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Canada’s leading magazine for the chemical sciences and engineering.
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September 2012
Canadian Chemical News | l’actualité chimique canadienne
SMALL-TOWN PHARMA
www.accn.ca� Chemical Institute of Canada
September 2012
Canadian Chemical News | l’actualité chimique canadienne
burning biofuels under the hood
Antibiotics in the wake of wonder drugs
Canadian Chemical News | l’actualité chimique canadienneCanadian Chemical News | l’actualité chimique canadienne
SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN
Canadian Chemical News | l’actualité chimique canadienneCanadian Chemical News | l’actualité chimique canadienne
SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN PHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMA
Canadian Chemical News | l’actualité chimique canadienne
SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN SMALL-TOWN
burning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hood
PHARMAPHARMAPHARMAPHARMAPHARMAPHARMAPHARMAburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hoodburning biofuels under the hood
Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake Antibiotics in the wake of wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugsof wonder drugs
September 2012 CAnAdiAn ChemiCAl news 3
Departments From the editor
letters to the editor
Guest ColumnBy Cathleen Crudden
Chemical news By Tyler Irving
society news
ChemFusion By Joe Schwarcz
5
6
9
10
29
30
TAble oF ConTenTs
FeaturesSeptember 2012 Vol.64, no.8
ChemisTry
ChemiCAl enGineerinG
business
burning QuestionsFinding the next incarnation of the combustion engine in the age of biofuels . By Sylviane Duval
small Timethe venom of a small rodent sparked a small drug company in a small New brunswick town. expectations for success are big.By Anita Lahey
16
24
20 waning of the wonder drugsWith bacterial resistance on the rise, where will we get the drugs of the future?By Tyler Irving
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national Chemistry week!october 13-21, 2012
NCW is an annual, week-long, celebration of the chemical sciences in Canada. it presents a great opportunity for youth to get connected with the wonders of the chemical sciences. get your children, classrooms and/or colleagues involved.
visit www.cheminst.ca/outreach
highlighted activities of 2012: Canadian Water experiment, “It's Chemistry, Eh!? ” youtube Contest, National Crystal growing Competition
Outreach
golD SpoNSorS Silver SpoNSorS
Canadian Society for Chemical technology | Professional Development
laboratory safety Course
disCounT FOR CIC/CSCT
memBers
Course outline and registration atwww.cheminst.ca/profdevContinuing professional Development presented by the Chemical institute of Canada (CiC) and the Canadian Society for Chemical technology (CSCt).
september, 17–18, 2012toronto, ont.For chemists and chemical technologists whose responsibilities include managing, conducting safety audits or improving the operational safety of chemical laboratories, chemical plants and research facilities.
advance your professionalknowledge and Further your Career
September 2012 CAnAdiAn ChemiCAl news 5
From The ediTor
exeCutive DireCtorroland Andersson, mCiC
eDitor Jodi di menna
NeWS eDitorTyler irving, mCiC
art DireCtioN & graphiC DeSigNKrista lerouxKelly Turner
CoNtributiNg eDitorSPeter CalamaiTyler hamiltonTim lougheed
SoCiety NeWSbobbijo sawchyn, mCiC Gale Thirlwall
marketiNg maNagerbernadette dacey, mCiC
marketiNg CoorDiNatorluke Andersson, mCiC
CirCulatioN michelle moulton
FiNaNCe aND aDmiNiStratioN DireCtorJoan Kingston
memberShip ServiCeS CoorDiNator Angie moulton
eDitorial boarDJoe schwarcz, mCiC, chairmilena sejnoha, mCiCbernard west, mCiC
eDitorial oFFiCe130 Slater Street, Suite 550ottawa, oN k1p 6e2t. 613-232-6252 | F. [email protected] | www.accn.ca
SubSCriptioN rateSgo to www.accn.ca to subscribe or to purchase single issues. the individual non-CiC member subscription price for 2012 is $100 CDN. the institutional subscrip-tion price for 2012 is $150 CDN. Single copies can be purchased for $10.
ACCN (Canadian Chemical News/ L’Actualité chimique canadienne) is published 10 times a year by the Chemical institute of Canada, www.cheminst.ca.
recommended by the Chemical institute of Canada (CiC), the Canadian Society for Chemistry (CSC), the Canadian Society for Chemical engineering (CSChe), and the Canadian Society for Chemical technology (CSCt). views expressed do not necessarily represent the official position of the institute or of the Societies that recommend the magazine.
ChaNge oF [email protected]
printed in Canada by Delta printing and postage paid in ottawa, ont.publications mail agreement Number:40021620. (uSpS# 0007–718)
indexed in the Canadian business index and available online in the Canadian business and Current affairs database.
iSSN 0823-5228
visit us at www.accn.ca
the fundamental purpose of any good magazine, in my view, is to make
people think. To relay information? Sure. To entertain with good story-
telling? Certainly. To report on important developments? Absolutely.
But ultimately, if we can engage a community of readers in a dialogue on a relevant
and topical subject, we’ve been successful.
That’s why our “Letters to the Editor” pages are so important. This is where we
can publish your points of view. Your comments help us to keep the discussion
alive with the rest of our readership, who, we know from experience, very much
want to read what their peers have to say in response to the stories we publish or
about something happening in the subjects we cover.
Lately, we’ve been getting several letters: insightful, thought-provoking, articu-
late letters. We couldn’t be more thrilled. You can read three of the most recent
letters we’ve received on pages six and seven of this issue. Keep the e-mails to the
editor coming! We’ll print your ideas and in this way help connect you to your
fellow readers.
In this issue we attempt to provoke your thoughts with a report by expert
story teller Anita Lahey. She writes about a company in New Brunswick that
illustrates how small enterprises are increasingly taking on the high-risk early
stages of pharmaceutical research. In our Q and A, we talk to Gerry Wright
about how our approaches to creating antibiotics are shifting in the face of
resistant strains of bacteria. We then move on to the question of how combus-
tion engine designs are evolving in the age of biofuels.
Hope you enjoy the read!
Write to the editor at [email protected]
6 CAnAdiAn ChemiCAl news September 2012
wither are you going, dFo?
The media has recently reported that Fisheries and Oceans
Canada (DFO) is closing its environmental chemistry and toxi-
cology programs. This action is short-sighted. I worked almost
33 years at DFO’s St. Andrews Biological Station (SABS) in St.
Andrews, N.B.
In 1988 DFO decided to separate chemistry and biology
and to place them in different organizational structures
and sometime in the 2000s, went a step further and orga-
nized two specialized chemistry centres, one on each coast.
These centres now appear to be closing. Instead of in-house
expertise and laboratories, DFO will rely on contracts for
environmental chemistry and toxicology work.
State-of-the-art analytical chemistry equipment is
very expensive and cannot be duplicated in several loca-
tions; maintaining it in just one or two laboratories is a
good decision. On the other hand, chemical expertise
and routinely-equipped laboratories should be present
in all DFO’s research establishments. Contracts cannot
replace them. Contracts are suitable for well-defined
tasks with precise endpoints, provided the results are
checked by in-house knowledge. Contracts are useless for
exploratory projects.
When I began work with the water pollution section (WPS)
of SABS in the late 1960s, my first project was to participate
in a study of salmon movement in the Miramichi estuary.
I concentrated on organic chemicals whose major sources
were two pulp mills and a wood-preserving plant, which
used, as it was common knowledge, creosote. I soon detected
a high concentration of pentachlorophenol in the effluent.
At the same time, WPS was also studying acidification of a
river receiving a tailings pond effluent in northeastern New
Brunswick. The investigation was carried out by a contract
awarded to a university and by in-house measurement of heavy
metals and pH in water samples. No cause of the acidification
was found, but when I added hydrochloric acid to a sample,
release of colloidal sulfur showed that the acidification was
caused by thiosalts formed by oxidation of pyrite in the mine’s
concentrator, and the rest is history.
Shortly afterwards, SABS was called on to investigate
massive herring kills in Long Harbour, Nfld. suspected to be
caused by yellow (elemental) phosphorus. Our tests demon-
strated its high toxicity to herring. Since it’s also highly toxic
to humans, this was dangerous work and could not have been
carried out without an in-house lab and chemical expertise.
As a result of our work, a company accepted responsibility for
the fish kills.
In another example from my time with DFO, a survey
of DDT in freshwater and marine fish was performed by a
contract, without in-house quality control. The contrac-
tor’s report did not mention PCBs, or even the presence
of unidentified peaks in the gas chromatograms, although
PCBs must have been present. This again is an example of
a failed contract, since, among other things, PCBs interfere
with the measurement of DDT.
