JANUARY 20 1 2
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JANUARY 20 1 2
Serving the chemical,
life sciences,
and laboratory worlds
JANUARY 2012
18
NEWS OF THE WEEK
3
SCIENCE & TECHNOLOGY
ENZYME MIMIC IS STELLAR
12
For an artificial enzyme, three-helix, two-metal
assembly has unprecedented catalytic activity.
4
4
New results in total synthesis
reinvigorate a 40-year-old
field of research.
BOOSTER SHOT FOR U.K. SCIENCE
Prime Minister David Cameron lays out a plan to
support life sciences research.
18
NIH BROADENS GENOME RESEARCH
Health agency will shift funds from genome
sequencing to medical applications.
5
5
21
MICHAEL MARLETTA
C&EN talks with the incoming
president of Scripps Research Institute.
ADVANCING PERSONALIZED MEDICINE
Major research institutions partner to
establish genomics centers in Connecticut,
New York City.
INVESTIGATING
METALLOPROTEOMES
Innovative methods help
scientists understand
complexity of proteins that
interact with metals.
SWITCHABLE FLUORESCENCE
Fluorophore-bearing particles remain dark until
they enter cells, then they shine at full intensity.
BRYOSTATINS RETAIN
PROMISE ▶
COVER: Shutterstock
BUSINESS
6
CONSUMABLES STRATEGY
Instrumentation companies take different
approaches toward the repeat-sale product
market.
GOVERNMENT & POLICY
10
21
TESTING FOR PESTICIDE EXPOSURE
Researchers are on a hunt for biomarkers to help
develop diagnostic tests for pesticide exposure.
6
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news of the week
MAKING A
BETTER ENZYME
PROTEIN DESIGN: Mimic narrows
efficiency gap with natural enzyme
tein design gearheads. To have two different metals and
have them go to their specific sites is exciting.” The way
Pecoraro and coworkers achieved this result is instructive for other researchers in the field, he says.
The work is “exciting,” says metalloprotein specialist Yi Lu of the University of Illinois, Urbana-Cham-
COPYCAT Three-helix bundle (top), a mimic of human carbonic
I
lored protein catalysts, a research team has prepared
an artificial enzyme that works uniquely well. The
simple assembly, of three helices and two different
metal ions, catalyzes reactions with efficiencies that
approach those of the corresponding natural enzyme
more closely than ever before (Nat. Chem., DOI:
10.1038/nchem.1201).
Melissa L. Zastrow, Anna F. A. Peacock, Jeanne A.
Stuckey, and chemistry professor Vincent L. Pecoraro
of the University of Michigan, Ann Arbor, designed,
created, and tested the artificial enzyme, which acts as
a hydrolase. The work could help the design of catalysts
for many applications.
Structurally much simpler than natural hydrolases,
the artificial enzyme includes just three linear α-helices
in an arrangement called a “three-helix bundle,” a Hg(II)
ion for structural stability, and an active-site Zn(II) ion.
Yet its efficiency in catalyzing the hydration of CO2 is
0.2% that of human carbonic anhydrase II, one of the
fastest hydrolases. And in catalyzing the hydrolysis of an
acetate, its efficiency is 1% that of the natural enzyme.
Such levels of efficiency are considered stellar in the
field of artificial enzyme design.
In 2009, for example, protein designers William
DeGrado of the University of Pennsylvania (now at
the University of California, San Francisco), Angela
Lombardi of the University of Naples, and coworkers
developed a four-helix-bundle enzyme with a di-iron
active site that catalyzes a phenol oxidase reaction. The
achievement was considered a major breakthrough in
protein design, but the synthetic enzyme’s activity was
only 0.01 to 0.1% that of natural oxidases.
The new artificial enzyme, DeGrado says, is “a monumental piece of work.” It represents, he adds, “the
culmination of a large body of data from Vince’s lab,
relating to the fine interplay between protein stability,
folding, and the structure of metal-binding sites” and is
“the beginning of a new chapter in what should prove to
be an exciting and rapidly expanding area of research.”
The artificial hydrolase is “the first really good example where both structure and reactivity have been effectively designed,” says computational protein designer
Vikas Nanda of Robert Wood Johnson Medical School,
in Piscataway, N.J. “There’s also a lot here for the pro-
anhydrase II (bottom), catalyzes hydration and hydrolysis with
unprecedented efficiency for an artificial enzyme. Hg(II) ion is yellow and
Zn(II) ions are red.
VINCENT PECORARO & COWORKERS/U OF MICHIGAN
N WORK that could lead to a new generation of tai-
paign. “Although de novo-designed α-helical bundle
proteins have been reported before,” he says, “designing functional activities into them has been very challenging,” and the efficiencies of the artificial hydrolase
are “quite impressive.”—STU BORMAN
WWW.C E N- ONLI NE .ORG
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JANUARY 20 1 2
Reprinted from
C&EN, Dec. 5, 2011
NEWS OF THE W EEK
U.K. RESEARCH GETS
A SHOT IN THE ARM
ment. Still, officials acknowledge that rapid changes
occurring in the industry need to be addressed.
“We need to create the right environment for scientists and business to work together and translate
research into new, cutting-edge technologies and medicines,” Minister of State for Universities & Science David Willetts said. “This will boost our economy, create
new jobs, and lead to better treatments for patients.”
Through its Medical Research Council, the U.K.
government is also investing close to $16 million in a
collaboration with AstraZeneca. Under the agreement,
the U.K. drug firm will make 22 compounds available
free of charge to academic researchers, who will study
the compounds’ efficacy against various diseases.
Separately, AstraZeneca has added $100 million to its
venture capital arm, MedImmune Ventures, to invest in
biopharmaceutical companies.
Leaders of U.K.-based health care, pharmaceutical,
and biotechnology industry associations welcomed
the strategy and initiatives. GlaxoSmithKline called
the plan “a very important next step on the journey
to make the U.K. the best place in the world to locate
pharmaceutical investment.”
Stating its commitment to work with the government to deliver on the promises, GSK said it is “positive about Britain’s future prospects as a place to research, develop, manufacture, and commercialize our
medicines.” —ANN THAYER
FUNDING: British government looks
to support the life sciences industry
B
RITISH PRIME MINISTER David Cameron out-
“I want
the great
discoveries
of the next
decade
happening
in British
labs, the new
technologies
born in
British
start-ups.”
—BRITISH PRIME
MINISTER DAVID
CAMERON
lined his government’s strategy for the U.K.’s life
sciences industry at a conference in London last
week. The plan, spelled out in two reports, includes a
$282 million fund to support medical research as well
as changes to the delivery of new therapies through the
National Health Service.
Britain’s ambition is not just to retain a foothold
but to take a bigger share of the global life sciences
market, Cameron said. “I want the great discoveries
of the next decade happening in British labs, the new
technologies born in British start-ups,” he said. New
funding will target the gap between idea generation
in the lab and market investment in a new drug or
technology.
With more than 4,500 companies, 165,000 employees, and $78 billion in annual revenues, the life
sciences sector has been growing faster than the U.K.
economy as a whole, according to the U.K. govern-
NIHEXPANDS
GENOME PROGRAM
RESEARCH: Federal sequencing effort
shifts funds to clinical applications
Reprinted from
C&EN, Dec. 12, 2011
(both)
T
HE NATIONAL Institutes of Health is broadening its genome-sequencing program to focus
more on medical applications. Although most of
the program’s budget will fund basic research at three
large-scale sequencing centers, nearly one-quarter of
the money will be redirected
to help push genomics into
clinical care.
“There have been some
remarkable medical successes
for genomics, but genome
sequencing has yet to find its
way into standard medical
practice,” Eric D. Green, director of NIH’s National Human
Genome Research Institute,
said at a Dec. 6 briefing. NHGRI, which runs the federal
sequencing program, hopes its future investments in the
program will accelerate the realization of genomic medicine, Green noted.
WWW.C E N- ONLI NE .ORG
4
ROBE RT BOSTON/WASHINGTON U IN ST. LOUIS
Large-scale
sequencing centers
face less NIH
funding for basic
research.
NHGRI plans to maintain its current level of funding
for the program and invest $416 million over the next
four years, Green said. The bulk of the funding, some
77%, will continue to support basic research at three
sequencing centers: the Broad Institute of Harvard University and MIT, the Genome Institute at Washington
University in St. Louis, and the Human Genome Sequencing Center at Baylor College of Medicine.
The remaining 23%, or about $100 million, will be
redirected to support three new priority areas aimed at
bringing genome sequencing into routine medical practice. These areas are finding causes of rare, inherited
disorders; evaluating the medical, ethical, and societal
impacts of using genome sequencing in clinical care;
and addressing the bioinformatics bottleneck created
by the deluge of sequencing data.
The shift in funds will cut the budgets of the three
sequencing centers, but the reductions won’t hit all at
once. NHGRI plans to reduce the base funding of each
center by about 5% each year over the next four years,
NHGRI Deputy Director Mark S. Guyer noted at the
briefing. That reduction in funding is expected to coincide with a drop in cost of DNA sequencing.
“We believe the cost of sequencing will continue to
decline,” Guyer said. As a result, NHGRI’s sequencing
program can maintain its high level of productivity
at even lower costs, he noted. As costs drop, money
will be redirected to other priorities, he said.—BRITT
ERICKSON
JANUARY 20 1 2
NEWS OF THE W EEK
SWITCH-ON
FLUORESCENCE
These groups shy away from water, which causes them
to aggregate, thereby compressing the fluorophores and
quenching their fluorescence. Common surfactants or
interactions with cellular components such as membrane phospholipids cause deaggregation. When the
BIOLOGICAL IMAGING:
groups are apart, the fluorophores are free to cut loose
Functionalized nanoparticles
and shine with their full fluorescence intensity.
light up upon entering cells
T
o demonstrate the power
of the fluorescence
switching, the researchers tracked
RESEARCH TEAM based at Ireland’s Unifluorescence after
versity College Dublin has demonstrated
Fluorophore
cellular uptake of
fluorescence-switchable polymer nanopardeaggregation
the nanoparticles
ticles in action. Bearing functional groups that turn on
by human breast
fluorescence for imaging when captured by cells, these
cancer and kidney
particles are not subject to the interfering background
cells. It takes about 15
fluorescence common with fluorophores that are alminutes for a diffuse Nonfluorescent
ways turned on.
pattern of red fluoAccording to Donal O’Shea, who spearheaded the
rescence to emerge
work, the unique “off ” to “on” switching “allows us to
Fluorophore off
Water
Surfactant
from the dark backuse the nanoparticles for real-time, continuous imaging of their uptake into live cells for the first time. Some ground as the particles enter cells and switch on. By
100 minutes, strong red fluorescence concentrates in
of the movies we have recorded are quite dramatic.”
Near-infrared fluorescence imaging using molecular individual cells. The particles don’t enter the nucleus,
so that area in each cell remains dark.
fluorophores is a popular method for investigating
biological processes, such as the cellular uptake of molTurn-on nanoparticles are “indeed a cool tool to
ecules, including drugs. An often-encountered
follow fluorescence within living cells,”
problem is background fluorescence from
comments Wendelin J. Stark, a funcfluorophores not inside the cells. The extranetional nanomaterials expert at the Swiss
ous light can mask imaging of events scientists
Federal Institute of Technology, Zurich
N
want to see or limit the imaging to snapshots in
(ETH). The inherent tendency of the new
N
N
time when the background fluorescence has been
nanoparticles to quench when close to one
B
removed.
another “is a different kind of switch for
F
F
fluorophores,” Stark notes.
