- The Accidental Scientist. How and why I became a scientist, and whether school had anything to do with it.
Before
I can move on to interpreting and analysing the traditionalist and progressive,
skills orientated or knowledge rich mantras in education – and their reactive
and proactive elements – I need to reflect; to purge the corruption of my
perspectives on science education first.
This is indulgent, but I hope it also brings insight to – what I believe
– is the foresight of my pending six further summer edublogs.
Here,
I am influenced by Graham Coxon, the talented and inventive musician and
guitarist with Blur. At Blur’s creative
and commercial peak, when he retreated from the front line of indie pop to
explore alternative American guitar bands, he talked of ‘unlearning’ the
guitar. He had by this point mastered
its texture, rhythm and delicious, squelchy nuance but he felt shackled by the
manifestation of his knowledge and experience.
To improve as a guitarist, he wanted to unlearn what he already knew, to
progress down an alterative, more folky, less conventionally pop avenue. This is – I think – a metaphor for individual
human progress and deep learning. We
have to take a step back from what we know, unpick it, analyse it and learn
another way (with lots of practice) in order to move forward as individuals, as
schools, as organisations, as nations and as global human society. We will not keep learning, keep improving, if
we always do things the same way, if we seek to maintain – and incrementally
improve – the status quo.
So,
back to me. Specifically me on 1st
February 2011: I am standing with about
2400 other people in the cavernous, tiered, ship-like decking of the campus
gateway on Pfizer’s Global Research & Development (R&D) site near
Sandwich in Kent, the headquarters of their European R&D. It is an impressive space, a statement of
intent, a showpiece. It oozes corporate
success and multinational riches. It is
a monument to the discovery of blockbuster medicines such as Diflucan (fluconazole,
for treating fungal infections), Norvasc (amlodipine for treating high blood
pressure) and Viagra (sildenafil – you know what this one is for…). The head of global R&D stands on the
podium and shuffles through some benign and carefully crafted powerpoint
slides. On slide 8 he says it, “Pfizer
intends to exit from the Sandwich site.”
Despite prior warning signs for the more discerning and more corporately
aware employees, there was an audible gasp is the room. This was a big shock.
A
few weeks later, after some intense, confidential and emotionally draining
employee consultation, I – as employee chair of the employee forum – was
standing on the same podium, in the same place, with the same audience sharing
the news of our enhanced, site specific, redundancy package; supported and
encouraged by then site head, Dr Ruth McKernan later chief executive of
Innovate UK. Then, after a protracted
period of further consultation, career guidance from redeployment consultants, career
experimentation leading a small STEM (science, technology, engineering &
maths) enrichment charity, unemployment, reflection and self-doubt it was that
enhanced redundancy package which enabled my intentional career change into
teaching, aged 41: as a teaching assistant from January 2013, PGCE in September
2013 and KS2/KS3 Science and maths teacher (now head of Science) from September
2014.
So,
it was in February 2011, aged 38, that I ceased to be a scientist. My subsequent pathway into teaching was
(later) planned, considered and intentional.
My pathway into science was purely accidental. This blog post documents my accidental
journey into science, shares some of my experience and insight from my 17 years
in industry and contextualises the perspective and questioning curious mind I
have brought into my teaching career.
Inevitably I entered the teaching profession with a fairly utilitarian
view of school science education based upon my experience in industry, a view
which remains confused during the international skills versus knowledge Twitter
wars of 2018 onwards…this indulgent purge sets me up for engaging more
purposefully, truthfully and open-mindedly in that debate in subsequent posts.
So,
from an educational qualification perspective I can explain very simply why I
became a scientist: I went to school;
learnt some stuff; got As in Chemistry, Biology, Maths and History at GCSE; considered
medicine as a career so chose Chem, Bio and Maths A levels; flunked Maths; went
to Kingston Poly to study chemistry; had industrial placement in industry;
needed to earn some money (and therefore get a job); had a 2:1 degree in
chemistry so became a graduate scientist in Zeneca and then Pfizer. Blah.
Next post.
That
is what happened, but why did it happen and how did it happen? Uh oh.
Cue long meander through family, school, home, character and experience;
and dipping my toe into the age old – frequently misplaced – chestnut of nature
Vs nurture.
Unless something seriously weird happened, we all
tend to think of our childhood as normal.
Everyone else’s is alien. This
sometimes becomes apparent when we spend Christmas with our partner’s family
for the first time. Looking back, my
early childhood was idyllic, blissful and happy yet far from normal. In comparison with my own children, I had
more freedom, I was more socially privileged, less disposably affluent, I was
far less integrated with my local community and I was (subconsciously) trapped
in an isolated, bucolic paradise.
For my father, I was child number six and the first
product of his third marriage. His life
was far more worthy of biography than mine:
born in 1917; son of a vicar;
boarding school; Cambridge – kicked out; Wye agricultural college; 2nd
world war – Italy and North Africa, a Lt. Col in the Royal Artillery; 1st
marriage – 2 boys, wife committed suicide just after the war when one was 3
years old and the other just 3 weeks old;
new wife – three more children; a pioneering and much respected farmer
in Devon; sold the dairy herd and experimented with intensive pig farming,
failed, sold farm; invested in a failed golfing contraption; separated from
second wife; long affair; played lots of golf; spontaneously married my Mum, 24
years his junior, where we pick up his story, because it is mine too.
For my mother, I was child number one of two in her
first and only marriage. She left her
London life behind to marry my father, following an apparently spontaneous
decision to ditch her affair with a married man. They bought a ramshackle North Devon
farmhouse with some semi-derelict, disused farm buildings and seven acres in
May 1971. (For £8100)! I appeared in August 1972 and a younger
sister joined us, as my childhood sparring partner, in October 1974.
Until I was four, my Dad worked as secretary and
head green-keeper at the Royal North Devon Golf Club; after that he grew
vegetables – at home – for local hotels.
In the early 1980s when I was about 10, he started growing flowers for
drying and my parents set up Withacott Dried Flowers, a small local
business. Initially it was a small,
sustainable project but it soon spiralled into quite an enterprise, in fear of
the never-ending school fees my parents chose to pay. He worked bloody hard. He was out in the garden, or the barns, from
dawn to dusk, except for the 1 o’clock news and his afternoon nap. He was a farmer; a grower; an ideas man. Apart from his army days in the war, and two
years managing a farm for someone else before he bought his own, he was his own
boss and a free spirit. He wasn’t a
businessman. Before I went to boarding
school at twelve, he was always at home.
He was a constant presence in my early childhood, yet he was somehow
distant as well.
While my father was busy doing, my mother was
everywhere. She was the dominant figure
in my childhood and she did everything for us.
Our home life was informal, with TV suppers, and a constant throng of
activity and heated discussion around the Aga in our rustic farmhouse
kitchen. She drove my sister and I
fifteen minutes each way to school, to the beach on sunny days, and for
occasional visits to friends’ houses. We
spent a lot of time in the car. Our cars
were third hand old bangers. Our
biennial holiday was a visit to an old friend of my Mum’s in the Wiltshire
countryside for a weekend in May. Our
food was simple and not lavish. The only
thing my parents spent money on was private school fees. My Dad received a small private income
(inherited from rich spinster Aunts) and made some pocket money with his
various enterprises. Family heirlooms
were sold and money was borrowed against the fantastic – yet flawed – dried flower
business.
My first school was a small local independent
school heavily subsidised by the Roman Catholic church (we weren’t
Catholics). It was mostly local farmers,
doctors and dentists and local business owner’s kids and I recall it as a
relentless but harmless drill. I was
timid and frail, a bit of a Mummy’s boy and I specifically remember missing
(and never mastering) long division due to another bout of tonsillitis (they
were whipped out aged 10). When I wasn’t
ill, it gave me a very solid, academic, head start in life. I don’t remember studying any science there
at all but recall learning why Thursday is called Thursday (after Thor) and
January called January (after Janus). I
also remember learning a lot about the Sabre Tooth Tiger. I’m not sure why. I also remember not knowing the answer to the
tiresome question, “which football team do your support?” I still don’t know today. This was – perhaps – an early sign that I saw
the world a little differently to most, and that I wasn’t remotely interested
in running with the pack.
At 8, I went daily to a local prep school which
closed down for economic viability reasons just before I was 12. There, I was exposed to lots of formal,
instructive, traditional teaching. There
were 8 forms spanning school years 4 – 8 (5 years) in modern money. I was one of only about 12 day pupils amongst
about 100 full time boarders, so a little bit of an outsider. Am I a natural outsider? Was it nurtured? Or do I actively seek to be an outsider; an
obstuse, over-analytical, obstinate, argumentative provocateur?
I started in form 2, moved to form 3 after three
weeks and then form 5 in my second year, form 6 and form 7. So by the top end we were in age groups,
approximately, but lower down we were accelerated – or held back – according to
ability. My maths teacher was excellent,
possibly the best teacher I’ve ever had; my memory served me very well in
history, geography and science; languages (mainly French and Latin grammar)
came naturally to me and I was put off reading until well into adult life by
“reading” 1984 by George Orwell aged 10.
Learning Science in a real lab from the age of 8 may have been
important. I remember watching mercury
flow around on the lab bench; watching a fractional distillation of crude oil
demo and playing with various models of polystyrene balls to represent the
different packing arrangements of atoms inside crystals. Most of all I remember
endless summers of pond dipping on the school lake, and taking samples of
various creatures back to the lab for closer inspection.
It was – I think – some of the stuff outside the
classroom that shaped the workings of my curious and creative mind far more
than all the conventional, subject-based, classroom learning. Aged 10, I became fascinated by
photography. I liked going for walks and
properly seeing, not just looking; focussing on composition. I liked the science of photography; the
variables – film speed, shutter speed and aperture, but it was the chemicals in
the dark room I loved the most, something about breaking the heat seal to
reveal the distinctive chemical aroma.
This resonated with my senses. I
also loved woodwork: carving bowls on
the lathe; perfecting a dovetail joint; the doing and the making. Before lunch, everyday, we would change into
“smocks and jeans” and roam the wilds of the North Devon countryside
surrounding the school. This may have involved
building dens in the woods, building a muddy dam on the small stream feeding
the lake, swinging from branches, climbing trees or listening to Queen, Jean
Michel Jarre or the early ‘Now’ compilations on our primitive cassette players. I recall no playground tussles, no
competitive games of football and no adult supervision during this time.
Outside of school there were ridiculously long
holidays, rarely with anyone else to play with other than my younger
sister. Days, even weeks, would go by in
my imaginary world with a seven acre playground of disused barns, a paddock and
garden to fuel my imagination. Was all
this blissful isolation the cause of my imagination, of my creative thinking;
or was it just a mirror to the happy little world that would have been going on
inside my head wherever and however I grew up?
When I wasn’t meandering through my imaginary world or building lethal
contraptions from old prams, wheelbarrows and bicycle wheel I ventured to the
neighbouring farm, initially seduced by the hypnotic rattle of a Massey
Ferguson tractor engine. There I would
spend hours watching farm activities: milking; calf feeding; pig feeding;
haymaking; silaging; harvest; even slurry spreading had its rustic charm! I chatted curiously to the farmer about his
antics; very interested in the detail about milk yields and bacterial inoculation
to accelerate the fermentation of fresh grass into silage. My particular fascination with cows, milk
production and dairy farming was further enhanced via conversation with Dad,
when he had the time, and also riding around the local farms on a milk tanker
to collect the milk from the bulk tanks with a local family friend. On those farms, I had an even bigger audience
of farmers to quiz with my incessant agricultural curiosity!
At 12, in 1984, I moved prep school (staying for 2
rather than 1 potentially unsettling year) and started boarding in Tavistock on
the edge of Dartmoor, 35 miles from home.
This was an even more socially and academically elitist establishment
than I’d experienced to date; full of the sons of naval officers, local
solicitors and high court judges. I
don’t really remember any particularly revelatory teaching, though with
hindsight my English teacher was clearly a Marxist as we spent quite a long
time interpreting the lyrics to Imagine by John Lennon. Regardless of the dry, unmemorable teaching,
learning surrounded by some intellectual big guns whom later won scholarship
awards to Eton, Winchester and Sherborne in Dorset was probably good for my
intellectual development. I wasn’t quite
bright enough to gain a scholarship to one of the top division public schools,
so my outrageously snobby mother sought out the socially acceptable, but
academically suboptimal, establishment of Milton Abbey School in Dorset. I managed to gain a scholarship award of 40%
off the fees by being able to do some quite challenging maths, write a
reasonable history essay, regurgitate some abstract scientific facts and spell
my name correctly.