These examples illustrate the importance of on-site labs
and chemical expertise, and the impossibility of replacing
such studies by contracts. There is a need to maintain
chemical and toxicological expertise in all DFO research
establishments. In response to the decision to eliminate it,
I wonder “Quo vadis DFO?” [Whither are you going, DFO?]
Vladimir ZitkoSt.Andrews, N.B.
budding business
Alanna Mitchell’s article “Water Works” (July/August 2012)
bemoans the fact that good ideas developed in the science
halls of our universities do not make it “out of the lab.” (One
exception pointed out was, sadly, picked up by a French
company, not a Canadian company.)
Most universities have a faculty dedicated to entrepre-
neurial pursuits. It seems obvious that the science folks
should partner with these budding business people to bring
the former’s ideas to fruition.
Indeed, within a university, there should be a requirement for
these two disciplines to cooperate by assigning a potential “good
idea” to a senior or graduate business student as a bachelor’s or
master’s project with the object of developing the idea into a
viable business model. I see a place for the engineering depart-
ment to become involved as well.
Gordon A. BoyceDartmouth, N.S.
leTTers To The ediTor
September 2012 CAnAdiAn ChemiCAl news 7
Correction: The Kingston, Ont. company, PARTEQ
Innovations, does not receive paid industry sponsors as stated
on page 25 of the July/August 2012 issue (“Water Works” by
Alanna Mitchell). The sponsors mentioned are associated with
PARTEQ’s spinoff, GreenCentre Canada.
Write to the editor at [email protected]. Letters are edited for length and clarity.
leTTers To The ediTor
ethics radar pinging
In response to the latest Canadian science budget (Letters
to the editor, , June 2012), I am feeling increas-
ingly torn. I am so fortunate to have a dynamic, wonderful
research group of motivated and ambitious students,
post-docs, undergraduates and others (our highly quali-
fied personnel!), and the most important thing I can do,
as their supervisor, is to repay their effort and loyalty by
supporting them for the rest of their careers as best I can.
I am torn because, in the past, I did everything in my
power to help them find their first “real” jobs in Canadian
academia, government and industry, and I will of course
continue to do so if that is their wish. However, these
days, with respect to academia, my ethics radar is pinging
loudly because I am concerned about the future of young
researchers in this country. I sense a moral dilemma. Can
we continue to promote academia to our young people when
they are faced with substantial cuts that potentially under-
mine their ability to do their job, if they can even get one?
Scholarships and equipment grants are under attack, and
these cuts hurt young people far more than older, estab-
lished people like me. Even the number of new professorial
jobs that I could see this year in Canada was very low as
universities grapple with budget challenges. Minor top-ups
to “starting” Discovery Grants do little to help these
new professors get their programs kick-started. We are
competing now with aggressive and highly funded universi-
ties in the Middle East, Asia and Europe that are wooing
our best and brightest with an increasingly loud siren call;
I've now personally witnessed top young Canadian-trained
highly qualified personnel move to assistant professor posi-
tions in Saudi Arabia, Germany, Korea and China in the
past two years thanks to funding packages that will allow
them a fair chance.
To lose a generation of researchers will be devastating to
Canadian science. We have little time to act to prevent this
enormous loss of talent.
Jillian BuriakProfessor of Chemistry
University of Alberta
September 2012 CAnAdiAn ChemiCAl news 9
Making molecules matter
l ast May, I left the 95th Canadian
Chemistry Conference and
Exhibition in Calgary full of
enthusiasm for my coming year as CSC
president. In particular, I was invigo-
rated by the enthusiasm for the Canadian
Society for Chemistry’s increasing role as
an advocate for science.
Advocacy is a complicated subject.
We were lucky in Calgary to have
Howard Alper, the current chair of
the Government of Canada’s Science,
Technology and Innovation Council,
NSERC president Suzanne Fortier and
University of California, San Diego chan-
cellor Marye Anne Fox, provide advice on
how best to advocate for science.
In my role as president of the CSC,
increasing our efforts at advocacy is at
the top of the list of things I plan to
accomplish. So when I finally boarded
the plane home from the conference,
I was energized for the coming year,
but also a touch tired after a week of
activities. When Rebecca — a talkative
40-something waitress — sat down
beside me, I saw my chances of catching
up on sleep evaporating.
Eventually Rebecca asked me what
I did. When I told her I was a chemist,
she asked what I “actually” did. So I told
her I was an organic chemist, and worked
on a class of molecules that have right-
and left-handed forms. I talked about
how these molecules have a big impact
on a variety of industries, including the
pharmaceutical industry, but how most
people don’t appreciate the impact that
handedness has on the properties of a
molecule. Before I got further, she asked:
“What’s a molecule?” Switching gears,
I talked about atoms and how they’re
by Cathleen Crudden
arranged in groups to make molecules,
and how chemists can actually control
this, including even how atoms are
arranged in space. A great example is
CH3CH2OH (ethanol, which we both
agreed is a very respectable and tasty
molecule) and its isomer CH3OCH3,
which has exactly the same number and
type of atoms, just arranged differently.
Rebecca was surprised to hear that this
new molecule had completely different
properties and was not at all something
you would want in a drink, even if it
wasn’t a gas at room temperature.
From there, we moved into the
discussion of research funding, and
I used the example of green energy.
Undoubtedly part of our energy future
will involve solar, wind and other
alternative energy choices, Rebecca
agreed. However, if we don’t invest now
to support early stages of research in
these areas, Canada will be buying such
technologies in the future, rather than
selling them. Surely that’s not where we
want to be as an advanced nation.
Of course it gets more complicated
when one realizes that predicting
tomorrow’s great discoveries is not a
trivial matter. Take NMR (Nuclear
Magnetic Resonance) spectroscopy
for example. When this technique was
first invented, it was thought to be a
toy for physicists. But now, this is one
of the most important tools in chem-
istry that allows us to look at molecular
structure. Perhaps more importantly,
NMR forms the basis of Magnetic
Resonance Imaging (MRI), something
that changes the lives of multitudes of
Canadians every day. The laser, the
telephone, digital cameras: these are all
examples of incredibly useful inventions
that came out of basic research.
Funding science is tricky business. Yes,
it’s very important to fund research that
will make an impact on people’s lives in
the near term. We can all understand the
value of things like energy, health, infor-
mation technology and green chemistry.
But equally important is funding research
for which the objectives may not be
immediately obvious, because predicting
the future is also a difficult task.
Luckily investing in the future isn’t.
NSERC and the other granting coun-
cils have a great track record of funding
research excellence in all its iterations
from basic to applied, and money given
to them to fund Canadian research goes
extremely far. So continued invest-
ment in NSERC, CIHR and the Social
Sciences and Humanities Research
Council of Canada (SSHRC) is a great
way to support the future of science and
the future of Canada.
Most importantly, scientists must
take the time to advocate for science.
What I learned on my plane ride from
Calgary is that being an advocate
doesn’t just mean talking to politicians
and policy makers. It also means talking
to people like Rebecca, and taking the
time to convince Canadians who don’t
necessarily work in the sciences of the
importance of what we do with their
tax dollars. If we’re successful, research
funding can be a priority for all of us.
Cathleen Crudden is the 2012-2013 President of the Canadian Society for
Chemistry and a professor in the Department of Chemistry at Queen’s University.
To find out more about the CSC’s advocacy initiatives go to www.cheminst.ca.
GuesT Column
10 CAnAdiAn ChemiCAl news September 2012
ChemiCAl news
EArTh ChEmISTry
the discovery of a bacterium that can use arsenic instead of phosphorus to construct its DNa is ‘flim-flam.’ that’s according to uni-versity of british Columbia micro bio logist rosie redfield, who this summer published what she says is the final word on the con-troversy that has come to be known by its twitter hashtag, #arseniclife.
in December 2010, Felisa Wolfe-Simon and her colleagues at the NaSa astrobi-
Canadian research disproves arsenic-based DNA
Neutralizer assay improves biological sensing
hEALTh
DNa probes designed to detect specific biomolecules coat the tips of gold electrodes, like these ones embedded in a silicon chip. a new assay developed at the university of toronto pairs each DNa probe with a neutralizer made of peptide nucleic acid (pNa). the technique increases the sensitivity of the probes, and allows for a single chip that can detect hundreds of analytes at once, from adenosine triphosphate (atp) to cocaine.
Imagine a portable electronic device that could analyse blood for up to 180 different components at once: sequences of DNA and RNA, proteins and even small molecules like adenosine triphosphate (ATP). It sounds like science fiction, but a discovery at the University of Toronto is bringing such a device closer to reality.
