JU N E 1 , 201 5

MONEY TALKS
NSF survey details academic
funding sources P.24
OPIATES FROM YEAST
Concerns raised over
engineered strain P.31

FILLING IN
THE DETAILS
A picture of how to treat
Alzheimers disease is
starting to emerge P.11

PUBLISHED BY THE AMERICAN CHEMICAL SOCIETY

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VOLUME 93, NUMBER 22

JUNE 1, 2015

BUSINESS
16
18

CONCENTRATES
GODAVARI BIOREFINERIES GIVES BACK

Indian biochemical firm stresses sustainable

production and improving local communities.
20

SAFC EXPANDS FOR BIOPHARMA

Sigma-Aldrichs custom manufacturing

arm looks ahead while awaiting
acquisition by Merck KGaA.
22

IMPROVING DRUG QUALITY

AND SAFETY

C&ENs Rick Mullin argues that FDA

should consider subjecting drug
companies with a demonstrated
quality culture to less scrutiny.

COVER STORY

ALZHEIMERS
DRUG
DEVELOPMENT
Positive data and better tools are
reinvigorating the field. PAGE 11
QUOTE
OF THE WEEK
Tribology
tends to be
a neglected
subject.

CONCENTRATES
ACADEMIC R&D SPENDING IN 2013

NSF data show a modest upward trend from past

years and a continuing focus on life sciences.

SCIENCE & TECHNOLOGY

27
29
30

CONCENTRATES
FROM THE SCENES
NEW FRICTION MODELS GAIN TRACTION

Rubber scientists keep rolling toward better tire

simulations by studying chemical properties.

NEWS OF THE WEEK

5

HELLO, SLEEPING BEAUTIES

Chemistry papers rank high among once-obscure

studies that much later racked up citations.
6

SHAPE-MEMORY MILESTONE

Metal alloy can be deformed millions of times and

still bounce back to its original shape.

BO N. J. PERSSON,
STAFF RESEARCHER,
JLICH RESEARCH
CENTER PAGE 30

GOVERNMENT & POLICY

23
24

PRINTING SKIN IN 3-D

P&G funds research to go from in vivo to in vitro

testing of its consumer products.
7

MOLECULAR ELECTRONICS ADVANCE

Improved single-molecule diode pushes a new

frontier for microelectronics.

23

CHINESE FIRMS SNAP UP AMBRX

Consortium can now access biotech firms novel

technology for making antibody-drug conjugates.
8

TRADE BILL PASSES SENATE

Move raises hopes for Pacific trade pact, but a

tough fight awaits in House of Representatives.
8

31

HEALING THE OZONE LAYER

New models show that international agreement

on halocarbons has decreased ozone depletion.
9

FOUNTAIN OF YOUTH QUESTIONED

THE DEPARTMENTS

GOOD VIBES FOR R&D TAX CREDIT

2
3
33
34

House of Representatives passes bill to make the

credit permanent; industry cheers.

COVER: Will Ludwig/C&EN

Study contradicts provocative theory that protein

found in blood of young mice can reverse aging.
9

MORPHINE FROM MICROBIAL MACHINES

Security concerns arise as a collaboration homes

in on engineering morphine-making yeast.
LETTERS
EDITORS PAGE
ACS COMMENT
OBITUARIES

CENEAR 93 (22) 140 ISSN 00 0 9-2347

36
36
40

ACS CAREER TIPS

CLASSIFIEDS
NEWSCRIPTS

LETTERS

ACOUSTIC THERAPY
THE PROMISING EFFECTS of ultrasonic

wavesafter harnessing the action of a

fluorinated contrast agenton amyloid
plaque clearance are doubtless stimulating
and of potential therapeutic value (C&EN,
March 16, page 5). But the article and the
original research ignore the physicochemical corner highlighted in other recent research, which unveils a complex issue.
Amyloid fibrils undergo breakage after
long irradiation times, resulting in shorter
chains of uniform size. However, fibril formation is also triggered at short irradiation
times by a reagglomeration step similar to
the one found in ultrasound-induced nucleation, and the process is pH-dependent
(Nature 2005, DOI: 10.1038/nature03986;
Proc. Natl. Acad. Sci. USA 2009, DOI:
10.1073/pnas.0901422106).
Molecular dynamics simulations also
shed light on mechanistic details. Fibril
disruption occurs at negative pressures
as bubbles are created and then undergo
collapse, mainly near the hydrophobic

EXCLUSIVE

residues of the transmembrane region.

Fragmentation of shorter amyloids will require longer irradiation times because the
number of peptide residues is insufficient
to serve as bubble nuclei (J. Am. Chem. Soc.
2014, DOI: 10.1021/ja502749f ).
It is true, as noted, that focused ultrasound may disrupt the blood-brain barrier,
but minor damage has been observed at
the kilohertz range in monkey models
(Cancer Res. 2012, DOI: 10.1158/0008-5472.
can-12-0128). Certainly, extra studies will
be needed, but chemistry with sound waves
should be more than a passive spectator.
I like the anonymous aphorism that most
key discoveries invariably emerge as something new from the past.
Pedro Cintas
Badajoz, Spain
REMEMBERING A BELOVED
PROFESSOR
IM WRITING IN RESPONSE to the

obituary of Hans H. Baer (C&EN, March 9,

page 50). I was one of Baers first-year or-

EXCLUSIVE

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Q U A N TA B I O D E S I G N . C O M

CEN.ACS.ORG

I READ WITH SOME amusement the let-

ter from John Neumeyer regarding the

use of acronyms in the literature without
identifying their meaning (C&EN, March
30, page 2). I used to believe that any combination of letters used to identify something was an acronym until a boss of mine
pointed me to the dictionary definition,
which says the letters must form something that can be pronounced as a word. All
of Neumeyers examples would meet this
criterion except his last: GMO.
Jon Green
Morrisville, N.C.

CHEMICAL & ENGINEERING NEWS

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ganic chemistry students at the University

of Ottawa in the late 1980s. His knowledge
and warmth in teaching organic chemistry
was so deeply rooted that it fostered a genuine environment for learning. His contributions in the classroom have resulted
in the training of many highly technical
individuals in science, engineering, law,
and medicine. He was a deeply respected
and adored professor and will be missed
dearly.
A. Victoria Nawaby
Grand Prairie, Texas

JUNE 1, 2015

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Copyright 2015, American Chemical Society
Canadian GST Reg. No. R127571347
Volume 93, Number 22

GUEST EDITORIAL

Proteins Gone Bad

The following is a guest editorial by Rudy M.
Baum, former editor-in-chief of C&EN.
STANLEY B. PRUSINER has a chip on his

shoulder. Despite his 1997 Nobel Prize for

the discovery of prions, it is clear that he
still bears psychic scars from the disbelief,
often bordering on scorn, that greeted his
1982 announcement that he had isolated
the agent that causes the neurodegenerative disease scrapie in sheep and that his
data indicated that this infectious, self-replicating agent consisted only of protein and
did not appear to contain any nucleic acid.
No DNA or RNA to encode its proteins.
Clearly heretical. Clearly, in many scientists minds, dead wrong.
I bumped into Prusiner at the annual
National Academy of Sciences garden party
held in late April. I reintroduced myself
weve met a couple of times over the years
but never established any kind of a relationshipand I recalled to him that I was sitting on the floor of the hallway outside his
University of California, San Francisco, lab
during the impromptu press conference in
February 1982 at which he discussed the discovery of prions after a story on his research
had appeared in the San Francisco Chronicle.
Thats not possible, he laughed. You
were a baby!
No, I replied, I was a 29-year-old reporter
just finishing up my first year as C&ENs
West Coast correspondent. I wrote the lead
News of the Week story on Prusiners work
(C&EN, March 1, 1982, page 4) based on
that press conference. Prusiner published
the prion hypothesis and the data that
supported it a month later in Science (DOI:
10.1126/science.6801762).
Its well-known that Prusiner doesnt
like and wont talk to reporters. He feels
hes often been treated badly by reporters, especially science writer Gary Taubes,
who wrote a less-than-flattering profile of
Prusiner in a 1986 issue of Discover.
At the garden party, Prusiner told me
that he had published a book in 2014,
Madness and Memory: The Discovery of
PrionsA New Biological Principle of Disease. Hed written it, he said, because he
didnt trust any other scientists or reporters to get the story of his research right.
After the garden party, I downloaded
Madness and Memory to my iPad and read

it in two days. It is a remarkable book, both

an autobiography and an account of four decades of scientific research that is reminiscent of James Watsons The Double Helix.
In the book, Prusiner provides a clear and
accessible account of the research in his lab
and others that led to the notion that prionsmisfolded versions of naturally occurring proteins of unknown functioncause a
wide range of neurodegenerative diseases.
Prusiners discovery of prions had implications that went far beyond what even he
could have imagined in the early days of his
research. His obsession with the etiology
of an obscure neurodegenerative disease
in sheep would, over three decades, lead to
an entirely new perspective on neurodegenerative diseases, many of which exact
a devastating toll on humans. Alzheimers
disease, Parkinsons disease, amyotrophic
lateral sclerosis (Lou Gehrigs disease), bovine spongiform encephalopathy (mad cow
disease), and chronic traumatic encephalopathy (CTE), to name a few, all may have
at their root links to prionlike misfolding of
proteins in the brain (see page 11).
But Prusiners personalitybrash, confident, more than a bit pushycoupled
with the seeming outlandishness of his prion hypothesis, engendered a deep-seated
hostility among many scientists, who insisted for years that some kind of virus was
the cause of scrapie and related diseases,
and some journalists like Taubes, who
spent more than a decade raising questions
about Prusiners science and integrity.
In Madness and Memory, Prusiner gets
at how science is really done. What comes
through is the importance of relationships
both friendships and productive collaborations as well as enmity and bare-knuckle
competition. The Prusiner who emerges
from Madness and Memory is not unlike
many other brilliant scientists Ive gotten to
know in my career. He is at times warm and
engaging, prickly, charming, thin-skinned,
charismatic, insecure, and vindictive.
Today, recognition of Prusiners contributions to neuroscience is secure. With
Memory and Madness, it would seem
that Prusiner has had the last word on the
subject.
Rudy M. Baum
Editor-at-large

Views expressed on this page are those of the author and not necessarily those of ACS.
CEN.ACS.ORG

JUNE 1, 2015

news of the week

JUNE 1, 2015 EDITED BY WILLIAM G. SCHULZ & SOPHIA L. CAI

SLEEPING BEAUTIES
WAKE UP
CITATIONS : Chemistry papers rank
high among those that emerge from
obscurity years after publication
TS THE DREAM of the underappreciated scientist.

A research paper that barely made a blip soon after

its publication is rediscovered decades later and recognized with citations in thousands of other published
science studies.
A new analysis of these so-called sleeping beauty
publications by researchers at Indiana University,
Bloomington, has found that they are not as rare as once
thought (Proc. Natl. Acad. Sci. USA 2015, DOI: 10.1073/
pnas.1424329112). And chemistry is a top producer of this
type of paper. Seven of the top 15 sleeping beauty studies
identified were published in chemistry journals.
The number of citations a paper gets has risen in importance as research institutions, individuals, and publishers increasingly use them to appraise the quality of
science. They rarely look for citations beyond the first
few years after a papers publication, however.
In contrast, sleeping beauties go decades with little
recognition before they are awakened with a wave of

citations. The phenomenon of a long-dormant paper

reemerging has long been considered rare.
The Indiana researchers were the first to search for
sleeping beauties in a wide swath of papers, examining
22 million citations across all science disciplines, explains Mark Newman of the University of Michigan, who
peer reviewed the paper for PNAS. They found that most
research papers follow a standard course: They are cited
the most in the years immediately following publication,
then citations gradually fade away.
But some papers emerge with a spike in citations decades later. For example, a 1906 Zeitschrift fr Physikalische Chemie paper that modeled adsorption now helps
clean up metals and pharmaceuticals from drinking
water; it started getting numerous citations in 2002.
The scientists still dont know exactly what wakes a
sleeping beauty or how to predict which papers will rise
from obscurity. A paper could contain a novel idea that
takes a while to become accepted, says Peter J. Stang,
editor-in-chief of the Journal of the American Chemical Society, which published two of the top 15 sleeping
beauties identified in the new study. Or perhaps a
method or idea that is old hat in one discipline suddenly rises to prominence in a new field, he suggests.
Chemistrys prominence among sleeping beauties
speaks well for the breadth and depth of chemistry,
Stang says. Chemistry has a lot of paradigm-shifting
ideas. It has impact and implications for a lot of different
disciplines.ANDREA WIDENER & MITCH GARCIA

RESEARCH AWAKENING
Seven chemistry papers are among the top 15 science papers not heavily cited until decades after publication
RANK IN
TOP 15

DESCRIPTION/MODERN-DAY APPLICATION

AUTHOR(S)

REFERENCE

PUBLICATION
YEAR

"AWAKENING"
NO. OF
YEAR
CITATIONS

Models adsorption of molecules from

solution/removal of metals and drugs from
drinking water

H. Freundlich

Z. Phys. Chem. 57, 385

1906

2002

2,685

Synthesis of graphitic oxide/production of

precursor to graphene

W. S. Hummers,
R. E. Offeman

J. Am. Chem. Soc.

DOI: 10.1021/ja01539a017

1958

2007

8,379

Describes wetting on porous surfaces/theory

behind superhydrophobic surfaces

A. B. D. Cassie, S. Baxter

Trans. Faraday Soc.

DOI: 10.1039/tf9444000546

1944

2002

4,523

Study of growth of gold colloids/design of

gold nanoparticles

J. Turkevich,
P. C. Stevenson, J. Hillier

Discuss. Faraday Soc.

DOI: 10.1039/df9511100055

1951

1997

2,477

Study of various emulsifiers/preparation of

surfactant-free emulsions

S. U. Pickering

J. Chem. Soc. Trans.

DOI: 10.1039/ct9079102001

1907

1998

1,083

Describes wetting of solid surfaces/theory

behind superhydrophobic surfaces

R. N. Wenzel

Ind. Eng. Chem.

DOI: 10.1021/ie50320a024

1936

2003

4,427

11

Reviews theory of solid and liquid evaporation

and condensation/theory behind adsorption
of solutes such as drugs and proteins

I. Langmuir

J. Am. Chem. Soc.

DOI: 10.1021/ja02268a002

1916

2003

2,813

NOTE: Papers as ranked by a beauty factor, a measure of the rate at which a paper rose from obscurity. Citations as of May 26, 2015. SOURCES: Proc. Natl. Acad. Sci. USA, Web of Science

CEN.ACS.ORG

JUNE 1, 2015

NEWS OF TH E WEEK

AN ALLOY WITH A
GREAT MEMORY

Y ADDING A TOUCH of cobalt to an alloy of

titanium, nickel, and copper, an international

team of researchers has come up with a shapememory alloy film that can be deformed at least 10 million times and still snap back to its original shape. The
finding represents a remarkable improvement on previous shape-memory alloys, which, at best, could
withstand only a thousand deformations before succumbing
to structural failure.
Shape-memory
alloys, as their name
implies, possess the
ability to return to
their original shape
after being stretched or
squished. Nickel-titanium
shape-memory alloys, for
example, are used as stents to
open blood vessels and as orth-

P&G LOOKS TO
ARTIFICIAL SKIN
BIOPRINTING: Firm explores

3-D printing of tissue to

replace animal testing

ROCTER & GAMBLE, the worlds largest pro-

ducer of household products, will help fund a

five-year research project to develop a commercial process for making three-dimensional printed
skin tissue. P&G wants to be able to
test the efficacy and toxicity of its
new products, including those for
beauty care, on artificial skin rather
than animals.
The P&G research project is in
association with the Singaporean
governments Agency for Science,
Technology & Research (A*STAR).
In the past week, A*STAR has invited scientists from Singapores
more than 25 research institutes to
apply for grants associated with the
LORAL

Cosmetics and
other firms hope
to use 3-D printing
of skin for product
testing. Shown
is LOrals skinfarming operation.

CEN.ACS.ORG

XIAN CHEN AN D RICHARD JAMES

Illustration shows
a theoretical
rendering of a
shape-memory
alloys crystalline
forms. The red
represents one
form, while the
other colors
represent variants
of another form.

MATERIALS SCIENCE: Titanium,

nickel, copper, and cobalt combo
withstands millions of shape changes

odontic wires. Other applications, however, have been

limited because this and other shape-memory alloys
tend to deform permanently or break apart after a certain number of deformations. The new alloy film shows
remarkable resilience, returning to its original shape
even after being deformed a record-breaking number of
times (Science 2015, DOI: 10.1126/science.1261164).
The alloys were designed to have improved properties, but we were surprised to discover this superhigh
fatigue life, says the University of Marylands Manfred
Wuttig, who spearheaded the work along with Eckhard
Quandt of the University of Kiel, in Germany. When
you do something like this, you expect to improve by a
factor of two or a factor of 10. This improvement was
astounding, Wuttig adds.
The alloy, which has the formula Ti54.7Ni30.7Cu12.3Co2.3,
seems to achieve its fatigue-defying ability by switching
easily from one crystalline form to another and back
again. The films contain Ti2Cu precipitates embedded in
the base alloy that act as sentinels, easing the transformation between crystalline forms.
This alloy shows incredible reversibility under the
most demanding conditions people can imagine, comments Richard D. James, an expert on shape-memory
alloys at the University of Minnesota, Twin Cities.
Whats also interesting to me is that theres a strategy
buried in there for making lots of phase transformations
reversible like this, James adds. Its probably the most
important thing to come along in shape-memory alloys
since the invention of NiTi.BETHANY HALFORD

project. P&G has not disclosed how much money it will

spend on the skin project.
To create artificial skin, a 3-D printer would deliver
skin cells and hydrogel, layer by vertical layer, into patterns that promote skin-tissue growth. The project is
just one component of a $44 million, five-year research
program between P&G and A*STAR designed to accelerate innovation at the household products giant. The
program expands on a research collaboration between
the two organizations that began in 2010.
P&G joins a handful of other consumer goods firms
seeking to develop 3-D bioprinting systems to replace
animal testing. Europe banned testing of cosmetics on
animals in 2013, and countries elsewhere in the world
are also pushing for alternative testing methods.
French cosmetics firm LOral recently agreed to
a tie-up with San Diego-based 3-D bioprinting firm
Organovo to develop a process for making printed skin
tissue. Organovo already offers printed liver tissue for
use in drug toxicity testing.
At LOrals skin-farming operations in Lyon,
France, technicians break down skin tissue from plastic
surgery patients into cells. They then feed the cells nutrients until they grow into skin patches 0.5 cm across
and up to 1 mm thick. LOral hopes that 3-D printing
will help it improve the precision, speed, and scale of its
skin-farming activities.ALEX SCOTT

JUNE 1, 2015

A SINGLE-MOLECULE
DIODE THAT WORKS
MOLECULAR ELECTRONICS:

Simple approach yields highperforming circuit element

ORTY YEARS AGO, scientists theorized that a

single molecule could function as a diodean

electronic circuit element that allows current to
flow in one direction but not the other.
Now, a team led by Latha Venkataraman and Luis M.
Campos of Columbia University and Jeffrey B. Neaton
of Lawrence Berkeley National Laboratory has demonstrated a simple way to make low-voltage, singlemolecule diodes that perform extremely well (Nat.
Nanotechnol. 2015, DOI: 10.1038/nnano.2015.97). In
fact, their rectification ratioa measure of how much
current flows in one direction across the diode versus
the otheris nearly 50 times as high as earlier designs.
In the ongoing push to make ever smaller and more
powerful circuitry, researchers have demonstrated
that various types of basic circuit elements crucial to
todays electronics can be miniaturized to the point
that their functions are controlled by a single molecule.
But single-molecule versions of diodes had remained
elusive: Many had been made, but they tended to work
poorly.
Those previous efforts had typically relied on asymmetric molecules featuring electron donor and acceptor
moieties to control the direction of current flow. These
diodes often had low rectification ratios and required a
substantial voltage push to work at all. In contrast, the
Columbia-Lawrence Berkeley team used symmetric
molecules, thiophene dioxide oligomers, and instead
induced asymmetry at the diodes electrodes.

