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Learn how current eventsare impacting yourwork.ScienceInsider, the new policy blog from the journal Science, is your sourcefor breaking news and instant analysis from the nexus of politics and science.

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Before research happens at the bench, science policy is formulated in the

halls of government. Make sure you understand how current events are

impacting your work. Read ScienceInsider today.

www.ScienceInsider.org

Breaking news and analysis from the world of science policy

Since 1848, AAAS has served as a prominent voice to advance science and as a valuable

resource for scientists, educators, and policy makers. For the past 100 years, part of

this mission has included publishing the journal Science, one of the world’s premier

peer-reviewed research journals. Working together to disseminate the most compelling

discoveries across all scientific disciplines, AAAS and Science continue to fulfill their

mission of advancing science for the benefit of all.

In addition to supporting Science, individual memberships are a driving force behind

critical AAAS programs and activities designed to strengthen the global scientific

enterprise. By becoming a AAAS member, you not only make a significant impact by

allowing AAAS to continue its mission of advancing science and serving society, but you

also gain powerful resources to develop your own career.

As a member, you’ll receive 51 issues of the journal Science delivered weekly as well

as online access to: groundbreaking research before it’s published; the Science online

archives dating back to 1880; and the current table of contents. In addition to all the

benefits provided by the journal Science, AAAS has partnered on behalf of its members

to provide substantial discounts with numerous organizations, including: Apple, VISA,

GEICO, Barnes & Noble, and more.

If you’re interested in becoming a AAASmember and changing the face of science, please

visit aaas.org. Join us. Together we can make a difference.

AAAS is here – bringing scientific expertise to policy making.

Good science policy is the result of politicians understanding science and scientists understanding policy. Toward this end,

AAAS manages the Science & Technology Policy Fellowships program, which embeds scientists and engineers in the federal

government for up to two years. From Congress to the State Department, each class of Fellows contributes to the policy-making

process while getting hands-on experience at the intersection of science and policy. As a AAASmember your dues support these

efforts. If you’re not yet a AAAS member, join us. Together we can make a difference.

To learn more, visit aaas.org/plusyou/fellows.

AAAS is here – helping scientists achieve career success.

Every month, over 400,000 students and scientists visit ScienceCareers.org in search of the information, advice, and opportuni-

ties they need to take the next step in their careers.

A complete career resource, free to the public, Science Careers offers a suite of tools and services developed specifically for

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successful careers.

As a AAAS member, your dues help AAAS make this service freely available to the scientific community. If you’re not a member,

join us. Together we can make a difference.

To learn more, visit aaas.org/sciencecareers.

To learn more, visit aaas.org/plusyou/project2061.

AAAS is here – promoting universal science literacy.

In 1985, AAAS founded Project 2061 with the goal of helping all Americans become literate in science, mathematics, and

technology. With its landmark publications Science for All Americans and Benchmarks for Science Literacy, Project 2061 set out

recommendations for what all students should know and be able to do in science, mathematics, and technology by the time they

graduate from high school. Today, many of the state standards in the United States have drawn their content from Project 2061.

Every day Project 2061 staff use their expertise as teachers, researchers, and scientists to evaluate textbooks and assessments,

create conceptual strand maps for educators, produce groundbreaking research and innovative books, CD-ROMs, and profes-

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As a AAAS member, your dues help support Project 2061 as it works to improve science education. If you are not yet a AAAS

member, join us. Together we can make a difference.

AAAS is here – bringing educational infrastructure to the developing world.

AAAS is helping the Rwandan government rebuild its educational infrastructure as a way to help drive economic growth and

development. By providing materials such as the Project 2061 Atlas of Science Literacy, lesson plans from Science NetLinks,

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To learn more, visit aaas.org/plusyou/rwanda.

AAAS is here – preparing minority students for careers in science.

Part of AAAS’s mission is to strengthen and diversify the scientific work force. To help achieve this goal AAAS partners with NSF

to present the Historically Black Colleges and Universities Undergraduate Program, a conference where students fromHBCUs get

experience presenting their research, networking with peers, meeting with representatives from graduate schools, and learning

about career opportunities. As a AAAS member your dues support these efforts. If you’re not yet a AAAS member, join us.