Electrostatic sensor systems use probes composed of short DNA sequences attached to an electrode. Since DNA is negatively charged, binding of the probe with a complementary strand results in a higher magnitude of charge. This change triggers the reduction of reporter ions electrostatically associated with the DNA strands, creating an electric current that can be measured. How-ever, there are drawbacks. “Traditional assays can only detect molecules with significant negative charges like DNA and RNA,” says Jagotamoy Das, who works under the supervision of Shana Kelley in the Department of Pharmaceutical Sciences at U of T. Additionally, because
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ology institute and the u.S. geological Survey published a paper in Science reporting on a new organism isolated from arsenic-rich mono lake in California. Called gFaj-1, it grew on artificial media that contained high levels of arsenic and very low levels of phosphorus. Secondary ion mass spectrometry (SimS) appeared to show arsenic as-sociated with its DNa.
Days after the publication, redfield posted a rebuttal on her blog. among her many objections was the claim that there wasn’t enough phosphate for growth. “if you starve bacteria for phosphate, they can be very economical with it,” says redfield. “my calcula-tions suggested there was just enough phosphate to explain the amount of growth they saw.” others joined in the fray, pointing out that the arsenate ester bonds that would be required to make arsenic-based DNa are unstable in water, with an estimated half-life of less than one second.
Despite these concerns, the original authors continued to insist that their results were valid and did not retract the paper. redfield then decided to solicit help in trying to replicate the findings herself. in her latest paper, also published in Science, her team used stringent DNa purification protocols that weren’t followed by the original authors. the arsenic dis-appeared, indicating it wasn’t covalently bound to DNa. moreover, the purified DNa was stable in water for months, something that wouldn’t be true of an arsenic-based molecule.
For redfield, the latest publication marks the end of the story. Still, she would have preferred to see a retraction of the original paper. “When researchers publish things that are not true, they should be apologising for them,” she says. “i don’t think anybody has apologised.”
September 2012 CAnAdiAn ChemiCAl news 11
Canada's top stories in the chemical sciences and engineering | ChemiCAl news
A group of researchers at the University of Victoria has dem-onstrated that calixarene molecules can be used to read infor-mation encoded on DNA-packaging proteins called histones. The discovery provides a new tool for the emerging field of epigenetics, the study of heritable information stored in mol-ecules other than DNA and RNA.
In the past, histones were thought of as spools around which DNA was wound. More recently, post-translational modifica-tions to the histones — for example, acetylation or methyla-tion of certain amino acids — have been shown to play a role in determining which genes get expressed at which times. This epigenetic ‘histone code’ can be probed by antibodies in en-zyme-linked immunosorbent assays (ELISAs). But such assays have shortcomings. “Some code elements are really similar and difficult to distinguish,” says Fraser Hof, professor of chemistry at the University of Victoria, noting that the failure rate with antibodies is over 20 per cent.
Hof’s group has been working on an alternative approach based on calixarenes. These cup-shaped macromolecules bind preferentially to certain histone code elements. In a paper re-cently published in the Journal of the American Chemical Society, Hof’s group described a new assay in which various calixarenes, each paired with a fluorescent dye, were exposed to peptides bearing the modifications of the histone code. The dyes were quenched by binding to the calixarenes, but histone code elements compete for the binding site. Since each calixarene has a different affinity for a given code element, a pattern of fluorescent responses results. Taken together, the signals lead to a unique ‘fingerprint’ for each code element.
TEChnIQuES
Calixarene tool kit can read epigenetic codes
Cup-shaped calixarene molecules can bind to the post-trans-lational modifications that are added to the amino acids of proteins called histones. here, a monobrominated p-sulfonatocalix[4]arene (spheres) binds to a trimethyl group (stick figures) which is attached to a lysine residue. Such a system could assist researchers probing the epigen-etic code, which regulates how genes are turned on and off in complex organisms.
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iN D
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the change in charge is often small compared with the background, such sensors are not sensitive enough to detect analytes at low — but still physiologically relevant — concentrations.
The new assay developed by Das and his colleagues relies on a neutralizer made of peptide nucleic acid (PNA). The charge of this synthetic DNA analogue can be tuned by adding cationic amino acids to the end, while its affinity for the DNA probe can be controlled by introducing mismatches to its sequence. A properly designed PNA sequence will neutralize the probe but will be dislodged when the molecule of interest binds to the probe instead. This results in a bigger charge difference than with DNA alone and allows for the detection of neutral molecules, even at low concentrations.
In a paper published in Nature Chemistry, the team shows that the new system works effectively with probes designed for DNA, RNA, ATP and even cocaine. Best of all, the electrodes can be miniaturized and embedded on chips, allowing for fast and portable systems capable of detecting hundreds of analytes simultaneously. A spin-off company founded by Kelley, Xagenic Inc., is working toward developing commercial systems. The technology could have applications in medicine, forensics and many other fields.
A set of only three calixarenes was sufficient to distinguish histone code elements with a high degree of reproducibility. “We really didn't expect this to work so well; I thought we were going to need up to 10 different sensors,” says Hof. Even better, the system works in real time, unlike ELISA. The team hopes it can be used to study the activity of the enzymes that add and remove histone code elements.
September 2012 CAnAdiAn ChemiCAl news 13
Canada's top stories in the chemical sciences and engineering | ChemiCAl news
replaced with tryptophan. The larger number of probes allows researchers to study many areas of the protein at once.
The technique is surprisingly simple, which Michnick says is precisely the point. “I hope this gives the protein community a license to try something that they probably wanted to try but didn’t have the nerve to, because they thought it was crazy,” he says. He adds that the technique could be applied not only to protein folding intermediates, but any conformational change in proteins including allosteric transitions and macromolecular assembly.
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Misfolded proteins are implicated in diseases from Alzheimer’s to Parkinson’s, but tracking the process by which they occur remains one of biochemistry’s greatest challenges. Now, a team at Université de Montréal has shown that a technique based on the fluorescence of tryptophan might be a better tool to probe protein folding than anyone previously thought.
The transitions involved in protein folding are notoriously diffi-cult to study as the half-folded intermediates don’t usually last long enough for their unique signatures to be unambiguously detected by traditional methods such as crystallography or nuclear magnetic resonance (NMR) spectroscopy. An alternate method is based on the fluorescence of tryptophan (while several amino acids exhibit fluorescence, tryptophan’s is the strongest). By measuring changes in the light emitted by excited tryptophan molecules, researchers can glean information about the local environment in a specific part of the protein.
“It has become dogma that tryptophan has to be at least partially buried in the folded structure in order to see a strong change in fluorescence between unfolded and folded states,” says Stephen Michnick, a biochemist at Université de Montréal. In a technical report published in Nature Structural and Molecular Biology Michnick and Alexis Vallée-Bélisle disproved that theory. They created mutant versions of the protein ubiquitin with tryptophan substituted in sites that were exposed on the surface of the protein. Fluorescence spectroscopy showed that even on these sites, the electronic differ-ences between folded and unfolded states was still enough to cause detectable changes in fluorescence. The team went on to create mutant versions of ubiquitin with up to 27 of its 76 amino acids
tryptophan technique illuminates protein folding
in this artist’s impression, yellow tryptophan fluoresces between two assembly states of the protein ubiquitin, which are drawn at a different scale. a team at université de montréal has shown how tryptophan can be used as an effective probe to monitor conformational changes in protein folding.
BIoChEmISTry
PhArmACEuTICALS
Pateamine A could combat muscle wastingCachexia - chronic and irreversible muscle wasting - is a common cause of death in patients with cancer or aiDS. New research shows that a molecule called pateamine a can interfere with the biochemical pathways that cause cachexia, and may point the way toward a therapy.
pateamine a is part of a family of cytotoxins first isolated in the early 1990s from marine sponges in New Zealand. it has since been shown that pateamine a is a general inhibitor of enzymes involved in the translation of genes into proteins. at high doses, this leads to cell death. however, at lower doses, pateamine a has been shown to have anti-tumour and anti-inflammatory effects, although it’s not yet clear how these effects occur.
imed gallouzi is an associate professor in the Department of biochemistry at mcgill university. his group has been studying the molecular mechanisms behind muscle wasting. Since cachexia is often triggered by inflammation, gallouzi theorized that the
anti-inflammatory properties of pateamine a might protect against muscle wasting. in research published in Nature Communications, the team demonstrated that cultures of muscle cells grown in petri dishes and treated with low doses of pateamine a (less than 0.125 μm) were protected from muscle wasting induced by inflamma-tion-causin g enzymes iFNγ and tNFα. those same low doses were also able to prevent muscle wasting in mice exposed to the same inflammation-causing enzymes and in mice injected with cachexia-causing tumours.
Why it is that low doses of pateamine a inhibit cachexia-inducing enzymes but leave others alone is still a mystery that gallouzi and his team are working to nail down. they are moti-vated by the fact that no cachexia therapeutic currently exists. “So far it’s an irreversible condition,” says gallouzi. “if we are successful, we would dramatically improve the quality of life for these patients.”