Science didn’t especially rock my world aged 12 –
15, nor did English or Maths. I think I
preferred History and Geography. Classic
school subjects. My history teacher was
brilliant. At the age of 15 my Dad had a
huge operation and was diagnosed with terminal colon cancer which had reached
his liver. He died in the middle of my
early French GCSE in November 1988. I
was awarded a B. In January I sat maths
early and was awarded an A. In June 1989
I sat the rest, gaining further As in Chemistry, Biology and History; a B in
Geography and Cs in English Lit, Lang and Physics. I really didn’t like Physics at school;
didn’t read enough (back then) to improve my English; I had an excellent
Biology teacher and for some unknown reason Chemistry made perfect sense to
me. Dad’s death conjured up notions of
medicine in my mind and the romantic idea of becoming a 1950s style village GP,
with a folding leather briefcase, big sideburns, an aura of learned wisdom and
widespread adoration from the local community.
So medicine was the aim and I therefore chose science based A
levels: Biology, Chemistry and Maths
(the latter because I thought I was some kind of maths genius having attained
an A grade with no revision or practice two months after Dad died).
With hindsight this was a ridiculous idea from an
establishment full of Tim nice but Dims from the Harry Enfield show. I didn’t work hard enough. My maths teacher didn’t bring complex
numbers, projectiles and calculus to life for me; a (combined cadet force) fake
war with helicopters and explosions going on outside during my biology
practical exam didn’t help; I was distracted by my pastoral responsibilities as
Head of House and school prefect; I had started to love Rugby; being a roadie
for the school band; going for long walks to explore the glorious local
countryside and cycling over Bulbarrow hill to find some beautiful young public
school girls who specialised in aloof pouting and ingratiating flicks of their
voluminous hair. Academic achievement
just wasn’t on Milton Abbey’s radar.
Their modus operandi was the churning out of charming toffs who’d go on
to become Army officers, take over Daddy’s farm or become an entrepreneur. Medical school generally wasn’t in their
sights.
After school finished I spent the summer working my
arse off on a local Devon pig and arable farm.
I was manning the grain drier and stores on results day. B in chemistry. C in biology.
N in maths for not sure, nearly or never again – I’m not sure
which! Clearly no self respecting
medical school was going to ping through an offer, and retaking was going to be
like starting over again, so Chemistry seemed like something to pursue, a B after
very little revision. Not bad. Always came fairly easily to me. I liked biology but didn’t love it. Chemistry was better. My teacher was good and I liked him; complete
space cadet but yes, he saw something in me.
I really enjoyed our open morning demonstration of chaos and clocks in
chemistry: a solution of inorganic compounds and complexes, swirling around in
a large beaker, mounted on a magnetic stirrer, and changing colour at random
and unpredictable intervals based upon the different oxidation states of
transition metals such as vanadium and chromium.
So with a little help from Mum, I whizzed up to
chat to Dr Will Bland at Kingston Poly and secured myself a place on a sandwich
degree course in Applied Chemistry with Business Administration. Why Kingston?
It had a reputation as one of the better polytechnics and was near
London if I wanted to hang out with my affluent school mates; all swanning
around Fulham, Battersea and Clapham, darling!
Why chemistry? Because I
could. Why business? Mother’s influence. She suggested all scientists were socially
inept nerds and that I was far too gregarious, posh (she didn’t use that word
because posh people don’t use the word posh) and too much like my former front
bench politician Uncle (her brother is John Nott, former defence secretary in
the Falklands war and in Thatcher’s cabinet 1979-1982).
What my Mum didn’t account for is that I have very
little interest in the machinery of business, very little interest in the
financial world, very little interest in making money for making money’s
sake. While my character was similar to
my Mum and my Mum’s side of the family; it turns out that my interests,
intellect and values were much more closely aligned with the more creative,
liberal and slightly anti-establishment trend on my Dad’s side of the
family. I am however grateful for the
business element of my degree because it is mostly common sense, so I could
bash out an essay on economics, a project on Marketing or research the history
of employee relations to bolster my grades where I didn’t work hard enough to
grapple with some of the complex and alien concepts in chemistry.
And now a long section on the Chemistry aspect of my degree course…a 15-20 minute read…extracted from my longer writing elsewhere.
According to modern scientific theory, Chemistry
has existed for nearly 14 billion years, since the first atomic nuclei formed
approximately 300,000 years after the Big Bang.
Physics, in terms of time, energy and subatomic particles pre-dates chemistry
by a mere 300,000 years (biology came along much later). Since then, stars have been and gone, where
atomic nuclei were joined by electrons, forming the first atoms: the chemical
elements of the periodic table. Our tiny
insignificant Planet Earth formed and cooled approximately 4.5 billion years
ago and those elements combined to form molecules of increasing complexity;
eventually due to a miraculous and improbably perfect set of conditions in the
primordial soup of 3.8 billions years ago, simple molecules called amino acids
appeared which reacted to form proteins.
Proteins developed an ingenious technique of replicating themselves via
some mysterious genetic substrate called RNA (our good friend DNA was to follow
much later); cells developed, life appeared and just 100 million years ago,
mammals started to evolve.
Fast-forward to approximately 6 million years ago,
when humans started to evolve from ape ancestors while only 300,000 years ago,
homo sapiens, our species of hominid evolved.
By that time, we now have evidence of the daily use of fire – perhaps
the most prevalent application of chemistry on the planet. Language started to develop approximately
70,000 years ago; there is evidence of counting which dates back 35,000 years
and then by 12,000 years ago we broke free from nature and started
farming. Since then humans have been on
a roller coaster ride of rapidly developing civilisation: cultures, religions
and nations with some useful, though rather toxic, inventions – such as money –
developed along the way. About 2500
years ago, 400 years BCE (before the Christian era), an ancient Greek dude
called Democritus first conceived the concept of an atom (a tiny “uncuttable”
particle), the tiny building blocks of which all matter is composed.
Despite the ancient Greeks intellectual
advancement, things didn’t really progress much scientifically for the next
2000 years. The scientific revolution
started with Copernicus and Galileo less than 500 years ago, and then
accelerated via Newton, whose theories of motion underpinned the science behind
the great period of invention, engineering and industrial productivity that has
become known as the industrial revolution throughout the 19th
century (1800s, or the Georgian, Regency and Victorian eras).
Lavoisier and Priestley just about snuck in some
Chemistry at the end of the 18th century (in the late 1700s) with
their respective discoveries of oxygen’s significance in Combustion and
Respiration but up until 1800, virtually all scientific advances were in the
field of Physics, with all notable discoveries, and therefore knowledge, in
Chemistry starting after Humphry Davy’s discovery of new (reactive metal)
elements such as Sodium and Potassium in 1808, and John Dalton’s proposal of
atomic theory in 1809, with the exception of some pioneering work on the
properties of gases by Robert Boyle in 1661.
Chemistry became a subject of serious scientific research after the
publication of the first periodic table of elements by Dimitri Mendeleyev in
1869 but only really came of age following the discovery of the electron by JJ
Thomson in 1897, followed by Ernest Rutherford’s and Niels Bohr’s pioneering
work on the structure of the atom in the early 20th century. So, Chemistry – as a human endeavour – is
only about 200 years old, with most of the Chemistry that is taught in schools
and on undergraduate courses at university, being based upon research that is
less than 100 years old.
I didn’t learn any of the contents of the above
four paragraphs at school, nor on my undergraduate Chemistry degree. Nor did I learn this as a practicing chemist
in industry. The above is self-taught
knowledge I have learnt over the last five years, partly through personal
interest, and partly because I think a history of the human understanding of
science; and the roots of the human scientific discipline of chemistry are an
essential place to start when teaching this glorious subject. Just like every other school pupil, and
perhaps the majority of chemistry undergraduates, I was taught chemistry as if
it had always existed, as if the textbooks and curricula were sacrosanct, as if
it was the truth, the whole truth and nothing but the truth. I was taught Chemistry at school, and
university, as series of facts and processes I must learn to pass an exam.
Bizarrely, I completely accepted this diluted,
testable, linear, uninspiring, often abstract, and now approximately 67 years
old (since A levels were introduced in 1951) approach to teaching science and
chemistry. I knew no other way. As with the vast majority of school children
and university students I was extremely compliant and there only seemed to be
two options throughout my education: completely shut down, ignore it and leave
with no qualifications; or blindly accept that this is the way the world has to
be and get on with it. When we’re young
we have no concept of how the adult world works, or how things could be
different, maybe better, maybe worse; so we happily – perhaps reluctantly –
doff our caps to the perceived wisdom of our elders.
I’m now going to summarise what I was taught about
Chemistry, and how I was instructed, at university, with some analytical
deviations along the way. I fully accept
that my recollections are now over 25 years old, and that my memory may play
tricks on me by filling in gaps with falsehoods that fit the story my mind is
trying to weave, but I will attempt to be honest, or sparse if I have
forgotten, with my memories.
On the first morning, meandering through the
suburban back streets of Surbiton, on the walk down to Penrhyn road to enrol, I
encountered a metaller (a long hair = someone wearing black jeans, a black
leather jacket with Megadeth embossed on the back and implausibly long and
straggly black hair). This was Ross,
soon to become affectionately known as Rockin’ Ross, the God of Rock. Having encountered a few ‘metallers’ at the
Imperial College open day, and on the medisix conference in Nottingham, I
assumed he would be a fellow chemist, on the basis that chemists (and
physicists) are often devoid of any discernable taste in clothes or music. How right I was, for Ross was the first
person I met on my course. And he
remains a good friend today. One of the
best. We arrived in the large foyer
outside the main lecture theatre, enrolled, found out our timetable and that
our course director was the aforementioned big affable man, Dr Will Bland and
that our course tutor was a Mrs Daphne Eadington (Daphers).
Daphers was a good sort with a slightly nervous
disposition. One of our first lecture
courses was titled, “Modern laboratory techniques.” This module allowed our development of basic
measurement and observation techniques in the lab. We had a rough lab book and the course was
assessed with a neat copy lab notebook containing neat and accurate write-ups
of our experimental investigations. The
techniques ranged from simple gravimetric techniques (weighing accurately on
four figure digital balances), melting point apparatus to the most exciting at
the time: infra-red spectroscopy. At A-level we’d heard about characterisation
techniques like infra-red and nuclear magnetic resonance spectroscopy, and mass
spectrometry but school could not afford such equipment; so it was thrilling to
be able to prepare a sample between two quartz discs, place it in the
IR-spectrophotometer and watch the plotter do some crazy things as the sample’s
IR spectrum revealed the substance’s unique chemical bond stretching and
vibrating fingerprint.
During our first year, the (approximately) forty
peers on my course, plus all the straight chemists (not sitting combined
courses) and a lot of biologists, geologists and Earth scientists, who were
going to need a solid understanding of chemistry, sat two modules titled
Foundation Chemistry I and II, one in the first semester and the other in the
second semester. Each lecture series on
these modules, and associated practical classes were split three ways: 1) organic chemistry, 2) inorganic chemistry
and 3) physical chemistry. I was a good
student and bought the four recommended core course texts: Fessenden
& Fessenden (Organic Chemistry); Cotton, Wilkinson and Gaus (Inorganic
Chemistry); Laidler and Meiser (Physical Chemistry) and Fifield and Kealey
(Analytical Chemistry). My course
notes have long since been disposed of, but I am still the proud owner of these
four tomes of chemistry information.[1] Now that I’m teaching, I sometimes dip into
them to try and remind myself of my formerly acquired detailed knowledge,
looking for deeper insight into the massively diluted topics I teach at school,
and it scares me how little of the content of these books – which were my
course bibles – I remember, or ever learnt in the first place.