Together we can make a difference.

To learn more, visit aaas.org/plusyou/hbcuup.

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As a part of its efforts to introduce fully open government, the White House is reaching out to the scientific community for a

conversation around America’s national scientific and technological priorities.

To enable the White House’s dialogue with scientists, AAAS launched Expert Labs, under the direction of blogger and tech guru

Anil Dash. Expert Labs is building online tools that allow government agencies to ask questions of the scientific community and

then sort and rank the answers they receive.

On April 12, 2010, AAAS asked scientists everywhere to submit their ideas to the Obama administration and at the same time

launched the first of Expert Labs tools, Think Tank, to help policy makers collect the subsequent responses. The result was

thousands of responses to the White House’s request, many of which are already under consideration by the Office of Science

and Technology Policy.

As a AAAS member, your dues support our efforts to help government base policy on direct feedback from the scientific

community. If you are not already a member, join us. Together we can make a difference.

To learn more, visit aaas.org/plusyou/expertlabs.

Call forPapers Science

SignalingScience Signaling, from the publisher of

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(PROTEOMICS: MASS SPECTROMETRY

LIFE SCIENCE TECHNOLOGIES

Instrument makers have now made mass spectrometer

technology so accessible that, for many users, it func-

tions almost as a black box: insert a sample in one end,

and a few minutes later a sophisticated chemical analysis

of it appears on a screen. For hard-core spectroscopists,

though, the focus is now on pushing the core technology in

new directions. In the past few years, that effort has given ba-

sic researchers some amazing new capabilities.

“In about 48 hours, you can actually identify and quantitate

the entire proteome from cells, a feat which was unimaginable

I would say even three, four years ago, and I’m frankly quite

astonished that it has occurred in my lifetime,” says Ian Jardine,

vice president of global research and development for Thermo

Fisher Scientific in Waltham, Massachusetts.

Jardine isn’t alone. In basic research labs and corporate R&D

departments, the latest generation of mass spectrometry tools

and techniques is pushing the method’s frontiers faster and

further than most scientists ever expected.

IT’S A TWISTEROne of the field’s recent breakthroughs came from Alexander

Makarov, an instrument builder and researcher at Thermo Fish-

er. Like many spectroscopists, Makarov found the performance

limitations of his equipment annoying. “He became somewhat

dissatisfied with the capabilities of time-of-flight mass spec-

trometry in terms of the attainable resolutions and mass ac-

curacies, because they’re pretty far away from what the com-

munity knows as being the ultimate best,” says Jardine.

The “ultimate best” mass resolution and accuracy have been

achieved in a few basic research labs, where scientists have

built ion traps with superconducting magnets. The high cost

and tricky maintenance of such machines puts them far out of

reach for most labs, though. To get around that, Makarov tried

a different approach: trapping ions inside a coaxial electrode

called an Orbitrap.

By wrapping one electrode around the other and leaving a

small space between them, Makarov was able to inject ions

into the space in a spiral path. The centrifugal force of the ions’

orbits balances the electrostatic forces of the electrodes, trap-

ping the ions in a series of tornado-like rings.

It’s not an entirely new idea. “In the literature during the 20th

century, occasionally people had suggested related ideas, but

no one could imagine how to actually implement it in a practical

perspective,” says Jardine. The key development was a sepa-

rate device called a C trap, which sits between the ion source

and the Orbitrap. The C trap catches the ions and sends them

into the Orbitrap chamber in a series of pulses.

Thermo Fisher introduced the Orbitrap in 2005, and has since

offered a range of Orbitrap-based devices for different types of

users. The biggest market by far, however, has been the bur-

geoning field of high throughput, or “bottom up,” proteomics.

“The ability to detect, sequence, and quantitate vastly com-

plex mixtures of peptides, and therefore proteins, is the pri-

mary experiment that the instrument is currently used for,” says

Jardine. Because of their high sensitivity, mass accuracy, and

dynamic range, Orbitraps are also popular with pharmaceuti-

cal researchers who need to detect minute quantities of small

molecule metabolites.