Specifically, the researchers

suspended an oligomer between
the tiny gold tip of a scanning tunneling microscope and a much
larger gold substrate. By immersing the molecule-electrode
junction in an ionic solution of
propylene carbonate, a polar
solvent, the team caused positive
and negative ions to accumulate
at the electrodes, thereby creating an asymmetric chemical
environment around the circuit.
Under those conditions, the diode
worked extremely well. When the
team replaced the polar solvent
with an apolar one, the device did
not work.
Noting that the data show
the rectification very clearly,
Northwestern Universitys Mark
A. Ratner says, The results are
impressive. It was Ratner together with Arieh Aviram who first
proposed single-molecule rectification on theoretical grounds 40
years ago. Ratner points out that
this methods reliance on a liquid
FLOW CONTROL A single-molecule
would likely cause challenges
diode consisting of a thiophene dioxide
when it comes to device applicaoligomer suspended between two
tion, however.
gold electrodes (top and bottom) in
Gemma C. Solomon, a mocontact with an ionic solution provides
lecular electronics specialist at
unprecedented control of current ow.
the University of Copenhagen,
C is blue, S is gold, and O is red.
notes that part of the strength of
this approach is that it does not require control over
the orientation of the molecule in the junction. That
simplification widens the scope of applicability of this
approach, she says.MITCH JACOBY

ACQUISITION Chinese consortium seeks Ambrxs bioconjugates pipeline

A Chinese consortium has agreed to
acquire Ambrx, a San Diego-based
biotech firm that harnesses nonnative
amino acids to create drugs known as
bioconjugates.
The consortium is made up of several prominent Chinese firms including
Shanghai Fosun Pharmaceutical, one of
Chinas largest drugmakers; WuXi PharmaTech, the worlds largest drug contract
research organization; and China Everbright, an investment firm controlled by
the Chinese government. Terms of the
deal were not disclosed.
A spin-off from the California labs of

Scripps Research Institute chemist Peter

G. Schultz, Ambrx develops antibodydrug conjugates and other bioconjugates.
Several of its drug candidates are undergoing clinical trials. Its pipeline also
includes, at the preclinical stage, a therapeutic protein for weight management.
Fosun says the acquisition will
strengthen its own drug discovery efforts. WuXi expects that access to Ambrx
technology will help it better serve customers worldwide.
Jimmy Wei, a partner in the Shanghai
office of the venture capital firm Kleiner
Perkins Caufield & Byers, says it makes

CEN.ACS.ORG

JUNE 1, 2015

sense today for Chinese firms to buy assets overseas. The [market] valuation
of companies in China is far higher than
in Europe or the U.S., he says. In recent
months, this financial strength has led
many Chinese players to look for Western
biotech firms they could acquire, he adds.
Ambrx has ongoing research pacts
with major drug companies that have collectively provided it with more than $200
million in funding, but it has been looking
for additional funds for some time. It tried
unsuccessfully last year to raise up to $70
million by listing on the NASDAQ stock
exchange.JEAN-FRANOIS TREMBLAY

VENK ATARAMAN GROUP/COLUMBIA U

NEWS OF TH E WEEK

NEWS OF TH E WEEK

TRADE BILL FACES

FIGHT IN HOUSE

rules, among other things, for the U.S. and 11 other nations, which together account for about 40% of the global economy. Negotiations are nearly complete after five
years of wrangling. Were very much in the endgame,
says U.S. Trade Representative Michael Froman.
Participating nationsJapan, Australia, Brunei,
Canada, Chile, Malaysia, Mexico, New Zealand, Peru,
Singapore, and Vietnamhave been reluctant to conclude talks on the trade pact without guarantees that
U.S. lawmakers wont change it.
Without TPA in place, our negotiators will not have
the tools needed to conclude the strongest possible
trade agreements, says the American Chemistry Council, a chemical industry trade association. In our view,
that makes TPA a necessity.
The group estimates that gaining unfettered access to
growing markets in the Pacific Rim has the potential to
boost U.S. chemical exports by $1.2 billion per year.
But the trade deal is controversial. Most House Democrats are expected to vote against the TPA measure
because they fear the U.S. will lose manufacturing jobs
to lower-wage countries if the Pacific pact is approved.
Consequently, Republicans will have to provide the bulk
of the 217 votes needed for passage.
But at least 40 conservative House Republicans,
wary of giving Obama additional authority, could also
oppose the legislation, making the outcome highly
unpredictable.GLENN HESS

LEGISLATION: Senate passes measure to

boost Presidents negotiating power

President Barack Obama the authority to conclude a landmark Pacific trade pact sets the stage
for what is expected to be a fierce battle in the House of
Representatives later this month.
The legislation, which the Senate passed last week
62-37, would give Obama so-called trade
promotion authority (TPA). It would allow
the White House to submit trade agreements to Congress for yes-or-no votes
without any amendments.
Chemical manufacturers strongly back
both the bill (H.R. 1314) and the underlying
trade dealthe Trans-Pacific Partnership.
The chemical industry ranks as one of the
nations top export sectors and stands to
profit from the Pacific agreement.
The pact would lower tariffs and set
environmental and intellectual property
SHUTTERSTOCK

Obamas industrybacked bid to

expand trade faces
formidable political
opposition.

HE SENATES APPROVAL of legislation granting

EARTHS OZONE
HOLE IS HEALING
ATMOSPHERIC SCIENCE: Model shows

that the Montreal protocol reversed

ravaging effects of halocarbons

AVING EARTHS protective stratospheric

ozone layer from destruction was a major environmental crusade 30 years ago, leading to the
regulation of halocarbons and other ozone-depleting
substances. But what would Earth look like today if the
1987 Montreal Protocol on Substances That Deplete
the Ozone Layerthe international agreement that restricted halocarbon refrigerants, solvents, and aerosolcan propellantshad not been put into force?
The grim outcome has been predicted with
an advanced atmospheric chemistry model by
researchers led by Martyn P. Chipperfield of the
University of Leeds, in England (Nat. Commun.
2015, DOI: 10.1038/ncomms8233). The team found
that the Antarctic ozone hole would have grown
by an additional 40% by 2013. Their model also
predicts that continued use of ozone-depleting
substances would have thinned the ozone layer
elsewhere around the globe by about 15%. And
CEN.ACS.ORG

NAT. COMMUN.

The Antarctic ozone

hole with (top) and
without (bottom)
the Montreal
protocol. Values are
in dobson units with
greater depletion in
blue and purple.

Arctic ozone holes would have become a regular occurrence. The Leeds model shows that the Antarctic ozone
hole is instead on track to disappear by about 2050.
It is indeed very rewarding to read that the Montreal protocol has already had a positive effect on our
planet, says Mario J. Molina, a chemistry professor at
the University of California, San Diego.
In 1974, Molina and F. Sherwood Rowland predicted
how halocarbons could chew away Earths protective
ozone layer by disrupting the sunlight-driven chain reactions that form ozone. Their prediction came true when
an ozone hole was first reported over Antarctica in 1985.
For people, the danger from ozone layer depletion
is increased exposure to the suns damaging ultraviolet radiation. Ozone depletion also contributes to
global warming.
With the Montreal protocol in place, halocarbon
atmospheric concentrations peaked in 1993 and have
since declined. The 1995 Nobel Prize in Chemistry
recognized Molina, Rowland, and Paul J. Crutzen (who
worked on the role of nitrogen oxides) for their contributions toward averting an environmental catastrophe.
The ozone story shows that once an environmental
problem is identified it is possible for the scientific
community to develop the necessary evidence and
work together with decision-makers in government to
address the challenge, Molina tells C&EN. That gives
me hope that eventually issues such as climate change
will be successfully addressed as well.STEVE RITTER

JUNE 1, 2015

NEWS OF TH E WEEK

REPRODUCIBILITY: Study
contradicts previous research on
mouse muscle rejuvenation

NEW STUDY contradicts a provocative theory

that a protein found in young blood reverses

some aging processes in older mice.
Scientists were excited by the discovery of a potential
age-mitigating substance, reported in the past few years
by Amy Wagers and colleagues at Harvard University.
These researchers improved the heart, brain, and muscle function of elderly mice by attaching the rodents
circulatory systems to those of young mice (C&EN,
May 13, 2013, page 41, and May 12, 2014, page 29).
The Harvard scientists went on to identify protein
growth differentiation factor 11 (GDF11) as the source
of the rejuvenation, reporting that levels of this protein
decreased as mice aged and that giving them doses of
GDF11 improved muscle and nerve cell growth.
But the Harvard team may have been fooled by
their immunoassays, says a Novartis group that also
researches aging. That team reports that GDF11 levels
do not decrease in aging mice (Cell Metab. 2015, DOI:
10.1016/j.cmet.2015.05.010). Whats more, the muscles
of mice given doses of GDF11 deteriorate, rather than
improve says team leader David Glass, executive director of the muscle diseases group at Novartis Institutes
for BioMedical Research in Cambridge, Mass.
The Novartis researchers say they were prompted
to test whether GDF11 has rejuvenating powers because the protein myostatin, which is almost identical to GDF11, has long been known to inhibit skeletal
muscle growth. In fact, Novartiss drug bimagrumab,
which is currently in clinical trials, is an antibody de-

signed to treat muscle wasting by blocking myostatin.

On the basis of their experiments, Glass and his
group conclude that the Harvard researchers tests
could not distinguish between myostatin and GDF11.
Indeed, the lack of specificity among antibody reagents
used in such immunoassays is an epidemic problem
in biological research, scientists are realizing (C&EN,
Feb. 23, page 39). The Novartis team also developed a
GDF11-specific immunoassay and found that GDF11 did
not decrease, and possibly even increased, as mice aged.
These disparate results are causing a dustup among
researchers. In a
commentary accompanying the Novartis
paper, Caroline E.
Brun and Michael A.
Rudnicki, from the
University of Ottawa,
bluntly state, Clearly, like the mythical
fountain of youth,
GDF11 is not the longsought rejuvenation
factor.
But Wagers notes
Scientists debate whether
that the Novartis
a protein, GDF11, can
group used very difrejuvenate elderly mice.
ferent methodologies than her group,
including the GDF11 dosage administered, in its experiments. She also says that GDF11 may exist in a number of
different forms, some not detectable by certain assays.
Nevertheless, Wagers says, we remain convinced
that at least one form of GDF11 declines in blood with
age, and that maintaining GDF11 levels in an appropriate physiological range is essential for muscle health.
Her lab is gearing up for the next salvo. We are looking forward to addressing the differences in the studies
with additional data very soon, she says.ELIZABETH
SHUTTERSTOCK

PROTEINS ROLE IN
AGING DISPUTED

WILSON

LEGISLATION Industry cheers passage of House bill to make permanent R&D tax credit
Drugmakers, chemical manufacturers,
and other businesses are welcoming a
May 20 vote by the House of Representatives to revive the tax credit for corporate
research and development. The move
would make the credit a permanent feature of the federal tax code.
The bill now goes to the Senate.
The R&D credit is one of the most
popular of the dozens of temporary tax
breaks that Congress routinely renews
every year or two, often retroactively
at the end of the session. The legislation (H.R. 880) approved by the House

would reauthorize the R&D tax credit on

a permanent basis, retroactive to Dec. 31,
2014. The measure would also increase
the value of the credit from 14% to 20%.
We strongly support making the R&D
tax credit a permanent part of the tax
code, not subject to yearly extensions, as
it has played a vital role in supporting the
search for cures and breakthrough medicines, says James C. Greenwood, CEO of
the Biotechnology Industry Organization
(BIO), a trade association.
Many specialty chemical companies
also rely on the R&D tax credit to help

CEN.ACS.ORG

JUNE 1, 2015

them remain competitive in the global

marketplace, says William E. Allmond IV,
a vice president at the Society of Chemical Manufacturers & Affiliates, an industry trade group. One of our members
told House staffers that 20% of their
workforce is involved with R&D, and 8 to
10% of company sales are used for R&D,
Allmond says.
President Barack Obama has threatened to veto H.R. 880, arguing it would
increase the federal deficit by more
than $180 billion over a decade.GLENN
HESS

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COVER STORY

PLAQUE ATTACK

ALZHEIMERS

NEXT CHAPTER
Early data for BIOGENS ADUCANUMAB are bolstering a field that
researchers say is finally heading in the right direction

Biogens
aducanumab
significantly
reduced the
amount of
amyloid (in red)
in the brains
of people with
early-stage
Alzheimers. Left,
pretreatment.
Right, after 54
weeks of the
drug.

LISA M. JARVIS, C&EN CHICAGO

TS NOT OFTEN that drug company executives will

BIOGEN

sing the praises of a competitors drug. But at a recent

neuroscience forum in Boston, nearly every suit on
the dais had good things to say about aducanumab, an
Alzheimers disease treatment being developed by Biogen.
The drug is an antibody that binds to amyloid-, the
protein that aggregates into the telltale plaques that coat
the brains of people with Alzheimers. In a small study,
it demonstrated something that to date has evaded the
field: It showed that removing amyloid plaques from the
brain could slow down progression of the disease.
CEN.ACS.ORG

11

JUNE 1, 2015

In a field plagued by failures, the possibility of a winner is making the entire

Alzheimers drug pipeline look better.
Maybe the disease, the most common
form of dementia, is not a dead end for
drug developers after all. As important,
success for aducanumab would prove
the amyloid hypothesisthe longstanding theory that the protein is the
main driver of the disease.
The data from the aducanumab
study are a sign that if you do things
right, you appear to be able to move
the dial, says Luc Truyen, head of neuroscience external affairs at Janssen,
the pharmaceutical arm of Johnson &
Johnson. That lifts everybodys boat.

COVER STORY

The data come at a time when everyone

could use a lift. Since 2002, 356 drugs have
entered human tests to treat Alzheimers,
according to Bernard Munos, founder of the
InnoThink Center for Research in Biomedical Innovation. Of those, only sevenall of
which offer only mild relief from the symptoms of the diseasehave been approved.
Most of the rest have flopped, including
many in the later stages of development.
Those failures hang over the industry
like a black cloud. It might then seem surprising that an early study could so thoroughly energize researchers. And, indeed,
many who publicly proclaim excitement
over Biogens data privately walk back their
enthusiasm, noting the small patient group
size and cautioning that the effect could
disappear when a larger group is tested.
Still, theres a sense among neuroscien-

in industry and academia are making inroads with other therapeutic targets, most
prominently tau, the diseases other hallmark protein. If specific details of disease
pathology remain blurry, researchers at
least contend that the larger picture of Alzheimers progression is coming into focus.
Ten years ago, we just didnt know that
amyloid was accumulating in the brain
15 years before symptoms, says Harvard
University neuroscientist Rudolph E. Tanzi.
We didnt know that tau tangles spread once
they form. We were shooting in the dark.

FATAL FLAWS
Aducanumab might be providing excitement, but researchers have been burned
before by early data. A low point came in

ALZHEIMERS IN THE U.S. BY THE NUMBERS

Americans who
have the disease:

Percent who are

women:

5.3

65% 51

million

Direct cost of
patient care in 2015:

Expected cost
by 2050:

Number of drugs that have

failed in Phase III trials:

Write-down taken by Johnson

& Johnson after failure of
bapineuzumab:

$226 $1.1 $340

billion

trillion

million

SOURCES: Alzheimers Association, InnoThink Center for Research

in Biomedical Innovation, companies

tists that this time is different for Alzheimers. Theyve learned from their mistakes
with earlier drugs, theyre armed with
better tools to detect and track the disease,
and theyve got compelling evidence from
large genetic analyses that amyloid- is
in fact a major driver of the disease. If the
amyloid hypothesis holds water, everyone
agrees that the Biogen drug is the vessel in
which to test it.
Moreover, their excitement extends beyond the possibility of getting an amyloid-targeted drug on the market. Researchers

2012, when several high-profile Alzheimers therapies failed in quick succession.

The drugs worked in various wayssome
were antibodies that sequester amyloid-
itself or its aggregated form, others were
small molecules that prevent amyloid-
from formingbut all had flaws.
The failures caused some critics to declare the amyloid hypothesis dead. Now,
researchers understand that the trials
were riddled with problems, not the least
of which was that the drugs werent always
being tested in people with Alzheimers.