O’Shea’steam circumvented this problem by designing poly(styrene-coBesidesbiological imaging and drug
O
methacrylic acid) nanoparticles covdelivery, the method “may also find
O
O
(O
)3 interesting use in low-cost, portable
ered with hydrophobic BF2-chelated
N
H
detection of surfactants, maybe in water
azadipyrromethene groups (J. Am.
Chem. Soc., DOI: 10.1021/ja208086e). Azadipyrromethene fluorophore analysis,” Stark adds. —STEVE RITTER
A
VIDEO ONLINE
Watch fluorescent nanoparticles turn on in kidney cells at cenm.ag/nanofluor.
Fluorophore on
Aggregation and
deaggregation
enable fluorophorebearing
nanoparticles to
switch from “off” to
“on.”
Reprinted from
C&EN, Dec. 5, 2011
PERSONALIZED MEDICINE Organizations plan genomics centers in Connecticut, New York City
Several major research organizations are
joining forces to establish two institutions that will explore the genetic underpinnings of human disease. The centers,
in Connecticut and New York City, both
aim to use personal genetic information
to advance drug development and create opportunities for company spin-offs
while improving health care.
The Connecticut project, the Jackson
Laboratory for Genomic Medicine, will link
Jackson Laboratory, a Maine-based nonprofit, with the University of Connecticut
Health Center and Yale University. It will
be located at UConn’s campus in Farmington. Funding over the next 10 years
will include $291 million from the state
and more than $800 million from Jackson
Laboratory, the project’s backers say.
The center will open new R&D opportunities in a state where drug firm Pfizer
is cutting more than 1,000 jobs (C&EN,
Feb. 7, page 5). The 173,500-sq-ft lab is
expected to be completed in 2014 and ultimately house more than 660 people.
The second project, the New York Genome Center, will link 11 academic medical centers and research universities in-
cluding Rockefeller University, Memorial
Sloan-Kettering Cancer Center, and Cold
Spring Harbor Laboratory at a yet-to-bedisclosed location in New York City. Genesequencing instrument firm Illumina and
drugmaker Roche will be collaborators.
About $125 million in private and public money will pay for the 125,000-sq-ft
facility, which is set to open next year.
Executive Director Nancy Kelley says
the center “will allow us to support the
world’s premier research and medical institutions, as well as their diagnostic and
pharmaceutical partners.”—MARC REISCH
Reprinted from C&EN, Nov. 7, 2011
WWW.C E N- ONLI NE .ORG
5
JANUARY 20 1 2
ADAPTED FROM J. AM. CHEM. SOC.
Fluorescent
L IF E T ECHN O LO G IES
BUSINESS
OPTION BLOCK
Life Technologies’
QuantStudio
system can
accommodate
five different
assay formats.
REPEAT SALES FOR
STABLE REVENUES
Instrumentation firms view CONSUMABLE PRODUCTS as a strategic business
ANNM. THAYER, C&EN HOUSTON
BUILD IT and they will come—again and
again. Having sold a big-ticket piece of
equipment, laboratory instrumentation
manufacturers hope customers will return
repeatedly for the consumable products
they’ll need to run it.
In the instrumentation business, consumables typically include anything beyond the instrument itself, which industry
managers like to call “the box.” Ranging
from sample-prep items and chromatography columns to life sciences reagents and
assays, these high-margin repeat-sale products can be a steady revenue source.
In 2011, worldwide sales of consumables
are expected to reach roughly $8.5 billion,
or about 20% of instrument industry sales,
and are to grow by 4% over 2010, according
to Strategic Directions International (SDI),
a Los Angeles-based research firm.
Each instrumentation firm approaches
the market differently, with consumables
that mirror its instrument types and customer needs. Life sciences research, for
example, uses large quantities of reagents,
assays, and test kits. Mass spectrometry
(MS) consumes less, because samples are
usually processed beforehand via chromatography, which requires columns and
sample extraction methods. Some suppliers offer products that work only with their
own equipment, whereas others provide
generic consumables.
Although strategies vary, instrument
makers consider consumables a strategic business. In tough economic times,
repeat-sale products can help sustain an
instrument supplier’s business. Customers
need consumables “no matter what” to run
their existing instruments, even though
their capital purchases may fluctuate, says
Franco Spoldi, director for consumable
products and business development at
PerkinElmer. “In general, the number of
“We would like to be instrument agnostic
in our development of new products.”
WWW.C E N- ONLI NE .ORG
6
JANUARY 20 1 2
NOT SURPRISINGLY, high-end equipment and infrastructure are the most likely
laggards along with basic lab equipment, all
down 3–4%, says Peter Lawson, executive
director at investment firm Mizuho Securities USA, about academic spending plans
over the next 12 months. “Reagents appear
better positioned,” he adds, “but still down
approximately 2%.” In Mizuho’s academic
spending survey, 25–30% of respondents
think purchases of consumables will be
down, compared with 42% who say spending on instruments will drop.
Lawson reports similar trends in the
market for gene sequencing, with funding
expected to be down and 29% of genomics labs cutting back. These large-volume
users have been delaying purchases of
both instruments and consumables. When
reporting third-quarter sales and earnings,
Illumina, which leads in this market, highlighted negative factors that it expects to
continue at least through 2011.
“We saw what we believe to be an unprecedented slowdown in purchasing due
to uncertainties in research funding and
overall economic conditions, as well as a
temporary excess of sequencing capacity
in the market,” Illumina Chief Executive
E LECTRONI C C H ANNE LS
Companies Offer Many Ways To Learn
About, Use, And Purchase Consumables
Mobile technology is starting
to put product information in
researchers’ hands literally
through smartphones and
tablets that are now appearing in labs. And instrument
suppliers are creating software applications, or apps,
to help customers search for
and use reagents and consumable products.
Agilent Technologies has
apps for calculating liquid and
gas chromatography parameters to determine equipment
setups. Likewise, Thermo Scientific has a GC column selector tool. And Waters has a
part selector app that allows
users to select ultra-performance LC sample plates, vials, filters, and columns. Once
users find a desired configuration, they can save or e-mail
it, or place an order.
In biosciences, Life Technologies has mobile apps for
cell imaging and viewing; plotting and comparing spectra;
and calculating common sci-
Officer Jay T. Flatley said when reporting
results in October. The excess capacity has
decreased the consumables revenue per
instrument owing to fewer runs.
Overall, consumables continue to fare
better than boxes. “Companies with high
consumables flow, such as Qiagen and
Life Technologies, appear more insulated
versus more instrumentation-exposed
companies like Bruker and Waters,” Lawson says.
Lawson ranks Thermo Fisher Scientific
among relatively well positioned firms,
with a product mix skewed toward consumables, service, and lower cost instruments. About $5.8 billion, or more than
half, of its annual sales are in lab supplies
and consumables. Within its $4.6 billion
analytical technologies segment, 44% of
sales are in consumables, 41% in instruments, and the rest in services.
The creation of Thermo Fisher in
everyday life,
mobile devices
are just beginning to be
adopted in the
lab. “More and
more companies are looking
into bringing
these devices
into the labs,”
AT HAND A researcher uses the MORE app to
search for chemicals.
says Maurizio
Bronzetti,
Online ordering remains
Eidogen-Sertanty’s business
popular, and suppliers contindevelopment director. Cost
ue to improve their websites
may be an issue and secuto make it simpler for customrity a concern, especially in
ers to find what they need. The
regulated industries such as
“find and decide experience,”
pharmaceuticals.
which may happen on a moEven so, companies “recbile device, is often apart from
ognize that bringing the dethe “buy experience,” says
vice closer to the experiment
Larry Milocco, senior market
has its advantages,” Eidogendevelopment manager at Life
Sertanty CEO Steven Muskal
Technologies. Many researchadds. And for scientists, “it is
ers shop from their desks, but
really important to be close
an agent completes the purto a device that gives them
chase. “We are trying to look
access to applications and
at how our customers want to
content that helps them exconnect with us,” he adds.
plore their ideas.”
entific parameters. Merck Millipore has an app for finding
filters and another for finding
data and research reagents
for histone modification and
epigenetics research. Another
app allows customers to view
its EMD Chemicals catalog,
with supporting product
documents and pricing.
Aggregated information on
commercially available chemicals is accessible through
Eidogen-Sertanty’s MObile
REagents app, which integrates with the firm’s other
chemistry apps. The MORE
app covers about 6 million
compounds from more than
50 suppliers. Chemical structure searches are possible
through a mobile device’s
camera and the app’s optical
structure recognition capability. And by using mobile devices’ ability to scan and print
bar codes, Eidogen-Sertanty
is trying to enable local inventory management.
Although ubiquitous in
WWW.C E N- ONLI NE .ORG
EIDOGEN-SERTANTY
samples that customers are running is only
increasing.”
Economic conditions in some of instrumentation’s biggest markets are dampening sales of both equipment and consumables. Stock analysts point out that spending by the pharmaceutical and biotech
industries, which accounts for about 30%
of the life sciences tools market, has been
declining. In the government and academic
arenas, which make up another 30% of the
market, budgets are at best uncertain, if
not down, and economic stimulus monies
are running out.
7
JANUARY 20 1 2
BUSINESS
2006 was one of several recent mergers
motivated at least in part by the desire to
strike a good balance between instruments
and consumables. The nearly $13 billion
deal combined Thermo’s strength in lab
equipment and instruments with Fisher’s
broad range of reagents, consumables, and
services. One expected result was more
overlap in R&D between the hardware and
consumables sides of the company.
Similarly, with its recent $2.1 billion
acquisition of Dionex, Thermo anticipates
linking its MS and lab information software
systems with chromatography units and
consumables from Dionex, rather than
those from other vendors. In 2011, Thermo’s combined chromatography business
will have $650 million in sales, with 27% in
consumables and 50% in instruments.
In another big consumables deal, Merck
KGaA , of Germany, acquired Millipore in
2010 for $7.0 billion. The resulting Merck
Millipore division, which is called EMD
Millipore in North America, is on track to
have about $3.2 billion in sales this year.
Targeting bioresearch and bioproduction
markets, the division has three business
units: bioscience, lab solutions, and process solutions.
Damien Tuleu, head of biomonitoring
for the company’s R&D group says the biomonitoring business model “is to design
and develop instruments which can be
used only with our consumables.” When
a customer buys a piece of equipment, “it
means you are going to capture the stream
of consumables,” he adds.
WEIGHTEDTOWARD consumables, the
biomonitoring group focuses on kits, systems, and services for quality control and
assurance. Its products are used to detect
microbial contaminants in pharmaceutical
samples or pathogens in food and beverages. The group falls within Merck’s lab
solutions unit, which provides reagents,
solvents, chromatography products, and
high-purity lab water systems.