14 CAnAdiAn ChemiCAl news September 2012
ChemiCAl news
the chirality or “handedness” of its monomer strongly influences the prop-erties of poly(lactic acid) (pla), one of the world’s most popular renewable polymers. both the random (atactic, top) and alternating (heterotactic, middle) patterns result in polymers that are amorphous, with relatively low melting points. in contrast, an isotactic stereo-block (bottom) polymer has a higher melting point. a new class of indium catalysts developed at the university of british Columbia could allow for faster synthesis of stereoblock pla that is more tolerant to impurities like water.
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Indium catalysts improve biopolymer synthesis
For years, starch-derived, biodegradable poly(lactic acid) has been a popular bioplastic, but its market penetration has been limited by undesirable mechanical properties and low heat tolerance. a series of indium catalysts developed at the university of british Columbia could provide a solution.
poly(lactic acid) (pla) is made by ring-opening polymerization of lactide, which itself is a condensed dimer of lactic acid. because lactic acid is chiral, there are several forms of pla. both the left-handed l form (plla) and the right-handed D form (pDla) have rela-tively low melting points, as do random (atactic) mixtures or alternating (heterotactic) mixtures of the two. however, if the polymer is made as a stereoblock - a chunk of plla followed by a chunk of pDla - its heat tolerance increases significantly.
ubC chemist parisa mehrkhodavandi has been studying the chiral catalysts needed to make stereoblock pla. While certain tin and aluminum complexes have been shown to se-lectively form plla over pDla, they have their drawbacks. “lactide derived from biological sources will always have some water in it, but most known catalysts are decomposed by water,” says mehrkhodavandi. they can also take days to react, and can be thrown off by any functional groups that might be added to the monomers to improve their properties.
in contrast, mehrkhodavandi’s group has developed unique catalysts based on indium. Not only are they more tolerant of water and functional groups, they are also much
PoLymErS
EnVIronmEnT
No trend in athabasca fish mercury levels: government studyAmong the many concerns arising from increased oil sands develop-ment is the potential for rising levels of mercury in Athabasca River fish. However, a study released this summer by Environment Canada (EC) found no significant trend in these levels since the 1970s.
The study is a response to one published in 2009 by Kevin Timoney of Treeline Ecological Research and Peter Lee of Global Forest Watch. Based on publicly available data from three fish sampling events — from 1976, 1992 and 2005 — that study concluded that mercury levels in Athabasca fish had risen significantly. The more recent study, published in the Journal of Environmental Monitoring, included a much broader range of data. It also attempted to account for inconsistencies in previous data gathering. For example, mercury concentrations are higher in older, larger fish as a result of bioaccumulation, so studies must be adjusted for body size. As well, mercury accumulates in some organs more
more active. “the aluminum system takes 12 days to do what we can do with indium in 30 minutes,” says mehrkhodavandi. the key to this reactivity, as confirmed in a recent paper published in the Journal of the American Chemical Society, is that the indium complexes have two metal centres as opposed to one.
Despite these advantages, there is still work to be done; for example, the enantioselectivity is still not quite as high as with the slower-acting aluminum complex-es. Nevertheless, the technology has been licensed by the commercialization organiza-tion greenCentre Canada, which is working with mehrkhodavandi and unnamed part-ners toward industrial application.
than others, so concentrations in fillet (muscle) tissue can’t be directly compared with whole body measurements.
“After we corrected for many of these things, we found no specific, discernible trend in mercury levels in the Athabasca River,” says Andre Talbot, one of the co-authors of the EC study. In response, Kevin Timoney says he welcomes the new study, but that “it is dangerous to confuse failure to find an effect with lack of an effect.” Both researchers agreed that inconsistent data gathering in the past has made it difficult to attribute mercury levels in fish to any one source, anthropogenic or otherwise.
In response to criticisms such as these, both the federal and Alberta governments are implementing what they claim will be a “world-class” monitoring program for potential pollution of the Athabasca. Talbot says that the current study should be viewed as a baseline for this new program.
16 CAnAdiAn ChemiCAl news September 2012
j ack Stewart, a biochemist, jokes that normally he would not be caught dead
cavorting with a biologist. But 12 years ago, an Australian biologist visiting
his labs at Mount Allison University in Sackville, New Brunswick, beckoned
him to look under a microscope. As Stewart peered at the tooth of a northern,
short-tailed shrew, the Australian said, “See that little groove? That’s where the
venom is delivered.”
“No, no,” Stewart protested. “This is just a local shrew!” But his colleague
knew his stuff: the diminutive shrew, which might be mistaken for a mouse and
is the most common small mammal in eastern North America, possesses a secret
weapon. As it bites its prey (often an insect), a poison in its saliva causes profound
paralysis. When Stewart asked how it worked, the biologist replied, “You’re the
biochemist, you figure it out.”
That unexpected encounter diverted Stewart from a 25-year research focus on
biochemical adaptations and ultimately led to the creation, in the unlikely locale
of small-town New Brunswick, of Soricimed Biopharma Inc., one of the tiny start-
ups that are increasingly taking on the high-stakes, early stages of drug research
and development. Named after the taxonomic family to which the shrew belongs
(Soricidae) and founded in 1995 by Stewart and Moncton businessman Paul
Gunn, the company employs five researchers in a 2,000-square-foot, state-of-the-
art laboratory in what was once a car dealership and a pub: a low-rise, ex-strip mall
on the outskirts of Sackville, a town with a single traffic light about a half hour’s
drive from Moncton. “We see the morning sun rising over the Tantramar Marsh
and Chignecto Bay at the top of the Bay of Fundy,” says Stewart.
small
Timethe big risks and big expectations of a small drug company in small-town New brunswick.
by Anita lahey
It’s in this idyll that Stewart awaits
the results of Phase 1 clinical trials that
began in July for SOR-C13, a peptide
designed, based on the properties in
the shrew’s saliva, to treat ovarian
cancer. [As ACCN went to press on
August 14, Soricimed announced
that the first patient had begun treat-
ment with SOR-C13 at the Juravinski
Cancer Centre in Hamilton, Ont.]
Should the study yield promising
results, Soricimed’s plan, typical of
the micropharma model that is trans-
forming the drug industry, is to partner
with a large American pharmaceutical
company for Phase 2 trials and beyond,
in what is known as a “co-development
deal.” “Large pharma has really cut out
early stage discovery and research,”
says Gunn. “They rely on companies
like us to bring research to a certain
stage.” The partners then divide clin-
ical development and market approval
September 2012 CAnAdiAn ChemiCAl news 17
business | pharmaCeutiCalS
of a drug, with the larger company
taking on the bulk of later-stage
development plus marketing and distri-
bution. The smaller partner receives an
upfront payment, “development mile-
stone payments” and, when (or if) the
product gets to market, a royalty. “It’s
much more capital-efficient than if we
tried to do everything ourselves,” says
Gunn. “The risks get shared.”
Gunn has his eye on risk for good
reason. Poised to spend a quarter of its
$10.5 million in capital on its Phase
1 trials, and in need of far more cash to
carry on to Phases 2 and 3 — up to $130
million expected to be covered through a
partnership with a large pharmaceutical
company — Soricimed is in sore need
of investors and public funds, both of
which its home province is short on. As a
recent Toronto Star article on Soricimed’s
plight reports, New Brunswick logs the
lowest cash injection from the Canadian
Institutes of Health Research of any other province by a long shot: $1.46 per capita,
compared to $26.03 for Ontario and Nova Scotia. Add to that the dim prospects
faced by your average biopharma start-up, even those situated in more flush locations.
Donald Weaver, Canada Research Chair in Clinical Neuroscience at Dalhousie
University in Halifax, who has co-founded seven biotechnology companies and docu-
mented the rise of the micropharma phenomenon, asserts that more than 90 per cent
of small biopharma ventures fail. “Drug discovery in general is high-risk,” says Weaver.
“It takes about 15 years to push a drug out, and this has only been going on about 15
years, so it’s a bit early in the game to say how micropharma is really performing.” That
said, having reached Phase 1 trials — which establish a safe dosage for Phase 2 trials
involving 50 to 100 patients — gives Soricimed a favourable outlook. “Most fail long
before Phase 1,” says Weaver. “And if you can get through Phase 1 successfully, that is
a major accomplishment, it’s a ‘pop the champagne cork’ time.”
Like most scientific research, early-stage drug development often involves
following hunches that lead nowhere. The road to SOR-C13 was different: the
hunch led to two potentially promising discoveries. What happened next shows why
small and nimble, when it comes to companies building new drugs, can work so well.