Ten years ago, we just didnt know

that amyloid was accumulating in the
brain 15 years before symptoms.
CEN.ACS.ORG

12

JUNE 1, 2015

Because researchers at the time lacked good

imaging tools and other biomarkers to detect the disease, people whose dementia had
other causes were included in studies.
The earlier trials were further flawed because they included people whose disease
was too far along to benefit from the drugs,
which slow down Alzheimers but dont
reverse its course. Many of the people
enrolled in the trials couldnt remember
their spouses name, Harvard neurologist
Bradley T. Hyman explained at the Boston
neuroscience event.
When you look at those individuals by
MRI or autopsy, theyve lost something
like a third of the substance of the brain,
Hyman said. At that point, thats really
organ failure.
Another cause of the disappointments
is poor drug design. You cant test the
amyloid hypothesis if you dont reduce
amyloid- production or clear existing
plaque, says Michael L. Hutton, chief scientific officer for neurodegenerative diseases at Eli Lilly & Co. Youve really got to
make sureprior to Phase IIIthat your
molecule is testing the hypothesis.
Unfortunately, Hutton notes, some
compounds that got far into the clinic before failing turned out to not actually hit
their intended targets. Researchers point
to Lillys small-molecule semagacestat and
J&Js antibody bapineuzumab as examples
of failures in drug design.
Its not a mystery why things went
so bad, says Dennis J. Selkoe, a Harvard
neurologist who was among the first to put
forward the amyloid hypothesis in the early
1990s. It all makes perfect sense in the
area of human endeavor. We were anxious
to move aheadI certainly wasand got
imperfect drugs and poor trial design.

THE RIGHT STUFF

Biogen appears to have taken the lessons
to heart, starting with the design of the
drug itself. Aducanumab stems from a pact
formed in 2007 between Biogen and the
Swiss biotech firm Neurimmune to develop
antibodies against aggregated amyloid-.
Neurimmune is founded on technology
developed by University of Zurich neuroscientist Roger Nitsch and takes what he calls a
reverse translational medicine approach.
Because aggregated proteins implicated in
diseases such as Alzheimers have a different structure or conformation than normal
proteins, he reasoned, the immune systems

YUMANITY

NEXT WAVE

Two Start-ups Push Beyond

Traditional Alzheimers
Drug Development
Ever since leaving his academic neurology post two
decades ago, venture capitalist Doug Cole had been on
the lookout for a worthwhile
investment in neurodegenerative disease. But for more than
a decade, he couldnt muster
enough confidence in the field
to back a biotech firm working
on tough diseases like Alzheimers or Parkinsons. The
fundamental biology of those
diseases was too unclear, and
running a clinical trial was
fraught with challenges.
Coles mind has clearly
changed. Last month, Flagship Ventures, where he is a
managing partner, joined several other firms to put $217
million into newly launched
Denali Therapeutics, a South
San Francisco-based biotech
founded by three former
Genentech executives, including onetime research chief
Marc Tessier-Lavigne, to
tackle neurodegenerative diseases. The hefty cash influx is
believed to be the largest first
round of financing in the biotech industrys history.
Denali is one of two neuroscience-focused biotechs
launched this year by highprofile founders. Cambridge,
Mass.-based Yumanity Therapeutics, unveiled in January
to much fanfare, has at its
helm biotech veteran Tony
Coles, who led Onyx Pharmaceuticals before it was
acquired by Amgen.
Their creation signals growing interest in a field that not
so long ago was seen as a
minefield for drug developers.
Company founders say the
right tools, including better
brain imaging and a grow-

ing body of genetic data, are

coinciding with improved
understanding of how to test
Alzheimers drugs. Were at
a very special time right now,
says MIT molecular biologist
Susan Lindquist, who is the
other big-name founder of
Yumanity.
Denali is providing few details about the targets or technology it will use. Chief Executive Officer Ryan Watts will say
that the company is founded
on the belief that genetics will
soon enable broadly defined
neurodegenerative diseases
to be broken into subpopulations, much like what has
already occurred in cancer. In
the process, new drug targets
will open up.
In its pursuit of Alzheimers
treatments, Denali will work
on inflammation, an area of
research that drug developers
have yet to broachat least
publicly. Although amyloid
plaques and tau tangles are
widely accepted as telltale
signs of the disease, in recent
years, inflammation is increasingly understood to speed up
its progress.
Some scientists say not
enough is known about whether inflammation is a cause or
consequence of the disease,
making drug discovery tricky.
Watts isnt deterred. If you
look at the human genetics of
Alzheimers, 60 to 70% of the
genes implicated are enriched
in the microglia, cells that
act as the brains personal immune system.
That has made inflammation a really hot space,
Watts says. Even if amyloid
and tau trigger the disease,
inflammation likely plays

CEN.ACS.ORG

FORWARD THINKERS

Yumanitys Coles (left) and

Lindquist are looking for novel
Alzheimers targets.
a role in accelerating it.
Another area of interest
for Denali is how neurons
die, a subject near and dear
to Watts, who studied it as a
graduate student at Stanford
University. One way to study
neuronal death in Alzheimers
is with assays that can parse
whether neurons are dying of
natural causes or because of
damage by disease. After identifying the players responsible
for the cell death, scientists
can tease apart which pathways are involved and eventually turn up drug targets.
With such big scientific
questions to tackle, Denali will
be built to last, says Chief
Operating Officer Alexander
Schuth. The firm is assembling a team of scientists with
a translational medicine group
at its core.
If Denali has at its foundation the belief that genetics
will expand the array of targets for Alzheimers drugs,
Yumanity is driven by the
use of model organisms to
point researchers to the best
targets.
Yumanitys search for Alzheimers drug candidates
hinges on phenotypic screeningthe testing of compounds
in whole cells or organisms
rather than against an isolated drug target. Phenotypic
screens have so far not been
used for Alzheimers drug discovery for two main reasons:

13

JUNE 1, 2015

Figuring out the target of a

hit from a phenotypic screen
can be tough, and the screens
themselves are a challenge to
set up.
Right now, it is so difficult
to grow neurons and have
them operating in normal
biology in the tiny format
you need for drug screening,
MITs Lindquist explains.
Lindquists lab has overcome those hurdles. By engineering yeast cells to express
proteins like amyloid-, compounds can be cheaply and
quickly screened. Although
yeast do not perfectly replicate human disease, you can
capture a lot of the biology,
she says.
The hits from the yeast
screens are put into neurons
derived from induced pluripotent stem cells, which
themselves were derived from
the skin cells of patients.
Researchers can then test
whether compounds that
worked in yeast will actually rescue the neurons of a
patient who has the disease,
Lindquist explains. The last
step is to return a promising
compound to the yeast and
use genetics to find its target.
Although Yumanity is further along in its work with
Parkinsons disease, the company has already been able to
use our yeast cells to connect
the pathology of amyloid with
several genes, Lindquist says.
I think the ability to use the
cell to tell you whats going to
make it better, and then figure
out how its working, will really
be illuminating.

GENENTECH

COVER STORY

of healthy people must develop antibodies against them.

Furthermore, a memory
of antibodies against aggregated amyloid- should
live on in the B cells in the
bone marrow of healthy aging people. Neurimmune
screened millions of B cells,
a kind of white blood cell, to
decipher the genetic information encoding antibodies with the right qualities,
including the ability to pass
through the blood-brain
barrier but not interact with
other tissues in and outside
of the brain, Nitsch explained at the Boston neuroscience event.
In a sense, the human body did much
of the work engineering this antibody,
says Jeff Sevigny, Biogens senior director
of neurodegenerative disorders. The companies then altered part of the antibody to
improve its performance.
The partners derived multiple antibodies from Nitschs technology and eventually
settled on aducanumab, which targets the
aggregated form of amyloid- and did well
at clearing the protein in animal studies.
When Biogen designed the much-lauded
study of aducanumab, our main task was
to ensure that 100% of the subjects enrolled had the disease, Sevigny says. The
firm says its study is the first to require
amyloid plaque buildup to be confirmed
by PET imaging. And the company only
included people who were in early enough
stages of the disease that lowering amyloid
could make a difference.
The strategy worked. Last December,
Biogen announced that preliminary results of its Phase Ib trial of aducanumab
were good enough that the drug candidate
would bypass Phase II studies and graduate
to Phase III, the last step before seeking
regulatory approval.
At a neuroscience conference in March,
the company provided more details: The
Phase Ib study of 166 people included about
30 people each at four dosage strengths and
40 who were given a placebo. PET scans
showed that the higher the dose, the more
plaque that was removed from the brains;
even better, the higher the dose, the better
that people performed on cognitive tests.
For scientists who have been plugging away at the amyloid hypothesis for
decades, the results were gratifying. No
doubt theres a little over-the-top enthu-

KNOWLEDGE BUILDING Genentech

researcher Sheng says half of the

companys neuroscience team is working
on the basic science of Alzheimers.

siasm, Harvards Selkoe says. You have

to be measured, but I think these results
are hard to explain away, scientifically, and
thats all that matters to me.
Still, much work lies ahead, Selkoe cautions. For starters, Biogen will need to
repeat the results in far more patients. One
big question for aducanumab is whether
brain swelling, a side effect observed in
all amyloid-clearing antibodies, will keep
patients from being given the highest, most
effective dose.

OTHER AMYLOID
BUSTERS
Although aducanumab has been getting the
headlines, the first drug to actually make
it to market could be Lillys solanezumab.
Whereas aducanumab targets aggregated
amyloid-, solanezumab binds to soluble,
monomeric forms of the protein. The antibody failed in two large Phase III studies,
but a subset of patients who were in the
early throes of the disease appeared to benefit from it. Lilly is well along in a Phase III
trial to test the drug in that narrower group
and expects to have results by October
2016. If they are favorable, the first diseasemodifying drug for Alzheimers could reach
patients in 2017.
The other advanced drug is a Merck &
Co. small molecule that blocks BACE, an
enzyme that helps trim a larger protein
down into amyloid-. Unlike earlier BACE
CEN.ACS.ORG

14

JUNE 1, 2015

inhibitorsincluding an antibody from Genentech and

small molecules from Lilly
and Bristol-Myers Squibb
that were pulled for reasons
of efficacy and toxicity, MK8931 has made it to Phase III.
Merck is expected to unveil
results late next year or in
early 2017.
Meanwhile, Genentech
is further behind with its
antibody crenezumab, which
binds to both monomeric
and aggregated forms of
amyloid-. The drug failed to
improve cognition in a Phase
II study, but as Lilly found
with solanezumab, people with a mild form
of the disease seemed to benefit. Genentech
recently launched a smaller Phase I safety
study of higher doses of the treatment in
people with mild to moderate Alzheimers.
Like Biogens aducanumab trial, this one
requires the disease to be confirmed by PET
scan.
At the same time, Genentech is deep into
a long-term study of crenezumab that could
support targeting amyloid. The five-year
Alzheimers Prevention Initiative (API),
a partnership between Genentech, the
National Institutes of Health, and Banner
Alzheimers Institute, seeks to determine
whether the antibody can stave off Alzheimers in an extended Colombian family
afflicted with a rare genetic mutation that
causes an early-onset form of the disease.
Carole Ho, who leads nononcology
early clinical development at Genentech
and plays a key role in the API study, says
the trial could have implications for the
broader Alzheimers population. In addition to testing the amyloid hypothesis, the
study is collecting vast amount of imaging
and biomarker data that the team hopes
will correlate with cognitive benefits.
That data could, in turn, be used as
clinical measurements, or end points, for
future Alzheimers studies. While we
have end points that have been used across
multiple trials in the past, we dont really
have good end points for the early stages of
the disease, Ho says.

BEYOND AMYLOID-
Even as researchers await clinical evidence
confirmingor refutingthe amyloid
hypothesis, they also acknowledge that

clearing amyloid is unlikely to be a cure.

The unifying theme of the data from
studies of solanezumab, crenezumab, and
aducanumab is that we may be able to
have an effect on the disease with antiamyloid therapies, but the magnitude of the
effect may not be transformative, Genentechs Ho says. It may be a start, but what
I see in the future is were going to be looking toward combination therapy.
The most obvious candidate to combine
with an amyloid--targeted agent is a drug
that takes aim at the other problematic protein in Alzheimers patients: tau. Whereas
amyloid- forms sticky plaques that coat
their brains, tau causes tanglessnarls of
aggregated filaments found inside neurons.
And the two are connected: Amyloid-
kicks off taus tangle formation by a yet-tobe-determined mechanism.
Just five years ago, tau was considered
a daunting drug discovery target. The
protein plays a critical biological role in
stabilizing microtubules, a structural and
transportation component in neurons. At
the same time, its hard to access because,
unlike amyloid- and its aggregates, tau
resides inside cells.
A cluster of recent discoveries is helping drug developers understand tau and
its role in cognitive decline. You can have
plenty of amyloid on the brain but barely
altered cognitive function, says Morgan
Sheng, Genentechs vice president of
neuroscience and molecular biology. But
after roughly 10 to 15 years of amyloid
accumulation, tau starts to misfold and
aggregate. Then you start to see signs of
dementia.

a neighboring healthy neuron, thereby

spreading the pathology throughout the
brain.
Buildup of amyloid- triggers the initial
accumulation of tau, but as Duff explains,
at some point the relationship decouples
and tau becomes a runaway train. That
means that even if a drug effectively clears
amyloid from the brain, if the disease has
progressed too far, tau tangles can still
spread and cause damage.
Duffs work helps fill in the picture
about how Alzheimers unfolds and also
opens the door to developing drugs that
block tau. Targeting tau inside cells is
tough, but a dysfunctional version of the
protein that propagates outside cells
would be more easily accessed by a drug.
Over the past five years, it is becoming
more and more accepted, if not proven,
that tau pathology might spread at least in
part between cells, Genentechs Sheng
says. That extracellular transmission
gives an opportunity for an antibody to
come and block the spread.
Another spur to the development of
anti-tau therapeutics is the advent of tau
radiotracers. Just as amyloid imaging
transformed clinical trials for drugs such
as aducanumab, an effective tau tracer will
allow researchers to pick the right patients
for trials and track drug efficacy.
Were seeing a really significant evolution with the advent of the tau tracer, says
Lillys Hutton, who prior to joining the
pharmaceutical industry spent a decade
studying tau pathology at the Mayo Clinic
in Jacksonville, Fla. Tau tracers have already
confirmed the observation from brain au-

We were anxious to move

aheadI certainly wasand got
imperfect drugs and poor trial design.
Researchers have learned that tau is not
just the secondary pathology that its been
relegated to, but perhaps it is as important
if not more important than amyloid, says
Karen Duff, an Alzheimers researcher at
Columbia University.
Duff is one of several researchers who
showed in recent years that dysfunctional
tau is self-propagating. Whereas amyloid-
plaques build up slowly and steadily over
many years, tau can spread in a prionlike
fashion, moving from a sick neuron to

topsies that, starting around age 60, everyone develops tau tangles. They are benign
unless amyloid plaques are also present.
Lilly is one of several companies working
on tau tracers, which Columbias Duff calls
the best thing thats happened in the last
year. Lilly already markets Amyvid, an 18Fbased tracer that detects amyloid plaques in
patients with cognitive impairment.
Although the science around tau is still
evolving, companies are forging ahead with
drug development, and industry watchers
CEN.ACS.ORG

15

JUNE 1, 2015

expect a flood of new candidates.

In January, J&J partnered with AC Immune to develop anti-tau vaccines in a deal
that includes ACI-35, which is in a Phase
Ib study. AC Immunes vaccines are built
to stimulate B cells to wage an antibody
response against phosphorylated tau, the
misfolded form of the protein that causes
tangles.
Genentech has been working with AC
Immune to find antibodies against tau
since 2012. Biogen and Neurimmune hope
to replicate their amyloid success with antibodies against tau.
Even though tau drugs trail antiamyloid
therapies by a decade, researchers are
excited by the possibility that they could
treat people with more advanced disease.
For amyloid treatment, you have to go
very early, almost preventative, Genentechs Sheng says. But tau maybe has a
little bit longer window of opportunity
such that patients who have already started
to show symptoms can be treated.

THE CHALLENGES AHEAD

Even as companies make progress against
amyloid and tau, a major gap exists in
understanding how the two proteins are
connected. If researchers could unravel the
mechanism by which amyloid triggers tau
proliferation and figure out how tau injures
neurons, promising drug targets might
follow.
If theres an area Id really like to see
progress from in the next five years, it would
be that really fundamental level of how amyloid and tau toxicity works, Lillys Hutton
says. No doubt there will be additional drug
targets to come out of that work.
And despite significant progress against
Alzheimers since the trial failures of 2012,
researchers are quick to acknowledge that
the challenges go beyond simply finding a
treatment. Drugs, whether taken for life or
for a short stint, are going to be expensive.
Companies would not be placing such
risky bets if they didnt expect financial
rewards.
Moreover, a stigma around dementia
lingers. As Hutton points out, people are
scared of Alzheimers, so they often dont
see their doctor about symptoms until
theyre past the point where the antiamyloid therapies now in the clinic could help.
Im optimistic therapies will come,
Hutton says. What Im less sure about is
how theyll get applied in the real world.

BUSINESS CONCENTRATES

POTASHCORP REVIEWS
SQM, ICL HOLDINGS

BASF TACKLES URBAN LIVING

PotashCorp of Saskatchewan is considering whether its investments in SQM and Israel Chemicals Ltd. make long-term sense.
The company has a 32% stake, worth about
$2.2 billion, in SQM, a Chilean iodine,
lithium, and potassium supplier. Its 14%
interest in ICL, an Israeli fertilizer and bromine chemicals maker, is valued at about
$1.3 billion. In March, three PotashCorpappointed directors resigned from SQMs
board over what they saw as inadequate review by SQMs management of a tax probe
and allegations of wrongdoing. In contrast,
PotashCorp says its investments in Jordanian and Chinese fertilizer suppliers are a
good strategic fit.AHT

As part of its 150th anniversary celebration, BASF hosted a symposium

in New York City last week on how public-private partnerships, with the
help of chemistry, can resolve challenges facing urban development. The
event was the third in a series of such Creator Space gatherings. Two were
already held, in Mumbai and Shanghai, and others are set for So Paulo,
Brazil; Barcelona; and Ludwigshafen, Germany. Each event is intended to
allow thought leaders to exchange ideas on challenges for which chemistry
can lend a hand, such as energy and food availability. The New York event
focused on providing guidance to government officials, developers, and
residents of the rapidly developing former industrial district in Brooklyn
known as Red Hook. Events included workshops on doing more with less
and a jam session on creating a carbon-neutral built environment. The
goal of the weeklong event, said Wayne T. Smith, CEO of BASF in North
America, was to support improvement in the overall quality of life.MSR

ness to the private equity firm One Rock

Capital Partners for an undisclosed sum.
The Germany-based ICL business makes
active ingredients for antacids and antiperspirants and products for dental applications. The sale, ICL says, will help it
focus on agriculture, food, and engineered
materials. In March, One Rock invested in
the organophosphonates maker Compass
Chemical.AHT

EVONIK PLANS SILICA

IN SOUTHEASTERN U.S.