I started keenly enough, taking notes in lectures,
reading the allocated pages of the books, asking questions and grappling with
the complex concepts presented to me. As
well as lectures and practical sessions, there was a tutorial system with the
relevant lecturers, or sometimes a post-doctoral researcher from their field of
expertise. Tutorials were in much
smaller groups than the lectures and this was where most of my learning was
done – where we could work through the substrate of lectures at a slower pace,
try out some model questions and bounce ideas and questions around with our tutor,
and each other. This is, and was, an
efficient model for learning; and was closer to how learning is embedded within
school. There were no tutorials in the
second year (maybe we could request them, but I was either too lazy, or had too
much pride; or they didn’t exist).
Lectures were a mixed bag. Foundation chemistry was in the main lecture
theatre with approximately 200 students from a variety of physical and life
based science courses. Chemistry options
later in the first year, business lectures and final year options were more
intimate, sometimes with less than thirty people. There were front row students, back row
students and middle rows students. I
started in the middle and drifted towards the back. Some of the doodles that Nick Whatley drew
next to me have mentally scarred me for life!
I listened attentively in lectures to start with, though my extravert
and gregarious nature, and the opportunity to sit next to some of the prettier
girls – especially the biologists – often distracted me from the task in
hand. Of course my ability to pay
attention in lectures was dependent on four main factors: my interest in the topic, the engaging style
of the lecturer, how hungover I was and who I was sitting next to. Initially, I was interested in all the
chemistry lectures but Dr Jim Betts quickly killed off any interest in physical
chemistry with his endless, regurgitated OHP [overhead projector] acetates (I
started my university days in a powerpoint free world). He droned on about ideal gases, Boyle’s law
and Avogadro’s constant – and showed us how their famous equations or numbers
were derived from first principles; my lack of a thorough understanding of
algebra and lack of willingness to really grapple with the vertex of where
maths meets physics meets chemistry let me down here; though whizzing through
some prescriptive content at breakneck speed with minimal audience involvement
was far from engaging.
Dr Will Bland first taught me inorganic chemistry,
with a much greater presence and passion than Dr Betts. However, the subject matter soon turned me
off: oxidation states, transition metals
and complexes never really rocked my chemical world. Lol, a good friend on the course and proper
Romford boy, nicknamed Dr Bland, ‘me old fruit and fibre’, due to his friendly,
big, cockney geezer appearance. Dr
Alistair Mann, affectionately nicknamed Sooty due to his uncanny resemblance to
Matthew Corbett – presenter of the Sooty and Sweep show – was our first organic
chemistry lecturer. He was good, not
terribly exciting, but he varied his pace and deepened my interest in all
things carbon.
In the second year, Dr Cooper taught us Organic
chemistry and he was a proper eccentric.
He taught without notes (always a good thing in my view) and drew great
big curly arrows all over the rotating blackboard. I struggled to keep up with his curly arrows
and it was around here that organic reaction schemes started to become
unfathomable to me – I could cope with electrophiles and nucleophiles; and
substitution and elimination reactions; and stereochemistry didn’t freak me out
too much but all the Sn1 and Sn2 stuff caused me to glaze over and imagine
where the next beer was coming from.
Being battered over the head with some complex and
abstract concepts in a lecture theatre has never really been an ideal way for
me to learn. Admittedly my focus was
suboptimal, but it was hard to get excited by such complex theory, and to
assimilate it in one sitting. Yet, that
is what I expected my mind to do. The
subject matter needed much more prodding and playing with than a 1 hour-long
information pass lecture. I needed to
give it all more time, but between beer, late nights, sleep and making friends
there didn’t seem to be enough time. I
was ill-disciplined and insufficiently motivated.
Chemistry is such a complicated subject, and as one
gets older you come to realise that scientists know more and more about less
and less. One particularly annoying
thing about being a scientist, is that when a ley person first meets you and
finds out that you are a scientist of some sort, first you get the Blind Date[2]
“whooooo,” followed by a discussion about medical ailments or some really big,
fundamental science question about a field of science you’ve not studied since
you were twelve like, “why is the sky blue?”
Virtually all the scientists I’ve met and worked with know loads and
loads about their teeny weeny specialism, but very little about anything
else. And I mean anything else. There are, of course, a few exceptions where
a scientist is extremely well-educated across the sciences and beyond; and
there are a few non-scientists who are far better scientific generalists than
Dr Felicity Fictional-Chemist who knows everything there is to know about the
allotropes of sulphur but couldn’t easily explain to you what causes the
seasons, or recite the balanced chemical equation for photosynthesis.
Most peoples’ knowledge deepens in one or two
particular areas throughout their adult lives, depending upon their profession,
their specialism and their personal interests.
Our general life experience broadens our understanding of how the world
works, but it is rare for adults’ knowledge to both broaden and deepen significantly. Some professions, for example primary school
teachers, require a broad, but often very shallow, knowledge about lots of
things. With the exception of their
personal interests and passions they need to know a tiny amount about loads of
things. As long as they are two steps
ahead of all the young children they teach, they can get away without being
founts of all knowledge. Secondary
school science teachers are required to know a little about a lot of things
(the secondary school science curriculum, plus their own specialism). Chemistry lecturers are required to know a
lot about their field of chemistry (but not all chemistry). Researchers know an awful lot, sometimes more
than anyone else, about a tiny narrow area of a tiny narrow field of chemistry. Unless we use our knowledge regularly, and
keep hooking new information onto it, it remains inaccessible to us – buried
deep within the recesses of our minds:
the old adage, ‘use it or lose it’ is sound advice here. So we end up forgetting most of what we
learnt in school and university. Indeed
recent research into dementia suggests that regular training and use of the
mind, particularly learning new things, (so not just sticking to one field of
existing expertise) may delay – if not prevent – the onset of dementia in old
age.
With the exception of the most astute and
insightful young people, children at school do not realise how little their
teachers or lecturers actually know.
Children are incredibly accepting of whatever is presented or taught to
them, as are many adults. This simple
fact explains the dominance and influence of the media on all our lives; and
how conventional schooling – as wonderful as it can be – is really just a form
of social conditioning to prepare individuals to become useful members of
local, national and global society. We
collectively assume that our teacher knows loads of stuff. We collectively assume the intellectual
authority and experience of our teachers, and our lecturers, yet many of them
have never done anything other than teach, or lecture. So they know loads about teaching and
lecturing but not much else. The
occasional bolshie smart Alec detects this weakness in their teacher or
lecturer and makes their life hell, but in the most part young people know very
little about anything so the natural hierarchy of school and university is
preserved. This is probably a good
thing, but it is not without its flaws.
As real chemistry that real chemists do is based
upon some fairly complicated principles, chemistry is built up in layers
throughout school and university. Even
before chemistry is called chemistry at primary school, we are taught about
rocks and materials. Different
properties of materials are observed and we are taught that materials behave
differently dependent upon the internal structure of the “particles” inside the
material. A little later, typically in a
general science class, the concept of elements (chemical substances made from
only one type of atom) and compounds (chemical substances made from two or more
different types of atom, chemically joined together) are introduced. Around this point chemistry suddenly becomes
an “exciting” practical subject with some very simple illustrative and
investigative practical work carried out using Bunsen burners and some cheap,
and readily available school laboratory chemicals (the good old dilute
hydrochloric acid, sodium hydroxide, copper sulphate, calcium carbonate and
potassium permanganate to name a few).
The purpose of this playing in the lab is to introduce children to the
concept of chemical reactions and to distinguish between chemical changes
(sometimes described as irreversible changes such as burning or rusting) and
physical changes (often described as reversible changes such as melting or
dissolving). Everyone is taught about
the pH scale, acids and alkalis. This introduces how substances can have very
different chemical properties and reactivity.
Links are made to common and tangible practices in farming and medicine
and a simplified version of chemical bonding is then introduced. At A-level our understanding of chemical
bonding and chemical reactions both broadens and deepens and the language of
chemistry notches up a gear but – in the most part – we’re still being pumped
full of facts. Then, at university,
chemistry is split three ways (before sub dividing further and further) into
the aforementioned Organic chemistry (chemical reactions and properties of
carbon based compounds), Inorganic chemistry (chemical reactions and properties
of all the other elements) and Physical Chemistry (studying physical properties
and applying the principles of Physics to solving chemical problems).
The point I’m trying to make is that although the
school and university Chemistry curriculum is built up in layers, I’m not
entirely sure that we can reason, or understand the reactions of the alkenes,
or alcohols at A-level because of our limited understanding of the reactions of
the metal carbonates at GCSE. And, as
everyone who has ever learnt any chemistry beyond GCSE, O-level or A-level can attest,
the early chemistry we are taught is a series of over-simplified lies, or
half-truths just to help us assimilate a few facts so that we can be tested on
them. I don’t – yet – have an easy
solution to this problem; but after several years of gradually deepening layers
of knowledge being pumped into my brain at school, this process continued at
university, with an enormous amount of prescriptive information to assimilate
in order to succeed on my course. Maybe
my mind needed those layers of prior knowledge to assimilate some of the new concepts,
equations, reaction mechanisms and terminology that was being bombarded at my
brain cells? Maybe I could only ever
become a good scientist with tonnes of seemingly superfluous knowledge pumped
into my head?
I remember a conversation with a peer in my first
or second year at university, when the ever-deepening complexity of Chemistry
was starting to dawn upon us, where we discussed if there could ever be an end
point to the depth of our knowledge of Chemistry, or science? It is this quest for knowledge, this quest
for understanding that drives academic scientists, albeit in miniscule nuggets
of very precise progress. While I would
never expect a 10 year old, or a 16 year old, to grapple with degree level chemistry;
I sometimes think it important to show them where all this teaching can lead,
to show them how complicated and wonderful the subject can be. Yet, this goes against mainstream educational
dogma, where we can only use age relevant words and diluted concepts for fear
of scaring off children from how complicated learning can be.
The above deviation is triggered by how my lateral
mind wasn’t stimulated by the series of factual and logical processes and
concepts I was exposed to in Chemistry at university. While my mind is more logical than many, with
some well honed mathematical reasoning skills and plenty of critical scientific
thinking; my mind works in a more creative, lateral way. I like to bounce ideas around, challenge
fixed viewpoints, solve problems that haven’t been solved before and debate the
best – or an alternative – way of doing things.
I didn’t realise this at the time, but I now know that I have a creative
mind, one that was not stimulated by incontestable, logically proven – albeit complex
– concepts. As well as my natural
affinity for the student bar, this probably explains why I wasn’t engrossed,
consumed and set alight by my chemistry lectures at university.
Chemistry courses at university don’t beat about
the bush. Well mine certainly
didn’t. There was no preliminary
discussion about what chemistry is, why we learn it or how we learn it, instead
courses charge full steam ahead with pumping knowledge into our brains. We were thrust into Boyle’s law of gases,
chemical bonding or oxidation states.
There was no flowering it up, no drama, no suspense, no sense of wonder;
just straight into the factual meat of the subject. Creative thinkers are stifled by this style
of teaching and learning. It is solely
focused on academic and logical thinkers, which – I concur – most scientists
need to be, but all of us?
While the theoretical principles of chemistry
didn’t thrill me in the lecture theatre, some applied aspects of the subject
interested me more. I lapped up
Environmental chemistry, taught by Dr Freddie Fifield, a tall, big hipped,
corduroy trousered and stuffy old tweed jacketed antique of a lecturer, with
the world’s largest abundance of grey, curly ear hair. Acres of the stuff. He was just the sort of charming and wise old
duffer a chemistry lecturer should be. Dr Elizabeth Tyrell managed to bring medicinal
chemistry alive with its natty term ‘retrosynthesis’ and tangible real-life
case studies of ibuprofen (Nurofen®) and salbutamol
(Ventolin®).
In the second year I learned to like Physical
Chemistry a little more, with lectures from Dr Foot (“Footie”) and Dr
Wyer. I was particularly interested in
phase diagrams and phase transitions, which – unbeknownst to me at the time –
would dominate the latter half of my Pharmaceutical Materials Science career
with Pfizer. Dr Cooper kept Organic
chemistry engaging yet utterly baffling.
I remember an in-ordinate amount of time being spent on the Wittig
reaction, but have absolutely no recollection of what a Wittig reaction
is. And a new (old) inorganic chemistry
lecturer (Dr Moseley) enthralled me with the complex Redox
(reduction-oxidation) chemistry of Vanadium, the most wonderful and fascinating
of all the transition (or d-block) metals, while boring me senseless about
chelates and the chelating agent, EDTA (ethylene diamine tetra-acetic acid).