Shortly after his encounter with the biologist, Stewart learned that research
into the shrew’s poison begun in the early 20th century “fell off the map” by the
1960s. “Nobody had discovered what the compound was.” Stewart got down to
business. Step one: trapping shrews, which he did in his own backyard, using live
Sherman traps baited with No Name pepperoni. “None of this highfalutin fancy
stuff,” he says. “Shrews go after the fattier food.”
Step two: with the help of student researchers in his lab, Stewart separated the
components in the shrew’s saliva then conducted a series of bio-assays, injecting
each component into mealworms (flour beetle larvae). “Anything that wasn’t
paralytic was eliminated,” he says. “Eventually there is only one thing left.” The
process took two years. Another year, and they’d isolated enough of the compound
to decode its amino acid sequence (a peptide is a sequence of bonded amino
acids), which meant they could have the peptide replicated. “We could essentially
order it, and start looking at its properties in the laboratory.”
They quickly learned the peptide stops nerve transmission. There was a
burgeoning field of research into toxic peptides being adapted for pain treatment,
so Stewart steered his investigations in this direction. Then came the twist. “A
couple of the cell cultures we were using started dying,” he says. “That is never
a good thing, until you realize they’re cancer cells.” The peptide, lo and behold,
had two functions: one end of the molecule blocked nerve transmission by hitting
sodium channels. The other end blocked calcium uptake by cells, which had a
profound impact on some cancer cells.
Stewart realized he was onto something and pitched his project at an investor forum
in Moncton. Paul Gunn, working in finance for a software company and “looking
for something to invest in on the side,” was intrigued. He and Stewart met and hit it
off. Gunn convinced the National Research Council (NRC), the Atlantic Canada
Opportunities Agency (ACOA) and several private investors to join him in backing
18 CAnAdiAn ChemiCAl news September 2012
Stewart’s research. “We had the happy problem of two very
interesting potential drugs,” says Stewart. “But we were very
tiny and poor. We couldn’t afford to run two development
programs. We decided we’d start both, pain and cancer, and
determine which direction the science would take.”
Cancer won. Epithelial cancers such as breast, ovarian
and prostate contain a calcium “channel” known as TRPV6
(transient receptor potential vanilloid family number
6) that, for reasons as-yet unknown, brings an abnormal
amount of calcium into cancer cells. This contributes to
tumour growth in two significant ways: it increases the rate
at which the cells divide, and it inhibits apoptosis (the usual
cycle of self-destruction when cells are under stress). Here’s
where the shrew comes in: one half of the saliva peptide
Stewart and his team had isolated — the non-paralytic
half — automatically binds to the TRPV6 channel, which
stops calcium from flowing into the cell. The stressed cell
is thus able to begin its normal “suicide circuit,” ultimately
shrinking the tumour. Further research with SOR-C13 —
the synthetic peptide modelled after the shrew’s — on cell
cultures, animal models and, finally, human tumours grown
in ice, have consistently shown a deadly effect on tumours,
without causing stress to other cells.
This lack of toxicity is a holy grail in cancer treatment —
as, it turns out, was the TRPV6 channel. “People have been
calling TRPV6 an excellent potential drug target for almost
as long as we’ve been doing this work,” says Stewart. “It’s
a common refrain in scientific papers. Our drug is its only
known inhibitor. The whole pain aspect is still sitting here
waiting for development, but the cancer swept us away.”
***
Soricimed has grown modestly in tandem with its promising
discoveries. In 2006, one year after incorporating, Gunn
left his job at Whitehall Technology to focus wholly on
the start-up. In 2007, Stewart took a leave of absence from
the university. The following year the Sackville lab was set
up, and by 2009 Stewart had retired from academia. The
company now has more than 100 shareholders and has raised
$6.5 million in equity, plus $4 million
from the NRC and ACOA. It wasn’t
easy, says Gunn. The Atlantic prov-
inces are not a hotbed of seed money
such as the $150-million venture
capital fund recently set up by Eli Lilly
& Co., which is largely focusing its
attention on the research of Quebec-
based micropharma firms. “You have
to work a lot more to get national
and international exposure because
people don’t come looking to Sackville
for the next cancer drug, the next
diagnostic drug, the next scientific
breakthrough.” Gunn has countered
this disadvantage in part by recruiting
two former big pharma executives
to his board, whose experience and
connections have proven instrumental
as Soricimed embarks on partnership
talks with big pharma representa-
tives. And although Sackville is not
swarming with biochemists, Stewart’s
connection to the university — plus
the fact that Soricimed is the only
game in town — allows him to hand-
pick and recruit top-notch scientists.
By pharmaceutical standards,
Soricimed remains miniscule, what
Gunn calls a “semi-virtual” company.
New ideas are investigated in-house,
then farmed out to third-party, contract
research organizations. “One will look
at toxicology,” says Gunn, “another at
analytical processes. At any one time
there could be a hundred to a hundred
and fifty people working on our stuff
from Vancouver to Newfoundland, as
well as in the U.S. and Europe.” This
approach has saved the purchase of
a quarter of a million dollars worth of
September 2012 CAnAdiAn ChemiCAl news 19
lab equipment, says Gunn, as well as
the need for researchers with specialties
Soricimed might only require occasion-
ally. The company can reign in or ramp
up research projects according to cash
flow and other factors. “We can turn on
or off work as we choose,” says Gunn.
“We’re not stuck with huge overheads.”
Weaver says that’s exactly why more
and more drug development is coming
out of universities and small biotechs:
“They have the capacity to be flexible.
If you start off in pain and all of a sudden
go, ‘Woah, it works better in cancer,’
you can do that shift overnight. Try
doing that in a huge corporation.”
Though small pharmaceutical ventures
have been popping up in Canada since
the 1990s, in the early days of the micro-
pharma trend, Soricimed remains unique
in its backyard. “When we went through
our application with Health Canada and the U.S. Food and Drug Administration,
they told us ‘We can’t find any other company in New Brunswick that’s done this
before. You should be in Montreal or Toronto or Boston, or anywhere but here.’ But
we have a very small footprint. We can be where we want.”
For the foreseeable future, that “where” is Sackville, despite the challenges
that presents for the company’s investment prospects. Should its Phase 1 trials
for SOR-C13 fail, Soricimed has more than pain treatment in its back pocket. Its
peptide’s habit of travelling straight to a tumour makes it a great candidate for a
diagnostic tool — an application the company is pursuing simultaneously. A study
involving 6700 provincial blood samples in New Brunswick is underway, which will
test SOR-C13’s ability to diagnose early-stage ovarian cancer, which typically shows
no symptoms before its progression to later, untreatable stages. And that’s not all.
The peptide might also be used to ferry traditional treatments through the body —
again, because it beelines right for the cancer hot-spots. “You could attach a chemo
drug and deliver it right to the cancer site, with less toxicity and using a lower dose,”
says Stewart. “We have a number of products — not as many as large pharma, but
we’d have to strike out a lot of times before we had nothing left.”
Anita Lahey is a freelance writer formerly based in New Brunswick.
Senior research techni-cian, Chris rice (above, left) consults with chief scien-tific officer jack Stewart in the lab at Soricimed biopharma in Sacksville, New brunswick. the com-pany is in phase 1 clinical trials for a cancer drug that is based on a peptide found in the saliva of the northern short-tailed shrew (below).
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In the face of reports of drug resistant strains of bacteria,
like Staphylococcus aureus and Clostridium difficile, finding
out exactly why the ‘wonder drugs’ of yesteryear appear to
have lost their punch — and more importantly, what can
be done about it — is critical. Gerry Wright, professor in
the Department of Biochemistry and Biomedical Sciences
at McMaster University, aims to answer these questions.
Using tools like environmental genome sampling and high-
throughput screening, he has gained new perspectives on
how bacteria evolve resistance and has identified strategies
that could lead to new drugs. ACCN spoke with Wright to
find out how we will create the antibiotics of the future.
ACCn you've said that the current situation with regard to antibiotic resistance “approaches perfect storm characterization.” how so?
Gw For over 70 years, we’ve benefitted from an ample supply
of antibiotics. Today, that’s being eroded by an upsurge in
antibiotic resistant strains of bacteria. At the very same time
the pharmaceutical industry is looking elsewhere; they no
longer see antibiotics as a profitable area of research. The end
result is this ever-growing disconnect between clinical need
and potential solutions, hence the ‘perfect storm.’
ACCn how have antibiotics been developed in the past?