EVON IK

In what the company says will be its largest

investment in North America in the past

FAST-FOOD INGREDIENT
VOWS PROLIFERATE

YU M! BRANDS

Evonik claims to
five years, Germanys
be the only firm
Evonik Industries
to make both
plans to build a preprecipitated silica
cipitated silica plant
(shown) and
in the southeastern
silanes.
U.S. Set to cost around
$100 million, the plant
will open in late 2017, Evonik says, and serve
regional tire manufacturers. Evonik markets
a silica-silane combination that imparts low
rolling resistance to tires. Evonik, which
already produces precipitated silica in
Chester, Pa., says its current global capacity
for precipitated and fumed silicas is around
550,000 metric tons per year.MM

Taco Bell and Pizza Hutboth owned

by Yum! Brandssay they will remove
artificial flavors and colors from their
menus this year. Todays customers want
simplicity, transparency, and choice in the
foods they eat, Taco Bell says. The company will stop using trans
fats and purchase certiTaco Bell is
fied sustainable palm
dropping
oil. It plans to remove
artificial
artificial preservatives
ingredients
and other additives by
from its
the end of 2017. Pizza
offerings.

ICL SELLING UNIT TO

INVESTMENT FIRM
Israel Chemicals Ltd. will sell its pharmaceutical, cosmetics, and gypsum busiCEN.ACS.ORG

16

JUNE 1, 2015

Hut announced a similar plan. Last month,

Panera Bread said it would remove a host
of artificial colors, flavors, sweeteners, and
preservatives by the end of 2016.MMB

RENEWABLE BASE OILS

MAKE THEIR DEBUT
Novvi, a joint venture between biobased
chemicals firm Amyris and Brazilian agriculture company Cosan, says it will begin
selling two 100% renewable oil products
derived from sugar. The oilsa poly-olefin and another base oilare targeted
for use in mass-market products including lubricants and motor oils. Traditional
poly--olefins are made from ethylene; the
Novvi product is made by oligomerizing
and hydrogenating farnesene, a biobased
C15 molecule made by Amyris.MMB

SAMSUNG WILL ADD

POLARIZERS IN CHINA
Samsung SDI will spend $180 million to
build a plant in Wuxi, China, that makes polarizer films for large-screen liquid-crystaldisplay TVs. The facility, scheduled to open
late next year, will have annual production
capacity of 30 million to 40 million m2,
about 10% of the entire polarizer market in
2014, Samsung says. Polarizers control display brightness, contrast, and other optical
features. They are typically made from polyvinyl alcohol and cellulose acetate films, but
Samsung recently launched polarizers that
substitute cheaper polyethylene terephthalate for cellulose acetate.JFT

BUSINESS CONCENTRATES

WACKER ADDS SILICONES

TECH LAB IN MOSCOW

WACKER

Wacker Chemie has opened a silicones

technical center in Moscow. The facility

A technician at
has a test lab for
work at Wackers
high- and ambienttemperature-curing new Moscow lab.
silicone elastomers
and ready-to-use silicone compounds
for the energy, electrical, and automotive
industries.AS

EU FIRMS DEVELOP
PRINTED TRANSISTORS
Germanys Merck KGaA is leading a consortium of 11 European companies and
four research institutes to develop processes for the high-resolution printing of
organic transistors. The project is funded
in part by the European Unions Horizon
2020 initiative. The partners include
French chemical maker Arkema and Finnish technology institute VTT. The consortium hopes to develop multifunctional

BUSINESS
ROUNDUP
CHEMTURA will license
its Emerald Innovation
1000 flame retardants to
Tosoh for manufacture
and distribution in Japan.
The Chemtura products
are meant to replace
decabromodiphenylether
and decabromodiphenylethane flame retardants.
EASTMAN CHEMICAL
is supplying its Amphora
3-D copolyester polymer
for use in n-vent, a 3-D
printing filament being
launched by Taulman

materials and optimize high-resolution

gravure printing and nanoimprinting
processes.AS

SANOFI BUYS DRUG

REVIEW VOUCHER
Sanofi will pay San Diego-based Retrophin
$245 million for its pediatric disease priority review voucher. PRVs, which can speed
up the review of a New Drug Application,
were introduced by FDA to encourage development of drugs for rare and neglected
pediatric diseases. Retrophin received
its PRV in March with FDAs approval of
Cholbam, a treatment for kids and adults
with bile acid synthesis disorders caused
by single-enzyme defects. Last year, Regeneron paid BioMarin $67.5 million for
a PRV; Regeneron and Sanofi later used
it to shave four months off the review
time for their cholesterol-lowering drug
alirocumab. Sanofi isnt saying how it
plans to use the Retrophin PRV.LJ

PURETECH TO GO PUBLIC
VIA LONDON OFFERING
PureTech Health, a Boston-based techtransfer and investment firm, intends
to raise at least $160 million in an initial
public offering of stock on the London
Stock Exchange. The firm uses a network
of more than 50 entrepreneurs and scientists across multiple disciplines to find
and assess scientific and technological
advances. It claims to evaluate more than

3-D. Eastman says the

new filament is suited for
creating aesthetic objects such as vases.
DSM and Zhejiang NHU
are forming a joint venture to develop engineering plastic compounds
made mostly from
polyphenylene sulfide
supplied by NHU. Based
in Xinchang, 150 miles
south of Shanghai, NHU
produces food and feed
additives, flavors, aroma
chemicals, and a range of
polymers.
CHEMOURS, the DuPont

performance chemicals
business that will soon be
spun off to shareholders,
has named E. Bryan Snell
president of its titanium
dioxide business. Snell
replaces B. C. Chong,
who is pursuing other
career opportunities.
KMCO, a specialty chemical maker in Crosby, Texas, has appointed John
C. Foley as president and
CEO. Foley was previously vice president of
Solvays Novecare business in North America.
Owner Resource Group,
a private equity firm,

CEN.ACS.ORG

17

650 ideas per year and currently has 12 life

sciences companies in its portfolio. A similar company, Boston-based Allied Minds,
raised $212 million in mid-2014 through
its London IPO.AMT

WUXI ENTERS LAB

CHEMICALS MARKET
The Chinese pharmaceutical services firm
WuXi PharmaTech has launched an online
platform for selling lab chemicals. LabNetwork aims to market to researchers worldwide WuXis catalog of more than 112,000
screening compounds, building blocks,
and other compounds. LabNetwork
also gives researchers access to roughly
200,000 compounds made by outside lab
chemicals suppliers. WuXi says it will add
other companies catalogs to LabNetwork
in the coming months.JFT

JUNO, EDITAS FORM

CELL THERAPY PACT
In a pact that combines two hot technologies, the T-cell-based therapies developer
Juno Therapeutics will pay $25 million to
Editas Medicine to use its CRISPR/Cas9
gene-editing capabilities. Editas also will
get $22 million in R&D support over the
next five years. Juno genetically engineers
a cancer patients T cells to detect and kill
diseased cells. Gene-editing technology
from Editas could help broaden the effectiveness of the engineered T cells beyond
certain blood cancers to solid tumors.LJ

owns a majority stake in

KMCO.
LANXESS will supply its
Keltan Eco ethylene-propylene-diene monomer
rubber to Freudenberg
Sealing Technologies for
use in making rubber
seals. Up to 70% of the
ethylene in Keltan Eco is
derived from sugarcane,
Lanxess says.
SCIEX will work with
New Objective to advance mass spectrometry capabilities for
proteomics and other
studies. The two Mas-

JUNE 1, 2015

sachusetts-based firms
will offer New Objectives
nanospray ionization
sources on MS instruments from Sciex to
increase sensitivity when
sample sizes are limited.
AMGEN has ended its
pact with AstraZeneca to
develop brodalumab, an
antibody that blocks the
IL-17 receptor. Amgens
decision was prompted
by reports of suicidal
ideation in Phase III trials
of brodalumab to treat
psoriasis and arthritis.
AstraZeneca is now considering the drugs fate.

GODAVARI

BUSINESS
SWEET SPOT Sugar,

refined in companyowned plants such as

this one, is the starting
point for Godavaris
chemical production.

SUSTAINABILITY YIELDS
SWEET SUCCESS
Indian biobased chemicals firm GODAVARI seeks to
blend social, ecological, and financial gain
JEAN-FRANOIS TREMBLAY, C&EN HONG KONG

BASIC ECONOMICS TEACHES that

companies exist to maximize their profits.

Godavari Biorefineries, an Indian producer
of sugar, ethanol, and biobased chemicals,
didnt get that memo. Its managers appear focused as much on philanthropy and
sustainability as they are on generating a
financial surplus every year.
Its an unconventional approach that is
working for the firm. Sales at the 76-year-old
company have risen steadily from $160 million in 2010 to $202 million last year, according to a recent financial report. Investors
seem to like what they see. Godavari succeeded in securing a $15 million cash injection last month from a private equity fund.
Godavari is an unusual company. On the
one hand, it does business in the standard
way of producing price-competitive materials at large, integrated complexes. On the
other hand, it funds medical services and the
education of young people in the communities where it operates and also lends money
to farmers that supply it with sugarcane.
We have a strong sense of social mission that started with my grandfather, who
was born poor, says Samir Somaiya, Godavaris third-generation chairman and managing director. We take a very long-term
perspective to business.
The company was founded in 1939, when
the elder Somaiya, after enjoying some suc-

cess as a sugar trader, decided to start up

his own sugar mill. In the decades that followed, Godavaris business thrived, partly
because it was protected by Indian import
tariffs. When his grandson Samir Somaiya
joined the company, those tariffs were in the
process of being dismantled. The company
had to close plants, a trauma that has guided
Somaiyas decision-making ever since.
I decided to never rely again on tariff
protection, Samir Somaiya says. He went
further than that, reorganizing the business so success doesnt depend on any
specific set of conditions. We dont want
to be vulnerable to any technology, any

one process, any customer, Somaiya says.

India is a major sugar exporter, and Godavari is one of Indias major sugar refiners.
Under Somaiya, a basic tenet has been to
extract more value out of sugarcane farming. Starting with sugarcane, Godavari
refines sugar, ferments ethanol, and derives
an ever-expanding range of biochemicals.
From plantation waste, it extracts energy
at cogeneration plants that are integrated
with its mills and chemical plants.
Ethanol is Godavaris starting point for
a family of downstream chemicals. It converts ethanol into acetaldehyde and then
acetic acid. From there it produces derivatives such as ethyl acetate, crotonaldehyde,
1,3-butanediol, and flavor and fragrance
ingredients.
The company calls itself one of the
worlds top 10 producers of ethyl acetate,
and it exports more than two-thirds of the
chemicals it makes. With the launch of new
biochemicals and the commissioning of
more power generation capacity this year,
the company expects its sales to surge by
25% to $250 million.
ITS UNUSUAL for a major biobased chemi-

Godavari
At A Glance
Headquarters: Mumbai
Plants: Four sites in the states of
Maharashtra and Karnataka
Sales: $202 million in 2014
Headcount: About 1,600, 30 in R&D
Businesses (% of sales):
sugar (40%); chemicals, including 1,3-butanediol, acetaldehyde,
ethyl lactate, and fertilizers (35%);
ethanol (17%); power (8%)

CEN.ACS.ORG

18

JUNE 1, 2015

cal maker to emerge from the sugar business, according to Sarah Hickingbottom,
business development manager for oleoand biochemicals at LMC International, a
consulting firm based in Oxford, England.
Most biochemical firms own a specific technology they use to produce chemicals from
purchased feedstock. Or they are chemical
companies that modify a petrochemical
process to use a biobased feedstock instead.
But as the biobased chemical business
matures, access to competitive feedstock
may win the day, Hickingbottom predicts.
Production processes in this relatively
new business will eventually become standardized. When that happens, having ac-

We dont want to be vulnerable to any

technology, any one process, any customer.
cess to cheap raw materials will be key.
As a major sugar exporter, India is advantaged, Hickingbottom says. But the
countrys output varies from year to year,
she notes. In poor harvest years, companies that maintain close relations with
local sugarcane growers will likely be in a
better position to secure raw materials.
In that context, its possible that Godavaris philanthropic bent may help the company businesswise, even if that wasnt the
point. Paul S. Zorner, an American member
of Godavaris board who has worked at and
advised dozens of biobased fuel and chemical companies, notes that the firm helps
fund the studies of thousands of young
people in the communities where it operates. Godavari also loans money, when the
need arises, to the 20,000 or so farming
families that supply it with sugarcane.
According to Somaiya, several family
foundations that he chairs pay for the edu-

cation of 35,000 students in communities

where Godavari operates. They also fund a
500-bed hospital and a rural health center.
Zorner first met Somaiya at a conference on sugar in South Africa. He has now
been on Godavaris board for seven years
because the two men share similar ideas
about how to extract value from sugar.
The companys manufacturing operations are highly efficient, Zorner claims.
Godavaris plants have a very good scale
and are well engineered both chemically
and mechanically, he says. The only thing
that is wasted is CO2, really. Godavari was
able to achieve this efficiency thanks to
Indias abundance of engineering talent,
he adds.
IN FACT, the companys biobased chemi-

cals are produced so efficiently that they

compete pricewise against identical
products obtained from petrochemical

American Chemical Society

BE DISTINCT
The ACS Career Consultant
Program can help you set your
resume apart from the rest.
Visit www.acs.org/BeDistinct
to get started.

Brought to you by the ACS Career Navigator www.acs.org/CareerNavigator

CEN.ACS.ORG

19

JUNE 1, 2015

sources. There was a time when companies

expected to receive a premium for renewably sourced chemicals, but according to
Zorner, its a rare case when that happens.
Even without a price premium, at least
one investor sees opportunity in Godavaris focus on products from renewable
sources. The Mauritius-based private equity fund Mandala Capital last month agreed
to inject $15 million in Godavari. The cash
will help to support product development
and pay for a new specialty chemical plant.
Mandala didnt respond to a request for
comment for this article, but in an earlier
statement, the firm said it endorsed Godavaris strategy of getting more value from
sugar.
The academic world also sees value in
Godavaris approach. Somaiya teaches a
one-month chemical engineering course
on biorefining every two years at Cornell
University. More broadly, Zorner says,
Godavari can serve as an inspiration to the
many parts of the world that have strong
agricultural sectors but little industry. It
just shows what you can accomplish with
the sun, water, and some manpower.

SIGMA-ALDRICH/SAFC

BUSINESS

cording to Roots Analysis, a London-based

market research firm.
But having to work
with separate contract
suppliers only adds to
the complexity. Onestop shops are a rarity in this field, Roots
points out.
MEET ME SAFC

can now make

drug conjugates
at commercial
scale in St. Louis.

FOR THE PAST DECADE, SAFC has been

SAFC EXPANDS FOR

DRUG CONJUGATES
CUSTOM MANUFACTURING business of Sigma-Aldrich

prepares for the future on the cusp of an acquisition

BY MIDYEAR, the lab products supplier Sig-

ma-Aldrich will be part of Germanys Merck

KGaA. But for now, its business as usual,
especially at Sigma-Aldrichs SAFC custom
manufacturing business. With $700 million
in 2014 sales, 25% of the firms total, SAFC
has been Sigma-Aldrichs fastest-growing
segment for most of the past five years.
At an SAFC press event last month in St.
Louis, Mercks pending acquisition of Sigma-Aldrich was the elephant in the room.
Little information about the future of the
merged company was offered, other than
assurances that the deal is on track.
SAFC President Gilles Cottier was
upbeat about what his business has been
achieving and said it will continue to do the
same when we are together with Merck.
Last year when the merger was announced,
the companies described a combination
of largely complementary offerings in biopharma production, SAFCs main market.
Overall, SAFC is active in custom pharmaceutical chemical manufacturing, ingredients and services for biologic drug production, and materials for the electronics
industry.
But its recent investment focus has been
on building technology in the three areas of

antibody-drug conjugates (ADCs), gene and

cell therapy, and gene-editing and cell line
development, Cottier said. In assembling
the pieces, he added, SAFC seeks to create
an ecosystem of products and services to
help customers develop and make drugs.
The technologies SAFC is pulling together are typically applied in the development and manufacture of biotech drugs, a
rapidly growing area in which therapies are
becoming increasingly complex to manufacture. SAFC loves complex challenges
because we can leverage our science and
our technical knowledge, Cottier said.
Chief among the challenges are ADCs.
Now largely targeting cancer, ADCs generally consist of a cytotoxic drug payload
chemically linked to a disease-targeting
monoclonal antibody. This multicomponent construct requires the handling
of biologics, potent compounds, linker
chemistry, and advanced analytics. Manufacturing tends to be done by specialized
contract firms with one or a few of these
capabilities.
With 7080% of ADC production outsourced by drug companies, the contract
manufacturing market should exceed
$1 billion per year in the coming decade, acCEN.ACS.ORG

20

JUNE 1, 2015

moving toward becoming one of this rare

breed. For biologic drug manufacturing,
it provides cell line development and supplies powdered cell culture media from
U.S. and European plants. At a facility in
Madison, Wis., the firm synthesizes cytotoxic payloads and linkers and plans to
soon expand R&D there. In April, SAFC
launched a program for preparing and
characterizing small amounts of ADCs for
customers preclinical work.
At the press event, SAFC debuted an expansion of its St. Louis facility, where it already conducts clinical-scale conjugations,
to offer large-scale manufacturing. The
plant makes SAFC the only commercialscale ADC supplier in North America, Cottier claimed. To complete the picture, in late
2014 the firm began working with Baxter
BioPharma Solutions, which will provide
sterile drug filling and finishing services.
The ADC drug market is expected
to reach $10 billion by 2024. At least
160 products are in preclinical and clinical development, said Cynthia Wooge,
SAFCs global strategic marketing manager. Of the three approved and 54 in the
clinic, SAFC is involved in 27 of them.
The linker, payload, and biologic portions of ADCs, especially newer ones at the
preclinical stage, are evolving, Wooge said.
And many ADC development programs are
getting fast-tracked by regulators. Its an
exciting time to be in this field, she added.
SAFC is looking beyond ADCs at other
bioconjugates and at building on its other
ecosystems. In April, Sigma-Aldrich
opened a cell culture technical center in
Singapore.
And last month, SAFC said it would
expand a facility in Carlsbad, Calif., so it
can offer clinical- and commercial-scale
production of viral products for customers
in the coming hot areas of gene therapy, viral vaccines, and immunotherapy. Cottier
and his team no doubt expect to be pursuing those markets in the years ahead when
SAFC and Sigma-Aldrich are part of a German company called Merck.ANN THAYER