Many of the biomonitoring group’s
products are sold to regulated markets,
where an instrument and the related
consumables may be incorporated into
an approved protocol. Because customers tend to be conservative about changes
that would require revalidating methods,
Tuleu explains, a supplier can retain consumables sales long after it sells a piece of
equipment.
Without large amounts of consumables,
biosciences instruments would be idle.
About 80% of Life Technologies’ nearly
$3.7 billion in annual sales are in consumables associated with its instruments.
Even when its customers’ R&D budgets are
shrinking, the company’s “consumables
product mix is positioned to grow faster
than the market,” said Morgan Stanley
stock analyst Marshall Urist in an early
2011 outlook report to clients. The company has a strong position in segments poised
for growth, including the leading area of
sample prep for RNA, DNA, and protein
analysis.
Another growth area is real-time polymerase chain reaction technology, also
called quantitative PCR. According to
Urist, “qPCR’s growth looks set to continue with the second-highest growth
indicator among consumables segments.”
SEGMENTS Spending on
life sciences instruments and
consumbles is expected to decline
this year.
Change in budget from previous year, %
4
◼ Consumables
◼ Instruments
3
2
1
0
0
–1
–2
–3
2008
09
10
11
12
SOURCE: Morgan Stanley Research
Life Technologies itself has predicted highsingle- to low-double-digit growth for the
qPCR market.
In October, the company launched the
QuantStudio 12K Flex qPCR system. The
high-end unit avoids the need for multiple PCR systems because it can conduct
various postsequencing gene expression,
genotyping, biomarker, pharmacogenomic,
and other experiments. Users can also run
digital PCR experiments using nanofluidic consumables and dedicated analysis
software.
Because of the huge growth in nextgeneration sequencing, a lot of researchers
are moving toward qPCR to confirm their
sequencing results. The trend is leading
to an uptick in both academic and commercial markets, says Larry Milocco, seWWW.C E N- ONLI NE .ORG
8
JANUARY 20 1 2
nior market development manager at Life
Technologies.
Target users include time-crunched
screening facilities, service providers, and
contract research organizations that want
high throughput and flexibility in the type
and number of assays they can run. “We are
trying to build products that are going to
scale with the research needs,” Senior Product Manager Ricardo Mancebo says.
CONSUMABLES ARE INTEGRAL to the
system’s capabilities because the system
can accommodate five interchangeable
blocks—including OpenArray plates, TaqMan array cards, and multiwell plates—to
match the size and type of experiment.
“Consumables are key to our product
strategy,” Mancebo says. In particular, he
calls the nanofluidic OpenArray plates
a “unique type of consumable” that can
be run on only two Life Technologies
instruments.
“A large part of our business was customer-configurable products,” Mancebo
says, with customers specifying the assays
they want in a given format for a specific
application. “More recently we have been
building fixed-content panels.” Drawing on
more than 8 million collected assays, which
Life Technologies manufactures itself, the
company is developing panels with customer input.
Similarly, significant advances in another
consumable segment, chromatography columns, have contributed to the emergence
of the ultra-performance liquid chromatography (UPLC) business. These systems use
stationary phases with particles of less than
2 μm in diameter for high resolution, speed,
and sensitivity. “The science happens in the
consumable,” says Michael Yelle, senior director for chemistry commercial operations
at separations specialist Waters.
The company launched its first Acquity
UPLC instrument in 2004. Innovations in
the materials science and the hardware of
the columns led to “a holistic instrumentation design,” Yelle says about the development process. The UPLC columns can
be connected through an eCord chip that
contains quality-control data and tracks
use and performance.
Although designed to work with its own
instruments, Waters’ columns can be used
with other manufacturers’ equipment. In
practice, however, the “attachment rate” is
usually high in UPLC, with customers typically preferring to use columns and instruments from the same company.
surface chemistry to prevent interference
covers any vendor’s instruments in a cusThe adoption of UPLC has helped drive
with samples.
tomer’s lab.
growth at Waters, according to Morgan
As instrumentation has advanced
“We have been keen on trying to create
Stanley’s Urist. But the shift from HPLC
with faster processing times and greater
a relationship with customers, not only at
to UPLC is expected to be “gradual rather
sensitivity, “sample prep has become the
the acquisition of the box, but also with
than abrupt,” at least in research settings,
bottleneck,” says Rebecca Duguid, segwhat comes after the acquisition,” he says.
he adds. Quality control and other regument manager for analytical sample prepa“We have a multivendor approach to all
lated testing settings offer faster growth
ration in Millipore’s biosciences group.
our accessories and consumables, and we
opportunities.
For the HPLC market, Millipore recently
would like to be instrument agnostic in our
Waters has a new line of columns, called
introduced the Samplicity filtration sysdevelopment of new products.”
XP, that can be used on both HPLC and
tem, which simultaneously prepares eight
So even as the company develops comUPLC systems. “If customers have an
samples.
plete systems around its own product offerinstalled base of HPLC, they can develop
PerkinElmer’s Spoldi calls sample prep a
ings, it also provides protocols and methods
methodology and run it on HPLC, and in the
“major pain point” for customers. In some
to allow customers to operate seamlessly
future when they migrate to UPLC they can
of the company’s focus markets, such as
on whatever instrument platform they are
use the same physical columns,” Yelle says.
environmental and food analysis, up to
using, Kerslake explains. Customers “don’t
Consumables are about a $300 million
60% of a lab’s workload can be consumed
want to be tied into a whole work flow from
business for Waters, or about 18% of its
by sample preparation. In addition to
one supplier when they can look at the best
overall sales. “We regard the consumable
of breed, even if they already
products as being key differenhave a competitor’s box or intiators and drivers of perforBUSINESS MIX Instrumentation companies differ in
strument in the lab.”
mance, and so the research and
amount of consumables they sell.
development of these products
takes a lot of focus,” Yelle says.
TO OFFER the range of prodMerck KGaAa
“One thing that differentiates
ucts that it does, PerkinElmer
Qiagen
Life Technologies
us in the consumables space is
conducts product development
Pall
our grounding in basic materials
and manufacturing in-house or
Illumina
science.”
through partners. And it invests
Thermo Fisher
Agilent Technologiesb
substantially “in new consumBrukerc
ables and newer technologies,
BESIDES MAKING the materiWaters
whether it’s advanced materials,
als, Waters designs hardware and
Mettler Toledo
different lamp sources, or other
assembles columns. Controlling
TOTAL INDUSTRY
pieces that allow an instrument
the synthesis and being verti0
20
40
60
80
100
to perform to the detection limcally integrated is “all-around
% of total sales
its required,” Kerslake says.
optimizing performance and
◼ Consumables ◼ Instruments ◼ Services & other
Similarly, Agilent Technolomaintaining quality and consisgies is looking to consumables to
tency,” Yelle says. These aspects,
a For Millipore business. b For life sciences and chemical analysis groups.
c Consumables percentage includes services.
help expand business, not only
he adds, are important to the
SOURCES: Company information, Strategic Directions International
with existing customers, but also
company’s customers in reguwith users of non-Agilent instrulated markets, such as pharmagreater efficiency, these customers want
ments. In March, the company launched its
ceuticals, where LC columns are frequently
consistency, reliability, and ease of use.
CrossLab supplies program for gas chroneeded for the life span of a drug.
“Without great sample preparation, you
matography, which supplies consumables
“Once we have launched a product and
can certainly compromise your results and
for several companies’ GC systems.
it is used in a regulated method, we will
analysis,” says Brian J. Kerslake, director of
The firm’s strategy is to sell products
continue to manufacture and support our
aftermarket solutions at PerkinElmer. The
across work flows, explained Life Sciences
customers that are using it,” Yelle says.
company also sells consumables for a variGroup President Nick H. Roelofs in a SepAnd these long product life cycles can help
ety of chromatographic and spectroscopic
tember presentation for analysts. In addieven out the peaks and valleys in demand,
methods. Its strategy is to “follow the path
tion to GC supplies, Agilent’s other consumhe adds.
of the sample,” he says, from collection and
ables include lab reagents and microarrays,
Consumables for sample preparation
preparation to analysis on the instrument
as well as LC and sample-prep products.
is another long-standing market for most
and ultimately to data handling.
Consumables make up about 20% of $1.3 bilfirms. Even though this business is mature,
Consumablesare part of PerkinElmer’s
lion in combined sales for Agilent’s chemical
it touches almost all analytical work and
analysis and life sciences groups and grew
continues to grow.
broader aftermarket business, which in22% for the 12 months ending on Oct. 31.
For example, Waters’ solid-phase excludes anything other than the box, such as
“It is a really nice renewable revenue
traction products (SPE) are widely used
parts, accessories, and services. Although
stream,” Roelofs said. “With our new
for bioanalytical sample prep, Yelle says.
the company doesn’t report its consummoves and portfolio expansions from
Its SPE devices and vials can be used in
ables sales, Spoldi says its business is “in
recent acquisitions, we are seeing a lot of
front of most analyses. The move toward
line with the industry.” PerkinElmer also
opportunity here.” ◾
lower analytical detection limits has led
offers a service and equipment manageto advances such as vials with optimized
ment program called OneSource that
Reprinted from C&EN, Nov. 28, 2011
WWW.C E N- ONLI NE .ORG
9
JANUARY 20 1 2
SHU T T ERSTO CK
GOVERNMENT & POL ICY
the importance of pesticide biomarkers for identifying worker protection practices that have
failed. He and others also
pointed out the need for
biomarkers to confirm
pesticide exposures in
worker compensation
claims.
“In mild to moderate pesticide overexposure, a nonspecific clinical presentation
is common,” said Amy K. Liebman, director
of environmental and occupational health
at the Migrant Clinicians Network, a group
dedicated to health care for migrant farmworkers. The availability of a diagnostic
biomarker could provide objective confirmation of a work-related illness, she said.
Biomarkers and diagnostics are also
needed for pesticide risk assessments and
to help interpret and design epidemiological
studies, OPP Director Steven Bradbury said.
Biomonitoring tools are a critical part of
Researchers, clinicians search for NEW BIOMARKERS
EPA’s long-term vision to integrate molecuto keep up with changes in product usage
lar and exposure science into its pesticide
BRITTE. ERICKSON, C&EN WASHINGTON
risk assessments, but EPA doesn’t have the
tools to get an in-depth understanding of
what exposure information means, he said.
In terms of where to start developing
Workshop participants agreed that new
THE ONLY DIAGNOSTIC routinely used
those tools, Dana Boyd Barr, a researcher
tools for monitoring pesticide exposure are
by clinicians to confirm a pesticide poiat Emory University’s Rollins School of
needed, and they grappled with how to prisoning case is a test that measures inhibiPublic Health, recommended that EPA
oritize which pesticides to study. They also
tion of the enzyme cholinesterase. The
focus on pesticides that are the most toxic
questioned how to deal with the variability
assay works well for diagnosing patients
and have the highest potential for human
of biomarkers over time and the instability
exposed to organophosphate pesticides,
exposure. Pyrethroids and pyrethrins are
of biomarkers in blood and urine samples.
which dominated the pesticide market in
some of the most widely used pesticides,
The test for cholinesterase inhibition,
the 1990s. But the use of organophosphate
yet no clinical test is available for them,
the gold standard in pesticide exposure, is
pesticides has been declining over the past
said James R. Roberts, associate professor
old and nonspecific. It measures exposure
decade as less toxic alternatives, such as
of pediatrics at the Medical University of
to pesticides that bind the cholinesterase
pyrethroids, have become available. There
South Carolina. Many other commonly
enzyme—any of the organophosphate and
are no diagnostic tests for these increasused pesticides, including organochlocarbamate pesticides—not exposure to one
ingly common alternatives.
rines, neonicotinoids,
particular pesticide.