The Orbitrap design isn’t perfect, however, and Jardine readily

acknowledges that there is still room for other types of mass

spectrometers on the market. In particular, triple quadrupole

mass spectrometers remain the workhorses of analytical labs,

where researchers know what molecules they’re looking for CR

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UPCOMING FEATURES

Breakthroughs in Imaging—June 18

Interactomics—July 23

Proteomics 2: Biomarkers—September 10

AAAS/Science Business Office Feature

Mass SpectrometryRaises the BarMass spectrometry is clearly having its moment in the sun. Once restricted to a

handful of well-equipped research laboratories, mass spectrometers have now

become almost ubiquitous. Even modestly funded scientists can usually get

their samples analyzed in a core mass spectrometry facility, and user-friendly

spectrometers are becoming a fixture of forensic and clinical labs world-

wide. By Alan Dove

“In about 48 hours, you can actually identify

and quantitate the entire proteome from cells, a

feat which was unimaginable I would say even

three, four years ago, and I’m frankly quite

astonished that it has occurred in my lifetime.”

www.sciencemag.org/products 921

Nanostructure initiator mass spectrometry (NIMS) al-

lows researchers to identify small molecules inside

complex tissues or whole organisms.

pharmaceutical and life science business operations.

In a typical experiment, researchers send a complex sample

through an ultraperformance liquid chromatography (UPLC)

system, then into the ion mobility stage, and finally through

the mass spectrometer, providing three dimensions of infor-

mation. “Each peak that comes off the UPLC is ionized and

then those components are separated according to their mo-

bility and separated then according to their mass to charge,”

says Reilly.

The combination of techniques allows researchers to sepa-

rate molecules that would otherwise be indistinguishable. For

example, isomers with identical chemical formulas would nor-

mally look the same on a mass spectrometer, but ion mobility

can often distinguish them. The additional separation can also

help untangle complex mixtures in proteomics experiments. In

a benchmark test on an Escherichia coli extract, for example,

conventional mass spectrometry systems can identify about

400 proteins. Sending the same extract through a SYNAPT G2

identified those proteins, plus about 300 more.

Because the shape of a molecule determines its migration

rate in ion mobility, the system could also bring entirely new

capabilities to mass spectrometry. In particular, a few pioneers

have been using mass spectrometers to study three-dimen-

sional protein structures. “There’s significant interest in the

shape of proteins, their tertiary structure, but that’s a very dif-

ficult thing to study,” says Reilly, adding that “it would be very

useful of course if we could use something as simple as a mass

spectrometer to do this work.”

Waters is also testing the new system’s ability to distinguish

different lipids in biological samples. “There’s a great deal of

interest in characterizing lipids according to their structural

characteristics. For example, cis and trans fats will have a sig-

nificantly different structure, and mobility can be used to distin-

guish between these two types of structures,” says Reilly.

THE LIPIDS OF OZThe researchers at Waters are not the only biochemists try-

ing to solve the lipid structure problem. “Ultimately the Holy

Grail for us would be to be able to get stereoisomerism. Could

we actually tell the analyst if they were looking at a cis or a

trans double bond?” asks Stephen Blanksby, senior lecturer

in chemistry at the University of Wollongong in continued»

and need highly accurate measurements of their levels. “When

you already know what it is you want to quantitate, then you’ll

switch to a triple quad,” says Jardine. “Because then you actu-

ally get higher sensitivity and better precision in the targeted

quantitative analysis.”

TEST-DRIVING A HYBRIDIn a triple quadrupole mass spectrometer, ions pass linearly

through three consecutive quadrupoles, sets of four metal rods

exactly parallel to each other. By applying different voltages to

the rods, technicians can sort out molecules of specific mass-

to-charge ratios with extraordinary precision. Besides having

high specificity, triple quadrupole instruments tend to be rela-

tively inexpensive and easy to maintain.

Those features have made triple quadrupoles a favorite of

clinical labs and other application-oriented users, but manufac-

turers are also trying to push the triple quadrupole technology

in new directions for basic scientists. One such effort is the

QTRAP, introduced by a joint venture of Applied Biosystems

and MDS Analytical Technologies in 2004. The joint venture

now operates as AB Sciex in Foster City, California.