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BUSINESS INSIGH TS

MORE CARROT, LESS STICK

To ensure DRUG SAFETY, FDA needs to engage in positive reinforcement
RICK MULLIN, C&EN NEW YORK CITY

SHU TTERSTOCK

WHEN GUY VILLAX, chief executive officer of

and continuous improvement. Compliance with regulations has

the Portuguese pharmaceutical chemical firm
nothing to do with quality, Villax contends. It merely maintains a
Hovione, rose to speak at a company press
lowest common denominator.
conference in Paris last October, reporters
Another federal agency, the Occupational Safety & Health Adin attendance were curious to hear what
ministration, already maintains a deans list of sorts. OSHAs Volhed have to say, their interest piqued by the
untary Protection Programs identify companies that have develtitle of his presentation: Why Margaret
oped safety and health management regimes that result in injury
Hamburg Needs Her Deans List.
and illness rates below national averages for their industries.
FDA is used
Presumably, everyone in the room
Speculating on why OSHA has pushed ahead with such a proto punishing
knew that Hamburg was the head of the
gram, Villax notes that OSHA oversees a portfolio of private and
poor-quality
U.S. Food & Drug Administration. Few
government workplaces that dwarfs FDAs plant inspection roster.
drug companies,
were aware of her deans list.
But FDAs resources are also stretched, and the agency has indibut it should be
In fact Hamburg, who stepped down
cated that it is open to the idea of an industry quality protocol that
rewarding the
good ones too.
on April 1 after a six-year tenure,
will fill in for inspections. For example, it has hailed best practices
didnt have one.
compiled by manufacturers of drug inactive ingredients. And the
Villax continues to promote the deans list, an idea he first
agency recently told C&EN it is exploring means of identifying firms
floated in a 2013 C&EN editorial. As Villax describes it, FDA
with quality management systems that exceed regulatory requireshould compile a list of companies that have demonstrated
ments and may consider a reduced level of oversight for such firms.
a quality culturea spirit of operation that promotes processes and products above and beyond the compliance stanWOULD THE PUBLIC TOLERATE a program in which drug and
dards enforced by the agency. The agency then could inspect
drug chemical makers police themselves? Villaxs ready answer
these companies less frequently.
that the public wants a capsule of quality, not a capsule of compliReporters at the Paris event may have been skeptical of
ancemay be a projection of his own views. Selling the deans list
the idea that quality culture is of equal importance to law
idea would be a challenge for FDA.
enforcement in assuring drug safety. Some despaired of
The agency should note that the chemical industry provides an
selling Villaxs deans list as a story idea to hard-bit editors
excellent example of a sector improving itself without the reguback at the ranch, while others may have written the idea
latory stick. Unlike the U.S. nuclear industry, which was nearly
off as a marketing scheme. But Villaxs metaphor, rooted
brought to its knees when utilities circled the wagons after the acin a chemical industry tradition of proactive performance
cident at ThreeMile Island, the chemical industry has thrived since
improvement, is in some ways in step with changes already
the deadly 1984 gas leak in Bhopal, India, thanks in no small part to
under way at FDA to improve quality assurance.
a performance improvement program called Responsible Care.
Earlier this year, FDA established the Office of PharmaResponsible Care succeeded in bringing about sizable improveceutical Quality within its drug safety division. OPQs remit
ments in health, safety, and product stewardship. As a result of Reis to streamline the regulatory process, develop product quality
sponsible Care, the industry claims, it has reduced process safety
knowledge management and informatics, and bring parity to the
incidents by 50% and hazardous releases to the air, land, and water
oversight of generic and innovator drugs as well as domestic and
by 75% over the past two decades.
international facilities.
Communicating that success to the public has been a tougher
While always a central concern, drug quality has become a burnjob. The word chemical is still largely reviled.
ing issue at FDA given the recent run of drug recalls and a spate of
But quality is revered in the chemical industry, largely because
contamination and counterfeit cases. By adding a nonenforcement
of the wave of change that followed the Bhopal disaster. Five
element to FDAs basic regulatory and inspection activities, agency
Past Midnight in Bhopal is required reading for management at
officials hope to create a uniform drug quality programone
Hovione, Villax says, referring to the book by Dominique Lapierre
quality voicespanning all manufacturing sites, domestic and
and Javier Moro detailing the safety failures related to the methyl
foreign, and all drug types.
isocyanate gas leak in Bhopal that killed thousands.
There is no mention of a deans list, a quality merit
Villax is serious about investing in quality. And
badge, or anything designed to identify high achievers Drug quality
Hamburgs successor, whoever it will be, should
as quality role models.
recognize the industrys quality culture as a huge rehas become a
FDA will need to consider such a list, however, if
source as FDA struggles to secure the drug supply for
burning issue
it wants to add something like superquality to mere
the American public.
at FDA given
compliance. As Villax sees it, the agency needs to
the recent run
use the carrot, and not the stick, to reward comViews expressed on this page are those of the author
panies that have internalized the essence of quality
of drug recalls. and not necessarily those of ACS.
CEN.ACS.ORG

22

JUNE 1, 2015

GOVERNMENT & POLICY CONCENTRATES

SUPREME COURT SNUBS

DRUG TAKE-BACK CASE
The Supreme Court last week declined to
hear a challenge that the pharmaceutical industry brought against a countys requirement that manufacturers pay for a drug disposal program. Last year, a federal appeals
court upheld a 2012 ordinance that made
Alameda County, Calif., the first jurisdiction in the U.S. to require pharmaceutical
makers to pay for collection and disposal of
unwanted prescription medications. The
challenge was brought by the Pharmaceutical Research & Manufacturers of America,
the Generic Pharmaceutical Association,
and the Biotechnology Industry Organization. The drug industry groups argued that
the ordinance interfered with interstate
commerce because it shifts the local cost of
doing business to out-of-state manufacturers. The high court turned down the case
without comment, allowing the appeals
court ruling that affirmed the ordinance
to stand. Alameda County adopted the
ordinance to prevent illegal resale and accidental poisoning from unwanted drugs, as
well as improper disposal, which can lead to
drinking water contamination.JM

SHU TTERSTOCK

USDA CLEARS USE OF

TWO MODIFIED CROPS
USDA has paved the way for commercial
release of two new genetically modified
crops intended to combat pests that have
grown resistant to currently approved bioengineered crops. One of the new crops is
a strain of cotton that is resistant to Dow
AgroSciences Enlist Duo herbicide, which
is a mixture of 2,4-D
and glyphosate, and
to glufosinate. The
other crop is a new
strain of corn developed by Monsanto
to tolerate corn rootworm and glyphosate. USDA granted
preliminary approval
for the cotton on
May 22, making it
the third crop, after
Dow AgroSciences
corn and soybeans,
genetically
to be approved for
modified cotton
use with Dows Ento tolerate its
list Duo. USDA also
proprietary mix of
the herbicides 2,4-D released favorable
and glyphosate.
assessments of Mon-

BILL ADVANCES TO
FUND MORE RESEARCH IN
MEDICINE AND CURES
A bipartisan bill that would boost research funding for the discovery of new
treatments and cures for devastating diseases is working its way through
Congress. The Energy & Commerce Committee in the House of Representatives unanimously approved the billthe proposed 21st Century Cures
Act (H.R. 6)by a vote of 51-0 in late May. The legislation would authorize
annual increases of $1.5 billion for three years for the National Institutes of
Health and provide an additional $2 billion annually for five years for a new
NIH Innovation Fund. At least $500 million of that fund would be used to
support research in precision medicine, antibiotics discovery, biomarkers,
and basic biomedical research. H.R. 6 would also provide $110 million annually for the next five years to FDA to streamline regulatory processes and
accelerate drug approvals. Lawmakers have changed the bill since it was
introduced in April, in part by adding a requirement that NIH develop a fiveyear strategic plan based on scientific, not economic, considerations.BEE

santos new corn the same day, making it

likely that the agency will approve that crop
as well. If approved, Monsantos seed would
become the first commercial corn that relies
on RNA interference, which involves silencing the expression of specific genes in the
rootworm. When a rootworm eats the modified corns roots, some of the worms essential genes are silenced and it dies.BEE

CLEAN WATER RULE

CATCHES FLAK
After a years-long tussle with Congress and
other stakeholders, the Obama Administration last week issued a regulation that spells
out which U.S. waterways are protected
under the Clean Water Act, the federal law
that controls water pollution and aims to
conserve wetlands. The detailed rule defines
and clarifies federal protections for tributaries as well as streams that are intermittent
or perennial. For example, it specifically
excludes from regulation ditches that have
seasonal flows of water, EPA says. The rule
came under immediate fire from industry
groups and congressional Republicans
representing agricultural states. The U.S.
Chamber of Commerce, a powerful business lobby, says the rule will significantly
broaden federal regulatory jurisdiction over
private activities on land and in waterways,
wetlands, and drainage ditches. Bills moving through Congressincluding H.R. 1732
and S. 1140would force EPA to scrap the
regulation and require the agency to rewrite
CEN.ACS.ORG

23

JUNE 1, 2015

the rule with broader input from stakeholders. In addition, the rule is expected to be
challenged in federal court.JM

TEXAS TIGHTENS RULES

ON AMMONIUM NITRATE
The Texas Legislature has passed a bill that
strengthens rules for storing and handling
ammonium nitrate, the source of the 2013
explosion at the West, Texas, fertilizer
facility that killed 15 people. Gov. Greg Abbott (R) is expected to sign the legislation
(H.B. 942), which will require ammonium
nitrate to be stored away from combustible
material. It also will give
+

H
O
the state fire marshal
new powers to inspect
N
N
H
H
O
businesses that store
O
H
the chemical and issue
citations for violations.
Ammonium nitrate
Companies will have
10 days to fix problems or face penalties.
State Sen. Brian Birdwell (R), whose district
includes the town of West, says the requirements will increase safety but wont burden
agribusiness. What weve done in the bill
were the right steps to swing the pendulum
to the middle, he remarks. Under the legislation, businesses will be required to file
reports with multiple state agencies and
local emergency response officials detailing
which chemicals are stored or used at their
facilities. The Texas Commission on Environmental Quality will make those records
available to the public.GH

GOVERNMENT & POLICY

2012 to 2013. Overall, academic spending in 2013 was $63.4 billion, up 58% from
$40.1 billion a decade earlier. That increase
is smaller when adjusted for inflationthe
2013 figures amount to $51.5 billion in 2003
dollars, up just 28% in the past decade
but it still represents an upward trend.
(The accompanying tables and graphs
show spending in current dollars, except
where noted.)
The life sciences remained the prevailing force in academic science and technology spending. That discipline consumed
59% of the overall R&D budget in both
2003 and 2013, the NSF data show. Engineering overall had the biggest increase
as a share of spending, up 79% over the
past decade. Chemistry saw a small de-

2013 ACADEMIC
SPENDING TRENDS
National Science Foundation data show flat SPENDING FOR
HIGHER EDUCATION RESEARCH institutions in recent years
ANDREA WIDENER, C&EN WASHINGTON

WORRIES ABOUT academic research

compare with the larger R&D community.

In addition, these numbers can influence recruitment of faculty and graduate
students.
According to NSFs most recent report,
academic spending was fairly stable from

funding fuel angst in university scientists

all over the U.S. Data released annually by
the National Science Foundation on academic spending trends give researchers a
chance to explore how their departments

U.S. academic science and

engineering R&D spending:

Chemistry R&D
spending:

$63.4

$1.7

billion

Math & computer sciences

4%
Social sciencesc
6%
Geosciences
6%

INTERACTIVE ONLINE
Compare the top chemistry departments head-to-head in
our interactive graphic of the top 100 chemistry spenders,
and view a table of the top 25 chemical engineering
spenders at http://cenm.ag/13rd.

billion

Math & computer sciences

4%
Social sciencesc
5%
Geosciences
5%

SPENDING
BY FIELD

Other sciences
2%
Life sciencesa
59%

Other physical
sciencesb
5%
Chemistry
3%
Other engineering
13%

The share of
total funding
for various
disciplines
remained
relatively
stable over the
past decade.

Materials engineering
1%
Chemical engineering
1%

Other sciences
2%
Life sciencesa
59%

Other physical
sciencesb
5%
Chemistry
3%
Other engineering
15%
Materials engineering
1%
Chemical engineering
1%

Academic R&D spending, FY 2003 = $40.1 billion

Academic R&D spending, FY 2013 = $63.4 billion

NOTE: Institutional fiscal years. Spending figures do not account for inflation. a Includes agricultural, biological, medical, and other life sciences. b Includes astronomy, physics,
and other physical sciences. c Includes psychology. SOURCE: National Science Foundation, WebCASPAR database, 2013 data

FUNDING SOURCES
Federal funding has
declined, and institutions
have contributed more to
academic R&D.

$ Billions
70

60
50

BIG MOVERS

All other sources

Industry
State & local government
Institutional funds
Federal government

Emory
University
moved up

24 43

40
30
NOTE: Institutional fiscal years
beginning with 1972, the first year
for which data are available.
SOURCE: National Science
Foundation, WebCASPAR database,
2013 data

places in
chemistry
spending
rankings

20
10
0
1972

U at Buffalo,
SUNY,
moved up

77

82

87

CEN.ACS.ORG

92

97

24

02

JUNE 1, 2015

07

12

places in
chemical
engineering
spending
rankings

SCHOOL SPENDING ON CHEMICAL R&D

This table ranks top chemistry spenders and breaks down funding sources
RANK

SHARE OF TOTAL EXPENDITURES IN 2013, %a

SPENDING, $ THOUSANDS

2013 2012 INSTITUTION

2003

2012

2013

FEDERAL
GOVT.

STATE/
LOCAL
GOVT.

87.4%

0.1%

4.3%

INDUSTRY

ANNUAL CHANGE

INSTITUTION

201213 200313
2007A

$18,099

$56,563

$46,430

Georgia Tech
Harvard U
Northwestern U
U of California, San Diego
U of Illinois, UrbanaChampaign
U of California, Berkeley
Rutgers U
Johns Hopkins U b
U of Texas, Austin

9,652
19,456
16,108
17,530
20,949

34,971
28,990
33,822
27,399
28,730

37,960
35,641
35,547
31,353
29,131

69.7
66.8
66.4
85.2
73.3

0.5
0.0
0.0
1.5
0.0

6.9
2.4
0.0
1.5
3.5

21.6
21.9
21.3
2.2
17.5

8.5
22.9
5.1
14.4
1.4

293.3
83.2
120.7
78.9
39.1

24,907
15,552
11,330
23,382

22,243
36,452
19,393
27,629

25,954
25,758
24,947
24,649

69.1
85.3
96.1
52.3

0.5
0.9
0.0
5.8

9.5
4.0
0.1
3.5

7.3
7.7
3.3
24.6

16.7
-29.3
28.6
-10.8

4.2
65.6
120.2
5.4

19

U of North Carolina, Chapel

Hill

16,045

20,378

23,595

79.2

0.0

1.8

15.5

15.8

47.1

12
13
14
15
16
17
18
19
20
21
22

11
27
26
12
14
31
20
18
16
15
9

15,191
15,546
10,856
19,703
10,657
14,701
20,804
15,164
18,097
11,260
20,184

23,076
18,944
19,216
22,588
22,056
17,327
20,328
20,523
21,045
21,380
24,698

23,168
22,968
22,450
22,378
21,896
21,762
20,950
20,668
20,633
20,276
19,297

67.0
51.5
69.7
37.1
64.2
49.6
70.5
72.2
80.7
15.0
70.0

0.0
5.7
0.0
0.5
0.3
0.0
0.0
0.0
0.0
0.8
0.1

2.3
7.6
3.0
2.0
1.7
9.1
0.9
1.6
7.4
8.1
14.9

27.7
29.1
22.3
30.4
28.2
36.0
22.3
13.3
9.8
45.2
10.8

0.4
21.2
16.8
-0.9
-0.7
25.6
3.1
0.7
-2.0
-5.2
-21.9

52.5
47.7
106.8
13.6
105.5
48.0
0.7
36.3
14.0
80.1
-4.4

23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50

23
48
25
17
10
38
22
37
21
29
35
30
42
32
47
39
45
33
49
61
43
34
52
40
44
51
55
28

U of Michigan
U of Wisconsin, Madison
U of California, Irvine
Texas A&M U
U of Notre Dame
Indiana U
Cornell U
U of Colorado
Stanford U
U of Akron
Massachusetts Inst. of
Technology
U of Massachusetts, Amherst
Emory U
U of California, Los Angeles
Pennsylvania State U
U of Washington, Seattle
U of Minnesota
Purdue U
Stony Brook U, SUNY
U of Arizona
U of Chicago
U of Pittsburgh
Princeton U
Rice U
Arizona State U, Tempe
Yale U
U of California, Davis
Florida State U
U of Southern California
U of Kansas
Michigan State U
Ohio State U
Vanderbilt U
U of Florida
U of California, San Francisco
U of Pennsylvania
Columbia U
Boston U
U of Utah
Total, listed institutions
TOTAL, ALL INSTITUTIONS

15,688
10,667
19,607
18,214
16,947
9,569
13,268
9,007
10,874
8,802
9,630
11,278
9,294
10,162
8,062
7,526
13,321
8,890
3,856
13,230
15,512
4,546
11,594
28,798
11,165
7,746
3,827
12,247
$688,500
$1,225,546

19,993
12,850
19,286
21,032
23,412
14,315
20,059
14,892
20,321
18,310
15,929
17,811
13,824
16,316
12,973
14,220
13,248
16,012
12,013
9,763
13,739
15,959
11,966
14,192
13,615
11,970
10,599
18,863
$1,005,233
$1,750,134

19,234
18,685
18,486
18,290
17,404
17,378
17,286
17,273
17,255
17,180
17,116
16,829
16,661
16,048
16,020
13,923
13,871
13,707
13,444
13,213
12,816
12,308
11,987
11,858
11,780
11,681
11,600
11,570
$1,002,314
$1,706,470