The key reason for the absence of dichlorophenoxy her“Unfortunately, choagnostic tests for pesticide exposure is a
TRADING PLACES Use of
bicides, and chlorolinesterase inhibition
lack of biomarkers. This makes it difficult
organophosphate pesticides has
picrin, also don’t have
is the only test we have
for physicians, who typically have little
dropped, leaving other pesticides
diagnostics, he noted.
for pesticide exposure,”
training in environmental health, to diagto fill the void.
Other people sugsaid Matthew C. Keifer,
nose acute cases of pesticide poisoning.
gested a more holistic
a senior research scienEpidemiological studies and pesticide risk
Millions of lb
100
approach. “Individuals
tist with the Marshfield
assessments are also being hobbled by this
80
are not exposed to a
Clinic Research Founlack of biomarkers.
60
single compound. We
dation’s National Farm
These problems came to light last month
40
want to come up with
Medicine Center in
at a stakeholder workshop hosted by the
20 ◼ Organophosphates ◼ Other
a comprehensive view
Wisconsin. Physicians
Environmental Protection Agency’s Office
0
of the individual enviregularly order the test
of Pesticide Programs (OPP). Experts from
1990
94
98
02
06
ronment,” said David
when it isn’t approprithe pesticide community congregated at the
M. Balshaw, a program
ate, such as in the cases
meeting to discuss opportunities and chalSOURCE: Environmental Protection
Agency estimates based on Department of
administrator at the
of herbicide poisoning,
lenges associated with advancing toxicology
Agriculture/National Agricultural Statistics
National Institutes
he said.
in the 21st century and developing biomarkService and EPA proprietary data
of Health’s National
Keifer highlighted
er-based tests for pesticide exposure.
SPRAY ZONE
Clinicians
have no way of
knowing when
farmworkers
have been
overexposed to
many common
pesticides.
DETECTING PESTICIDE
EXPOSURE
WWW.C E N- ONLI NE .ORG
10
JANUARY 20 1 2
Institute of Environmental Health Sciences.
Balshaw described a program on exposure
biology led by NIEHS to develop new technologies and biomarkers to characterize
the entire personal environment, including
chemical exposures as well as dietary intake,
physical activity, and psychosocial stress.
Balshaw also highlighted an NIEHS effort to improve the way biomarkers are
measured. “Biomarkers in this case are not
a single gene or protein,” he said. NIEHS
is coming up with new ways of detecting
biomarkers, focusing on arrays and other
techniques to understand how the entire biological pathway responds, Balshaw noted.
Along similar lines, Dean P. Jones, a medical biochemist and professor at Emory University, pointed out that his lab can measure
approximately 10,000 chemicals—including 1,500 to 2,000 metabolites—in a drop of
blood in 20 minutes using high-resolution
mass spectrometry. The analysis provides
a “relatively complete understanding of
metabolic pathways,” he said.
So far, high-resolution mass spectrometry hasn’t found its way into the clinic for
routine medical exams. But Jones predicts
that it might not be too long before that
happens. “The methodology has been
around for about 30 years,” he said, adding
that it took about that long for nuclear magnetic resonance—NMR—spectrometry to
go from being a basic lab research tool to
the clinical imaging technique called MRI.
Jones referred to the concept of the
exposome—all of the exposures of an individual over a lifetime and how those exposures relate to disease. “If we had a system
where we could collect samples and collect
exposure information throughout life, then
we would really have a new opportunity in
terms of epidemiology to be able to look at
disease associations,” he said. The biggest
limitations right now are in the informatics
side, he noted.
IN ADDITION to debating what to measure,
workshop participants pondered how often
to take samples. Biomarker concentrations
vary over time, so a single spot sample
doesn’t provide the whole picture, said
Lesa L. Aylward, principal at the Colorado-
based consulting firm Summit Toxicology.
Variation is often significant within one
person and within one day, she noted.
For biomarkers related to chemical
exposures, interpretation of the results
“is not as simple as higher concentration
equals higher exposure,” Aylward said. “If
you understand the pharmacokinetics of
the compound, you can improve how you
use biomonitoring for patients,” she added.
In the end, there are many different
needs for pesticide-specific diagnostic
tools. Public health advocates are pushing EPA to require the pesticide industry
to develop such tests for their products as
part of the approval process. Without such
requirements, diagnostic tests will not be
created, the advocates say.
“If industry can’t come up with a test for
pyrethroids, surely they are not going to
come up with a test for the newer nicotinoids or fipronil,” a chemical used on dogs
to control fleas, South Carolina’s Roberts
said. “Coming up with it on their own,” he
warned, “is just not going to happen.” ◾
Reprinted from C&EN, Oct. 31, 2011
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SCENE
PUBLISHED BY THE
AMERICAN CHEMICAL SOCIETY
WWW.C E N- ONLI NE .ORG
11
JANUARY 20 1 2
SCIENCE & TECHNOLOGY
THE BRYOSTATINS’ TALE
With the promise of treating CANCER, ALZHEIMER’S, AND HIV, this family of marine natural
products continues to intrigue scientists more than four decades after its discovery
ONE JUNE DAY in 1968 marine biologist
Jack Rudloe went down to collect specimens from the docks at his local marina
on the northern Florida coast of the Gulf
of Mexico. As the man behind Gulf Specimen Co., Rudloe was used to catching
some of the Gulf ’s more interesting creatures—electric rays, bonnethead sharks,
and live jellyfish—for aquariums and
research centers throughout the country.
But on this day, his
mission was simBRYOSTATIN BOUND
pler: Gather some
A hypothetical
marine organisms
model, based on
computational
studies, of
bryostatin 1
binding to PKC.
of which have been
that were abundant
structurally characand easy to collect
HO
terized. Since they
(inexpensive, in other
O
CH3O
were first plucked
words) and send
A
B
O
O
O
O
from obscurity more
them to Jonathan L.
OH
than 40 years ago,
Hartwell’s anticancer
O
the compounds have
drug discovery group
OH H
O
O
had a colorful history.
at the National CanC
They were hailed as
cer Institute (NCI).
OH
O
key compounds in the
Amongthe dozen
OCH3
fight against cancer,
organisms Rudloe colO
but over the years,
lected “shotgun style”
O
bryostatin 1, the mostthat day, was a small
Bryostatin 1
studied member of
brownish spray that
the family, failed to
looked like
impress. In more than three dozen clinical
seaweed. Despite its appearance,
trials to fight various forms of the disease,
the material was not
it gave mostly mediocre results, both on
a plant but rather a
its own and in combinations with other
colony of the bryocancer-fighting drugs.
zoan Bugula neritina,
tiny filter-feeding critters, each about a milTHECOMPOUNDS have also fallen out of
limeter long that clump
favor as drug candidates for a more practitogether in a branching
cal reason: Harvesting them from the natustructure. B. neritina
rally occurring bryozoan is impractical,
is, in fact, a pest
and their long chemical syntheses were too
that fouls
unwieldy for drugmakers.
floating docks
Recently, however, the cloud that was
and boats
hanging over the bryostatins has begun to
in waters
lift. Animal tests show that bryostatin 1
worldwide.
enhances memory and could be used to
Rudloe put
treat Alzheimer’s disease and strokes. And
a few handfuls of
some preliminary studies show it could
the bryozoan
help eradicate HIV. What’s more, chemthrough a
ists have dramatically whittled down the
meat grindnumber of steps it takes to make these
er, packed it
molecules. This year, three total syntheses
in isoproof bryostatin natural products were pubpyl alcohol,
lished, with the shortest being just 36 steps.
and sent it
Finally, as chemists have found a way make
to Frederbryostatins faster, there’s been a push to
ick, Md. “It
make analogs of these compounds so that
was just sheer
scientists might get a better handle on how
luck,” he says,
they operate biologically and make simpler
that he had picked
molecules that would be more practical
an organism armed with moldrug candidates.
ecules that could fight cancer,
George R. (Bob) Pettit, a natural prodAlzheimer’s disease, and HIV.
ucts expert and chemistry professor at
Those compounds are the bryostatins,
Arizona State University, was one of the
a family of 20 macrolide lactones, 18
people driving research to find cancerWWW.C E N- ONLI NE .ORG
12
JANUARY 20 1 2
ADAM LESSER & BRIAN LOY/STANFORD
BETHANYHALFORD, C&EN NORTHEAST NEWS BUREAU
because bryostatin 1 is so
fighting agents
potent, those 18 g have
from marine orHO
been enough to supply all
ganisms back when
OH
CH3O
the clinical trials using
Rudloe scooped
O
O
O
the compound.
those first handfuls
1968
OH
of B. neritina. In the
First samples of Bugula neritina
O
screened for anticancer activity
early 1970s Pettit
BRYOSTATIN 1 works by
OH H
O
O
began collecting
modulating the activities
bryozoans from
1976
of a family of enzymes
OH
O
A compound that would come to be
the Gulf of Califorknown as protein kinase
OCH3
known as bryostatin 1 identified for the
nia, in Mexico, and
C,
or
PKCs.
Once
actiO
first time in extracts from B. neritina
the Sagami Gulf,
vated, these enzymes
O
collected from the California coast
in Japan. But it
phosphorylate certain
Bryostatin 2
was extracts from
proteins and play an im1982
a sample of B. neportant role in intracelluStructure of bryostatin 1 reported
ritina taken from the California coast that
lar signaling cascades. PKCs first attracted
most interested Pettit and the folks at NCI.
the attention of biologists because they are
1990
the target of phorbol esters, the archetypal
First total synthesis of bryostatin 7
tumor promoters.
PETTIT’S GROUP spent most of the late
in 79 steps by Satoru Masamune and
But while phorbol esters make tumors
1970s trying to isolate the compounds recoworkers at Massachusetts Institute
grow like crazy, bryostatin 1 suppresses tusponsible for the antineoplastic activity in
of Technology
mor growth—even though they both bind
bryozoan extracts. By 1981, Cherry L. Herto the same
ald, a scientist working in Pettit’s lab, had
1991
part of PKCs.
isolated the first milligram of what would
HO
18 g of bryostatin 1 exIt’s a phebe known as bryostatin 1 from that CaliO
CH3O
tracted from 14 tons of B.
nomenon that
fornia collection of B. neritina. “I dashed
neritina collected off the
still puzzles
it off to the National Cancer Institute and
O
O
O
O
OH
California coast
biologists. “Of
the activity was tremendous,” Pettit reO
the known
calls. “It was clear we had to determine the
OH H
1998
activators of
structure.”
O
O
First total synthesis of
PKC, bryoUsing 500 kg of B. neritina, Pettit’s
OH
bryostatin 2 in 72 steps by
statin 1 is the
research team isolated 120 mg of bryoO
O
David A. Evans and coworkonly known
statin 1. They crystallized the material and
O
ers at Harvard University
agent that is
determined the compound’s structure,
O
a functional
which they reported in 1982 (J. Am. Chem.