Gw Probably the grandfather of antibiotic discovery is Paul
Ehrlich, who in 1909 systematically tested a series of chemi-
cals — primarily dyes and arsenic-based compounds — for
their activity against Treponema pallidum, the organism that
causes syphilis. The result of this first high-throughput screen
was Arsphenamine (also known as Salvarsan), a drug whose
effectiveness was nothing short of stunning for its time. In the
1930s sulfonamides (sulfa drugs) were identified by Bayer AG
and used to treat a wide variety of bacterial infections.
20 CAnAdiAn ChemiCAl news September 2012
However, then as now, the most effective drugs came
from natural products, which have consistently been of low
toxicity and highly effective as drug molecules. The classic
example is penicillin: Alexander Fleming identified the
organism that produces it in the late 1920s, and by the early
1940s scientists had been able to purify and manufacture
it. The time between 1940 and 1960 was really the golden
era of antibiotic discovery. Small molecules produced by
microbes, in particular fungi and soil-dwelling bacteria, were
the source of the chemical scaffolds for almost all antibiotics
in use today. Synthetic chemistry played a huge role in the
elaboration of these natural scaffolds to create new drug
molecules. The only significant antibiotic compounds that
were completely synthetic were the quinolones and fluoro-
quinolones, identified in the 1960s and early 1970s.
ACCn much of your work focuses on studying how bacteria develop resistance to antibiotics. What have we learned about this over the years?
Gw Bacteria produce chemicals for almost every purpose,
from signalling molecules to antibiotics that keep the compe-
tition down. If microorganisms produce antibiotics, they have
to have a way of protecting themselves, so the evolution of
antibiotic resistance goes hand in hand with the evolution of
antibiotics. Now that we can sequence the genomes of these
organisms, we can trace these resistance genes. And because
bacteria can share genes between species, these resistance
genes show up even in bacteria that don’t produce antibiotics.
In 2006 we had a paper in Science where we sampled
the collection of all the antibiotic resistance genes in the
genomes of non-pathogenic soil bacteria; we call this the
antibiotic resistome. What we found is that these bacteria
are resistant to many different antibiotics, on average some-
where between seven or eight of the 20 that we screened.
Of course, there is the possibility that these microbes may
With bacterial resistance on the rise, where will we get the drugs of the future?
by Tyler irving
Waning of The Wonder drugs
September 2012 CAnAdiAn ChemiCAl news 21
ChemisTry | aNtibiotiCS
have somehow been exposed to man-made versions of the
antibiotics we were looking at. So last year some of the same
people did a similar screen of the genomes of organisms that
had been frozen in permafrost 30,000 years ago. And a few
months later, we did the same for bacteria isolated from
Lechuguilla Cave in New Mexico, where the bacteria had
been cut off from the surface for at least 4 million years. In
all cases, the result was exactly the same; they are all intrin-
sically multi-drug resistant.
What this shows is that we have failed to understand
the chemical ecology of antibiotics. We are lucky that the
bacteria that cause disease have, by and large, been highly
drug-sensitive, at least for the last 70 years or so. But our work
shows that the resistance genes are out there in the genomes
of non-pathogenic bacteria. On top of that, we’ve created a
massive selection pressure to move those genes around.
ACCn you’re referring to the use of antibiotics in everyday products?
Gw Absolutely. The organisms that produce antibiotics have
been doing so on a microgram scale, in very confined envi-
ronments. Even so, resistance has spread around the world
among bacteria that live in those environments. But a situa-
tion like we’ve had over the last 70 years, where compounds
like penicillin get applied on gram or kilogram scales, is
unprecedented in the history of this planet. Human use of
antibiotics has provided an evolutionary pressure to move
resistance genes from organisms that don’t cause disease into
those that do. The fact that we have this problem of anti-
biotic resistance in what were almost universally sensitive
organisms 70 years ago is the proof of this.
ACCn Why haven’t drug companies kept up with the problem of resistance?
Gw Let me use an example: The first penicillin-resistant
organisms were actually discovered before penicillin was
made into a drug. These organisms produce enzymes called
beta-lactamases that destroy penicillin. They were never
really that much of a problem until the 1950s, when those
beta-lactamase producing genes started to spread around.
So medicinal chemists began tinkering with the structure
of penicillin to render it impervious to these enzymes. The
bacteria responded by evolving point mutations in those
enzymes, and the cycle continued; it’s been a real arms race.
By the 1990s, we ended up in a situation where we had
basically exhausted our ability to tinker with existing scaf-
folds. There are only so many ways that you can differentiate
drug molecules before they start becoming lousy drugs, with
issues of toxicity, bioavailability and so on. What we need
at this point is new scaffolds, and that’s really what’s been
gerry Wright, shown here in his lab at the michael g. Degroote institute for infectious Disease research, suggests that previously discarded chemical scaffolds might be one potential source of new antibiotics. an example is daptomycin, shown above. originally discovered in the mid-1980s but rejected due to toxicity issues, the com-pound was finally commercialized in the 2000s, when new experiments showed that toxicity could be controlled with careful dosing.
22 CAnAdiAn ChemiCAl news September 2012
lacking. The last really new scaffold was a lipo-peptide called
daptomycin, discovered in the early- to mid-1980s. So we’ve
exhausted our ability to make new derivatives and at the
same time we haven’t discovered any new scaffolds.
ACCn if that’s true, where are the antibiotics of the future going to come from?
Gw There are scaffolds that have been looked at but were
discarded because we already had better drugs around.
Daptomycin is a good example; when it was first discovered
by Eli Lilly in the 1980s, early studies found that it was associ-
ated with toxicity, so it was dropped. Later, a new company
called Cubist felt that they could deal with the toxicity by
changing the dosing. They bought the rights and showed
that, using appropriate dosing, it was perfectly viable; it’s
now making something on the order of $700 million to
$900 million a year. So that’s one possibility.
I also think there’s always a great opportunity to keep
looking to natural products. During the 1990s, a lot of drug
companies worked very hard on using computer models to
make synthetic antibiotics and that unfortunately has not
worked. We haven’t yet figured out the rules for making
molecules that will get into bacteria and kill them. So I’m
biased toward natural products, and here we can really
benefit from our ability to sequence genomes.
Today we can sequence a bacterial genome in an afternoon
for a thousand dollars, and that price keeps dropping. We’re
no longer even limited to the species we can grow in the lab,
which we know make up less than 10 per cent of the organ-
isms that live in a gram of soil. Instead you can extract all of
the DNA and sequence it directly, so you know everything
that’s produced in there. Of course, you don’t necessarily
know which genes will produce antibiotics, but you might
find an interesting chemical scaffold worthy of investigation.
I think there are tremendous opportunities there.
Finally, another route we’ve taken in my lab with my
colleagues Eric Brown and Mike Tyers is combining mole-
cules. That takes advantage of what we’re now beginning
to understand from systems biology, which is that a single
molecule usually can’t completely shut down an organism’s
ability to grow; in other words, true antibiotics are rare.
There’s a lot of redundancy in microbial metabolism, with
biochemical pathways having all sorts of backups. It’s kind
of like the internet; it’s very hard to shut down by unplug-
ging one computer, but if you unplug two, three or four, you
can at least start to affect the local networks. We can now do
high-throughput screens for combinations of molecules, and
we’ve been very successful in identifying some that can kill
bacteria and fungi too.
ACCn What will these changes mean for the way chemists work?
Gw I think chemists are going to have to get more comfort-
able dealing with natural products, since this is really where
we’re going to find the new antibiotics. It’s tough because
they are complex and challenging, with multiple stereo-
centres — not the kind of thing that is easy to work with.
But more broadly I think this is going to really be an era of
partnership. It has already been to some extent in the past,
but the antibiotic field has not seen the level of co-operation
between biologists and chemists that anti-hypertension or
anti-cholesterol drugs have, for example. It will be medicinal
chemists, analytical chemists and biological chemists working
with geneticists who will help us find the new scaffolds.
Another aspect is making sure these things get from
the lab to the clinic. I think it’s evident that if we wait for
the pharmaceutical industry to do this, we’re going to be
waiting for a long time. On the other hand, history has
shown us that the large pharmaceutical companies are very
receptive to acquiring bright technologies and moving them
down the clinical pathway. I think a lot of this research is
going to get done in academic labs and in small biotech
companies. The critical element is to make sure that we
get sufficient interest by funders, whether those are venture
capitalists, angel investors, government or private sector.
There are lots of reasons to be hopeful, but the pump needs
to be primed.
ACCn is this a war we can win?
Gw I don’t like the war mentality much, and in fact it has been
part of the problem. We’re not at war with these organisms,
we’re just trying to control their growth. If we think of them as
agents of evolution, as opposed to something we need to eradi-
cate, we will have much better success in the future.