I have mentioned tutorials and lectures but so far
I haven’t mentioned practical sessions.
There were, of course, lots of these.
A practical session would last between 2.5 and 3 hours, and there were
two, sometimes three a week. Add to this
approximately 4 to 6 hours of chemistry lectures and 4 to 6 hours of business
lectures, so our total contact time added up to approximately 20 hours. 14 hours more than my friends studying
geography! There were also some
lectures in maths – to help underpin all the deriving scientific equations from
first principles that dominated my studies in physical chemistry. Computing was starting to dominate the world,
so we were all taught how to use outmoded MS-DOS software packages like GRAPHPLOT
and MINITAB, before being trained to use Lotus-123 spread-sheets and Word
Perfect word processing before Microsoft took over the world. Those 20 hours were supposed to be about half
of it. I should have been finding
another 20 hours a week to study, read, and write-up practical
investigations. Writing this now, it
seems pathetic that I couldn’t find this time amongst my busy social, drinking,
eating and sleeping schedule; but I was – for a while – the archetypal lazy
student, having the time of his life.
Practicals were an opportunity to mess around and
banter. This is one of the best aspects
about being a scientist – putting the world to rights, discussing the meaning
of life, and trying to make others laugh is what makes lab life go round. Chemistry is – famously – a practical
subject, yet did I love practicals? Not
especially. I have always liked
debating, discussing and grappling with new knowledge: asking lots of questions,
being curious; but I am perhaps a rarity in that I never particularly enjoyed
school or university practical sessions.
Later on, in industry, I loved being in the lab; but carrying out a
tried and tested experiment, where your teacher, or lecturer, knows what will
happen doesn’t thrill me that much. I
think there are three reasons why I didn’t especially like practicals: Firstly,
I wasn’t relaxed – I always feared I would make a mistake or do something
wrong, perhaps break something; or add the reactants in the wrong order or at
the wrong addition rate. Secondly, my
practicals often did go wrong. When I
was supposed to filter a crystalline residue, I often ended up with nothing:
zero yield. Sometimes I would make
something, but it would be a sticky mess and far less elegant than my
classmates’ beautiful crystalline offerings.
Thirdly, and this is the deal clincher, I never really felt I was
learning anything. Despite all the
diatribe above, I actually quite liked having twenty tonnes of facts pumped
into my brain. I liked the technical
meat of chemistry lectures, even if some of them went over my head, or were
monosyllabic and dull.
In an illustrative practical, the actual science is
dealt with elsewhere – in lectures, or assignments or – at school – in desk
based lessons. All one is doing is
following a set of instructions, a bit like assembling a bookshelf or setting
up a new computer, and then being quietly pleased with the end result. Some of the time we were learning practical
skills that would benefit us if we were going to become synthetic organic
chemists, or industrial process chemists.
Skills are an important part of learning science, but I wanted the
substance, the explanation too.
Occasionally, there was an element of surprise, which is a good way to
tantalise students with new knowledge but in the most part we were following
recipes that had been carried out hundreds of times before.
As a teacher, I fully appreciate that practical
lessons are an opportunity to make science exciting and different from more
deskbound school subjects, but – in my opinion – if taught creatively and with
a variety of activities and tasks – science is a pretty exciting subject with
or without practical investigations.
They have their place, but they are not always the holy grail they are
made out to be. If we got to design our
own practical investigations that would have been a different matter: designing an experiment, or series of
experiments, to prove or disprove your own personal hypothesis can be
thrilling, particularly when the results are magically revealed for the first
time.
Clearly it is more exciting to learn chemistry via
practical activities, than by conventional rote learning, but it can be
terribly inefficient. At school, a
simple practical can consume an hour, while the teaching point in question
could be explained in 5 minutes. It
depends on what else you want to teach, or cram into your chemistry
course. Personally, I’d prefer greater
efficiency with mandated (curriculum) factual learning with fewer illustrative
practicals, to free up more time for creative, pupil-led investigations – off
curriculum; if it helps to inspire and generate greater enthusiasm for science,
or chemistry. There are the less
academic but highly practically skilled individuals who we want to keep on the
science bus to consider – it is always great seeing a pupil who struggles with
the depth of content they are required to learn suddenly master a practical,
mechanical or electrical skill. They are
often king for a day, in place of the curious, more cerebral minds. The modern world needs a lot more
electricians, plumbers and skilled practical people than it does Professors of
Chemistry, so it is essential to keep developing these skills in school science
labs, but there are not too many prospective electricians sitting chemistry degrees.
My most memorable university practical sessions
were in Medicinal chemistry in the second year.
My practical partner was Robin Farmer, who – along with Henry from my
Clayhill house in the first year and someone unaffectionately known as Matt the
Twat, I shared a four bedroom house with.
Robin and I were good friends. He
was loud, northern and obnoxious. I was
equally loud, southern and fractionally less obnoxious. We were both quite studious in comparison to
some of our fellow reprobates on the course but also rather competitive with
each other. I still frequently failed to
produce good yields[3]
from our reactions, but we were often the first to finish, giving us more time
to prey upon our friends and contemporaries in some weird ‘who can be the most
obnoxious twat league.’ Happy yet
strange days.
I will return to the notion that chemistry is a practical subject in a later blog. This was something that was debated extensively in the Materials Science labs at Pfizer and also on my science PGCE course prior to starting my second career, in teaching. For now I will leave you with two thoughts: it is predominantly a practical subject, but there are many ways of being a great scientist without fantastic practical skills. Secondly, virtually every practical skill honed in a school science laboratory is completely outmoded within a modern industrial or hospital setting.
My degree featured a sandwich placement for a year in industry…so now for my Eureka moment, my moment where the doing of Science, rather than just the learning of science, brought it all alive for me…another 20+ minutes read complete with some optional “brief technical interludes!”
After
my third and final summer of working all hours on Brian Jones’ pig and arable
farm in Sheepwash, Devon I returned to the South-East of England. Not to my familiar stomping ground of Penrhyn
road student union; but to small, temporary accommodation adjacent to
SmithKline Beecham’s R&D facility, near Tonbridge in Kent. Like every other science based job I’ve had,
I started my first day wearing a tie, never to wear a tie again – until the interview
for, or first day of, the next science based job.
I
was assigned to the mass spectrometry[4]
lab, in the spectroscopy group of the analytical sciences department. I overlapped for one week with the previous
student; and two weeks with a summer student (the previous year’s student)
before spending most of my year with Duncan, my supervisor; and Brian the lab
leader. Brian interviewed me, but it was
his boss – the head of the spectroscopy section, Dr Mike Webb, Kingston Alma
Mater, who initially lured me in to the wonderful world of chemical
development. Mike was a lively
character, with carefully crafted mannerisms in the style of Mick Jagger. Our mutual love of the Rolling Stones was –
quite possibly – a deal clincher in my interview success. While he was a notch up the convoluted
hierarchy from Brian and Duncan, he was more playful and distracting than both:
frequently popping into the lab to re-connect with lab life, and – presumably –
avoid the tiresome rigmarole of climbing the slippery pole of corporate middle
management. At the time of writing, he
is now a very senior figure within Glaxo SmithKline.
For
my first few days, I tiptoed tentatively around my first taste of
industry. Paul, my predecessor, made me
laugh with impressions of Brian’s meticulous mannerisms and Duncan seemed
friendly enough. Initially, I was pre-occupied
with finding some fellow students to share a house with for the year. My temporary accommodation was only available
for a maximum of three weeks, and I wanted to avoid ending up sharing with
uber-geek, Dan, my temporary room-mate.
While
the site seemed quite big to me, I now know that this was a small and intimate
Research and Development facility in comparison to most others in the
Pharmaceutical industry; with approximately 120 employees on site. For the majority of my year, this included 8
undergraduate placement students (including me), with the occasional Masters
degree, or SmithKline Beecham sponsored PhD student temporarily on site for 1-3
months. But when I started in September
1993, along with the 8 new placement students, there was a scattering of the
previous year’s students who hadn’t quite finished, and some summer placement
students too; so – upon arrival – the small site was awash with 12, maybe 15,
undergraduates. So, it felt like quite a
youthful, vibrant place to be; not exactly a university campus but quite
relaxed and modern, and not alien or oppressive to a 22 year old undergraduate.
I
distinctly remember my first morning coffee break. Everyone, in small workgroups, spilled out
from various buildings at ten o’clock and then walked down the path, lined with
ornamental flower beds, and descended upon the canteen. While most of the more experienced employees
sat in groups of three or four at tables, the burgeoning throng of
undergraduates huddled in one corner of the room. I was uncharacteristically quiet on that
first day. Just on the first day. Later on in my career, when starting a new
job I always vowed to play it cool, to not give too much of my character away
too soon. Such vows are futile. I am, by default, a gregarious and verbose
individual. Many would use stronger
language to describe their first impression of me. Holding myself back, is like King Canute
trying to hold back the tide. I can,
however, rein myself in on the first day of employment, just to suss out the
lie of the land; form my own first impressions and preserve a modicum of decorum
and self-respect.
On
this first coffee break, of this first day, of this first period of formal
employment within science based research and development, during my first foray
into industry; my eyes were drawn to a female, all dressed in black. She was wearing leggings, tightly clamped to
some long, thin, double crossed legs.
She exuded a calm, confident aura with a subtle, enigmatic smile. Her twinkling blue eyes, set against her
soft, pale complexion and thick dark hair were enticing; but it was her soft
southern Irish accent and delicate manner that beguiled me most.
This
first glimpse of Cathriona convinced me to start project house share. After a few days, four of us had formed a
bond, found a house and both the present, and the future, seemed exciting. I immersed myself in work and play, and
within two weeks had made some good new friends; enjoyed some boozy nights out
and was quickly learning the craft of mass spectrometry. Cathriona was going out with Mark, an
outgoing student. He was a bit of a
tit. So I subconsciously bided my
time. This biding of my time included a
day of riotous and drunken tomfoolery at the annual SmithKline Beecham fun day.
SmithKline
and French (a US company) merged with Beecham pharmaceuticals (a UK company) in
1989, to form SmithKline Beecham[5]. In September 1993 they still had six or seven
R&D (research and development) sites dotted around the dormitory
settlements of London, just outside the M25.[6] The annual fun day was a way of saying thank
you to their employees and their respective families. The UK R&D division hired the grounds of
a large country estate and coached in over 2000 people, with no expense
spared. There was an incredible buffet,
free drinks and a heavily subsidised bar, fairground rides, medieval jousting
and an inter-site “It’s a knockout” competition hosted by Stuart Hall (who
hosted the original BBC TV show), whose name has since fallen into
disrepute. I managed to make it on to
the Tonbridge and Walton Oaks[7]
team.
It’s
a knockout involved all sorts of ridiculous obstacles, giant costumes and lots
of water. It was a lot of fun. Then there was lots of drinking. By the evening, I was well oiled. There was dancing and a very pretty girl from
the Brockham Park site. I adorned one of
the large foam horse costumes from it’s a knockout, mock cantered around the
dance floor staging, fell off the stage in a drunken stupor, cavorted with the
pretty girl’s larger and not quite so pretty friend and moonied, out the back
window, from the back row of the coach on the way back home.
Twelve
days in to my first dalliance with real science, I had made quite an
impression. Duncan – my supervisor –
must have been quite worried. He alluded
to this event, and indeed many other similar breaches of sensibility throughout
the year, in my leaving card a year later: A brilliant year: a vindication of a
private school education, though the behavioural side was frequently
monstrous! By the time Duncan wrote
this, he was my scientific superhero, friend, and the single most influential
factor of my accidental journey into science.
There
was a lot more riotous partying and drunken debauchery throughout the year:
funded by a reasonable salary, another student loan, some money I was lucky to
inherit for my 21st birthday and a fairly healthy overdraft. While I spent a stupid amount of money on
beer; my excessive expenditure included the purchase of separates stereo system
(Kenwood amp, Tannoy speakers, Sony CD player, Aiwa tape deck), loads of CDs, a
holiday to Prague (to stay in the British
Embassy with my Godfather, the British ambassador at the time), and most
notably my first ticket to the Glastonbury festival of music and performing
arts in Somerset, in June 1994.