Bryostatin 3
2000
antagonist of
Soc., DOI: 10.1021/ja00388a092). “We were
First total synthesis of
most phorbol
blessed,” Pettit says of the ease with which
bryostatin 3 in 88 steps by Shigeru
ester functions,” says Gary E. Keck, a chemthey crystallized the compound.
Nishiyama, Shosuke Yamamura, and
istry professor at the University of Utah
The structures of 17 other bryostatins
coworkers at Japan’s Keio University
who has been studying the bryostatins for
would follow (extracts from Rudloe’s
the past decade.
samples became known as bryostatins 4
2008
In fact, a number of natural products
through 8). But it was bryostatin 1 that
First total synthesis of bryostatin 16 in
activate PKCs. Like bryostatin 1, they bind
NCI began to focus on as a potential drug.
42 steps by Barry M. Trost and Guangto a region of the enzymes known as the C1
In 1991 the institute undertook a massive
bin Dong of Stanford University
domain. When a small molecule fills this
isolation of bryostatin 1 from B. neritina
C1 cleft, a PKC enzyme opens to receive its
off the California coast, collecting some
2011
substrates. The binding also makes the C1
14 tons of the animal, which Pettit recalls
◾ First total synthesis of bryostatin 1
region hydrophobic, enabling PKC to move
shipping to NCI in 120 55-gal drums.
from the cytosol, where it resides in the
From those 14 tons, researchers isolated
in 58 steps by Gary E. Keck and coabsence of activation, to a membrane. That
18 g of bryostatin 1 (J. Nat. Prod., DOI:
workers of the University of Utah
membrane could be the cell membrane,
10.1021/np50077a004 ).That’s enough to
◾ First total synthesis of bryostatin 9
the nuclear membrane, or membranes of
fill a typical salt shaker up just a quarter
other cell organelles. Once stuck to the
of an inch, Pettit estimates. Nevertheless,
in 43 steps by Paul A. Wender and
Bryostatin time line
Adam J. Schrier of Stanford University
This year, three total syntheses of
bryostatin natural products were published,
with the shortest being just 36 steps.
WWW.C E N- ONLI NE .ORG
13
JANUARY 20 1 2
◾ Total synthesis of bryostatin 7 in
36 steps by Michael J. Krische and
coworkers at the University of Texas,
Austin
SCIENCE & TECHNOLOGY
CH3O
HO
O
membrane, PKC
covered that PKC plays
connections in the brain and preventing
O
O
O
O
finds its protein
a critical role in the prothe death of neurons,” Alkon says. “It also
OH
targets and
cess. “It’s a very powerful
has the potential of enhancing memory in
O
phosphorylates
regulator of molecular
normal patients or aging patients or deOH H
O
O
them, setting
switches that send signals,
pressed patients. We believe that there is a
O
off the signaling
especially at the most
tremendous potential here.”
OH
O
cascade.
important junctions in
Alkon recently received approval to beOCH3
PKC-actithe brain called synaptic
gin a Phase II clinical trial using bryostatin
vated proteins
junctions—the connec1 to treat Alzheimer’s. He wants to partner
O
are involved
tions in the brain between
with a private-sector company before movBryostatin 7
in some of the
neurons,” he says. “We
ing forward, however.
most important
discovered when we form
cellular functions, Keck points out. They
memories we actually induce the formaBRYOSTATIN 1’S ability to activate PKC has
make cells grow. They make cells morph
tion of new synapses, and that’s regulated
also recently gotten attention for treating
into different kinds of cells. And they are
by protein kinase C and a whole host of
another disease—HIV. Patients with HIV
involved in apoptosis, or programmed cell
other molecular players in the orchestra
who take the antiviral drug cocktails still
death. “The most critical processes of the
that protein kinase C regulates.”
retain latent reservoirs of the virus in their
cell turn out to be heavily regulated by this
With this understanding, Alkon’s
cells. That’s why the cocktails don’t cure the
family of enzymes,” Keck notes. “That’s
team wondered whether PKC might be
disease but merely treat it. Once a patient
why bryostatin 1 can have such a wide
relevant to the memory loss associated
goes off the therapy the virus reawakens.
range of biological effects. It’s not like a
with Alzheimer’s disease. “It turns out
But PKC “can activate transcription faclot of agents that target one specific site in
that the central molecular pathways of
tors that can rouse slumbering HIV provian enzyme and inhibit its activity. This is
the pathophysiology of
ruses,” according to
very different.”
Alzheimer’s disease all
Warner C. Greene ,
HO
Despite promising results as a cancer
involve protein kinase
who directs virology
O
CH3O
treatment in animal studies, bryostatin 1 has
C,” Alkon explains.
and immunology
O
O
O
O
stalled in Phase II clinical trials. It has failed
This led Alkon to sevresearch at the J.
OH
to show significant activity against tumors
eral compounds that
David Gladstone
O
either on its own or in combination with
activate PKC, of which
Institutes in San
OH H
O
O
other chemotherapeutic agents. “The bryobryostatin 1 was the
Francisco. “So
O
statins still haven’t quite found the right
most potent.
bryostatin 1 is a drug
OH
O
niche,” says Peter M. Blumberg, chief of the
“We found that PKC
that’s under active
OCH3
Molecular Mechanisms of Tumor Promoactivators are remarkinvestigation for an
tion Section at NCI. “By understanding the
ably effective in animal
eradication treatO
mechanism of the bryostatins we might be
models of Alzheimer’s
ment,” he says, alBryostatin 9
better able to pinpoint which are the specific
disease in addressing
though he’s quick to
subclasses of cancers in which this would
virtually all of the aspoint out that such
represent the rational therapy.”
pects of Alzheimer’s disease,” Alkon says.
therapy is still in the early stages. No animal
These compounds “enhance memory.
testing has been done with bryostatin 1 and
They correct memory deficits. They restore
HIV, Greene notes.
ALTHOUGH ITS STATUS as a cancerlost synapses and prevent the loss of synEven if clinical tests prove the medicinal
fighting agent may have taken a hit, bryoapses. They prevent the death of neurons.
potential of bryostatins, treatments based
statin 1 has started to gain some traction in
They prevent the amyloid plaques. And
on the compounds will have to grapple
treating other diseases, particularly in illthey prevent the neurofibrillary tangles. All
with supply. In the late 1990s, the nownesses associated with memory loss, such
of those are hallmarks of Alzheimer’s disdefunct company CalBioMarine Technoloas Alzheimer’s disease and strokes.
ease,” Alkon continues.
gies tried aquaculture, growing B. neritina
Researchers
“There’s no one therapy
on what Dominick Mendola, the company’s
led by Daniel
HO
except activators of
former president, describes as a giant “unAlkon ,scientific
O
CH3O
protein kinase C that
dersea box kite” off the California coast.
director and prodoes that.” These findAlthough they succeeded in growing the
fessor at BlanchO
O
O
O
OH
ings, he argues, suggest
bryozoan, the company eventually went
ette Rockefeller
O
a new way of looking at
under as postponed clinical trials demolNeurosciences
H
Alzheimer’s disease.
ished demand for the bryostatin 1 it was
Institute at West
O
O
Animaltests with
ready to supply, and the firm was unable to
Virginia Univerbryostatin 1 have also
secure venture capital funding in the early
sity, were trying
OH
shown that it restores
2000s to stay afloat.
to work out how
OCH3
memory after strokes
The bryostatins, current research sugmemories are
O
and traumatic brain ingests, don’t actually come directly from B.
stored on the
Bryostatin 16
juries. “Essentially what
neritina, but rather from a bacterial symmolecular level
it’s doing is building new
biont that lives within the bryozoan. The
when they disWWW.C E N- ONLI NE .ORG
14
JANUARY 20 1 2
PIO N E E R
Undersea Treasure Hunter
compound appears to protect the organism’s larvae from being eaten by predators.
Scientists have tried to isolate the symbiont so that they might create bryostatins in
a petri dish.
To date, however, no one has been able
to culture the bacterium. “It may be missing some capabilities it needs to live outside of its host,” says Margo G. Haygood,
a professor at Oregon Health & Science
University who has been studying how the
symbiont makes the bryostatin skeleton.
was a kid, that naturally occurring material—plants, animals, microorganisms—
would really be the best place to look
for drugs,” he recalls.
In 1965, Pettit was lured away from
his position at the University of Maine,
where he’d explored natural products
from fungi, plants, and arthropods, and
joined the faculty at ASU. Working in
tumor-fighting natural products—the
bryostatins, the combretastatins, the
spongistatins, and the dolastatins, to
name just a few. A synthetic dolostatin
analog, named monomethyl auristatin
E, recently received approval from the
Food & Drug Administration to treat two
types of lymphoma as part of a drug-antibody conjugate, named Adcetris, which
is marketed by Seattle Genetics and Takeda Pharmaceutical
Pettit
(C&EN, July 25, page 10).
“Pettit has been an outstanding leader in natural products
research, particularly in the
search for new drugs for the
treatment of various types of
cancer,” says longtime Journal
of Natural Products Associate
Editor Richard G. Powell. “The
contributions of Pettit and his
research group to this area of
research since the early 1960s
have been quite numerous, the
research meticulous, and under
his leadership the group has been outstandingly successful in the discovery
of new compounds useful, or potentially
useful, for cancer chemotherapy.”
“He can truly be regarded as one of
the great pioneers in natural products
drug discovery who was among the
first to explore the realm of marine
organisms as a source of potential antitumor agents,” adds Gordon M. Cragg,
a National Institutes of Health special
volunteer with NCI’s Natural Products
Branch. “Pettit is an outstanding and resourceful scientist totally committed to
improving the treatment and quality of
life of cancer patients worldwide.”
PETER J. K ISS/ CURR. BIO.
The bryostatins, and many other natural
products, might never have been mined
from the sea for their disease-fighting
compounds if not for the efforts of
George R. Pettit. Known to his friends as
Bob, Pettit has been searching the sea for
cancer-fighting compounds for more than
40 years, as a chemistry professor at Arizona State University (ASU) and director
of the ASU Cancer Research Institute, a position he still holds.
It was a convergence of events
in his childhood and teenage
years, Pettit tells C&EN, that led
him to cast his eye toward the
ocean to seek cancer cures. Pettit grew up on the Jersey Shore,
just half a mile from the ocean,
and spent much of his childhood
exploring the interesting invertebrates that lived there.
At age 15, Pettit began working in a medical center lab in
Monmouth County, N.J. As part
of his duties, he had to assist the
hospital pathologist in doing postmortem exams, where he saw the ravages of
cancer firsthand. “It made such a shocking impression on me that I still haven’t
recovered from it,” he says.
Pettit began thinking of all those
squishy creatures he had played with
at the beach as a child. Physically, they
seemed so vulnerable. And yet they’d
managed to survive and evolve over
billions of years without being gobbled
up by predators. Pettit reckoned their
chemical defenses must therefore be
highly evolved, and he wondered whether those same defenses might also fight
cancer. “I always thought, even when I
collaboration with the National Cancer
Institute (NCI), Pettit began what he
describes as the first worldwide exploration of marine invertebrates as new
sources for anticancer drugs.