7.6
1.2
13.5
5.0
0.4
10.2
10.3
3.4
1.0
2.8
0.8
7.8
9.0
1.4
1.9
3.0
0.8
14.6
3.6
3.4
0.4
1.0
3.0
3.2
0.9
1.1
0.7
0.1
4.2%
4.0%

20.8
45.2
8.7
31.7
4.6
15.8
18.2
44.9
23.4
10.7
42.6
36.4
15.9
26.8
26.3
17.8
28.1
19.6
11.7
24.3
21.5
11.4
32.0
12.9
4.5
9.3
22.8
14.5
19.8%
21.6%

-3.8
45.4
-4.1
-13.0
-25.7
21.4
-13.8
16.0
-15.1
-6.2
7.5
-5.5
20.5
-1.6
23.5
-2.1
4.7
-14.4
11.9
35.3
-6.7
-22.9
0.2
-16.4
-13.5
-2.4
9.4
-38.7
-0.3%
-2.5%

22.6
75.2
-5.7
0.4
2.7
81.6
30.3
91.8
58.7
95.2
77.7
49.2
79.3
57.9
98.7
85.0
4.1
54.2
248.7
-0.1
-17.4
170.7
3.4
-58.8
5.5
50.8
203.1
-5.5
45.6%
39.2%

1
2
3
4
5
6

1
3
5
4
8
6

7
8
9
10

13
2
24
7

11

California Inst. of Technology

70.9
53.4
66.7
57.6
89.9
72.8
66.3
48.4
66.7
78.8
55.3
52.2
54.5
64.0
63.4
65.8
70.3
50.4
79.2
71.0
73.7
86.4
58.6
75.0
92.2
76.8
68.9
83.8
68.2%
66.6%

0.0
0.0
0.5
0.0
1.7
0.2
0.2
1.2
2.2
0.0
0.0
0.0
10.3
3.9
0.0
0.0
0.0
0.0
1.0
0.0
0.1
0.0
0.4
0.0
0.0
0.0
0.0
0.4
0.8%
2.0%

1.2%

-17.9% 156.5%

NOTE: Institutional fiscal years. a Figures might not sum to 100% because other funding sources, such as nonprofit organizations, are not listed. b Includes funding for the Applied
Physics Laboratory.
SOURCE: National Science Foundation, WebCASPAR database

CEN.ACS.ORG

25

JUNE 1, 2015

GOVERNMENT & POLICY

TOP 25 UNIVERSITIES IN 2013 R&D SPENDING

Many top-spending universities dont pour a lot of money into chemistry
RANK

SPENDING, $ MILLIONS

OVERALL CHEMISTRY

1
2

9
12

27

46

13

75

11

9
10
11
12
13
14
15

25
3
20
28
33
48
18

16

22

17
18
19
20
21
22
23

26
15
47
37
19
43
2

24

25

470

INSTITUTION

PHYSICAL
SCIENCESb
CHEMISTRY LIFE SCIENCESa ENGINEERING (INCL. CHEM.) GEOSCIENCES

Johns Hopkins U c
U of Michigan
U of Washington,
Seattle
U of California, San
Diego

OVERALL

$25
23

$871
788

$879
250

$180
50

$39
18

$149
22

$33
183

$2,150
1,310

17

785

122

45

114

22

23

1,112

31

610

126

67

165

43

56

1,067

12

1031

12

1,043

23

641

139

81

49

29

58

998

811

72

20

20

17

46

987

24

701

34

35

29

140

942

18
36
21
17
17
12
21

668
538
570
587
730
590
536

76
58
131
102
37
63
105

66
77
101
47
30
42
105

22
32
29
31
10
115
22

29
12
35
29
11
21
27

73
194
33
59
29
14
46

934
911
901
855
847
846
841

19

119

420

107

51

77

59

834

18
22
12
16
21
13
38

273
299
647
670
426
455
21

321
279
48
33
101
156
503

57
46
28
41
93
32
57

53
128
4
6
95
11
16

69
22
22
17
15
39
107

58
22
42
21
44
52
22

830
796
790
788
774
743
726

29

217

165

60

229

41

722

659

15

16

28

718

$493

$14,240

$4,191

$1,493

$1,074

$1,090

$1,377

$23,465

$1,706

$37,585

$10,729

$4,646

$3,199

$2,739

$4,496

$67,891

U of California, San
Francisco
U of Wisconsin,
Madison
Duke U
U of North Carolina,
Chapel Hill
U of California, Los
Angeles
Harvard U
Stanford U
U of Minnesota
U of Pittsburgh
Columbia U
Cornell U
Massachusetts Inst.
of Technology
Pennsylvania
State U
Texas A&M U
U of Pennsylvania
Yale U
U of Colorado
Ohio State U
Georgia Tech
U of Illinois, Urbana-Champaign
U of Texas MD
Anderson Cancer
Center
Total, listed
institutions
TOTAL, ALL
INSTITUTIONS

MATH &
COMPUTER
OTHER
SCIENCES SCIENCES

NOTE: Institutional fiscal years. Total may not sum because of rounding. a Includes agricultural, biological, medical, and other life sciences. b Includes astronomy, chemistry,
physics, and other physical sciences. c Includes funding for the Applied Physics Laboratory.
SOURCE: National Science Foundation, WebCASPAR database, 2013 data

cline as a share of the overall budget, from

3.1% to 2.7%.
For universities, the federal government remained by far the dominant player
in research support. But the amount of
federal spending peaked at $39.7 billion
in 2011 and then began a slow decline.
Industry support has risen slowly, but institutions themselves also picked up some
of the slack. Their spending on research
climbed to $13.3 billion in 2013, almost
double the amount they provided a decade earlier.
The trends in chemistry department
spending were also generally upward

from 2012 to 2013. California Institute of

Technology, the top-funded chemistry department, spent $46.4 million in 2013, with
87% of those funds from the federal government. That was down from Caltechs
2012 spending numbers, but it received
more than double the overall money it
spent in 2003.
The top-spending chemical engineering department, the University of Texas,
Austin, shelled out almost the same as
Caltechs largest-spending chemistry department, $46.2 million in 2013. However,
only 33% of that chemical engineering programs spending was supported by federal
CEN.ACS.ORG

26

JUNE 1, 2015

dollars. An almost equal amount37%

came from industry.
Only a handful of the highest-spending
chemistry departments were in the countrys top-spending research institutions
for science and technology overall. The top
research spender in 2013, Johns Hopkins
University, had the ninth-ranked chemistry
department in terms of spending. Other
top 10 highest-spending chemistry departments in the top 25 for overall spending
were the University of California, San Diego; Harvard University; Georgia Institute
of Technology; and the University of Illinois, Urbana-Champaign.

SCIENCE & TECHNOLOGY CONCENTRATES

STED IMAGING WORKS

WITH QUANTUM DOTS

NAT. COMMUN.

Most classes of fluorescent labels have

been successfully used in the superresolution microscopy method known as stimulated emission depletion, or STED. The
glaring exception has been quantum dots.
In STED, one laser beam excites fluorescence and a second laser beam turns off
the fluorescence in all but a small defined
region. Quantum dots havent worked
because their broad excitation spectra
overlap the emission band, making it hard
to identify an appropriate wavelength
for stimulated emission shutdown of the
fluorescence. Stefan W. Hell of the German Cancer Research Center and the Max

Planck Institute for Cellular fibers

labeled with redBiophysical Chemistry and coworkers emitting quantum
dots can be better
now report success- resolved with STED
ful STED microsimaging (left)
copy with commer- than with confocal
microscopy (right).
cially available redemitting quantum
dots (Nat. Commun.
2015, DOI: 10.1038/ncomms8127). The
researchers excite ZnS-coated CdSe
quantum dots with 628-nm light and
shut down the fluorescence with 775-nm
light. By repeating the process in different
spots, they build up images with spatial
resolution of about 100 nm. The quantum
dots survive more than 1,000 scans, which
suggests they would be suitable for timelapse STED imaging, according to the
researchers.CHA

TRAFFICKING PROTEIN
HELPS CLEAR AMYLOID-
FROM BRAIN
A protein in brain blood vessels called
PICALM may help flush out amyloid-
the peptide associated with Alzheimers
diseaseinto the bloodstream, suggesting
a possible new therapeutic target for the

Chemists at MIT have created a stable aromatic

anion composed solely of pnictogensthe elements that make up the periodic table column to
the right of carbon (Science 2015, DOI: 10.1126/
science.aab0204). Christopher C. Cummins and
Alexandra Velian made the inorganic aromatic ring,
which has the formula P2N3, by transferring diphosphorus to the azide anion using a sodium cryptand
cation. They crystallized a complex of the resulting
salt and determined that the anion is planar and has an
aromatic -electron system, as indicated by electron
This image shows
the electron density
structure calculations. Until now, the chemists note, to
of an all-pnictogen
isolate compounds with multiple bonds between pairs
aromatic anion. P =
of phosphorus atoms, chemists had to use bulky suborange, N = blue.
stituents to block the reactive bond. But no such bulky
groups were needed to isolate P2N3. This stabilization
is best construed as aromaticity, Cummins and Velian point out, an effect
traditionally reserved for the domain of organic chemistry.BH

disease. Berislav V. Zlokovic of the University of Southern California and colleagues

studied PICALM, in part, because singlenucleotide variations in the gene that
encodes PICALM have been linked to an
increased risk of developing Alzheimers.
Zlokovics team found that the brains of
patients with advanced Alzheimers had
significantly lower levels of PICALM compared with those of healthy people (Nat.
Neurosci. 2015, DOI: 10.1038/nn.4025). And
PICALM levels in Alzheimers-affected
brains correlated inversely with the
amount of amyloid- and extent of disease
progression. To study the proteins role
further, the researchers genetically engineered mice so they had only one copy of
the PICALM gene. Compared with normal
mice, these animals accumulated more
amyloid- in their brains. On the basis of
data from a series of cell microscopy experiments, the scientists think that, in cells
lining brain blood vessels, PICALM helps
pull in amyloid- from the brain and then
passes the peptide off to cellular machinery
that spits it out into the bloodstream.MT

FISH MAKE THEIR

OWN SUNSCREENS
Fish and some vertebrates can produce
the sunscreen compound gadusol through
biosynthesis pathways, according to an
CEN.ACS.ORG

27

JUNE 1, 2015

investigation conducted by Taifo Mahmud

of Oregon State University, Corvallis,
and coworkers (eLife 2015, DOI: 10.7554/
elife.05919). The unexpected finding may
lead to efficient routes for producing
biobased sunscreens and antioxidants for
use in cosmetics, pharmaceuticals, and
other products. Bacteria, fungi, algae, and
some marine invertebrates are known to
produce mycosporine-like amino acids,
gadusols, and related compounds that
absorb ultraviolet radiation. The compounds are essential
OH
for shielding organisms
HO
regularly exposed to
HO
intense sunlight. Conventional thinking in
O
OH
this area indicates that
OCH3
bacteria, fungi, and
other simple organGadusol
isms synthesize these
compounds, but higher organisms acquire
them through their diets. Unexpectedly,
the Oregon State team found that zebrafish make gadusol on their own. They also
found that the gadusol biosynthesis gene
cluster is present in other fish, birds, reptiles, and amphibians not known to produce gadusol, raising a question about the
clusters function in those species. And in
a demonstration with potential commercial significance, the group showed that
engineered yeast containing the fish genes
can produce and secrete gadusol.MJ

CHRISTOPHER CUMMINS

PNICTOGEN RING BOASTS

AROMATICITY

SCIENCE & TECHNOLOGY CONCENTRATES

PERSISTENCE BY
STRUCTURE
Life is short for some organic compounds
dissolved in lakes and long for others. But
what controls their life spans? The answer
depends, at least in part, on specific structural motifs found in a lakes dissolved organic matter, reports a team of researchers
led by Anne Kellerman and Lars Tranvik of
Uppsala University, in Sweden (Nat. Geosci.

2015, DOI: 10.1038/ngeo2440). The team

investigated the persistence of dissolved
organic matter in 109 freshwater lakes in
Sweden by using ultra-high-resolution
mass spectrometry and optical spectroscopy. They found that reduced, aliphatic,
and nitrogen-containing compounds are
among the most persistent. In contrast,
oxidized, aromatic compounds are much
less persistent, they say, because degradation processes in the lakes work more
quickly on those species. The results challenge a paradigm
in geological science that
emphasizes extrinsic influencessuch as temperatureas primary
factors dictating the
persistence of organic
matter. Instead, the
team argues that intrinsic
influences, such as molecular
structure, play an important role
in determining the persistence of
organic matter. The team also stresses that
the observed persistence patterns are not
unique to Swedish lakes but likely found
elsewhere as well.SE

TETRAFLUOROETHYLENE
IS GOOD FOR MORE
THAN JUST TEFLON
Tetrafluoroethylene (TFE) has long been
used as an economical feedstock for making fluorinated polymers. Researchers have
also used the fluorinated olefin as a starting material in organic synthesis, but
the chemistry remains relatively underdeveloped. Two research teams
are now reporting reactions that
broaden the scope of TFEs use as a
reagent. In one case, a team led by
Masato Ohashi and Sensuke Ogoshi
of Osaka University, in Japan, has
used TFE in nickel-catalyzed reactions with ethylene and aldehydes
to make fluorinated aldehydes and
ketones and with ethylene and other
alkenes to make -olefins with fluoroalkyl chains. The reactions proceed through an unprecedented five-membered nickelacyclic intermediate (J. Am.
Chem. Soc. 2015, DOI: 10.1021/jacs.5b03587;
Organometallics 2015, DOI: 10.1021/acs.
organomet.5b00218). In a second case, Yusuke Takahira and Yoshitomi Morizawa of
Asahi Glass, in Yokohama, Japan, have used
TFE and other fluoroolefins in ruthenium
CEN.ACS.ORG

28

JUNE 1, 2015

carbene-catalyzed cross-metathesis reactions with enol ethers to make ether-functionalized fluorinated olefins (J. Am. Chem.
Soc. 2015, DOI: 10.1021/jacs.5b03342). The
Asahi researchers believe their method of
combining inexpensive fluoroolefins with
a hydrocarbon counterpart will enable
easy synthesis of new fluorinated building
blocks for polymeric materials and medicinal chemistry.SR

FRAMEWORKS FIGHT
CHEMICAL WEAPONS
With their ability to hydrolyze the phosphate ester linkages in chemical warfare
agents, zirconium-based metal-organic
frameworks, or MOFs, are being eyed
as materials for filters in gas masks and
other decontamination equipment. Now
two groups are reporting improvements
on this technology. Chemists in Spain,
led by the University of Granadas Jorge
A. R. Navarro and Elisa Barea, boosted
the hydrolytic powers of MOF UiO-66
by incorporating lithium alkoxide in its
structure (Angew. Chem. Int. Ed. 2015, DOI:
10.1002/anie.201502094). The researchers wove this modified version of UiO-66
into a textile by spraying a suspension of
the MOF onto silk fibroin fibers. In other
work, Northwestern University chemists
led by Omar K. Farha and Joseph T. Hupp
explored a newer kind of Zr-based MOF
dubbed MOF-808that can hydrolyze
stand-ins for chemical warfare agents 350
times as fast as UiO-66 (Angew. Chem. Int.

Zr = purple, O = red, C = gray

Ed. 2015, DOI: 10.1002/anie.201502155).

UiO-66 uses a dozen small organic connectors to bridge its Zr nodes; MOF-808
uses only six organic connectors to link
Zr nodes. The difference leads to more
reactive nodes as well as wider channels in
MOF-808, which chemical warfare agents
enter more easily.BH

OMAR K. FARHA

Photosynthesis produces oxygen and carbohydrates from water and carbon dioxide
efficiently, giving living things oxygen to
breathe and food to eat at the same
time. The detailed way in which it
accomplishes this feat is something scientists would like
to better understand,
in part to perhaps
mimic photosynthesis.
Tingyun
Kuang, JianRen Shen, and
coworkers at
the Chinese
Academy of
Sciences, in Beijing, and Okayama
University, in Japan,
Overall structure
have now moved
of photosystem I/
that goal one step
light-harvesting
closer to realization
complex I
by determining the
supercomplex from
first atomic-resolupea plants.
tion crystal structure
of the pea plants
photosystem I/light-harvesting complex I,
a huge photosynthetic protein supercomplex found in higher plants (Science 2015,
DOI: 10.1126/science.aab0214). One view of
the structure (shown) makes it look like a
pointy-headed jack-o-lantern, in which subunits of photosystem I surround the eyes
and a series of light-harvesting complex I
proteins sit below the mouth. The structure,
which reveals specific interactions between
the supercomplexs components, including
numerous pigments and other cofactors,
could lead to a more in-depth fundamental
understanding of the highly efficient energy
transfer and photoprotection mechanisms
of plant photosynthesis.SB

SCIENCE

DETAILED ANALYSIS OF
PHOTOSYSTEM/LIGHTHARVESTING COMPLEX

SCIENCE & TECHNOLOGY

from the SCENEs

FROM THE MATERIALS SCENE

ELECTRONIC STENT
MONITORS BLOOD
VESSELS
Over time, stainless steel stents implanted
to open a narrowed artery can cause inflammation and turbulent blood flow that
lead to new blockages. Now researchers
have designed a dissolvable stent carrying a suite of onboard electronic sensors,
drug delivery particles, data storage, and
electronic communications capabilities to
detect and overcome these problems (ACS
Nano 2015, DOI: 10.1021/acsnano.5b00651).
Dae-Hyeong Kim of Seoul National
University and colleagues integrated
temperature and blood-flow sensors
into a magnesium alloy stent, along with
electronic memory to store the collected
data. The electronics are made out of nano-

FROM THE ENVIRONMENTAL SCENE

SHU TTERSTOCK

CLEANING UP LEATHER
PROCESSING
Turning animal hides into supple, richhued leather is a complex, multistep
process that creates a lot of wastewater. Now researchers have developed a
leather processing
approach that eliminates most of that
waste by replacing
water with a deep
eutectic solvent
a salt in a liquid
state (ACS SustainResearchers are
trying to replace
the water in leather
processing with
salt-based solvents.

membranes of silica,
magnesium oxide, and
zinc oxide, which hydrolyze in the body to form
harmless compounds.
Whats more, the magnesium stent itself acts
as an antenna that can
both broadcast data and
use the energy of radio
waves to power
the electronics.
As the electronic
This smart,
stent dissolves,
dissolvable
it delivers ceria
magnesium stent
nanoparticles
could keep arteries
that reduce inopen without causing
flammation,
inflammation.
and gold and
silica nanoparticles that release the drug
rapamycin when heated with infrared

able Chem. Eng. 2015, DOI: 10.1021/

acssuschemeng.5b00226). Tanning
a hide normally involves chemically
cross-linking its collagen by soaking
it in a solution containing chromium,
which could be oxidized to produce
a carcinogenic form of the metal. Instead, Andrew P. Abbott of the University of Leicester, in England, and colleagues added a chromium solution to
an ionic solvent consisting of choline
chloride and ethylene glycol, and they
then painted the material onto cowhides. Because the leather proteins are
charged, the hides suck in the solvent,
which is oppositely charged, along
with the chromium, Abbott says. The
researchers found they could then skip
another wastewater-generating step
that adds oil back to the hide because
the solvent itself creates a sumptuous
feel when absorbed into a pelt.