24 CAnAdiAn ChemiCAl news September 2012
the Macdonald Engineering Building infa-
mously burned to the ground in 1907. But now,
over a century later, nobody minds that Jeffrey
Bergthorson and his team like to play with fire in
the safe confines of their newly renovated lab on the build-
ing’s first floor. The researchers carefully blend the right mix
of fuel and air to create small, flat flames about three centi-
metres in diameter. Then they use laser diagnostics to probe
the combustion chemistry of different fuels. These flames
are the Number One apparatus of the Alternative Fuels Lab.
The Number Two apparatus is no less unexpected: a tube
containing a mix of fuel and oxidizer through which they
blast a shock wave that raises the temperature of the fuel so it
catches light. With this, they measure the time it takes for the
mixture to ignite.
“Nothing in here looks like a jet engine,” smiles
Bergthorson, who is an assistant professor in the Department
of Mechanical Engineering. “But these apparatus allow us to
study the fundamental principles that precede engine design.”
Bergthorson is part of a cross-Canada team, led by McGill
plant science professor and Green Crop Network director Don
Smith, that’s working on developing new kinds of fuel and the
engines that can burn them. The network, called BiofuelNet,
was one of the winners of the Government of Canada’s 2012
Networks of Centres of Excellence competition, announced
in May, which supports promising collaboration between
phD student Sean Salusbury (left) and jeffrey bergthorson use an impinging-jet apparatus to produce a flat, stagnant flame, ideal for taking measurements at mcgill’s alternative Fuels lab where they study the combustion and emissions from alterna-tive and traditional fuels.
perfecting the process of making biofuels is not enough. We need machines that can efficiently burn them. researchers in mcgill’s alternative Fuels lab are figuring out what the next incarnation of the combustion engine will look like in the age of biofuels.
by sylviane duvalQuestions
oW
eN eg
aN
September 2012 CAnAdiAn ChemiCAl news 25
ChemiCAl enGineerinG | bioFuelS
September 2012 CAnAdiAn ChemiCAl news 25
researchers and industry. Instead of
processing crops that could be used
for food, they’re developing ways to
turn waste, such as wheat straw, corn
stover (leaves and stalks) or even wood
salvaged from demolished buildings,
into fuel. (Growing crops isn’t out of the
picture entirely though: BiofuelNet is
also looking at the energy potential of
“purpose-grown biomass” — things such
as willow trees or fast-growing grasses
that aren’t edible and don’t require
prime agricultural land.) Bergthorson’s
expertise, however, is in the combus-
tion, not the creation, end of things:
Once you’ve created a biofuel, how does
it burn? And how can engine design
be tweaked to get a bigger waste-into-
energy bang for the buck?
When Bergthorson was completing
his PhD at Caltech during the early
2000s, the “burning” questions in aero-
space technology related to advanced
high-speed propulsion and, therefore,
combustion. Before turning his atten-
tion to how alternative fuels might
benefit the commercial aviation
industry, he studied supersonic combus-
tion for hypersonic aircraft.
Jet fuel is strictly regulated. It must
meet strict standards for energy content
per litre, composition, viscosity,
surface tension and other physical and
chemical properties — tough criteria
that make it impossible to use oxygen-
containing biofuels such as ethanol or
first generation biodiesel in aircraft. As
well, the industry has put its foot down
on the stratospheric cost of retooling
the fuel supply system at airports and
upgrading the global airline fleet for
non-compatible fuels.
The combustion engine isn’t going
away. “Renewable source or otherwise,
jet fuel has got to be a hydrocarbon
similar to petrofuel,” says Bergthorson.
“There aren’t any disruptive technolo-
gies because nothing else has the high
power-to-weight ratio or the necessary
energy density. Hydrogen takes up too
much space, and the power density of
batteries is too low. There isn’t going to
be an electric jumbo jet.”
The question is not whether alterna-
tive fuels burn — we already know that
any hydrocarbon burns in the heat and
pressure of an engine. It is how they
burn — the way their physical and
chemical properties affect the perfor-
mance of the engine — and what comes
out of the proverbial tailpipe.
One issue is materials compat-
ibility. Alcohol- or vegetable-oil-based
biofuels, for example, are corrosive and
can wreck rubber seals by changing the
way they swell. (It’s serious business: the
space shuttle Challenger tragedy was
caused by rubber seal failure.) Another
issue is physical properties. A biofuel
with a different viscosity than petrofuel
will spray into the engine differently,
change how the fuel and air mix and,
therefore, affect combustion. Both are
problems for Bergthorson’s collaborators
at other universities.
Bergthorson himself is experimenting
with different blends of alternative fuels
to see what happens to the sequence
of chemical reactions that converts
fuel and air into carbon dioxide and
water. This includes extinction behav-
iour (how easy it is to blow out the
flame), flame speed and stability; type
and quantity of emissions; fuel droplet
evaporation; and reignition at low
temperatures. The last point is crucially
important for restarting the engine after
a flameout incident at 30,000 feet.
However, lighting a small flame in a
lab and kickstarting a jet engine on a
runway are worlds apart. Between the
two lie gas-turbine combustor experi-
ments and the inherent complexities
added by the fuel spray and evaporation
processes. Instead of this, Bergthorson
has adopted an experimental and
modeling approach that allows him to
assess the effect of industrially relevant
turbulence levels on the flame without
using an actual combustor — and
without cramming a jet engine into
his lab. The results will inform other
research work to integrate alternative
fuels into transportation and power
generation systems and help develop
new engine designs that improve effi-
ciency and reduce emissions.
Soaring petroleum prices, concerns
over climate change, European cap-and-
trade schemes that affect airlines and the
International Air Transport Association’s
goal to reduce its carbon footprint by 50
per cent by 2050 — it all adds up to very
keen interest in research that explores
bio-derived fuels that will keep costs and
emissions down. Bergthorson is involved
in several large scale collaborative efforts
26 CAnAdiAn ChemiCAl news September 2012
with industry. Pratt & Whitney Canada, for one, has called on him —
as well as experts at Université Laval, Ryerson University, the National
Research Council’s Gas Turbine Research Laboratory, the Indian Oil
Company and other partner organizations and universities in India — to
investigate the performance of different biofuel and petrofuel blends.
“Synthetic kerosene has been approved for use in jet engines. It
meets the fuel standards but because it is made from gasified coal, its
environmental footprint is worse than petrofuel,” says Bergthorson.
“Bio-derived fuels are now being shown to be engine-compatible and
carbon friendly. The industry is already certifying hydro-treated vege-
table oils, thereby opening the doors for widespread adoption.”
Could we also see these blends at the neighbourhood gas station in
the future? Bergthorson shakes his head.
“True, we could obtain fuels similar to gas or diesel from these
processes,” he says. “But because they have to meet the standards
for jet fuel, they need more processing and that leads to higher costs.
There will be cheaper solutions for the gas tank than bio jet fuel.”
In another collaboration, Bergthorson is working with Rolls Royce
Canada, five Canadian universities and the National Research Council
on novel fuels for gas-turbine engines.
Rolls Royce’s Energy Division converts aviation gas turbine engines
into power-generation systems suitable for remote or off -shore uses or for
peak power generation by replacing the combustor and other key parts.
“The first two things a customer
cares about when buying an engine are
cost and reliability,” says Bergthorson.
“But increasingly, they are asking if
they can burn this, that and the other
fuel depending on what is available
and what is cheapest.” The research
on gaseous fuels (syngas or biogas
blended with natural gas) and liquid
fuels (biodiesel, alcohols and upgraded
pyrolysis oils blended with petrodiesel)
will provide data that will help Rolls
Royce meet ever-tightening emissions
standards for these engines. As a result,
Rolls Royce will be in a better posi-
tion to evaluate what alternative fuel
mixtures will work in existing engines
and what design changes can be made
to next-generation engine combustors
to allow further fuel flexibility.
This story first appeared in the winter 2012 issue of McGill University’s
Headway magazine.
particles within a flat, stagnation flame are illumi-nated by a laser sheet in order to study reaction rates. in this way, researchers can compare the performance of standard and alternative fuels.
SeaN
Salu
Sbu
ry
the Department of Chemistry invites applications for a probationary (tenure-track) faculty position at the rank of assistant professor in inorganic Chemistry with an anticipated start date of july 1, 2013. the successful candidate will be expected to establish an independent, externally funded research program, and to develop and teach innovative courses in chemistry at the undergraduate and graduate levels. the Department of Chemistry (www.uwo.ca/chem) is a large research-intensive department with strong programs in many areas of chemistry and with several interdis-ciplinary links to research groups in other departments in the Faculties of Science and engineering and the Schulich School of medicine & Dentistry. the Department of Chemistry is home to world class research facilities and has strong affiliations with Surface Science Western (www.surfacesciencewestern.com), the Western Nanofabrication Facility (nanofab.uwo.ca) and the integrated microscopy unit (www.thebiotron.ca).
interested candidates should send two hard copies of their application package which includes an up-to-date curricu-lum vitae, a teaching philosophy and a statement of teaching interests, a description of research accomplishments, and a 5 page research proposal, together with the names, mailing and e-mail addresses and telephone numbers of three referees to:
Dr. k. m. baines, Chair | Department of Chemistry, Western universityChemistry building, room 003 Dock 11
1151 richmond Street N, london, ontario, N6a 5b7, Canada
the deadline for receipt of two printed copies of the full application is September 30, 2012. applications sent by e-mail will not be considered.