While
I had seen a few bands before Glastonbury, the combination of this melting pot
of cutting edge musical culture; a big loud stereo and my voracious reading of
the NME, Q and Select magazinespropelled
my obsessive musical journey for the next few years. While I was slowly – unbeknownst to me at the
time -becoming a scientist; I was heavily pre-occupied with my love of music,
the subject of a separate version of my life…
While
my journey into music obsession is not relevant here, it consumed a lot of my
time; and a lot of my money. Not just
buying albums and going to gigs but reading a lot of books and magazines about
music. It was an all consuming hobby and
interest, and one – with hindsight – which may have detracted from me becoming
a scientific researcher, or an academic at university. If I had voraciously consumed scientific
literature and conference attendances, the way I gorged on the rough guide to
Rock or the music monthlies then maybe I’d be a Professor by now; but that
wasn’t my path.
I
look back with great nostalgia on this year; and in the forefront of my mind
are all the social, musical, emotional, and cultural experiences but beneath
all that, this was the year I became a scientist. This was the beginning.
At
the time, the culture of working and earning a reasonable income enabled my
social life, my drinking, my partying, my silly-arsing about. I enjoyed mixing
with a range of quite different people, of quite different ages; I enjoyed the
culture of work; of working with some interesting people in a state-of-the-art,
cutting edge scientific environment. The
institutionalised worlds of school and university seemed to be behind me; and I
enjoyed being part of something more permanent, something more purposeful,
something with more autonomy and more freedom; and something I was paid
for. Everything about working in a lab,
with other scientists, still surrounded by some young kindred spirits; but also
a handful of wise old sages – it all seemed to click for me; seemed to resonate
with my very being.
Neil,
a friendly Northern lad, casa-nova and computer scientist; Marion, a chemist
from Omagh, in Northern Ireland, working in the NMR[8]
lab; myself and the aforementioned Cathriona moved into 1A, Goldsmid Road,
Tonbridge in late September 1993. Marion
and Cathriona were civil to each other but never best buddies. Their upbringings either side of the Irish
border, and their very different characters, not conducive to a deep
connection. Neil was very different to
me but we got on like a house on fire.
He was a great guitarist but played too much fiddly diddly Steve Vai,
Joe Satriani and Eddie Van Halen self-indulgent crap while standing in front of
the mirror and checking his hair. Apart
from these shortcomings I liked him a lot, and we both lost our Glastonbury
virginity together – along with lots of
my Kingston friends – in June 1994.
Cathriona
and I happened in October. Before
Cathriona there were drunken fumbles and lots of passing unrequited loves. After Cathriona there were some more drunken
fumbles and a couple of insignificant romantic dalliances before Amanda, my
wife, best friend and love of my life came along in 1999. Cathriona was the one who got away. She was lovely. Gorgeous.
Apart from Amanda, she was the only girl I’ve loved. We spent an intense four months together;
before my drunken debauchery, my immaturity and my gregarious social instincts
ground us down. From October to
Christmas was lovely – I’d never really got the girl (I wanted) before, so this
was special. After Christmas, she came
back from Ireland a little homesick. She
was a bit low and my energetic persona was too much for her at times. I was too young to calm down, to be the
sensible boyfriend she seemed to want; so she slipped away and we ended in
February. The right time, right place
soon became the wrong time and wrong place.
It
was a little awkward in the house to start with. I grew closer to Neil and Marion. We hosted some riotous parties, much to the
delight of the under 35s at work!
Speakers were thrown out of windows, curtains ripped down, windows
smashed (by accident); beer and piss soiled the carpets. In my mind, I was in a punk band, trashing
hotel rooms while in reality I was working for a large multi-national science
based company and staring down the barrel of a life of science, conformity and
financial security. Cathriona was more
sensible, more grown up; she had less deferred teenage angst, no supressed
parental loss to rinse out; so she gravitated towards a mysterious older man
and spent most of her time away from the den of iniquity that 1A Goldsmid Road
became.
Duncan
liked a good party. As did his wife
Katy. And Martin the German Schnapps
obsessive. There was a lot of fun in
pubs and at house parties that year. Sending out late night search parties for
a drunken and wandering Katy and blagging a sandwich from a consultant in a
late night A&E department are also particularly memorable. Brian, Duncan’s boss and head of the mass
spectrometry lab didn’t have the aura of a party animal. He had a young son, Robert, who he was always
– understandably – keen to get home to, leaving Duncan and I together in the
lab late into the evening on occasion.
I was never in early enough to witness Brian’s daily ritual, at 7:45
every morning, of neatly removing his patterned tank top over his neatly
trimmed and angular beard, and folding it neatly into his brief case before his
work day commenced. On the surface he
was the archetypal analytical scientist: quiet, understated, with very precise
and impossibly neat handwriting. He wore
a lot of brown and beige and liked order and tidiness. He was vociferous in his
dislike of Jeremy Clarkson, who had dared to describe his beloved Citroen
diesel as, “about as interesting as Lincolnshire” in a review on Top Gear. This led me to write the following, rather
unkind, two line poem about him:
He looks
like a weasel,
And likes
to drive a diesel
This is clearly my greatest literary work.
I really liked
Brian. Our paths briefly crossed when I
was at Pfizer, many years later. He was
a good man, and he was funny, kind and very supportive of me, if a little
infuriated by my exuberant, youthful and energetic idiocy. Back when I was 21, he was representative of
the scientific stereotype. The
stereotype which puts people off science: introverted, cautious, quiet,
straight, sensible, and completely devoid of any style whatsoever. While Duncan was my “boss”, Brian ran the lab
and was more mature and autocratic than Duncan.
I was Duncan’s first student, so it was sometimes a little hard for Brian
to let go of the apron strings of supervising undergraduate underlings.
The lab lobby opened via
double doors from the expansive foyer of the brand new two-story building
F. To the left was the NMR lab and to
the right, us, the mass spec lab. From
the lobby there was a single door into our write-up area, a comfortable and
expansive galley of four wide desks and some over-head filing cupboards. Two large windows over looked the lab.
The mass spectrometry
(mass spec, or MS) lab was light and airy.
On the left was the prep bench, for dissolving and diluting samples, and
a couple of fumehoods.[9] To the right, some cupboards and empty
benching; later to be filled with an open-access mass spectrometer for the
synthetic chemists to come and test their own samples. At the front of the lab there was a VG Trio
electron impact, single quadrupole mass spectrometer, with chemical ionisation
functionality hyphenated to a gas chromatograph (a GC-MS system). To the rear was an enormous Sciex API-III
pneumatically assisted electrospray (ionspray) triple quadrupole mass
spectrometer coupled with a high performance liquid chromatograph (HPLC) to
create a state of the art HPLC-MS/MS system.
The Sciex was equipped with two Apple Mac computers, one for the complex
software to control the instrument and the other for processing data. Around both large instruments (the VG Trio
rig was approximately 2m wide x 2m deep x 1.5m high, while the Sciex rig was
approximately 4m wide by 2 m deep x 1.5 m high) were a plethora of vacuum pumps
and other ancillary equipment. At the
far end of the lab was the large glass frontage to the building, letting in
lots of light and providing a great view of the site. The lab was temperature controlled and air
conditioned.
In September 1993 – just
as you now, dear reader – I had no idea what any of this meant. To the untrained eye, state of the art
analytical equipment just looks like a big grey box. It is all a long way from the stereotypical
idea of a science laboratory; full of multi-coloured, bubbling potions. Before I dive deeper into the technical
shenanigans of my enlightening first year in industry, I should explain
something we can all comprehend: carpet.
The mass spectrometry lab at SmithKline Beecham Pharmaceuticals in
building F, old powder mills, Leigh, Tonbridge, Kent was carpeted. Since then I’ve seen a lot of science
labs. This was one of only two science
labs I have seen carpeted in my life.
The other was the neighbouring NMR lab.
Why would you carpet a lab?
Well, the sample
quantities involved in mass spectrometry are very small and any large volumes
of liquids could be contained in the fume-hoods; or the flammable solvent
cupboards, complete with spill trays at the bottom. The main reason for the carpet is one of the
same reasons we carpet our houses: to
absorb sound. Carpet is very effective
at absorbing sound, so when the mass spec department heard that the loudest and
most verbose prospective scientist to ever walk the land was coming to work
with them for a year, they decided to carpet the lab! More seriously, mass spectrometers need to
work at very low pressures (very high vacuum), which means lots of pumps. Vacuum pumps make a tedious, constant
whirring sound. The carpet was installed
to absorb as much of this sound as possible.
This made the lab a very welcoming environment to work in.
There is of-course a flip
side: dust. Carpets have an insatiable
capacity for dust particles. Dust
particles are notoriously unfriendly to expensive and complex scientific
equipment. As the lab contained over
half a million pounds worth of highly specialist equipment (the very new and
shiny Sciex API-III cost £330,000 in late 1992), Brian was reluctant to let the
cleaners in to “hoover” the carpet. So,
this was my privilege. Every Friday
afternoon at 4pm, I, humble mass spectrometry undergraduate placement student,
had to hoover the lab. Within a week or
two, I found out that Duncan was a big fan of Queen, the rock band. Every Friday, I delighted in camping it up
and impersonating Freddie Mercury in the video to their hit single “I want to
break free.” Sometimes this drew an
audience of, perhaps, five or six people.
Not quite Queen at Live Aid in 1985…
|
A brief technical interlude: Mass Spectrometry
Mass spectrometry is an
analytical technique which probes the chemical structure of molecules.
A molecule is a chemical
substance made of two or more atoms covalently bonded together. Covalent bonds, as opposed to ionic bonds,
involve the sharing of electrons between atoms. This allows the outer orbital, or shell, of
electrons to be “full” for each atom involved in the chemical bond. The specific chemistry of each type of atom
(or chemical element) determines how many chemical bonds it can form. For example, hydrogen atoms can only share
one electron so can only form one single covalent chemical bond. Oxygen atoms can share two electrons and
therefore form either two single bonds, with two other atoms or one double
bond with one other atom. Nitrogen
atoms can share three electrons, and therefore form three single bonds; a
double bond and a single bond; or a triple bond. Carbon, the most versatile of atoms, and
justifiably known as the main element of life, can form four single bonds;
one double bond and two single bonds or a triple bond and one single bond.
All medicinal drugs are made of
molecules; so are most pesticides, plastics and polymers, dyes, flavours,
fragrances, petrochemicals and virtually all the many millions of chemicals
in animals and plants are molecules.
Most of the main components of food, cosmetics and healthcare products
are all molecules. So characterising
and identifying molecules is extremely important in many parts of the
pharmaceutical, chemical and food industries.
Mass spectrometry’s origins lie
in the measurement of the mass of atoms.
All molecules are made of atoms.
A chemical substance made of just one type of atom is called an
element; so all the known chemical elements appear in the periodic table,
that colourful table full of weird and wonderful names which adorned your
chemistry lab wall at school. With the
exception of hydrogen [a hydrogen
nucleus contains just one proton], all atoms contain protons and neutrons
in the their nucleus, orbited by electrons.
In terms of mass; protons and neutrons have a relative mass of 1 while
the mass of electrons is negligible.
In terms of electric charge neutrons are neutral [they have no charge]
while protons have a net positive charge of +1 and electrons have a net
negative charge of -1. An individual
atom has virtually no mass: many millions atoms of a chemical element would
be required to provide just 1 gram of that substance. However, the mass of all known matter on
Earth is due the mass of atoms. So
atoms can be said to have relative mass to each other. Rounded to the nearest whole number the
atomic mass of some common, and important elements are listed below:
Hydrogen (H): 1 Carbon (C): 12 Nitrogen (N): 14 Oxygen (O): 16
So the relative molecular mass
of water [H2O] is (2 x 1) + 16 = 18. Carbon dioxide [CO2] is 12 + (2
x 16) = 44. An oxygen molecule [O2]
will have a relative molecular mass of 2 x 16 = 32.