“The QTRAP system is a hybrid instrument that combines

triple quadrupole and linear ion trap technology into a single

platform, so it is actually quite unique, as it is the only sys-

tem in the marketplace that combines both of those technolo-

gies together,” says Gary Impey, senior project manager for AB

Sciex. The hybrid system provides the quantitative capabilities

of a triple quadrupole with the qualitative capabilities of an ion

trap. “So what that gives us is the ability to quantitate and now

to qualitatively say ‘Yes, that’s the analyte I thought it was,’”

says Impey.

Though it doesn’t offer the mass accuracy and resolution of

an Orbitrap, Impey says the QTRAP may be a better choice

for some users. “From a metabolite ID strategy point of view,

[QTRAP] offers higher throughput and more efficient workflows

in that area than would, say, an accurate mass high resolution

instrument,” says Impey.

Indeed, while mass spectrometer makers previously com-

peted head-to-head, many of the newest breakthroughs appeal

to distinct niches of the market rather than trying to supplant

other designs. Like Thermo Fisher, AB Sciex also continues to

make more traditional mass spectrometers, such as conven-

tional triple quadrupoles without ion traps. “In some cases spe-

cific application areas won’t require those qualitative capabili-

ties per se. It really comes down to a cost-per-sample basis. I

think from a competitive point of view in terms of price, triple

quads still offer a high level of value,” says Impey.

THE SHAPE OF THINGS TO COMEThe ion trap isn’t the only component that mass spectrometer

makers are trying to improve. Last June, Waters in Milford,

Massachusetts, introduced its SYNAPT G2 system, which adds

an ion mobility system before the mass spectrometer. “Ion mo-

bility separates ions on the basis of their size and shape and

charge state,” explains Tim Reilly, Waters’s vice president of

((

LIFE SCIENCE TECHNOLOGIESAAAS/Science Business Office Feature

PROTEOMICS: MASS SPECTROMETRY

“Mass spectrometry as a

field continues to surprise all

of us in terms of its ability

to continually renew itself

and keep improving.”

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922 www.sciencemag.org/products

DOI: 10.1126/science.opms.p1000044

Alan Dove is a science writer and editor based Massachusetts.

form MALDI spectrometry

on the sample while moving

it in a two-dimensional scan

pattern. Image processing

software can take the mass

spectrum, correlate it with

the sample movements, and

reconstruct an image with

detailed data on the distribu-

tion of proteins in the tissue.

The technique is pow-

erful, but it comes with

a hefty pricetag. “The in-

strumentation you use to

do the matrix deposition can be quite expensive, on the or-

der of $200,000,” says Gary Siuzdak, director of the Scripps

Center for Mass Spectrometry at the Scripps Research

Institute in La Jolla, California. In addition, the matrix introduc-

es background ions that can confound analysis of small mol-

ecules in the sample.

To avoid those problems, Siuzdak and his colleagues have de-

veloped a new imaging method called nanostructure initiator

mass spectrometry (NIMS). Rather than deposit a matrix over

the sample, NIMS places the sample over a nanostructured ma-

trix, making it much simpler than MALDI. “Really all you have

to do is cut the slice of tissue off, put it on top, and then you’re

ready to analyze it,” says Siuzdak. He estimates that a typical

mass spectrometry–equipped lab could add the capability for

“a couple thousand dollars.”

Besides being simpler and cheaper, NIMS is also more sensi-

tive to small molecules. “These polymers that we have don’t

ionize very well, they generate little to no background signal,

and of course there’s no matrix interference because there’s

no matrix,” says Siuzdak. So far, his team has used NIMS to

study the localization of different lipids, phosphopeptides, and

carbohydrates in several types of tissues.

While techniques like NIMS, which Siuzdak’s group first re-

ported in 2007, are just getting started, more established mass

spectrometry methods are entering a sometimes-awkward

adolescence. “With proteomics the technology is mature, and

now the challenge in terms of mass spectrometry–based pro-

teomics is to show that it has really good applications,” says

Siuzdak. Meanwhile, metabolomic mass spectrometry has al-

ready proved its utility in clinical labs, where testing for meta-

bolic disorders has become routine.

