or swing-out rotors are available. It uses
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system of automatic rotor detection to
ensure complete safety. The HiCen GT
sits comfortably on any benchtop and can
accommodate samples of up to 1,000 mL.
The HiCen range features an assortment of
models both with refrigeration and without.
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display ensure that all settings can be
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one of 30 programs. All components are
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easily changed. The HiCen GT Centrifuge
operates with low noise levels because of
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balanced rotor.
Herolab
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Cell Isolation Products
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recent FDA guidance issued for tissue and
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grade reagents should be used in drug-
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advances adipose-based research programs from preclinical to
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Newly offered instrumentation, apparatus, and laboratory materials of interest to researchers in all disciplines in academic, industrial, and governmental organizations
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Field-Flow Fractionation
A series of new products for Field-
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able. The new Postnova SC2000
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