The SCENE news channels are brought to you by C&ENs Journal

News & Community group. To subscribe to weekly e-mail newsletters
from any of our six SCENEs, go to http://cenm.ag/newsletters.

CEN.ACS.ORG

29

JUNE 1, 2015

ACS NANO

A selection of stories from C&ENs six online TOPICAL NEWS CHANNELS

light. Rapamycin can open narrowed blood

vessels. Tested in dogs and other animals,
all the components of the electronic stent
function, dissolve over time, and do not
trigger any adverse side effects.

FRO M THE BIO LO GICAL SCE NE

ENGINEERING BENDY
NEURONAL ARRAYS
Researchers in Japan have grown sturdy,
yet flexible, grids of cultured nerve cells on
a patterned hydrogel film. This neuronal
array can be rolled up or squeezed without
disrupting the neurons biological functions
(ACS Biomater. Sci. Eng. 2015, DOI: 10.1021/
acsbiomaterials.5b00020). When connected
to electrodes or grown with other cell types,
the arrays could help scientists study brain cell
function or test new drugs. Neurons are usually grown in plastic or glass dishes in the lab,
but they grow better on soft, gel-like surfaces.
Matsuhiko Nishizawa of Tohoku University
and colleagues printed compounds that encourage cell growth in a microsized grid pattern on dried collagen films. They then poured
a suspension of neurons over the films. Within
15 hours, the neurons had arranged themselves
at the nodes of the grid and sent out fingerlike
extensions to connect to other cells. The team
activated specific sections of the grid using
microelectrodes to watch how nerve signals
rippled through nearby cells.

JLICH RESEARCH CENTER

SCIENCE & TECHNOLOGY

lifetimes, and high

friction during braking. Accommodating some of those
criteria, such as low
rolling resistance
and high braking
friction, is tricky
because they seem
opposed to one
another, Persson
says. If researchers understood the origins
of those parameters in detail, much of the
design work could be done through computer modeling. Instead, he says, engineers
mainly analyze tire design through trial and
error, which is slow and costly.
One important rubber property is viscoelasticity, the tendency of the material
to deform under a pressurelike the one
caused by a cars weight pressing a tire
against small road bumps. Those interactions cause rubber molecules inside a tire
to move and vibrate. The extent of that
energetic molecular commotion, which
depends on the nature of the rubber and
roughness of the road, strongly influences a
tires rolling resistance and overall friction
properties.
BO KNOWS TIRES

Bo Persson
of the Jlich
Research Center in
Germany develops
computational
and experimental
techniques to
understand friction
between tires and
road surfaces.

HOW THE RUBBER

MEETS THE ROAD
New tribology advances broaden understanding
of TIRE FRICTION MECHANISMS
MITCH JACOBY, C&EN CHICAGO

LIKE OTHER EXPERIENCED DRIVERS,

when Bo N. J. Persson steps on the gas,

applies the brakes, or heads into a turn, he
automatically checks road and traffic conditions to make sure hes driving safely. But
unlike most motorists, Persson also thinks
about rubber viscoelasticity, shear forces,
and road surface topography.
For 20 years, Persson, a staff researcher
at the Jlich Research Center in Germany,
has been trying to understand the fundamental processes that cause frictionespecially between automobile tires and road
surfaces. Hes developed a mathematical
theory that encompasses numerous aspects of this everyday phenomenon, which
is critical to ensuring that automobiles
hug the road securely. Several pieces of the
friction puzzle remain missing. But one of
them, which describes the conditions un-

der which polymer chains on tire surfaces

briefly stick to roads, has just been uncovered. The finding helps provide a more
complete picture of rubber-road tribology,
a topic that includes friction, wear, and
lubrication.
Tribology tends to be a neglected subject, Persson says. One reason it typically
isnt covered in university courses, he says,
is the absence of a rigorous theory describing the underlying phenomena. Yet the
details of rubber friction, though complex
in nature, have major practical applications
for manufacturing tires and other products. If you understand the details at the
most basic level, then you can start making
logical tire design changes, he asserts.
A successful tire design needs to meet a
few main performance criteria, including
low rolling resistance, low wear rates, long
CEN.ACS.ORG

30

JUNE 1, 2015

BUT A NEW STUDY conducted by Persson

and coworkers, including Seungkuk Nam,

a rubber friction specialist and mechanical engineer at Hankook Tire, in Daejeon,
South Korea, shows that shearing between
the tire surface and the road also contributes significantly to tire friction under
some conditions. This shearing is the result
of small-scale dragging of polymer molecules as the tire rolls down the road.
In the study, the team analyzed friction
properties of three tire tread compounds
those used in summer, winter, and all-season formulationson two asphalt road surfaces and on a sandpaper surface. They used
a stylus instrument and an atomic force
microscope to measure the topographies
of the tire and road surfaces on multiple
length scales. They conducted friction measurements as they dragged the materials on
the surfaces at a variety of temperatures but
at low speeds to avoid frictional heating.
The team found that dragging forces
between the tire and road caused a type
of sticking friction arising from polymer chains adhering to the road surface,
stretching, breaking free, and reattaching repeatedly (J. Chem. Phys. 2015, DOI:
10.1063/1.4919221).
Persson emphasizes that the new results

apply only to low sliding speeds and dry

surfaces. He explains that on wet surfaces,
a nanometer-thick film of water between
the rubber and the road inhibits shearing
processes, leaving mainly the viscoelastic
contribution to friction.

MAKING OPIATES
IN YEAST

IN ADDITION TO uncovering a new com-

Just one step remains to complete a pathway from glucose to

morphine, so scientists ponder FUTURE SECURITY CONCERNS

ponent of tire friction, the study again

confirms the accuracy of Perssons mathematical theory: Velocity- and temperaturedependent data calculated using the theory
closely match the measured data. Perssons
theoretical formulation, now available as
software modules from Multiscale Consulting, is used by several tire industry scientists, who rave about it.
For example, Toshio Tada, a research
manager at Sumitomo Rubber Industries,
in Kobe, Japan, uses the software to help
design tires that perform well on wet roads.
Until recently, there was no reliable predictor for wet grip performance, he says.
Time-consuming and expensive trialand-error testing using prototype tires was
inevitable.
Now, Tadas group can predict friction
coefficients for various types of road surfaces and conditions and knows which tire
material and mechanical properties are
most important for friction. The advance
has enabled Sumitomo to reduce the duration of R&D programs, he says.
Hankooks Nam is similarly enthusiastic.
His team puzzled over results of tests designed to evaluate variations in road surface
roughness and braking performance. He acknowledges that for a long time, we struggled to figure out which properties of road
surfaces are important for rubber friction.
Since using the new software, the Hankook
group has gotten a good grip on those friction parameters. We now quantitatively
understand the role of surface roughness
on multiple length scales, he notes.
Some unknowns still remain, however.
For example, Nam says, its still difficult to
use theory to predict what happens when
dust, rubber particles, and other microscopic debris work their way between the
tire and the road. Its also challenging to
understand how viscoelasticity is affected
by interactions between polymer chains
and the carbon and silica particles commonly used in tire manufacturing.
Answering those questions and others,
in part, will help further the understanding
of tire friction. And with that, scientists
may soon finally know what happens when
the rubber meets the road.

CELIA HENRY ARNAUD, C&EN WASHINGTON

FOR THE BETTER part of a decade, scien-

tists have been trying to engineer microbes

to produce morphine and other opioid
painkillers directly from glucose. Some say
such engineered microbes could reduce
global reliance on poppy farming to make
painkillers. Others want to create microbes
like these as a platform for producing improved painkillers and therapeutics.
So far, researchers have managed to program yeast to perform parts of the pathway
from glucose to morphine. Two teams have
now come closer than ever to cobbling the
pieces together. And their success is raising
concerns about what to do when an efficient morphine-producing yeast strain is finally developed, given its potential use not
only for the legal production of painkillers
but also for the illegal production of drugs.
In two publications, the teams report
the front and back halves of the morphine
biosynthetic pathway. Vincent J. J. Martin
and coworkers at Concordia University, in
Montreal, took care of the back half, engineering yeast to produce morphines immediate precursor, codeine, starting from
(R)-reticuline, an intermediate in the pathway (PLOS ONE 2015, DOI: 10.1371/journal.
pone.0124459). Last year,
Christina Smolkes group
at Stanford University reported yeast that could make
codeine, morphine, and
several other opioids, but
the researchers started from
thebaine, an intermediate
further down the pathway.
For the front half of the
pathway, John E. Duebers
group at the University of
California, Berkeley, in collaboration with Martins group, engineered
yeast that can produce (S)-reticuline
from glucose (Nat. Chem. Biol. 2015, DOI:
10.1038/nchembio.1816). They chose (S)reticuline as their target because its an
intermediate along the pathway to making
more than 2,500 members of the benzyl-

isoquinoline alkaloid family. Morphine and

related compounds make up one branch
of this family. Other benzylisoquinoline
alkaloids have promising anticancer and
antibiotic activity, Dueber says.
A significant hurdle on the way to (S)-reticuline was an early step, the hydroxylation
of the amino acid tyrosine to form l-3,4dihydroxyphenylalanine, better known as
l-DOPA. After yeast feed on glucose, they
naturally produce tyrosine. Martins group
was trying to find an enzyme that could efficiently convert the tyrosine to l-DOPA. William C. DeLoache, one of Duebers graduate
students, developed an enzyme-based biosensor to make the screening process easier:
It turns l-DOPA into betaxanthin, a yellow
fluorescent pigment. So when a candidate
enzyme successfully creates l-DOPA from
tyrosine, the test solution changes color.
The researchers guessed that sugar beets
possessed the enzyme they were looking for.
Thats because the beets distinctive purple
color arises from a compound generated
after the tyrosine-to-l-DOPA conversion.
Dueber and his team lucked out with one of
the first sugar beet enzymes they tried.
After that, Dueber collaborated with
Martins group to find an
enzyme called norcoclaurine
synthase to fix another bottleneck in the pathway. Martin has been involved with
several plant genome projects in Canada. Through
our plant genomic efforts,
we had candidates we could
test and give John to put in
his yeast, Martin says.
In the second part of
the pathway, Martin and
his coworkers identified enzymes that
could produce the codeine precursor thebaine from (R)-reticuline. In earlier work,
Smolke and her coworkers thought they
had engineered yeast that could generate
both (R)- and (S)-reticuline (Nat. Chem.
Biol. 2008, DOI: 10.1038/nchembio.105).

Were not
blind. We see
potential
misuses
of the
technology.

CEN.ACS.ORG

31

JUNE 1, 2015

SCIENCE & TECHNOLOGY

HO

OH
HO
HO

HO

O
HO

H3CO
NH

OH

HO

HO

Glucose

HO

H3CO
H

step

NH2

HO
NH2
L-DOPA

But it turned out that the plant enzymes

engineered into Smolkes yeast produced
only (S)-reticuline.
Without (R)-reticuline, the next enzyme
in the pathway didnt work, so the yeast
couldnt go on to produce thebaine, which
put the brakes on the journey toward morphine. Martins group has now shown that,
when fed (R)-reticuline, Smolkes original
enzyme works quite well. With this enzyme, Martins yeast produced codeine, a
precursor of morphine. If fed supplemental
codeine, the yeast also produced morphine.
The two new reports are missing only
one step to complete the pathway from
glucose to morphine: the conversion of
(S)-reticuline to (R)-reticuline. Martin and
Dueber expect that step will be reported
within the next year. After that, it will be
feasible to develop a yeast strain capable of
converting glucose to morphine.
Even then, plenty of engineering will
still be needed to make such a morphineproducing yeast strain efficient. When
youre doing metabolic engineering, you
have to be careful to optimize each step
and balance everything carefully, Martin
says. If you lose efficiency at any of the
steps, by the time you get to the 10th step,
you dont have any product left.
But the very fact that the end is in sight
has spurred Dueber, Martin, and others
to start thinking about what precautions
might be needed to safeguard against

H3CO

HO

O
H3CO

O
H

NCH3

Thebaine

O
H

HO

Codeine

NCH3

H
HO

NCH3

Morphine

PIECING TOGETHER A PATHWAY The biosynthetic pathway

OH

JOHN DUEBER/C&EN

L-Tyrosine

(R)-Reticuline

HO

H3CO
NCH3

H3CO

Norcoclaurine (S)-Reticuline

OH

HO
HO

H3CO

HO

NCH3 Missing

between glucose and morphine in yeast is nearly complete. Still missing

is the conversion of (S)- to (R)-reticuline. The compounds pictured here
are key intermediates. One roadblock was an early reaction converting
L-tyrosine to L-DOPA. The ask on the left contains a yeast strain with a
color-changing biosensor (appears orange here) that detects L-DOPA. The
ask on the right contains a strain that produces (S)-reticuline.

misuse of such a yeast strain.

When Dueber and Martin
saw how quickly the individual
pieces of their collaboration fell
into place, they started to worry
that the technology could be
used to produce illicit narcotics.
Were not blind. We see potential misuses of the technology, Martin says. We want to be
ahead of the curve. Lets not ignore it. Lets
deal with it because its going to happen.
Someone who was motivated to make
morphine could probably engineer an efficient yeast strain in two or three years,
Dueber says. We felt it was imperative to
contact policy experts to start thinking
about this now rather than waiting until it
becomes a reality and having a reactionary
response, he says.
THEY APPROACHED Kenneth A. Oye, a

science policy researcher at Massachusetts

Institute of Technology, and Tania Bubela,
an expert on public health law and biotechnology policy at the University of Alberta,
to make recommendations for controlling
the efficient morphine-producing yeast
strains that they think are on the horizon.
Those recommendations, which address
the potential for home-brew opiates, appeared in a commentary in the May 21 issue
of Nature (2015, DOI: 10.1038/521281a).
Oye, Bubela, and J. Chappell H. Lawson,
also of MIT, make recommendations related to the engineering, screening, security,
and regulation of engineered yeast strains.
They recommend designing yeast strains
to be used in production labs that are less
appealing to criminals because the strains
require unusual combinations of nutrients.
They also recommend that the genes in
the pathway be added to the list used by
DNA synthesis companies to screen legal
CEN.ACS.ORG

32

JUNE 1, 2015

purchasers. In addition, they call for the licensing of labs that work with such strains
and for making the release and distribution
of the strains illegal.
Smolke agrees that its important to
start discussion about future regulatory
needs, but she calls the commentarys
focus on home-brew morphine inflammatory and unbalanced. She argues that
it downplays the problems of the current
supply chain involving poppy farming for
both licit and illicit drugs, such as security
issues and environmental effects.
The authors envision circumstances in
which anybody could gain access to these
strains and make morphine beer with a
home-brew kit, she says. They dont acknowledge that when you have these highly
engineered strains, they dont grow well.
Although Dueber and Martin have assembled most of the pieces for morphine
production in yeast, their main interest is
in using the yeast as a platform for synthesizing new natural products. In the case of
morphine, the main benefit would not be
making a direct replacement of morphine
but making an analog of morphine that has
better properties, Dueber says.
The platform gives the researchers the
ability to produce chameleon molecules,
Martin says. These compounds, such as
(S)-reticuline and thebaine, could be used
in a variety of reactions to make many different structures.
And that potential as a platform for
natural product diversification is exactly
why Dueber and Martin are so eager for the
regulatory conversation to start now.
No one can make morphine and codeine from glucose at this stage. Were just
publishing the recipe, Martin says. Lets
deal with this now. The last thing we want
to do is shelve a really useful technology because of the perceived potential for risk.