In the first 25 years of this research
effort, he never once took a vacation, Pettit says. All his family trips were to sites
where he could collect specimens. And he
often enlisted his five children to help him
collect underwater creatures. “They were
our expeditionary force,” he jokes.
Over the years, Pettit and his colleagues have collected some 14,000
specimens from the sea and elsewhere.
And from them he has identified myriad
She adds that, despite efforts, no one has
been able to transfer enough of the symbiont’s biosynthetic machinery into another
organism, such as Escherichia coli, to make
the bryostatin skeleton.
And that has left the bryostatins’ fate in
the hands of chemists. With their complex
skeleton and multiple stereocenters, the
bryostatins are a trophy for any synthetic
organic chemist up to the challenge. Until
recently, however, total syntheses of bryostatin natural products weighed in at more
WWW.C E N- ONLI NE .ORG
15
JANUARY 20 1 2
than 70 steps—too unwieldy to make large
amounts of the molecules.
In 2008, Stanford University chemists
Barry M. Trost and Guangbin Dong reported the synthesis of bryostatin 16 in only 42
steps (Nature, DOI: 10.1038/nature07543 ).
And there’s been a flurry of activity in the
field in 2011. A team led by the University
of Utah’s Keck and graduate student Yam
B. Poudel reported the first total synthesis
of bryostatin 1—the one that’s been used
in all the clinical trials—in 58 steps (J.
SCIENCE & TECHNOLOGY
Am. Chem. Soc., DOI: 10.1021/ja110198y ).
To that end, Krische says, his group is
Paul A. Wender and graduate student
now aiming to use the synthetic methods
Adam J. Schrier, also at Stanford, prepared
they developed to make analogs of bryobryostatin 9 in 43 steps (J. Am. Chem. Soc.,
statin in as few as 12 steps. He’s in good
DOI: 10.1021/ja203034k ).And Michael J.
company in the bryostatin analog game.
Krische and coworkers at the University
Wender has been making simplified verof Texas, Austin, set a new record for maksions of the bryostatins for 25 years, and
ing the molecules
Keck has been creating
when they prepared
bryostatin analogs for
bryostatin 7 in just 36
the better part of the
O
O
steps (J. Am. Chem.
past decade.
OH
Soc., DOI: 10.1021/
“We need to unO
ja205673e ).
derstand collectively
OH H
O
O
Therecent synas a community that
theses are also highly
natural products are
convergent, with
not made in nature
OH
O
the longest linear
to do what we ask of
OCH3
O
sequence clockthem. Bryostatin is
O
ing in at 31 steps for
not made in B. neritina
Merle 23
Keck’s synthesis, 28
for the purposes of
for Trost’s, 25 for
addressing HIV or
Wender’s, and just 20 for Krische’s. And
cancer or Alzheimer’s,” Wender says. “The
each shows off a different use of chemisnatural product traditionally has been
try. Trost takes advantage of a palladiumoften perceived as being the drug, when in
catalyzed union of two alkynes to create
fact an emerging emphasis is that it’s a trethe bryostatins’ macrocyclic structure.
Keck makes use of a pyran annulation
method to unite the A-ring and C-ring
subunits with simultaneous formation
of the B-ring. Wender uses a similar macrocyclization strategy, employing the
Prins reaction to wed an aldehyde with a
hydroxyallylsilane. Krische uses Keck’s assembly strategy but decreases the number
mendous lead. And if we could learn what
of steps to make each fragment by employnature is teaching us in this lead, we could
ing hydrogenative carbon-carbon bond
then, using modern science, translate that
formation. Each strategy gives chemists
into molecules that would be more effecflexibility to make a range of analogs.
tive than what nature has produced.”
“In natural product
More than 100
synthesis, I feel that
bryostatin analogs—
HO
it’s really important
dubbed bryologs—
O
to select targets that
have come out of
O
O
O
represent authentic
Wender’s research
OH
unmet challenges in
group over the years.
O
terms of the chemistry
“We’ve been trying to
OH H
O
O
and biology,” Krische
understand the lesson
says. “With sufficient
of bryostatin and then
resources, it’s pretty
to use what we have
OH
O
clear that one can
learned to come up
OCH3
O
complete the total
with agents that are
O
synthesis of nearly
superior to the natural
Merle 28
any natural product.
product,” he says.
So I think now it’s inFor example, they
cumbent upon synthetic organic chemists
have learned that an alkoxy group at a cernot only to make the target but to focus
tain position in the bryostatin backbone is
on how the target is made,” with an eye
critical. They’ve determined the structure
toward flexibility, he says. “It’s important
of the C-ring and its surrounding functo select natural products where the syntional groups are also important, as that’s
thesis of the target is not an end point but
the portion of the molecule thought to bind
a beginning.”
to PKC. Finally, they’ve figured out how
to simplify bryostatin’s A- and B-rings , so
the analogs maintain the same shape as the
bryostatins but are easier to make.
WENDERPOINTS to the analog from his
lab known as “picolog” as one of the most
promising. It can be made in fewer than
30 steps. It’s 100 times more potent than
bryostatin 1 in some in vitro anticancer
tests, and it’s shown promise in treating
mice with leukemia.
While Wender sees potential new
therapies from bryostatin analogs, Keck
is more restrained. “Any talk of drugs
based on bryostatin at this juncture is
really premature because we don’t know
yet what kinds of structures you need to
elicit a particular kind of response,” he
says. “What we’re doing is making a toolbox of compounds that vary in structure,
and then going in and finding out in great
and gory detail what those compounds
do biologically. The goal is to link specific
structural features with specific biological
responses.”
“The goal is to link specific structural
features with specific biological responses.”
WWW.C E N- ONLI NE .ORG
16
JANUARY 20 1 2
Theanalogs made in Keck’s lab are
known as Merle compounds, named after
country music legend Merle Haggard, of
whom Keck is a friend and “probably the
world’s greatest fan.” Keck says his collaborator, NCI’s Blumberg, told him he needed
succinct identifiers for his analogs that
wouldn’t change from publication to publication. “I said, ‘I know just the thing. We’ll
give them Merle numbers because nothing
lifts my spirit like a Merle number,’” Keck
recalls.
Keck believes the substitution around
bryostatin 1’s A-ring is critical. His group,
in collaboration with NCI’s Blumberg,
compared analogs that were simplified
around either both the A- and B-rings
(Merle 23) or just the B-ring (Merle 28).
Those that were simplified around the
A-ring did not behave like bryostatin but
instead behaved like the tumor-promoting
phorbol esters. “This was a big surprise
because these things look very much like
bryostatin. They look nothing like phorbol
esters, and yet to the cell, well, I guess the
cell does not have ChemDraw,” Keck says .
“There’s a great opportunity to make im-
O
O
OH
encounter as you go through the
portant findings in biolO
development process,” such as
ogy just from looking at
OH H
O
O
problems with solubility, permeanalogs that people are
ability, or metabolic stability.
making,” Keck adds. “If
OH
O
Having a synthesis that lends
nothing else, there’s a
OCH3
itself
to modifications makes the
great deal to be learned
( )
6 O
bryostatins
attractive, but “it’s
about the fundamental
O
still going to be a hard sell,” Cartbiology that’s relevant
Picolog
er says. “I think the dogma in big
to cancer, Alzheimer’s
pharma has always been that we
disease, and other disdon’t do total synthesis. It’s just not practieases through this kind of research.”
cal.” Still, he notes that some companies are
So will one of the bryostatins or their
challenging that dogma. He points to Eisai’s
analogs ever become a drug? It’s tough to
drug Halaven, which is an analog of a natusay. “In my view there are two key things
ral product made via a 62-step synthesis.
in advancing a natural product into drug
For the bryostatins ever to make it to
development,” says Guy T. Carter, a conpatients will require a tremendous devotion
sultant with natural products discovery
of resources and a strong willingness on the
consulting firm Carter-Bernan Consulting .
part of those in charge to stick with such a
“One is making enough material to start
project, Carter notes. “That bit of wisdom
with, and the other is the ability to make a
that’s required to see it through to the end
broad range of analogs in sufficient quantiproduct is something that is in short supties in order to address whatever issues you
DRUG DEV E LOP ME NT
Taking The Long Route
Drugmakers have been known
to shy away from molecules
that must be made via
lengthy multistep syntheses.
But taking the long route,
chemically speaking, to make
a medicine is not unheard
of. Late last year the pharmaceutical company Eisai
introduced Halaven (eribulin
mesylate), a compound that
requires 62 chemical transformations to make.
Halaven is used to treat
patients with late-stage
metastatic breast cancer. It
is an analog of halichondrin
B, a natural product first
isolated from the sea sponge
Halichondria okadai in 1986
by researchers in Japan (Pure
Appl. Chem., DOI: 10.1351/
pac198658050701). The
molecule is a beast, with a
54-carbon backbone and 32
stereogenic centers. A team
led by Harvard University’s
Yoshito Kishi completed the
first total synthesis of halichondrin B in 1992 (J. Am.
Chem. Soc., DOI: 10.1021/
ja00034a086). Kishi’s team—
working with collaborators at
Eisai, where Kishi was a scientific adviser—began making
analogs of the compound
soon after.
An intermediate in the
Harvard synthesis containing only the macrolide sector
was screened at Eisai and
found to retain bioactivity.
Eisai chemists then created
a range of analogs based
on the structure, settling
on Halaven as the most
promising by the late 1990s.
Although simpler than its
parent structure, Halaven is
“a very challenging target by
anybody’s assessment,” according to Frank Fang, vice
president of U.S. process
research and development at
Eisai. The structure features
a complex ring system and 19
stereocenters.
Fang says that Halaven’s potency and unique
biological profile made it too
attractive a target to pass up
simply because it could be
WWW.C E N- ONLI NE .ORG
ply,” he says. “It’s much easier to say ‘no’
to something like that than to say ‘this is
something special and therefore we need
to devote the resources to make it happen.’
Pursuit of challenging targets like the bryostatins, while risky, has great potential for
creating major breakthroughs in medicine
and eventually profits for the company.”
John A. Lowe, a medicinal chemistry expert with the consulting firm JL3Pharma,
doesn’t see pharma executives running out
to make bryostatin analogs just yet, but
notes: “It certainly is intriguing how much
more approachable the bryostatins or their
analogs are when you start talking about
potential commercialization. It’s now
competitive with the other things that are
going on, and I don’t believe anybody believed that would be the case 20 years ago
when the structures were elucidated. That
in itself is pretty impressive.” ◾
Reprinted from C&EN, Oct. 24, 2011
is not so much the number
of steps but the types of purifications that are employed
during the processing of the
material.”
Chromatography, for
example, takes a lot more
time and generates
a lot more waste
OCH3
than crystallization,
Fang notes. “If you
H
can take a 60-step
O
O
O
O
HO
synthesis and get rid
H
H
of most of the chroO
O O
H2N
matographies and
O
replace them with
O
crystallizations, then
it’s a much more
manageable process
Halaven (eribulin mesylate,
than even a 10- or
counterion not shown)
15-step synthesis
that has entirely
chromatographic purificaa total of 62 steps to make
tions,” he says.
