ACCN, the Canadian Chemical News: September 2012

September 2012

Canadian Chemical News | l’actualité chimique canadienne

SMALL-TOWN PHARMA

www.accn.ca� Chemical Institute of Canada

September 2012


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


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

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6

9

10

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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

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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


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

[email protected]

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.

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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


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


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


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.”


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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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.


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.”


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.


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


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


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


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.


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


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.


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.


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

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ChemiCAl enGineerinG | bioFuelS


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


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


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


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

LooKing for a JoB in Your fieLd?the Chemical institute of Canada can help you fi nd your chemistry, chemical engineering or chemical technology dream job with our online job site. be seen by some of Canada’s top employers of chemical scientists, engineers and technologists. post your resume, view jobs, create job alerts and more.

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ACCN, the Canadian Chemical News: September 2012

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