Regardless of their specialties, though, mass spectrometrists

agree that the technique will likely continue to make new break-

throughs. Says Thermo Fisher’s Jardine, “Mass spectrometry

as a field continues to surprise all of us in terms of its ability to

continually renew itself and keep improving.”

AB Sciex

www.absciex.com

Applied Biosystems

www.appliedbiosystems.com

MDS Analytical

Technologies

www.moleculardevices.com

Scripps Research Institute

www.scripps.edu

Thermo Fisher Scientific

www.thermo.com

University of

Wollongong

www.uow.edu.au

Waters

www.waters.com

(PROTEOMICS: MASS SPECTROMETRY

LIFE SCIENCE TECHNOLOGIES

Wollongong, Australia. Blanks-

by adds, “That’s a real challenge

to us and I don’t currently have

the answer, but we have some

ideas that we’re pursuing.”

Meanwhile, Blanksby and his

colleagues have solved a slight-

ly different problem: determin-

ing where the double bonds

are in long, unsaturated lipids.

Previously, scientists could de-

tect the presence of double

bonds using a technique called

collision-induced dissociation,

which smashes molecules of an inert gas into the lipid to dis-

sociate it. Collision-induced dissociation is a powerful technique,

but not quite powerful enough. “While the mass and the colli-

sion-induced dissociation spectrum can tell you that there is a

double bond present, it doesn’t tell you where the double bond

is,” says Blanksby.

To address that, he and his colleagues borrowed a technique

from traditional organic chemistry. Ozone reacts rapidly with

carbon-carbon double bonds and cleaves them, leaving predict-

able end products. Performing the reaction inside a mass spec-

trometer allows Blanksby’s team to determine exactly where

the cleavage occurred within a complex lipid molecule, revealing

where the double bond was.

The method, dubbed OzID, is easy to implement on conven-

tional triple quadrupole mass spectrometers. “They’ll normally

have a mechanism to introduce helium or nitrogen or argon into

the mass spectrometer to allow for those collision-induced dis-

sociation experiments. All we’re really doing is hijacking that ex-

isting plumbing in the instrument and using it to introduce ozone

vapor instead of the unreactive gases that are normally used,”

says Blanksby.

With the new-found ability to locate double bonds, investiga-

tors are now performing “top down” lipidomics experiments, in

which they analyze crude cell extracts and try to identify all of the

lipids in them. They’ve already made some interesting discover-

ies. For example, many biological lipids that initially appeared to

be single molecules have turned out to include different isomers,

with double bonds in different locations. “Whereas previously it

would have been assigned mass spectrometrically as one mol-

ecule, it might actually be a mixture of four components, which

raises really interesting biochemical questions, such as, Why

does nature require that complexity?” says Blanksby.

INSIDE THE MATRIXWhile Blanksby studies the complexity of lipids, other research-

ers are using a mash-up of mass spectrometry and microscopy

to explore the complexity of whole tissues and organisms. The

most common way to do these experiments is with matrix-as-

sisted laser desorption ionization (MALDI), in which research-

ers deposit a chemical matrix atop a tissue section, then per-

AAAS/Science Business Office Feature

www.sciencemag.org/products 923

Electronically submit your new product description or product literature information! Go to www.sciencemag.org/products/newproducts.dtl for more information.

TIME-OF-FLIGHT SPECTROMETER

The BenchTOF-dx mass spectrometer is a compact reflectron time-

of-flight (TOF) instrument designed to generate classical electron

impact ionization spectra for gas chromatography (GC) and compre-

hensive GC applications. The BenchTOF-dx enhances the benefits

of standard TOF spectrometers for better handling of challenging

compounds. The instrument’s capability to generate classical spec-

tra enables laboratories with proprietary spectral libraries to harness

the performance of TOF mass spectrometry while maintaining the

use of their current library system. The instrument incorporates

groundbreaking new ion optics and electronics to deliver full spectral

information with sensitivity normally associated only with the best

quadrupoles running in selected ion monitoring mode.