Positions are subject to budgetary approval. Applicants should have fluent written and oral communication skills in English. All qualified candidates are en-couraged to apply; however, Canadians and permanent residents will be given priority. Western University is committed to employment equity and welcomes applications from all qualified women and men, including visible minorities, aboriginal people and persons with disabilities.
products + Services
September 2012 CAnAdiAn ChemiCAl news 29
save the date
sept. 30–oct. 3, 2012
51st annual Conference of
metallurgists
Niagara Falls, ont.
www.cim.org/Com2012
october 10–12, 2012
pacific rim Summit on industrial
biotechnology & bioenergy
vancouver, b.C.
www.bio.org/events
october 14–17, 2012
62nd Canadian Chemical engineering
Conference (CSChe 2012)
vancouver, b.C.
www.csche2012.ca
october 26, 2012
24e Colloque des étudiants et
étudiantes de 1er cycle en chemie
Sherbrooke, Que.
pages.usherbrooke.ca/colloque-chimie/
may 27–29, 2013
3rd Climate Change technology
Conference
montreal, Que.
www.cctc2013.ca
June 15–19, 2013
World Congress on industrial
biotechnology & bioprocessing
montreal, Que.
www.bio.org/events
July 13–18, 2014
international Conference on Chemistry
education, 2014
toronto, ont.
www.iCCe2014.org
Grapevine
hadi mahabadi, past chair of the CiC
board, was appointed by the governor
general as an officer of the order of
Canada on june 29, 2012. mahabadi
is president of CanWin Consulting inc.
and was formerly vp and Director of
the xerox research Centre of Canada.
the award recognizes his significant
contribution to polymer science and
his commitment to promoting scien-
tific development in Canada.
stephen withers, professor of
chemistry and biochemistry at the
university of british Columbia, was
elected a Fellow of the royal Society
of london in july in recognition of his
contribution to the understanding
of the reaction mechanism of en-
zymes. the award, which recognizes
excellence in science, places Withers
among the ranks of isaac Newton,
Charles Darwin, albert einstein and
Stephen hawking.
Chemical engineers grant allen
from the university of toronto,
ajai Dalai from the university of
Saskatchewan, biao huang from the
university of alberta, robert legros
and paul Stuart from École polytech-
nique and molly Shoichet from the
university of toronto were all named
fellows of the Canadian academy of
engineering in june.
Find more news from the CiC at accn.ca/societynews. is there something going on that you think we should write about in this section? Write to us at [email protected] and use the subject heading “Society News.”
soCieTy news
In mEmorIAm
The CIC wishes to extend its
condolences to the families of John
Breau, MCIC, Robert Jenkins,
MCIC, Frank Martens, MCIC and
J.E. (Ted) Newall, HFCIC.
Things to know
The Advocacy Task Force of the
CiC participated in the federal gov-
ernment’s “pre-budget Consultations
2012” this august by submitting re-
sponses to a five-part questionnaire
that made recommendations under
the prescribed headings of economic
recovery and growth, job creation,
demographic change, productivity
and other challenges. although the
CiC regularly participates in advo-
cacy activities through the Canadian
Consortium for research as well as
the partnership group for Science
and engineering, this is the first year
the institute has submitted inde-
pendent recommendations to the
government. to read the brief go to
www.cheminst.ca/advocacy.
The board of directors of the Ca-
nadian Society for Chemistry is seek-
ing nominations for the positions of
vice president, director of industrial
liaison, director of Subject Divisions
and director of outreach, opening in
june 2013. interested and qualified
individuals should submit a letter of
intent for their desired position along
with their Cv to cscboard@cheminst.
ca. the deadline for applications is
monday, September 17, 2012, after
which time the CSC nominating com-
mittee will review the submissions.
registration for the 62nd Canadian
Chemical engineering Conference
being held in vancouver, b.C., october
14-17, 2012 is now open. register by
September 10 to take advantage of
early registration fees. information can
be found on the conference website at
www.csche2012.ca.
ChemFusion
30 CAnAdiAn ChemiCAl news September 2012
How sweet it is
b osco chocolate syrup — notable
for its cameo as fake blood in
Alfred Hitchcock’s 1960 Psycho
shower scene — is still around, though
it has undergone a significant transfor-
mation over the years. First introduced
in 1928, the sweet sauce’s main ingre-
dients were corn syrup and cocoa with
sugar and malt extract added for taste
and xanthan gum as a thickener. The
main difference from the 1960s is that
high fructose corn syrup is now one
of the ingredients because it achieves
the same degree of sweetness with less
sugar, a more expensive ingredient.
The substitution of high-fructose corn
syrup for cane sugar is a pattern that
became common in the food industry in
the decades that followed Hitchcock’s
landmark film. Sugar tariffs and large
subsidies introduced in the 1970s for
corn growers in the U.S. made the tech-
nology for producing high fructose corn
syrup popular as a cheaper way to add
sweetness to foods and beverages. Since
high fructose corn syrup is a liquid, it is
easier to transport and blend than granu-
lated sugar, particularly when it comes to
formulating beverages. Its popularity is
waning today as its ubiquity in things like
carbonated beverages has been pointed
to as a contributor to obesity, cardiovas-
cular disease, diabetes and non-alcoholic
fatty liver disease.
Corn syrup and high fructose corn
syrup are not identical products. Corn
starch, which is used to make both
products, is a white powder, chemically
composed of polymers of glucose. This
means it consists of hundreds of glucose
molecules joined together either in a
straight chain known as amylose or in
a branched chain version called amylo-
pectin. Treating the starch with dilute
hydrochloric acid breaks down the
chains, yielding a mix of individual
glucose molecules along with maltose,
which is two glucose units joined
together, and various short glucose
chains known as oligosaccharides. To
make corn syrup commercially, instead
of using an acid, a mixture of corn starch
and water is treated first with alpha
amylase, a bacterial enzyme that breaks
the starch down into oligosaccharides,
followed by the addition of gamma-
amylase, an enzyme isolated from the
Aspergillus fungus that converts some of
the oligosaccharides to glucose. In the
case of high fructose corn syrup, another
bacterial enzyme, D-xylose isomerase,
is used to convert some of the glucose
into fructose. Fructose is sweeter than
glucose, so an equivalent amount of
high fructose corn syrup is sweeter than
regular corn syrup.
While corn syrup is made of corn
starch, the two substances are different in
more ways than you may think. You can’t
walk on corn syrup, but you can walk on
a liquidy mix of water and corn starch.
Well, maybe not walk, but you can run.
That’s because a mixture of water and
corn starch is a non-Newtonian fluid.
Isaac Newton did more than watch
apples fall. He was also interested in the
viscosity of liquids and determined that
the viscosity can be changed by altering
the temperature. Try warming up some
honey in the microwave and see how
easily it then flows. Non-Newtonian
fluids can changed their viscosity not
only in response to temperature change
but also in response to pressure. When
pressure is applied to a viscous water-
starch mixture, it momentarily becomes
a solid but quickly reverts to a liquid.
That’s why you can run across a basin
filled with water and corn starch. Your
weight provides enough pressure to
solidify the corn starch. But you can’t
dilly-dally. You have to take the next
step before the mixture reverts to a
liquid state.
If making a pool of corn starch is
too big a challenge, which it prob-
ably is, you can impress your friends by
making a small batch in a bowl. (For a
Hitchcockian twist, add some food dye
and it looks like blood.) Then slap it hard
with your hand. Everyone will expect the
guck to fly all over the place, but if done
right, the fluid’s non-Newtonian nature
guarantees that nothing happens. (But if
your slap is too timid, you’ll end up with a
bloody mess!)
Joe Schwarcz is the director of McGill University’s Office for Science and Society.
Read his blog at chemicallyspeaking.com.
by Joe schwarcz
62nd Canadian Chemical engineering Conference
vaNCouver britiSh Columbia, CaNaDa
oCTober 14–17, 2012energy, environment and Sustainability
62nd Canadian Chemical engineering Conference
vaNCouver britiSh Columbia, CaNaDa
oCTober 14–17, 2012energy, environment and Sustainability
www.csche2012.ca
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