ACS COMMENT

Revised Undergraduate Guidelines

THOMAS J. WENZEL, CHAIR, AND CLARK R. LANDIS, VICE CHAIR, COMMITTEE ON PROFESSIONAL TRAINING

for a certified degree. Most compelling to

CPT is the fact that the properties of large
molecules and aggregated systems are different from those of small molecules and
that students need to understand these differences. The effect of scale
on the properties of matter
emerges in several related
areas. Therefore, the 2015
guidelines require that the
curriculum for certified
graduates include the principles that govern macromolecular, supramolecular,
mesoscale, and nanoscale
systems. Although a
dedicated in-depth course
would meet this requirement, we anticipate that
most departments will
distribute these principles
across multiple courses required for the certified degree.
Another change in the 2015 guidelines
involves equipment that students use in a
hands-on fashion. A functioning nuclear
magnetic resonance spectrometer for undergraduate use remains a
requirement. In addition,
students completing a certified degree will now need
hands-on use of on-site
equipment from at least four
of five categories: optical
molecular spectroscopy,
optical atomic spectroscopy,
mass spectrometry (including GC/MS and LC/MS),
chromatography and separations, and electrochemistry.
Furthermore, several facets
of safety infrastructure
and practices have been
Landis
strengthened in the 2015
guidelines.
The roles of online and virtual instruction
in the curriculum are evolving rapidly. CPT
recognizes that some online instruction
can enhance learning but that it presents
guideline challenges. One concern relates to
faculty workload and the amount of credit
awarded for online classes. The 2015 guidelines state that online activities that are substitutes for classroom instruction should be
CEN.ACS.ORG

33

JUNE 1, 2015

assigned at least the same instructor contact

hour value as equivalent face-to-face classroom experiences. Another concern relates
to the quality of the experience for the student. The 2015 guidelines state that courses
taught partially or wholly online should provide at least the same skill development and
content as the corresponding face-to-face
experience. General chemistry lab experiences that prepare students for foundation areas must be primarily hands-on and
supervised. CPT will continue to work with
the community for insights about the scope
of these modes of instruction within the
chemistry curriculum.
The 2015 guidelines continue to emphasize flexibility in designing curricula.
Curricular innovation is encouraged. The
guidelines dont specify topics to be covered
in foundation courses, although CPT does
publish supplements that provide guidance on common topics and skill-building
activities within these areas. We encourage
the use of active-learning pedagogies in the
classroom and lab in order to promote student skill development in areas of problem
solving, chemical literature and information
management, laboratory
safety, oral and written communication, teamwork, and
ethics.
Throughout the revision
process, CPT attempted to
balance desired attributes
such as excellence, rigor,
and continual improvement
against flexibility, which in
turn fosters innovation and
enables adaptation to the institutions environment.
We thank the community
for participating in our efforts. Many people attended
open meetings that we held
throughout the process and sent comments
to us. That feedback was essential in helping
us craft the final set of guidelines. We look
forward to working with the community in
the implementation of the 2015 guidelines
and promoting continued excellence in undergraduate chemistry education.
COU RTESY OF CLARK R. LANDIS

Societys Committee on Professional Training (CPT) has been responsible for approving chemistry programs to offer certified
undergraduate degrees. The ACS guidelines,
which set standards aimed at
desired learning outcomes
and the resources needed
to provide an excellent and
rigorous education, have
evolved over the years to
keep up with changes in
education and the chemistry
profession. CPT approved
revised guidelines and evaluation procedures for bachelors degree programs at its
January 2015 meeting in New
Orleans. The guidelines can
be found, with supplemental
documents, on the CPT web- Wenzel
site at www.acs.org/cpt.
As CPT evaluated programs under the
previous version of the guidelines, which
were released in 2008, it became apparent
that revisions were needed to provide programs with additional flexibility. One example concerns limits on maximum teaching contact hours with students. The limits
were intended to ensure that faculty and
instructors have enough time for grading,
curriculum and professional development,
research, and other professional activities.
Some programs were out of compliance
because uneven teaching loads from one
term to another caused violations of the
guidelines. We heard from the community
that teaching schedules with alternating
busier and lighter terms could enable more
research and curriculum development,
activities that CPT wants to promote. Also,
laboratory instructors had problems meeting the limit of 15 contact hours per semester when lab sections were four hours long.
As a result, we modified the guidelines.
Other changes in the 2015 guidelines
seek to improve student preparation for
postbaccalaureate careers. However, the
committee does not prescribe a one-sizefits-all curriculum for approved programs.
Consider polymers, which are important
to society and a major source of jobs for
professional chemists. CPT debated the essential role of polymers in the curriculum

PHYLLIS GRABER JENSEN

FOR 75 YEARS, the American Chemical

Views expressed on this page are those of the

authors and not necessarily those of ACS.

PEOPLE

ELI PEARCE DIES AT 86

Polymer chemist, ACS PAST-PRESIDENT supported
women and minorities in the sciences

sor at New York University Polytechnic

School of Engineering and a past-president
of the American Chemical Society, died at
a Brooklyn hospital on May 18 of complications from a broken hip and kidney disease.
Eli was extraordinary in so many
waysa brilliant polymer scientist, a great
leader at his university and
within ACS, a passionate
advocate for chemistry
education reform, and a
man who worked tirelessly
his entire life for everyday
chemists and to ensure that
women and minorities had
equal opportunities for
advancement in society and
in their professions, says
Madeleine Jacobs, former
ACS executive director and
chief executive officer who
worked closely with Pearce.
Born Eli Perlmutter to Russian immigrants, Pearce changed his name as a young
man to circumvent anti-Semitism in the
working world. He received a B.S. degree in
chemistry from Brooklyn College in 1949
before serving in the Army during the Korean War.
Pearce earned a Ph.D. in chemistry from
Polytechnic Institute of Brooklyn (now
NYU Polytechnic School of Engineering)
in 1958, studying under polymer chemistry
pioneer Herman F. Mark and completing
his thesis with Charles G. Overberger.
Early in his career, Pearce worked for
DuPont, J.T.Baker, and Allied Chemical
before becoming director of the Dreyfus
Laboratory at Research Triangle Institute.
In 1974, Pearce accepted an invitation from
Mark to join the faculty at Polytechnic Institute of Brooklyn.
Pearce was named University Professor
of Chemistry & Chemical Engineering in
1990; he served as director of the Polymer
Research Institute from 1980 until 1996
and as dean of arts and sciences from 1982
until 1990.
He published more than 250 papers on
his research, which focused on polymer
synthesis, degradation, and flammability.

Pearce garnered many awards, including the 2006 H. F. Mark Medal from the
Austrian Research Institute for Chemistry
& Technology. In 2009, he was named an
ACS Fellow.
An emeritus member of ACS, Pearce
served as the societys president in 2002
and director-at-large on the ACS Board of
Directors from 1999 until
2000 and again from 2001
until 2003. He was also a
councilor with the Polymer
Chemistry Division from
1982 until 1998 and an ex
officio councilor from 2004
until 2015.
Pearce was a strong supporter of the ACS Committee on Minority Affairs and
the ACS Scholars Program
and was instrumental in establishing the Senior Chemists Committee, Jacobs says.
Pearces first marriage, to Maxine
Horowitz, ended in divorce. His second
wife, Judith, to whom he was married for
32 years, died in 2012. He is survived by his
son, Russell; his daughter, Debra PearceMcCall; his stepson, Michael Ruby; his
stepdaughter, Elizabeth Ruby Lyden; and
10 grandchildren.SUSAN AINSWORTH
PETER CUTTS PHOTOGRAPHY

Eli M. Pearce, 86, a retired research profes-

OTHER OBITUARIES
David John Ager, 62, a principal scientist

at DSM and a fine chemicals expert, died in

Raleigh, N.C., on April 25.
Born in Northampton, England, Ager
received a B.Sc. in
chemistry at Imperial
College London in 1974
and a Ph.D. in organic
chemistry at Trinity
College at the University of Cambridge in 1977.
After working as a
postdoc at the University of Southampton
and a senior demonstrator at the University
of Liverpool, Ager moved to the U.S. in 1982
to become an assistant professor of chemCEN.ACS.ORG

34

JUNE 1, 2015

istry at the University of Toledo in Ohio.

In 1986, he started his industrial career
at NutraSweet Co., developing expertise
in fine chemicals and pharmaceutical
intermediates. He worked as a fellow at
NSC Technologies from 1995 until 1999,
when he joined Great Lakes Fine Chemicals. Ager was also founder and director of
two consulting companies: RCCorp and
54 Inc.
In 2002, Ager joined DSM as a competence manager. In 2006, he was named a
principal scientist with DSMs pharmaceutical products business group in Greenville, N.C. He played a pivotal role in the
recent launch of DSM InnoSyn, a process
R&D service unit.
During his career, Ager was credited
with several patents, authored many journal articles on chiral chemistry, contributed to chemistry textbooks, and served as an
expert witness in federal patent litigation.
He joined ACS in 1982.
Agers wit, vibrant personality, broad
knowledge, and lecturing skills made him
a sought-after speaker at international
symposia for decades, according to his
colleagues.
He is survived by his wife, Susan LaJoie;
daughter, Tracy Bourdon-Thomas; sons,
Steven, Christopher, and Paul; stepson,
Graham LaJoie; stepdaughter, Christine
LaJoie; and eight grandchildren.SJA
Newman Bortnick, 93, a retired Rohm

and Haas corporate research fellow and a

former member of the
ACS Board of Directors, died in Andorra,
Pa., on April 20.
Born in Minneapolis, Bortnick earned
a B.S. in chemistry
in 1941 and a Ph.D. in
organic chemistry in
1944, both from the
University of Minnesota, Twin Cites.
He then began a long career with Rohm
and Haas, rising through the ranks to become a corporate research fellow.
Bortnicks work led to the discovery,
development, and manufacture of acrylic
and engineering plastics. He discovered
Primene tertiary alkyl primary amines,
which are formulated into lubricants and
fuel additives, industrial surfactants,
solvent-based dyes, and oil-based metalworking fluids and are also used as oilfield and refinery chemicals and chemical
intermediates.

He is credited with more than 100 patents and numerous scientific articles. After
retiring in 1990, he remained a consultant
to Rohm and Haas until he was 89.
Bortnick was an emeritus, 75-year
member of ACS. He was a councilor for the
Philadelphia Section from 1968 until 1982
and again from 1990 until 1998 and served
on the board of directors as a director-atlarge from 1983 until 1988.
Bortnick was also a fellow of the American Association for the Advancement of
Science and the Royal Society of Chemistry
and a lifetime member of the Chemical
Heritage Foundation.
In 2000, he received the Outstanding
Achievement Award from the University of
Minnesota.
Bortnick was an active member of the
Springfield Township, Pa., community and
supported the Philadelphia Orchestra as
well as many other arts, social service, and
civic organizations.
His colleagues remember him warmly
for his many contributions to science and
society, for being an upbeat and effective
mentor, and for his love of adventure, international travel, and family.
His wife Lillian, to whom he was married
for nearly 70 years, died in 2012. He is survived by his son, Karl; daughters, Lynn Bergman and Wendy Lefkowich; six grandchildren; and three great-grandchildren.SJA
David G. Karraker, 91, a retired Savannah

River National Laboratory researcher,

died in Aiken, S.C., on
Feb. 27.
Born in Anna, Ill.,
Karraker served in the
Army during World
War II. He completed
a B.S. in chemistry
and mathematics
from Southern Illinois
University in 1947 and
a Ph.D. in chemistry at the University of
California, Berkeley, in 1950.
Early in his career, he worked at Argonne
National Laboratory before joining Oak
Ridge National Laboratory. In 1953, he
moved to Savannah River National Laboratory, where he would remain for 53 years.
Karraker was an authority on actinide
chemistry, according to colleagues. He also
developed expertise in Mssbauer spectroscopy, focusing on the study of neptunium.
Karraker joined ACS in 1958 and was an
emeritus member.
According to his family, he enjoyed play-

ing tennis and duplicate bridge, listening to

jazz, reading, raising camellias, and traveling overseas.
Karrakers wife of 62 years, Mildred,
died in 2011. He is survived by his son,
Mark; daughters, Emily Owens and Frances
French; and six granddaughters.SJA
James A. Kiernan Jr., 94, a retired Merck &

Co. executive, died at his home in Naples,

Fla., on April 17.
After growing up in Maplewood, N.J.,
Kiernan earned a B.A.
in chemistry from Cornell University in 1942.
He served in the Navy
during World War II as
a communications officer on the U.S.S. Picket
in the Pacific Fleet.
Kiernan then carved
out a 40-year career
with Merck, working primarily at various
locations in New Jersey. For five years, he
was managing director of the firms pharmaceutical facility in So Paulo, Brazil. He
was an emeritus, 72-year member of ACS.
He was a life master bridge player and a
longtime member of Baltusrol Golf Club in
Springfield, N.J., where he won numerous
tournaments.
Kiernan is survived by his son, James III;
daughters, Mia Laughlin and Kristina; six
grandchildren; and one great-granddaughter. His wife of 62 years, Patricia, predeceased him in 2005.SJA
William P. OConnor Jr., 61, a retired in-

dustrial chemist, died in Pittsburgh on

March 29 from complications after a stroke.
Born in Munich to American parents,
OConnor received a B.S. in chemistry from
the University of Pittsburgh in 1979. He
earned a masters degree in chemistry from
Duquesne University in 1989 and an M.B.A.
from the University of Pittsburghs Katz
Graduate School of Business in 2000.
OConnor spent most of his career as a
research chemist with Neville Chemical
in Pittsburgh before retiring in 2005. He
joined ACS in 1982.
He loved chemistry and had a variety of
other interests, including music, according
to his fiance and lifelong companion, Joyce
Bevc. He played drums in several bands.
In addition to Bevc, survivors include his
sister, Mary Elyse Kaye, and his niece and
nephews.SJA
Richard P. Wool, 67, a professor of chemical
CEN.ACS.ORG

35

JUNE 1, 2015

and biomolecular engineering and director

of the Affordable Composites from Renewable Sources (ACRES)
laboratory at the University of Delaware,
died on March 24.
Born in Cork, Ireland, Wool completed
a B.Sc. in chemistry
with honors at University College in Cork in
1970. He earned an M.S.
in 1972 and a Ph.D. in 1974, both in materials science and engineering from the University of Utah.
After serving as an assistant professor
of chemical engineering at City College of
New York from 1975 until 1977, Wool moved
to the University of Illinois, Urbana-Champaign, where he was a professor of materials science and engineering until 1994.
He then moved to the University of
Delaware to serve as director of the Center
for Composite Materials and a professor of
chemical engineering. Later, he launched
the universitys ACRES program.
In his research, Wool and his colleagues
used a broad range of sustainable feedstocks
to make pressure-sensitive adhesives, composite resins, foams, and synthetic leather.
He published more than 200 papers and
two books and is credited with six patents.
He was chief executive officer and founder
of Crey Bioresins and Eco-Leather Corp.
Wool served as a guest professor at Trinity College Dublin in 2002, cole Polytechnique near Paris in 1991, and the Polytechnic University of Milan in Italy in 1984.
In 2013, he received the Presidential
Green Chemistry Challenge Award sponsored by the Environmental Protection
Agencys Office of Chemical Safety & Pollution Prevention in partnership with ACS
and other groups. In 2011, Wool received the
ACS Award for Affordable Green Chemistry.
He was a fellow of the Royal Society of
Chemistry and the American Physical Society. He joined ACS in 1974.
His family remembers him for his generosity, kindness, humor, wisdom, and love
of sailing and playing his guitar.
He is survived by his wife, Deborah,
whom he married in 1969, and daughters,
Sorcha Rocklein, Meghan, and Breeda.SJA
Obituary notices of no more than 300
words may be sent to Susan J. Ainsworth at
s_ainsworth@acs.org and should include an
educational and professional history.

ACS career tips

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NEGOTIATE. As circumstances change,

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OPTIMIZE ONE CAREER. Another approach to solving the two-body problem is
to designate one persons career as primary, and all decisions are made to optimize
that career path. The other partner works
around that limitation, usually by moving
into a more flexible career path. Although
this allows one partner to succeed to the
best of his or her ability, the other partner
will have to be creative in finding work. The
partners will need to guard against resentment caused by the feeling of giving up my
career or the pressure of being the primary
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LEARN TO LOVE TRAVEL. Sometimes,
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and it becomes necessary for the partners
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strain of maintaining two households,
as well as the emotional strain of
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be worked out with current employers, or

is finding a new employer, or even a new
career, going to be required? Or in different
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ALL OF THE ABOVE. Many couples dont
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out fairly. Whats important is to make all
decisions jointly and discuss changes in
roles and responsibilities as they occur.
In the end, something will have to give. It
may be one career, or it may be the structure of the relationship itself. By carefully
considering and discussing all possible options, couples can arrive at the decision that
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THE DEPARTMENT OF CHEMISTRY at Temple

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newscripts
LESSONS IN LOVE AND CHEMISTRY

ACS members visit

www.ACSInsightLab.com/
JoinNow
to fnd out more
and join today!

CEN.ACS.ORG

40

JUNE 1, 2015

MIK AKO MIKURA

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ACS Insight Lab!

immy and Mary

conception may play a role in
sitting in a tree,
a babys health. Working with
K-I-S-S-I-N-G. First
mice, the researchers found
comes love, then comes
that folic acid deciency
marriage, then comes Jimmy
led to epigenetic changes
Jr. in the baby carriage!
in sperm that resulted in a
This timeless ditty has long
30% increase in birth defects
served as a useful social com(Nat. Commun. 2013, DOI:
mentary on puppy love and
10.1038/ncomms3889).
relationships. Being June, the
Scientists have previously
month most associated with
shown that low folic acid levweddings, Newscripts ofers
els in moms during pregnanJimmy and Mary: Folic
a sampling of recent research
cy are linked to birth defects.
acid is key.
on ROMANCE AND ITS
The researchers suggest that
CONSEQUENCES, from the
fathers with unhealthy habits
tree to the baby carriage and beyond.
may have lower levels of folic acid and
First, in order to get to the tree, anthromay not metabolize it in the same way as
pologists at the University of Utah provide
healthier dads-to-be.
evidence that Jimmy has evolved better
In another study with folic acid connecnavigation skills than Mary. By testing
tions, researchers in Norway took a look
and interviewing members of the Twe and
at old church records to determine that
Tjimba tribes in Namibia, the researchers
exposure to diferent levels of ultraviolet
found that the men were signicantly betradiation during the suns 11-year solar cycle
ter than the women in visualizing spatial
has an impact on birthrate and life expecrelationships and manipulating images in
tancy (Proc. R. Soc. B 2015, DOI: 10.1098/
their minds (Evol. Hum. Behav. 2014, DOI:
rspb.2014.2032). They found that children
10.1016/j.evolhumbehav.2014.09.009).
born in extra-sunny yearsthat is, years
The men traveled a lot more than the
with a lot of sunspots and maximum solar
women, and the men who did best on the
activitylived on average 5.2 fewer years
tests had traveled farthest and had children
than children born in years with the lowest
with more women. The study ofers another
solar activity. The overexposed children also
cog in the wheel of human evolution, in this
had fewer children and fewer grandchildren
case the relationship between navigation
than those born during the suns lulls.
and reproductive success. The authors did
not comment on the male preference of
refusing to stop to ask for directions when
lost, even when politely asked to do so.
As to falling in love, scientists have
known that humans bond emotionally
as we gaze into each others eyes, which
is a process mediated by the hormone
oxytocin. Japanese researchers have now
shown that mutual gazing also mediates
bonding between us and our dogs (Science
Oxytocin gaze: Mutually chemical
friends.
2015, DOI: 10.1126/science.1261022). This
nding seems to be important for couples
like Jimmy and Mary who might decide to
Sunlight promotes production of vitaget a dog as a test run for having kidsthe
min D, but it also can degrade folic acid. The
oxytocin gaze is critical for helping moms
Norwegian researchers suspect a connecbond with their newborns.
tion with their ndings. There are probably
The researchers found via urine testing
many factors that come into play, they
that oxytocin levels spike in both humans
note, but the conclusion of our study is that
and canines when the two species interact.
you should not sunbathe if you are pregnant
This instinctual bonding mechanism likely
and want to have a lot of grandchildren.
played a role in the domestication of dogs,
they believe.
Speaking of having children, researchSTEVE RITTER wrote this weeks column.
ers in Canada have found that Jimmys diet
Please send comments and suggestions to
and smoking and drinking habits before
newscripts@acs.org.
SHUTTERSTOCK

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