Halaven, Fang points out
Step count, Fang says,
that the synthesis is fairly
is nothing to be scared of.
convergent; the longest lin“Our feeling at Eisai is that
ear sequence is 30 steps.
natural products represent
“The number of steps of a
a large space of untapped
synthesis is one feature that
potential new medicines,” he
people tend to focus on besays. “We’re not deterred by
cause it’s easy to remember,”
a chemical obstacle. If the
he says. “But what really is
biological activity warrants it,
critical to the successful
we’re more than happy to go
implementation of a process
after a compound.”
in commercial manufacturing
made only through a lengthy
synthesis. “The perception
wasn’t so much that this was
an obstacle but rather it was
a challenge that we knew how
to deal with,” he says.
And even though it takes
17
JANUARY 20 1 2
SCIENCE & TECHNOLOGY
MERGING METALS
INTO PROTEOMICS
Tackling the systemic study of METALLOPROTEINS
JYLLIANKEMSLEY, C&EN WEST COAST NEWS BUREAU
proteins work in living organisms, more and more researchers
are probing the complex interactions
of huge ensembles of proteins as they
act together in cells. Many studies
involve all the proteins found in cells,
tissues, or organisms, collections known as
proteomes. The systematic study of those
proteins—their structure, function, localization, and modifications, as well as how
they change in response to different stimuli—is called proteomics.
Anessential subset
ESSENTIAL ELEMENTS
The zinc-finger protein
of the proteome is the
Zif268 binds to DNA to
metalloproteome, conregulate transcription.
sisting of all the proteins
that contain or interact
with metals when they
do their jobs. Estimates indicate that 9%
of eukaryotic proteins bind zinc, 33% of
all proteins bind various metals, and 40%
of all enzyme-catalyzed reactions involve
metals, including Mg, Zn, Fe, Mn, Ca, Co,
Cu, Ni, Mo, W, Na, K, and V.
Because the metalloproteome is so imacid sequence. Instead, ligands may come
portant, scientists have devised innovative
from different loops of a protein, different
techniques to better understand its comsubunits, or even two different proteins,
plexities, including not only conventional exmaking it difficult to use simple sequence
perimental strategies but also bioinformatics
searches to look for protein homology.
techniques. Using those methods, they have
begun to systematically catalog the roles of
various metals in protein function.
INSOME CASES the problem can be addressed by looking for what Bertini calls
Bioinformatics is necessary because
metal-binding patterns. By mining the
traditional experimental techniques to
Protein Data Bank for structures of known
purify and investigate individual enzymes
metalloproteins, Bertini, University of
are slow and difficult, says Ivano Bertini,
Florence chemistry researcher Claudia
a chemistry professor at the University of
Andreini, and colleagues determine arFlorence, in Italy. And just as biologists
rangements of metal ligands along peptide
generally now take advantage of gene and
chains and how the ligands bind to metalprotein databases for insights into how
binding domains. For a metal bound to
biological systems work, he adds, “we
three histidine (H) ligands, for example, a
should have something to target metal ions
metal-binding domain might look somein biology.”
thing like HXHX60H, where X is amino
One of the challenges in using information technology to study metalloproacids other than histidine.
teomes, however, is that metal-binding
Bertini, Andreini, and coworkers used
sites in proteins are three-dimensional
that approach to look for zinc-binding
and don’t always follow a set linear amino
proteins in the proteomes of bacteria, arWWW.C E N- ONLI NE .ORG
18
JANUARY 20 1 2
THOMAS S PLETTSTOESSER/WWW.SCISTYLE.COM
TO UNDERSTAND how
chaea, and eukaryotes. From the Protein
Data Bank, they found 744 zinc-binding
patterns, which they then used to search
the proteomes. They found that, on average, 4.9% of bacterial, 6.0% of archaeal, and
8.8% of eukaryotic proteomes are composed of zinc proteins (J. Proteome Res.,
DOI: 10.1021/pr0603699 ).
Examining the function of those proteins, the researchers found that most prokaryotic zinc proteins perform some kind
of enzymatic catalysis, and two-thirds of
them have eukaryotic homologs. Eukaryotic
proteomes add to those catalytic enzymes
a cohort of zinc proteins that regulate DNA
transcription—principally zincfinger proteins, which likely
evolved to meet the complex
needs of cell compartmentalization and differentiation
in eukaryotes.
More recently, Bertini and
Andreini have expanded their
database-mining approach to look
at 3-D representations of metalbinding sites, focusing specifically on a “minimal functional
site” that includes not just a metal
and its ligands but everything within a 5-Å
radius of the metal ligands. The reactions
catalyzed by metalloenzymes are not governed by metal and ligand identity alone, but
also by the geometry and environment of
the active site, Bertini notes. The additional
structure information is therefore critical
for predicting function. Two proteins with
different overall structures but the same
metal functional sites likely do similar
chemistry, possibly through convergent
evolution of unrelated proteins. In contrast,
different metal functional sites found in otherwise similar proteins may have divergently
evolved to do different things.
The researchers used minimal functional site analysis to examine nonheme
iron proteins, which are proteins that bind
iron without using a porphyrin ring. The
researchers found that they could group
the sites into five structural clusters (J. Mol.
Biol., DOI: 10.1016/j.jmb.2009.02.052). A
similar effort focusing on zinc sites in proteins yielded 10 clusters of highly similar
structures and seven “pseudoclusters” with
broadly similar features (PLoS One, DOI:
10.1371/journal.pone.0026325). Comparing
and contrasting the active site structures
within a cluster can yield clues about how
the proteins evolved or how they catalyze
their respective reactions, Bertini says. The
structural clusters can also help predict the
function of uncharacterized proteins.
Bertini and Andreini are also working
with Janet M. Thornton of the European
Bioinformatics Institute, located in England, to develop a database of the properties
and roles of metals in metalloenzyme catalysis. The database is called Metal MACiE;
MACiE stands for Mechanism, Annotation
& Classification in Enzymes. Metal MACiE
pulls together information on the 3-D structure of metalloenzyme active sites as well as
a step-by-step description of the reactions
they catalyze (Bioinformatics, DOI: 10.1093/
bioinformatics/btp256). Although the database has only 188 entries so far, it will be
a useful resource for additional systemic
studies of metalloenzymes, Bertini says.
put tandem electrospray ionization mass
spectrometry (ESI-MS) to identify proteins
in Pyrococcus furiosus, a species of archaea
that optimally grows at 100 °C (Nature, DOI:
10.1038/nature09265). After separating P.
furiosus biomass through 2-D liquid chromatography—with fractions from one column
further separated on a second—Adams and
coworkers turned up 343 metal peaks for
proteins that variously bound Zn, Fe, Mn,
Co, Ni, Mo, W, V, U, and Pb.
Comparing the sequences of the proteins underlying those peaks, they found
that 158 of the peaks contained proteins
without a previously identified metal-binding domain. Following up on some of those
unknowns, Adams and coworkers identified some novel metalloproteins, including
one with a new type of Mo site. They also
found that the U and Pb peaks most likely
came from the organism misincorporating those elements into proteins. Further
study of proteins vulnerable to metal misincorporation could reveal mechanisms of
metal toxicity, Adams notes.
Nigel J. Robinson, a biology professor
at Durham University, in England, used
a similar approach to determine which
proteins predominantly bind Mn2+ or
Cu2+ in the periplasm, the space between
the cell wall and inner membrane, of the
cyanobacterium Synechocystis PCC 6803.
Although the microbe requires both metals
for photosynthesis, Mn2+ binds weakly and
Cu2+ binds strongly to proteins, raising the
question of how Mn2+ manages to compete
successfully for binding sites.
Analyzing periplasm proteins, Robinson and colleagues turned up something
completely unexpected: two proteins with
similar structure and metal-binding ligands,
one of which contained Mn2+ and the other
Cu2+, although both preferred Cu2+ (Nature,
DOI: 10.1038/nature07340). Further investigation revealed that the proteins fold and
incorporate their metals in different parts of
the organism. The Mn-binding protein folds
in the cytosol, where researchers believe
all copper atoms are already tightly bound
to proteins, then gets exported to the periplasm. The Cu-binding protein, in contrast,
gets sent to the periplasm unfolded and
picks up Cu2+ there. “This highlights the fact
that which metals bind to which proteins
in vivo is determined by the cell controlling
the availability of metals,” Robinson says.
METALLOPROTEINS are not limited to
organisms. Viruses, too, may include metals
in their proteins. University of Cincinnati
BUT FOR ALL THAT can be learned from
chemistry professor Joseph A. Caruso and
mining databases and comparing structural
colleagues have used chromatography and
and functional information, the databases
MS techniques to look at bacteriophage λ,
are only as good as the information they
a virus that infects and replicates in bactehouse, which must originate in experiment.
ria. Although the genome and proteome of
Michael W. W. Adams, a biochemistry prothe virus have been well studied, its metal
fessor at the University of Georgia, divides
complement has not. The virus encases its
genomes into thirds: We know for certain
genetic material in a protein cage and then
what proteins are encoded and what the
injects it into a bacterial cell to replicate.
proteins do for about one-third of any
The protein cage contains a number of
particular genome, we have a good idea
cysteine and methionine residues, which
about another third, and “we have no idea
are common metal ligands. Caruso and
whatsoever” about the remaining third, he
colleagues found that bacteriophage λ insays. Of the unknown third, “potentially a
corporates Zn, Fe, Mn, Co, Ni, and Cu, most
lot of them are metal-containing proteins,”
likely in two proteins in the virus’s cage
Adams says.
(Metallomics, DOI: 10.1039/c0mt00104j).
Historically, determining the metal conScientists are interested in engineering
tent of a protein has often been an experibacteriophage λ to produce nanoparticles
mental afterthought. Scientists purified a
or deliver drugs, and understanding the role
protein and then perhaps discovered that
that metals play in the virus may further
it needed a metal to be structurally sound
those efforts, Caruso says.
or perform a catalytic function. Some
In other application-oriented work,
researchers, Adams included, are now
Caruso and colleagues have
reversing that approach by
done metalloproteomic
looking for metal content
STRUCTURE-FUNCTION LINK The most common ligands
screens for biomarkers to
first, by separating proteins
in nonheme iron sites vary depending on protein function.
predict disease. In one case,
on ion-exchange columns
they looked for a particular
or gels and then assaying
form of the iron-transport
for metal content. In all
Electron transfer
protein transferrin as a signal
cases, researchers note, it
Redox catalysis
for leaking cerebrospinal fluis important to purify and
id after head injury (Analyst,
characterize proteins in
Nonredox catalysis
◼ Cysteine
DOI: 10.1039/c0an00207k).
their native forms because
◼ Histidine
Another study involved
proteins that are unfolded
◼ Aspartic acid/glutamic acid
Structural centers
◼ Tyrosine
identifying possible markers
or denatured will lose their
◼ Asparagine
◼ Other N donors
for narrowing of brain artermetal cofactors.
Sensors
◼ Other O donors
ies after hemorrhagic stroke
In one set of studies, Ad0
20
40
60
80
100
120
(Metallomics, DOI: 10.1039/
ams and colleagues used a
Number of ligands bound to iron
c0mt00005a).
combination of inductively
Chromatography comcoupled plasma mass specNOTE: Data are based on an analysis of all ligands bound to iron in 86 nonheme iron sites.