JJ Thomson’s pioneering work at
the Cavendish laboratory, leading to the discovery of the electron in 1897,
for which he was awarded the Nobel prize for physics in 1906, opened up the
field of mass spectrometry, based as it is on the measurement of mass to
charge ratio. But it was his protégé,
Francis Aston, who built the first mass spectrograph; later being awarded a
Nobel prize for chemistry in 1922.
Early mass spectrometers – those based on the bombardment of atoms
with a high energy beam of electrons – removed an electron from the atom (or
molecule) to create a positively charged ion, or positively charged molecular
ion. Neutral species cannot be
analysed or detected by mass spectrometers.
So the removal of the one electron gives the ion a mass/charge [m/z] ratio
of 1+, meaning that the mass of the ion can be measured. The precise physics of how this works is
too complex to go into here.
Early work by Aston and his
contemporaries, during the first three decades of the 20th century
[1900 – 1930] utilised mass spectrometry to prove the existence of chemical
isotopes. A neutral, non-ionised atom
will always contain the same number of protons as it does electrons, as the
charges cancel out. The chemistry of
an atom is determined by its electronic structure [the number of electrons in
its outer shell], while the mass is determined by the contents of the
nucleus. The elements of the periodic
table are organised based upon their atomic number [the number of protons in
the nucleus, and therefore also equal to its total number of electrons]. For many elements, the average number of
neutrons in the nucleus equals the number of protons, e.g. Carbon contains 6
protons and 6 neutrons to create an average atomic mass of 12; Oxygen 8
protons and 8 neutrons, atomic mass 16; but in reality the number of neutrons
in the nucleus of a atom can vary: these are isotopes. The vast majority of Carbon atoms are 12C,
but 13C atoms containing a seventh neutron and the radioactive 14C
atom, contains two extra neutrons.
Because the number of protons (and therefore electrons) doesn’t
change, the chemistry of different isotopes does not vary; however their
physical properties and radioactivity can vary. Most elements have a dominant isotope, but
there are some exceptions, notably chlorine which has a 3:1 ratio of isotope 35
to isotope 37, creating an average atomic mass of 35.5; and Bromine which has
a 1:1 ratio of isotope 79 to 81, creating an average atomic mass of 80.
The discovery and measurement of
chemical isotopes was of huge importance to the Manhattan project, which
developed the first nuclear weapons that ended the second world war.
After the discovery of isotopes,
mass spectrometry found a niche application measuring volatile (easy to
evaporate) hydrocarbons in the oil industry in 1940s.[10] It wasn’t until the 1960s that it was
developed for the characterisation of more labile (fragile) natural products
and drug molecules. By the 1980s it
was an integral analytical tool in the testing and development of novel
pharmaceuticals but the real revolution came in the late 1980s and early
1990s, since when it has become an essential analytical tool in the
biotechnology revolution.
Prior to this revolution, it was
a very useful technique in combination with NMR [nuclear magnetic resonance]
spectroscopy and FT-IR [Fourier transform infra-red] spectroscopy, in the
structure elucidation of novel molecular entities. At its simplest mass spectrometry can
provide useful information about the molecular mass of a chemical substance
and also key molecular fragments (after destruction inside the mass
spectrometer) gleaning important structural information about the
molecule. Combined with other
structural data from NMR and FT-IR it is now an indispensable tool in the
development of new medicines.
As well as identifying the
molecular mass and chemical structure of drug molecules, their impurities,
degradants and metabolites it has numerous other applications: for example
identifying low levels of antibiotics in cow’s milk; in forensic science; in
DNA and gene sequencing; and in police breathalysers.
To try and explain some of the
complexity included above, some pictorial information is shown for the drug
molecule, Aspirin below:
Trade name: Aspirin
Chemical name: Acetyl salicylic acid
Chemical formula: C9H8O4
Molecular mass (mw) : 180 Da
[(9 x 12) + (8 x1) + (4 x 16) = 180]
Fig. 1 Chemical structure of Aspirin with Fig. 2 Standard notation of the chemical
structure of
all the atoms labelled. Note the
four bonds Aspirin without carbon atoms (and
hydrogen atoms
from each carbon atom, two from
each oxygen,
bound to carbon atoms) labelled.
and just one from, or to, each
hydrogen.
|
Paul, the outgoing mass
spectrometry student, and Rachel, a summer student and the previous year’s
student; co-trained me on the VG Trio mass spectrometer. I was taught how to calibrate it, how to
retrieve samples from the sample store, how to prepare samples for analysis,
how to use the instrument and how to interpret simple electron impact mass
spectra. I was also taught how to record
results in my lab book, on the LIMS [laboratory information management system]
database, and how to file any paperwork generated. After a slightly nervous start, I took to it
all quite quickly and became an effective mass spectrometer operative. Initially, I was essentially a technician but
as some of the mass spectra produced required higher levels of interpretation I
needed to tap into some of my organic chemistry knowledge.
By working on one
instrument, one technique and one set of interpretative skills (based upon some
prior knowledge) my knowledge and application developed quickly; increasing my
confidence. This is the big difference
between work and school, or university.
Repetition leads to quick mastery of new skills. Whereas at school, or university, you may
hear about a concept once or twice, read about it once; practise a related practical
skill and then move on to something else – unless one puts in a lot of extra
hours, the process of learning is grossly inefficient, as one is encouraged to
dart about from lecture to lecture, practical session to practical session, or
lesson to lesson. Another major
difference between working in industry and academic study is that someone else
is dependent upon your effort and dedication.
In academic study it is only really oneself who seeks to benefit from
any particular assignment, conversely in industry there will be another cog in
the machine dependent upon your, albeit tiny, cog. I liked mastering a new skill, and I liked
learning about mass spectrometry.
During A level chemistry,
I may have stumbled across the concept; and I recall being quite
intrigued. During my first two years at
Kingston, there was little reference to mass spec; so virtually all of it was
new to me. As one progresses through a
scientific career, we find ourselves knowing more and more about less and
less. I was quickly learning lots about
a narrow field of analytical chemistry, itself only one part of all chemistry,
less than one third of all science. As I
delved deeper into the wonderful world of mass spectrometry, I started to
ponder the worth of all the prescriptive detail I was required to remember for
my chemistry A level. As it turned out,
my embedded knowledge of organic chemistry functional groups was quite useful;
all the curly arrowed reaction schemes which went in one ear and out the other,
during Dr Cooper’s lectures at university, less so.
Once Paul and Rachel
returned to university or wherever they were heading, it was just Brian, Duncan
and me left in the large, modern, specialist laboratory. I would occasionally slip next door to chat
with Marion, or go to wind up Neil, or flirt via the primitive incarnation of
MS-DOS email with Cathriona, while she was chained to an HPLC instrument in a
lab somewhere upstairs. Most of the
time, I was either testing samples, or interpreting mass spectra. Brian helped here initially but I quickly
worked out that Duncan, my immediate supervisor, was the true intellectual
force in the mass spec lab, maybe in the whole Analytical Sciences department.
Dr Duncan Bryant had
joined SmithKline Beecham in early 1992.
Prior to that he spent two years as a post doctoral researcher at the
University of Maryland in Baltimore, following a PhD conducted partly at the
Open University and partly at Imperial College in London. He studied for a degree in chemistry at
Imperial college before that. He knew an
awful lot about mass spectrometry, and organic chemistry too. During my year, I got to know Duncan very
well professionally and personally and we became good friends. When I left in 1994 we remained in contact;
he came to both my stag party and wedding in 2000. In 2005, he tragically died from a heart
condition aged only 40. As I mine my
memory while writing this chapter, and dig into the mass spectrometry
literature, I note that he became chair of the molecular spectroscopy group at
the Royal Society of Chemistry and there is an annual Duncan Bryant award within
that field of study.
I was extremely lucky to
have Duncan as my supervisor, and even more fortunate to know him as a
friend. Beyond his intellectual prowess
in chemistry, he was an all round intellect.
A handful of us went to the weekly pub quiz at the Primrose in
Tonbridge, and every Sunday evening we also attended the pub quiz at the
Cardinal’s Error, also in Tonbridge.
Duncan had sought out the Cardinal’s error due to its unique moniker. He was a real ale aficionado; a shameless
Queen fan and a huge fan of dub reggae, notably Scientist and King Tubby. As well as lighting my scientific touch
paper, he is responsible for turning me on to two of the great 20th
century symphony composers: Shostakovich
and Sibelius. He was a rare mix of
gifted, academic scientist; cultured intellect and hilarious drinker. He was a big Alexei Sayle fan, and like all
good intellectuals he was quite a leftie, also partly responsible for shifting
my politics to the left of centre. Back
in 1993 and 1994, we had a lot of fun and I learnt loads from him.
He obviously trusted me
and spotted something in me that I didn’t fully realise at the time, that I
still don’t fully realise now; that I was also quite a competent intellect
too. My academic pedigree and paper qualifications
don’t really stack up here, but as – after Duncan – one of the funniest and
sharpest minds I know is one Simon Lee, painter, decorator and 1990s
Glastonbury festivals friend, who left school very angry at sixteen; I learnt
early on that qualifications bear little correlation to the quality of one’s
mind; they only correlate to the quality of one’s conscientiousness and
compliance. Conscientiousness and
compliance are clearly important in the modern world; but do they make the
world go around, do they – on their own – fulfil us and give us purpose? More on that another time…
After a few weeks of
learning the ropes on the VG Trio and watching Brian’s meticulous beard
stroking as he pondered the molecular fragment ions on some of my mass spectra,
Duncan decided that I could be the first undergraduate student trained to use
the Sciex API-III. This was very
exciting because the Sciex looked much like the WOPR – the super computer in
the 1983 film “War games” starring Matthew Broderick and Ally Sheedy. It was also exciting, as I was beginning to
understand that electrospray ionisation mass spectrometry was at the cutting
edge of analytical technology, particularly in the study of large, fragile,
organic molecules; peptides and proteins.
At interview I had some
well prepared patter about polarity; stationary and mobile phases and
chromatography. I knew little of mass
spectrometry, nor was I expected to, so I wasn’t really quizzed on it. When I was first assigned to the mass spec
lab, fear of the unknown led to some mild disappointment that I wasn’t working
in the chromatography labs. There were
some prettier girls up in the chromatography labs, notably Cathriona. At first, Duncan’s bendy, mildly eccentric
intellectualism and Brian’s precise form of pedantry weren’t quite the match
for pretty girls and a tangible, university linked application of analytical
chemistry. How wrong I was.
Science is a bit like a
great album. If it makes sense straight
away, or hooks you on first listen; you’ll soon tire of it. If it is complex, abstract, awkward; perhaps
a little mysterious – it will lure you in, get under your skin and stay with
you forever. My conversations with
Duncan enlightened me in a way Dr Elizabeth Tyrell’s; Dr Andrew Cooper’s; Dr
Alastair Mann’s or Mrs Daphne Eadington’s lectures never could. I had a 1:1 audience with a real, practicing,
pioneering scientist and I learnt a lot by bouncing around a mixture of ideas,
questions and playful banter. My deep
voyage into molecular spectroscopy was built on some solid foundations from A
level chemistry: simple organic
chemistry reactions (e.g. carboxylic acid + alcohol à ester + water); calculating molecular mass from
chemical formulae and the names of key functional groups within molecules
(alcohol, aldehyde, ketone, carboxylic acid, ester, alkane, alkene, amine,
amide, etc); but in the most part I was learning on the job, learning by asking
questions and trying things out.
To be a great molecular
spectroscopist, or mass spectrometrist, it helped if you were both a great
synthetic organic chemist and a great analytical scientist. To be a successful chromatographer required
analytical skill but not a deep knowledge of organic chemistry. Chromatographers develop methods and separate
mixtures. Chromatography is a versatile
range of techniques useful for separating impurities and mixtures; and it can
be used to quantify components in a mixture.
There are generally two methods developed in projects using chromatography:
1) assay – to quantify the % purity of the active ingredient in the drug
substance (e.g. white powder), or in the drug product (e.g. tablet / inhaler /
cream) and 2) impurity profile – this will quantify all the relative % amounts
in a mixture. Chromatography will prove
that you have a mixture. It can separate
the components in a mixture. And there
is a lot of skill and complex science in developing robust and reliable
chromatographic methods, but chromatography cannot identify the components in a
mixture. A technique such as mass
spectrometry is needed for that. The
process of structure elucidation to identify unknowns in a mixture really
indulged my curiosity. It was like
solving a mystery with every sample.