ALMSCO

For info: +44-(0)-1443-233920 www.almsco.com

HUMAN CYTOKINE ARRAY

The Quantibody Human Cytokine Array 4000 can detect quantita-

tively the expression of 200 different proteins in a single experiment.

The kit consists of five quantitative, multiplex enzyme-linked immu-

nosorbent assay-based slides: The Quantibody Human Inflammation

Array 3 detects 40 inflammation markers. The Quantibody Human

Chemokine Array 1 detects 40 chemokines. The Quantibody Human

Growth Factor Array 1 detects 40 growth factors. The Quantibody

Human Receptor Array 1 detects 40 soluble cytokine receptors.

The Quantibody Human Cytokine Array 4 detects 40 cytokines and

related proteins. These glass-slide antibody arrays feature standard

concentration curves run alongside unknown samples to give quan-

titative results with picogram-per-milliliter sensitivity.

RayBiotech

For info: 888-494-8555 www.raybiotech.com

SINGLE QUADRUPOLE GC/MS

The Thermo Scientific ISQ single quadrupole gas chromatography/

mass spectrometry (GC/MS) system features a unique, nonventing,

full-source removal capability. Featuring the new ExtractaBrite

ion source, the ISQ system offers simplified operation and

maximum uptime for uninterrupted productivity across routine

GC/MS applications, including forensics, toxicology, food safety,

and environmental. This robust and rugged system provides high

throughput sample analyses and 24/7 operation. The ExtractaBrite

removable ion source is designed to provide maximum uptime

and productivity by extending the length of time between required

source maintenance. For today’s fast-paced gas chromatography

methods, advanced electronics allow the ISQ to acquire and write

data to disc at accelerated rates for high-speed data acquisition in

real-world applications.

Thermo Fisher Scientific

For info: 800-532-4752 www.thermo.com/getready

PEPTIDE SYNTHESIZER

The Syro Wave is a microwave and parallel peptide synthesizer that

combines the proven performance of the established MultiSynTech

robotic synthesizer with Biotage microwave technology. It is the only

system on the market to offer both microwave and parallel peptide

synthesis capabilities. Prior to this combination, peptide synthesis

labs have had to invest in both standalone parallel systems for pro-

ductivity and cost efficiency, and standalone microwave systems for

difficult or longer peptides. The new system increases productivity,

yield, and purity while cutting costs and saving time.

Biotage

For info: +46-18-56-59-00 www.biotage.com

Newly offered instrumentation, apparatus, and laboratory materials of interest to researchers in all disciplines in academic, industrial, and governmental organizations

are featured in this space. Emphasis is given to purpose, chief characteristics, and availability of products and materials. Endorsement by Science or AAAS of any

products or materials mentioned is not implied. Additional information may be obtained from the manufacturer or supplier.

(LIFE SCIENCE TECHNOLOGIES

AAAS/Science Business Office Feature

PROTEOMICS: MASS SPECTROMETRY

PROTEIN SOLUTION CONCENTRATION

The miVac sample concentrator provides an efficient and cost-effective alternative to

traditional membrane centrifugation techniques for the concentration of protein solutions

prior to separation through size-exclusion chromatography or electrophoresis or to analysis

with X-ray crystallography. The membrane centrifugation process often results in loss

of valuable sample because of protein binding to the membrane. The miVac sample

concentrator ensures complete sample recovery even when taking proteins to very high

concentrations. The miVac also offers the benefit of reduced spending on consumables.

The instrument provides high performance, precise temperature control, and ease of use

within a small benchtop footprint.

Genevac

For info +44-1473-240000 www.genevac.co.uk

Submission

deadline

August 1

imagination at work

* For the purpose of this prize, molecular biology isdefined as “that part of biology which attempts tointerpret biological events in terms of the physico-chemical properties of molecules in a cell”.

(McGraw-Hill Dictionary of Scientific andTechnical Terms, 4th Edition).

GE Healthcare Bio-Sciences AB,Björkgatan 30, 751 84 Uppsala, Sweden.© 2010 General Electric Company– All rights reserved.

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