SOURCE: J. Mol. Biol.
bined with MS techniques
trometry (ICP-MS) to look
to study metalloproteins
for metals and high-throughWWW.C E N- ONLI NE .ORG
19
JANUARY 20 1 2
SCIENCE & TECHNOLOGY
ACS C HE M. BIOL.
isotopes, such as 69mZn, 59Fe,
could be improved, says David
64Cu, 99Mo, and 187W. BiotechW. Koppenaal, chief technology
officer of the William R. Wiley
nology professor Peter-Leon
Environmental Molecular SciHagedoorn and colleagues
ences Laboratory at Pacific
have dosed Escherichia coli
Northwest National Laboracultures with the isotopes and
tory. Right now, combining
tracked where the metals go:
techniques such as ICP-MS to
More than 99% of Cu is locatget metal content and ESI-MS
ed in the protein CueO, a multo get protein sequences means
ticopper oxidase involved in
doing them separately and corCu homeostasis (J. Biol. Inorg.
relating the data. Koppenaal’s
Chem., DOI: 10.1007/s00775lab and others are working on
009-0477-9), and 90% of
technology to use one or more
Fe resides in superoxide
chromatography columns to
dismutase, ferritin, and bacteseparate samples, then split the
rioferritin (Metallomics, DOI:
eluent into two streams: one for
10.1039/c1mt00154j). Under
elemental analysis through ICPZn stress, E. coli shuttles Zn to
ALIGHT X-ray fluorescence reveals metals in proteins
MS and the other for molecular
ZraP, which Hagedoorn proseparated on a gel. MW = protein standard, CA = carbonic
mass analysis through ESI-MS
poses is a novel prokaryotic
anhydrase, Tyr = tyrosinase, Hb = hemoglobin, Mix = mix of CA,
or other techniques.
Zn storage protein that scavTyr, and Hb.
Asimultaneous, integrated
enges Zn in the periplasm. His
approach enables unequivocal
group has also looked at how
lose-1,5-bisphosphate carboxylase oxygenand global determinations of metal-protein
P. furiosus distinguishes between chemically
ase, commonly known as RuBisCO, a critiassociations, allowing the researchers to
similar Mo and W in its metalloproteome (J.
cal enzyme in carbon fixation and the most
collect “richer and more precise informaBacteriol., DOI: 10.1128/JB.00270-10).
abundant protein in leaves (Metallomics,
tion,” Koppenaal says. One of the projects
One additional method to study meDOI: 10.1039/c1mt00051a ).
that Koppenaal and colleagues are worktalloproteomes originated with the U.S.
ing on is investigating the photosynthetic
Protein Structure Initiative (PSI) to demachinery of cyanobacteria. “We’ve done
termine the 3-D structures of all proteins.
OTHER WAYS to detect metalloproteins in
a lot of proteomics work on the system,
The initiative organizes sequences into
gels include X-ray fluorescence mapping,
and now we want to complement that work
families and then solves the structures of
which allows simultaneous imaging of mulwith better characterization of the proteinselected representatives of each family.
tiple metals to get identity and quantity.
associated metals, metabolite-associated
At Brookhaven National Laboratory, Case
Adding X-ray absorption near-edge strucmetals, and free metals,” Koppenaal says.
Western Reserve University proteomics
ture analysis can also reveal metal oxida“Understanding the dynamic among those
professor Wuxian Shi and colleagues develtion states. Argonne National Laboratory
metal pools is an important part of the
oped a high-throughput X-ray absorption
scientist Lydia Finney and coworkers used
whole picture.”
spectroscopy (HTXAS) technique to identhe X-ray techniques to study the effects
A slightly different approach to metaltify and quantify metals in nearly 4,000
of Cr3+ and Cr6+ spiked into blood serum,
loproteomics is to separate proteins by 2-D
proteins selected for PSI analysis.
demonstrating that Cr3+ compounds progel electrophoresis and then analyze the gel
The combination of crystal structure,
moted as nutritional supplements bind to
bands for metals. Norbert Jakubowski, a sciHTXAS information, sequence homology
serum proteins and form some Cr6+ speentist at BAM Federal Institute for Materials
comparisons, and bioinformatics mining of
cies, contrary to marketing claims (ACS
Research & Testing, in Germany, has used
protein sequences for likely metal ligands
Chem. Biol., DOI: 10.1021/cb1000263 ).
gel electrophoresis plus laser ablation ICPhelped clarify the metal-binding sites in
Finney is now collaborating with WorcesMS to analyze Se enrichment in proteins
the proteins (Genome Res., DOI: 10.1101/
ter Polytechnic Institute biochemistry proand to profile cytochrome P450 expression
gr.115097.110). Although the project previfessor José M. Argüello to investigate metalin rat livers (J. Anal. At. Spectrom., DOI:
ously screened all proteins by HTXAS, in the
trafficking pathways in bacteria by mutating
10.1039/c003889jand 10.1039/c0ja00077a ),
next phase the scientists will analyze only
known copper transport proteins. The
as well as to look for Cd in spinach.
those proteins that have been crystallized.
ability to simultaneously image multiple
Plants can take up Cd and other toxic
For all the work that has gone into studymetals is critically important to the study,
metals from soil, potentially reducing plant
ing metalloproteins, there is still much to
she says. “We’re specifically interested in
growth and contaminating the food supply.
learn, Adams says, pointing again to the
what happens with copper, but we also see
Researchers suspected that Cd was displacone-third of the genome about which “we
big changes in other metals,” Finney says.
ing other metals in enzymes, rendering
don’t have much of a clue.” It took roughly
“Their homeostasis is very intertwined.”
them nonfunctional, but they didn’t know
100 years to get the knowledge that we
In yet another approach to metal dewhich proteins Cd affected. Jakubowski
have now, he notes. How long it will take to
tection, researchers at Delft University
and colleagues analyzed protein extracts
close the gap, even with new, high-throughof Technology, in the Netherlands, take
of spinach leaves and found that Cd mainly
put proteomics, remains to be seen. ◾
advantage of an on-site nuclear reactor to
substitutes for Mg in the active site of ribuenrich protein samples with rare nuclear
Reprinted from C&EN, Dec. 12, 2011
WWW.C E N- ONLI NE .ORG
20
JANUARY 20 1 2
C&EN TA L KS W ITH
MICHAEL MARLETTA
Incoming SCRIPPS PRESIDENT discusses move to administration, challenges for research institute
JYLLIANKEMSLEY, C&EN WEST COAST NEWS BUREAU
Marletta’s leadership style is one of
inclusion without bureaucracy. He appreciwill take the reins as president of Scripps
ates Scripps’s flat organization and likes to
Research Institute, a private, nonprofit retreat meetings “kind of like a group meetsearch organization focused on biomedical
ing,” he says, with people presenting their
research. Excited to lead the organization,
latest results or problems and getting input
Marletta nonetheless will be challenged to
from the crowd on the next steps to take.
maintain funding for the institute as its tra“I don’t have the market cornered on good
ditional sources of money tighten their belts.
ideas,” Marletta says, but “there’s still one
Marletta, 60, moves to Scripps after a
person that’s going to make decisions,” he
30-year academic career that saw him serve
adds.
as a professor at several universities, most
Looking ahead, Scripps must keep its
recently in the chemistry department at the
emphasis on fundamental research to unUniversity of California, Berkeley.
derstand biology, with a focus on human
At Scripps, Marletta succeeds Richard A.
health and disease, Marletta says. His chalLerner, who served as president for more
lenge will be to ensure the institute has the
than two decades. Lerner tried to recruit
funding to retain current faculty members
Marletta to join Scripps’s faculty several
and recruit new ones, as well as to provide
times over many years, “but I truly liked
the instruments and other infrastructure
being at a big, complicated university,”
that enable Scripps scientists to do topMarletta says. “I enjoyed the full spectrum
Marletta
notch research.
of things I was doing, including teaching
Scripps has historically had two main
undergraduates.”
streams of funding: federal grant money, principally from the NaAnd when he chaired the Berkeley chemistry department,
tional Institutes of Health, and agreements with pharmaceutical
Marletta found that he also enjoyed leading people beyond his lab
companies that gave Scripps unrestricted funds in exchange for first
group. “When I think I know what every day is going to look like,
when the challenges in front of me are only ones that I create, that
rights to capitalize on Scripps’s discoveries. Scripps’s budget for 2012
is when I get a little bored,” he says.
includes about $317 million from grants, $30 million from pharmaceuAfter stepping down as department chair in 2010, Marletta
tical companies, and $44 million from other sources, Marletta says.
started exploring job options in administration, but he had some
requirements. One was that he could continue to maintain his lab
JUST LIKE other federally funded scientists, however, Scripps
group and research into the catalytic and biological properties of
researchers are affected by government budget cuts, Marletta says.
redox enzymes. “That’s an exciting piece that I can’t imagine doing
And pharmaceutical companies now want agreements that are
without,” Marletta says.
more targeted to specific research, he says.
The other involved family. His son is in 11th grade, and Marletta
Going forward, Marletta has his eyes on other sources of funddidn’t want to move him during his final years of high school. Any
ing. “Private philanthropy is clearly one of the most important and
organization hiring Marletta had to agree to allow him to commute
immediate solutions to our financial stability,” he says, and he has
between work and Berkeley.
already been meeting with potential donors.
Scripps accepted those conditions; Lerner, in fact, has kept a
He also aims to focus on improving the return on Scripps’s intelsuccessful research program going while serving as president, and
lectual property. As agreements with pharmaceutical companies
the president’s office connects to adjacent lab space.
expire and Scripps regains control over when, how, and with what
Marletta started at Scripps part-time as president-elect on July 1,
return its discoveries are translated into medical therapies, licensspending a couple of days a week at Scripps headquarters in La Jolla,
ing income “will be an important part of our financial picture,” MarCalif., or its second campus in Jupiter, Fla. Come January, his reletta says. He acknowledges that the effort will require institutional
search group will move to La Jolla. Marletta plans to spend weekdays
investments in technology transfer and translational infrastructure.
at one of Scripps’s locations and weekends in Berkeley.
Marletta says that he’s more excited now about
As he has gotten to know the Scripps organization and
the opportunity to lead Scripps than he was when he
people over the past few months, Marletta says, what has Research is
learned that he would get the job. “It’s not like everysurprised him is how enthusiastic the faculty and staff all
thing is wonderful. There are challenges, but that’s why
seem to be about his arrival. Given Lerner’s long tenure, “an exciting
I took the job,” he says. “But the people that I’ve met
piece that I
there has been some uncertainty about what the leaderand how they feel about the place and what they’re docan’t imagine ing, that makes my excitement level higher.” ◾
ship change may bring, “but it hasn’t taken on any tone
doing without.” Reprinted from C&EN, Dec. 19, 2011
of negativity that I’ve seen,” Marletta says.
DAVID FREEMAN /SCRIP PS RESEARCH IN ST IT U T E
ON JAN. 1, 2012, Michael A. Marletta
WWW.C E N- ONLI NE .ORG
21
JANUARY 20 1 2
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