Most of the samples we
tested in the lab were intermediates in synthetic chemistry reaction
routes. Samples were dissolved, diluted
and injected into the mass spectrometer.
A simple molecular weight test would take a few minutes; if the chemist
wanted to have an indication of purity, and then identify any unknowns, several
runs on the Sciex would be required, taking maybe 10 to 15 minutes. Sometimes the interpretation and analysis of
the ensuing mass spectra would take 30 minutes, sometimes over an hour. Occasionally we would carry out HPLC-MS-MS on
final drug substance, or a key intermediate; fully characterising and
identifying each chromatographic peak.
Including sample preparation time, and characterisation time this could
be a big, day long, job. Some days, I
would be chained to the Sciex in the lab, preparing samples, working through
the backlog of samples and intermittently bantering with Duncan, or Marion, or
Paul from the NMR lab next door. Other
days, I’d be at my desk, interpreting mass spectra; recording, reporting and
filing data. The best part of the job
was reporting the results to the synthetic chemists.
|
A brief technical interlude: The Chemical Development
Process
I am conscious that a lot of
this chapter has veered into technical jargon, inaccessible to the lay person
or untrained chemist. Much of this
brief technical interlude became apparent to me later in my career, while
working at Pfizer from 2001-2011; but it is relevant now to help you, dear
reader, try to make sense of the chemical development process and some key
terms.
A medicine can be delivered as a
tablet, an injection, a cream, an oral liquid or an inhaler (there are other
dosage forms). Common to all these
dosage forms is the API, or active pharmaceutical ingredient. At SmithKline Beecham (and other
pharmaceutical companies), the API was referred to as the Drug Substance (DS)
and the final dosage form (e.g. tablet) referred to as the Drug Product
(DP). In chemical development, we were
only concerned with the drug substance.
At SmithKline Beecham, Tonbridge
in 1993 and 1994; chemical development was split into three unequal parts:
synthetic chemistry, process chemistry and analytical sciences. The process chemists, including some
chemical engineers scaled up reaction processes onto the pilot plant. The pilot plant was used for manufacturing process
trials but also to manufacture drug substance for clinical trials. I had little to do with the process
chemists.
By the time a potential medicine
reaches chemical development, the final intended drug molecule is known. The synthetic chemists’ aim is to create a
safe, cost effective, impurity free and commercially viable synthetic route
to this known, novel chemical substance.
An example of a synthetic route is shown below.
There is a lot of chemistry
within one synthetic route. Initially
this work will be carried out on a small scale, with specialist reaction
vessels and equipment in fume-hoods within conventional synthetic chemistry
labs.
The intermediates or final drug
substance will then be submitted for characterisation by a range of
analytical techniques; and as the route and chemistry develops, more specific
analytical methods will be developed.
This is where the analytical sciences department takes over; working
closely with the chemists to qualify, quantify and develop their reaction
schemes.
Structure elucidation – either
proving the chemist has made what he or she thinks they have made, or
identifying unwanted products from a reaction, or low level impurities, is
carried out using a combination of NMR (nuclear magnetic resonance), MS (mass
spectrometry) and IR (infra-red spectroscopy). IR offers a fingerprint spectrum for a
molecule and NMR probably provides the most structural detail but mass
spectrometry can also provide useful structural information, as well as the
molecular weight of the analyte. NMR
and IR are non-destructive techniques (i.e. the sample can be retained for
further use or analysis) while mass spectrometry is a destructive technique. Where mass spectrometry comes into its own
is in its sensitivity. Very little
sample is needed.
A tiny amount of material is
required for analysis and it can detect chemical substances down to very low
levels. In June 2017, at a small
education meeting of science teachers, there was a talk from the resident mass
spectrometrist at the British museum.
It was a nostalgic trip down memory lane for me. He gave a brief background into
electrospray ionisation mass spectrometry and then described how they could
analyse a tiny fragment of a glaze on an ancient piece of pottery. The subsequent identification of the dyes
and pigments in the glaze allowed them to make links to trading routes and
helped with dating the item of pottery.
Mass spectrometry is now an immensely powerful tool not just in drug
development, but in art history; anthropology; archaeology; forensic science
and food safety testing.
A brief technical interlude: Chromatography
Chromatography is a far more
widespread and commonly used analytical technique than mass
spectrometry. At school we are taught
that chromatography is used to separate different coloured dyes in ink, paint
or food colourings. Hopefully your
science teacher explained that the different coloured dyes in the mixture
being analysed are separated on the basis of their differing solubility in
the solvent (typically water or ethanol at school). This is a classic, very visual and engaging
piece of analytical chemistry taught in school. We all have to understand it just a tiny
little bit to score well in our chemistry GCSE. After too many years of studying and
applying chemistry I have learnt that this is just the tip of the
chromatography iceberg; an over simplification of some complex chemistry for
little purpose other than satisfying an exam specification.
In a chromatographic technique
there is a stationary phase and a mobile phase. One will be polar and the other non
polar. Depending on the affinity of
the molecule, or molecules, being analysed for the polar phase or the
non-polar phase will determine the separation. Water is a polar solvent. So a dye which dissolves well in water will
also be quite polar (like dissolves like).
Such a dye will travel further with the water, and therefore travel
further up the paper in classic school paper chromatography. This means the dye has greater affinity for
the polar, mobile phase and less affinity for the non-polar stationary
phase. A dye which doesn’t really like
water very much (does not dissolve well in water, has low polarity) won’t
travel with the water; instead it will prefer to hang out with the less polar
stationary phase, in this case the paper.
This principle is applied to gas
chromatography and liquid chromatography.
The latter technique is the most versatile in the analysis of polar
and semi-polar drug molecules. Most drugs
have to dissolve and work their magic in living systems (the cells of our
bodies), where the universal solvent is water; so they are inherently polar
molecules. In a high performance
liquid chromatograph (HPLC), the stationary phase inside the separating
column can be polar (normal phase HPLC, Cathriona’s speciality) or more
typically nowadays non-polar (reverse phase HPLC) with the solvent (often an
aqueous [water] and organic solvent mixture) being the opposite polarity of
the stationary phase. Method
development involves “playing around” with the polarity of each phase, to
optimise the separation of all the products of a reaction mixture. For both GC and HPLC there are a range of
detectors available for use. Mass
spectrometry is a popular choice in the pharmaceutical industry because of
its specificity, its sensitivity and the option of further qualitative
analysis (e.g. structural elucidation) of the components of the mixture. An
HPLC-MS-MS system has become one of the jewels in the crown of analytical
chemistry within the pharmaceutical industry.
|
The
walk from the mass spec lab, into building A (endearingly old) or the first or
second floor of building B (quite modern), where the synthetic chemistry labs
were became a regular occurrence. I
loved entering the labs, with their fumehoods full of complex, entangled
glassware, and their glass guards annotated with chemical structures. A synthetic chemistry lab bears considerable
resemblance to a university lab, even a school lab; while the complex,
expensive and state of the art analytical sciences labs were a million miles
from anything I encountered at school or university. So, a synthetic chemistry lab was a little
closer to home, to my sphere of reference at the time; less intriguing but closer
to most people’s general perception of chemistry: lots of potions, reactions, sights and
smells, instead of a soulless, mysterious big grey box full of abstract and
unfathomable tricks.
Sometimes
my discussions with the chemists were brief, depending on the predictability
and simplicity of the results. On other
occasions, longer discussions ensued – either because there was an unexpected
result, or a new impurity had been identified, or the particular chemist
enjoyed indulging my new found love of mass spectral interpretation, or –
sometimes – the particular chemist enjoyed nurturing or tutoring my
understanding of organic chemistry reaction schemes. Some of the chemists were aloof, introverted,
perhaps even nonchalant; but most gave me a lot of time, and seemed genuinely
interested in what I had to say. This
boosted my scientific confidence.
There
were some quirky, and rather odd individuals:
One guy who shall remain nameless, I enjoyed speaking with a lot, but he
had a rather unfortunate habit of rummaging in his trousers during
conversation. Another guy, partial to
the burgeoning rave scene of the time, was mysteriously removed from the
organisation. There were rumours that
one of the intermediates he was synthesizing was one reaction step away from
MDMA (the drug molecule better known as Ecstasy). Others spoke in strange voices while adorning
distasteful brown ties and jackets. Some
had spectacularly unkempt beards. But
most were just regular guys – whatever that means. The chemist who took me under his wing most
of all was the affable, fun-loving, charming and rather brilliant chemist, Dr
David Ennis. He was working on some
B-lactam antibiotics, in the wake of SmithKline Beecham’s success with Augmentin
(amoxicillin and clavulanic acid). He is
now vice-president of chemical development at AstraZeneca. Another chemist whose career was going
stratospheric who also gave me a lot of time, was the equally fun-loving and
very personable, Dr Dave Lathbury. I
also have fond memories of collaborative discussions with Ian Andrews, Jerome
Hayes, Steve Smith and Richard Atkins.
Collectively
these guys proved that I was good listener (contrary to popular belief), a fast
learner and that some of the chemistry to which I was exposed during my first
two years at Kingston, and during A level must have some how infused with the
unconscious neurons of my mind. This
proves to me, that exposure to ideas, to hooks, to concepts at school or
university can be useful later on in life; even if you don’t consciously commit
it to memory for an exam or test at the time.
It also proves to me that stored, remembered, rote, regurgitated
knowledge is not the key; rather the ability to discuss, to listen, to
assimilate and apply new information seems more important. Yes, some facts and some language is key here;
but is success in a technical, niche, scientific career really dependent upon
the 10 years of rigid science curriculum learning at school? Not sure.
We’ll revisit this another time…
Upon
reflection, what my technical and social interactions with the chemists
highlighted to me was that I was a highly collaborative, people-orientated
scientist. Working with one, two or a
handful of others in a lab, in a narrow field of science can be a lot of fun;
the joy of finding things out and solving problems was certainly part of the
attraction of science to me; but more significantly it was sharing my findings
with others, discussing data, making decisions and working collaboratively
which I enjoyed most.
This
was my Eureka moment. Suddenly, I was
deeply engaged with one tiny aspect of chemistry (and an even smaller aspect of
science), and I was relishing solving problems that had never been solved
before; using and applying a nascent development of an important analytical
technique; working with state of the art equipment and technology; but most
importantly I was working with others, collaborating with others, I was working
in a team and between teams; across departmental interfaces. I was part of something new, something bigger
than myself, something bigger than one small team of individuals. Essentially my work, and all the learning
associated with it, had purpose; and more importantly I had a pervading sense
that those around me, who I really enjoyed working with, shared the same sense
of purpose.
The
majority of my year was split between developing my practical, theoretical and
collaborative science skills. I loved
lab life, I loved the cerebral nature of interpreting mass spectra, I loved
learning from and working with Duncan (Bryant), Dave (Ennis) and Mike (Webb)
and loved being a fully integrated member of the mass spec team, working
collaboratively across departmental interfaces.
This was the year I fell in love with science, and the possibilities of
science. Duncan (and to a lesser degree,
Dave and Mike) had far greater influence over me than any number of university
lecturers, or schoolteachers ever did, or could. They used and applied science in their work,
rather than merely knowing science and passing it on. For the first time, I found a way of
channelling my extraversion and gregarious nature into being an effective
scientist. Those three individuals saw
something in me, encouraged something in me, and nurtured something in me that
I had not previously realised existed.
They were nothing less than inspirational.
The
only condition of my industrial placement year, from Kingston university’s
perspective, was that I carry out some research; which would ideally become
part of my final year dissertation.
Duncan had big plans for me. We
adapted the ionspray (nebuliser gas assisted electrospray) source of the Sciex
API-III mass spectrometer to allow the toggling between standard zero grade
air, and deuterated[11]
ammonia (ND3). My research
project was titled “Hydrogen / Deuterium exchange in ionspray mass
spectrometry.” This work allowed me to
identify labile[12]
protons [hydrogen atoms] in organic molecules, including proteins and peptides;
and ultimately compare the number of labile protons in a native and denatured
protein [myoglobin]. Working with
Duncan, and then independently, to gather and process a lot of data for this
project was fulfilling. By the time I
had written up all my results, published an internal report and presented my
work to the analytical sciences department, I felt an immense sense of
pride. This had consumed three months of
my working life. I am pleased to have
had the opportunity to work on such cutting edge and beneficial technology – it
is part of my “Eureka – yes! I am scientist year”; but I think it also
confirmed that I don’t have the consistent focus, single-mindedness or deep
enough interest in any one particular field of science to be a proper research
scientist.
| A brief technical interlude: Electrospray mass spectrometry, protein analysis and labile protons As alluded to earlier, mass spectrometry analyses molecular ions and identifies their mass. Mass spectrometry can only separate, analyse and detect charged species; so molecules have to ionised before introduction into a mass spectrometer. Traditional ionisation techniques are often harsh and break the molecular ion into ionised fragments (smaller parts of the molecule). The beauty of electrospray (and nebuliser gas assisted electrospray, ionspray) is that the ionisation occurs at atmospheric pressure. Tiny charged droplets are created in the ion source, which evaporate to form charged ions. The pressure difference between the ion source and the vacuum chamber of the mass spectrometer is huge, so the combination of “tiny holes” and “very big pumps” are used to overcome this challenge. Ionisation in the aqueous state at atmospheric pressure makes ionspray a very “soft” ionisation technique. This means it can be used for analysing fragile, labile drug molecules and large organic molecules such a proteins without fragmenting the molecule. Electrospray doesn’t ionise molecules by removing electrons to create positively charged ions, instead it protonates, or ammoniates by adding H+ or NH4+ ions to molecules basic centres to create positively charged molecular ions. Therefore molecules need to be polar entities, to be suitable for analysis by electrospray. In a triple quadrupole analyser like the Sciex, a molecular ion can be selected and then MS/MS analysis can be carried out, bombarding and fragmenting the molecular ion to allow more detailed mass spectral analysis and structural elucidation. Proteins Proteins are biological polymers, or macromolecules. Living cells in animals and plants contain many different proteins of many different shapes and sizes, with a broad range of functions. Proteins are much larger and more complex molecules than conventional drug molecules. Aspirin and Paracetamol have molecular masses of less than 200 mass units, and some of the largest “small molecule” medicines – notably the corticosteroids, used as preventive treatments for asthma or COPD (chronic obstructive pulmonary disease), have masses in the region of 500 mass units. One of the smallest known proteins (insulin) has a molecular mass of approximately 5800 Da, ten times larger than the largest small molecule medicines. Most proteins are significantly larger than Insulin. Horse myoglobin (found in muscle cells) has a mass ~16,900Da; Haemoglobin approx. 64,000Da and monoclonal antibodies are in the region of 150,000Da. The large molecular size of proteins is based upon their unique sequence of amino acids, made from just 20 naturally occurring “monomers” which we, humans, digest and extract from the proteins in food (meat, fish, eggs, milk, beans, pulses etc). Amino acids are joined via peptide bonds (or amide functional groupings) to create the proteins primary structure. As so many amino acids are chemically joined together, each with a variety of functional side groups in their side chains or “R groups”, they can interact to form secondary, tertiary and sometimes quarternary structures. It is the these higher tier intra-molecular interactions (physical bonding with the protein molecule), as opposed to the chemical bonding within the primary amino acid sequence; which gives the protein its unique 3D structure, and function. We often describe this a protein folding. The two previous challenges with the analysis of proteins by mass spectrometry are 1) the fragility of the large complex molecules and 2) their large mass being way beyond the range of any conventional mass scanner. Electrospray ionisation overcomes this by being soft enough not to destroy or fragment the molecule during ionisation. Secondly as mass spectrometers measure mass to charge ratio, electrospray ionisation will protonate numerous basic centres in a protein molecule to create multiply charged ions. These multiply charged ions can be de-convoluted by specialist mass spectrometry computer software to identify the molecular ion as shown below. Labile protons Hydrogen atoms in organic molecules are described as protons by chemists. A labile proton is an intra (part of, or within) molecular hydrogen atom which is quite reactive; so it can easily be “lost”: substituted or eliminated in chemical reactions. Inside mass spectrometers, labile protons can be exchanged with deuterium atoms. Each exchanging proton for a deuterium will increase the mass by 1 mass unit. So carrying out H/D exchange experiments in mass spectrometry will give the chemist, or analyst, useful information about the chemical structure of molecular or fragment ions, and some information about the chemistry of different functional groups within the molecule. This is another powerful tool in the mass spectrometrist’s armoury. It is particularly powerful for protein chemists to try to solve and identify protein folding and structure. As proteins can exist in a native or denatured state, the number of exposed labile protons in their structures can vary greatly. In the native (or natural state) – which is how they exist in nature, particularly in living systems or natural products (animal cells, plant cells, raw eggs, fresh milk etc) – they will be folded into complex, twisted shapes which determine their functionality, their chemistry and their solubility. When they are denatured by changes in temperature, pH or agitation (mixing force), their complex secondary, tertiary and quarternary structures can unfold; releasing, exposing or simply making many more labile protons available for exchange, as those protons are no longer involved in intra-molecular hydrogen bonding or other physical interactions within the molecule. In my project, the largest protein I studied was Horse Myoglobin in the native and denatured states. I calculated that there are 262 possible protons available in a myoglobin molecule. In my experiments in 1994, I observed a range of 200 – 255 labile protons in the denatured (unfolded) state; while only a range of 185 – 194 protons exchanged in the native state. This was one hell of an Eureka moment for both Duncan and me! N.B. The most common example of a native and denatured protein is egg albumin (or egg white). When raw it is slimy, gloopy, transparent and NATIVE. When it is cooked it is more rigid, white, opaque and DENATURED. One of the most annoying things about being a science teacher is the over simplification of physical changes as reversible (e.g. melting, dissolving, evaporating) and chemical changes as irreversible (chemical reactions – fizzing, colour changes etc). Cooking is certainly irreversible – baking a cake, or cooking egg white cannot easily be reversed; but too many science teachers, and more alarmingly science textbooks automatically describe cooking as a chemical change. If you burn or brown something, then yes, there is chemical change; but gently cooking egg white is an irreversible, PHYSICAL change. The chemical bonding within the protein has not changed, but the complex intra-molecular interactions have irreversibly changed. When we melt a crystal of ice we break physical interactions in the crystal lattice. These can easily reform upon re-freezing as water molecules are simple and regular and the inter-molecular (between molecules) hydrogen bonds rigid, repeating and easy to reform (in the right conditions). The difference with the intra-molecular[13] (within molecules) is that they form in very specific conditions within nature (in living cells). If broken due to small changes to temperature, pH or vibration / agitation; there are simply too many interactions, and they are too complex to reform; so proteins are irreversibly denatured when cooked; but unless very strongly heated, they may remain chemically intact, or unchanged… |
My
transformative year ended with the annual SmithKline Beecham Analytical
Sciences Colloquium at Robinson college, Cambridge. We all stayed in college accommodation, while
the students were away in the summer, attended lots of science talks, drank a
lot and ended our evening having a good old fashioned knees up in a bedsit with
a piano.
It is easy, as I write this – 25 years on – to identify my year at SmithKline Beecham as the year I became a scientist, as the year I became properly interested in chemistry, and as the year that inspired my career in science. At the time, I lived each week as it came, without any concrete plans for the future, other than drinking lots of beer and going to lots of raucous gigs. I was on a journey, but there was no clear destination.
After my Eureka year, I went back to university, worked my socks off as I could finally see the purpose of gaining a good degree, got a 2:1, decided against a PhD due to my errant, meandering and creative mind not being keen on settling tenaciously to one narrow field of research. I got a job as a graduate chemist with Zeneca Agrochemicals: formulating colloidal suspensions of fungicides and herbicides. I loved the creative, collaborative and communicative elements of the job; the “cooking with chemicals” to design and develop new products. I enjoyed working with engineers to transfer processes into manufacturing and travelling to Scotland, Austria, Switzerland, Amsterdam and the US as part of my role.
After 6 years, I’d fallen in love with Amanda and got married. We had truly settled in Kent which ceased to be an option for continuing employment with Zeneca, once Syngenta formed in 2001. So while I’d have liked to take up the opportunity to become an international corporate scientific playboy, family life in the garden of England won the battle and a sideways move to Pfizer ensued.
At Pfizer, I initially joined as a “bioneer” formulating freeze dried proteins. Then I moved on to controlled release technology, trying to get Viagra to work in the evening – and the morning! Then, fed up with endless project plans, microsoft project and its ensuing gantt charts I crafted a move into the Materials Science group where I specialised in the solid state and powder properties of potential drug substance for treating asthma and chronic obstructive pulmonary disorders (COPD) via dry powder inhalation devices.
Throughout my 17 years in industry I immersed myself deep in narrow fields of technical detail, I endlessly bounced ideas and experiments, problems and solutions, around with other scientists, I was curious, creative and collaborative and then, as mentioned about five hours ago at the beginning of this outrageously long post, I decided that I’d done science and it was time to pass the baton on…
This leads on to summer blog number 3 – which I promise will be shorter. And more about education, science, skills, knowledge than my self-indulgent, accidental journey into science…
[1] Note that I write ‘information’ and NOT ‘knowledge’. Knowledge is something that is acquired, grappled with and understood. A text book contains someone else’s knowledge which may with effort, concentration and time become your knowledge too – but the reading of it, or the blind copying of it is merely information.
[2] 1980s and early
1990s ITV dating show presented by the late Cilla Black
[3] In chemistry you can
predict a 100% yield from a reaction, which is the largest possible mass of
product depending on the mass of the ingoing reactants and their stoichiometry
(how much of reactant A reacts with reactant B etc – this relates to both
molecular mass, the specific chemical groups that can react in the molecule and
the concentration of the reactants). The
yield is then calculated by dividing your produced mass (once filtered and
dried) by the total possible mass and multiplying by 100. Stoichiometry is a complex concept to explain
here in a couple of sentences.
[4] I’ll explain what
mass spectrometry is in more detail, a little later in the chapter…
[5] Later, in 1995, Glaxo would takeover Wellcome to form
Glaxo Wellcome. In 2000, GlaxoWellcome
merged with SmithKline Beecham to form Glaxo SmithKline, commonly known as GSK,
still one of the largest pharmaceutical companies in the world in 2018.
[6] The M25 is the London orbital motorway. It is 117 miles, or 188km, long and passes
through parts of Kent, Surrey, Middlesex, Buckinghamshire, Hertfordshire and
Essex.
[7] Walton oaks was
another smaller R&D site near Reigate in Surrey, who partnered
Tonbridge. SB’s veterinary medicines
were developed there. Pfizer later
bought SB animal health and the site.
Walton Oaks is now, in 2018, Pfizer’s European commercial headquarters.
[8] NMR: nuclear
magnetic resonance spectroscopy. I used
to understand this. It is a complex
analytical technique involving very large magnets. I’ll talk about it a bit later.
[9] A fumehood is a
contained work bench, attached to the building’s extraction system. These allow noxious solvents and hazardous
chemicals to be worked on, with little or no risk to the scientist.
[10] Griffiths, Jennifer,
“A brief history of Mass Spectrometry”, Anal. Chem. 2008, 80, 5678-5683
[11] Deuterium is an
isotope of hydrogen. Instead of the
atomic nucleus of hydrogen containing a single proton, deuterium contains a
single proton and a single neutron. So
deuterium has an atomic mass of 2 while hydrogen has an atomic mass of 1. The chemistry of hydrogen and deuterium is
very similar. So using deuterated
ammonia gas, ND3, [ammonia is a gas with chemical formula NH3]
allows deuteration of molecular ions; and labile proton and deuterium exchange
in molecules.
[12] Reactive, or easily
exchangeable
[13] Molecules need to be
quite large and complex for intra-molecular interactions and hydrogen bonds to
form. Intermolecular (between 2 or more
separate molecules) hydrogen bonds are the basis behind crystallography and the
rigid, repeating patterns found in molecular crystals. Typically proteins cannot form molecular
crystals as they are too large and floppy, but they can form intra-molecular
interactions (sometimes called physical bonds) which determine their structure,
function and purpose in living organisms.