Discoveries of the last six decades
60 years of
innovation
To celebrate the international year of chemistry, James Mitchell Crow looks back
at some of the discoveries and developments made by chemists over the past six
decades that have made the biggest difference to our lives, and to understanding
the world around us
TIME @ LIFE PICTURES / GETTY IMAGES
1950s: radiocarbon dating
Where do we come from? What
was life like for our ancestors?
Such questions have long played
on the mind of humans, and thanks
to chemistry – and the action of
cosmic rays – we now have a good
part of the answer.
Shortly before the second world
war, researchers studying Earth’s
upper atmosphere made a discovery
that would revolutionise our ability to
peer into the past, allowing us to date
ancient sites and artefacts produced
by people as much as 50 000 years
ago. Cosmic rays colliding with the
top of the atmosphere were found
to be generating neutrons, which
react with nitrogen-14 to form
carbon-14, ejecting a proton in the
process. This produces a steady
input of radioactive carbon into the
biosphere, which decays with a halflife of about 5600 years.
It was Willard Libby and his
colleagues at the University of
Chicago, US, that turned this
observation into a tool to accurately
date objects from our distant past – a
discovery that won Libby the 1960
Nobel prize in chemistry.
All organisms absorb carbon-14
during their lives, through
photosynthesis or by consuming
food, but stop absorbing any more
at the point of death. From that
point onwards, their radiocarbon
component slowly falls as it decays
back to nitrogen-14. Libby showed
that this steady decline in carbon-14
reveals any organic object’s age.
38 | Chemistry World | March 2011
Willard Libby received
the 1960 Nobel prize
in chemistry for his
pioneering work on
carbon-14 dating
During his work to establish
the technique’s reliability, Libby
discovered how challenging
archaeology had been up to that
point. ‘The first shock we had was
when our advisors informed us
that history extended back only
5000 years,’ Libby recalled during
his Nobel acceptance speech. ‘We
had thought initially that we would
be able to get samples all along the
curve back to 30 000 years. In fact,
it is at about the time of the First
Dynasty in Egypt (around BC3100)
that the first historical date of any
real certainty has been established.’
The laborious early techniques
for measuring the amount of
radiocarbon in a sample required
literally counting the slow decay
of radiocarbon atoms in a sample
using a gieger counter. ‘Today, using
accelerator mass spectrometry
[AMS] we actually measure the
carbon-14 atoms individually,
and not the decay that comes off
of them, so we can now measure
much older samples in a much
shorter amount of time – instead
of months, something in the order
of tens of minutes,’ says Stewart
Fallon, head of the radiocarbon
dating laboratory at the Australian
National University in Canberra.
AMS needs so little material
that specific compounds can be
chromatographically extracted from
a sample for dating individually.
Thanks to Libby’s work, history
now extends far further back
in time. The technique has also
proved to be useful in fields outside
archaeology. Fallon uses it to study
the uptake of radiocarbon by giant
corals in the sea since the burst
of carbon-14 released into our
atmosphere during the era of nuclear
weapons testing. This data gives an
accurate picture of ocean circulation
over the past 50 years, information
that can be used to test ocean current
models, which are being developed
in part to help predict the impact of
climate change.
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TEXAS INSTRUMENTS
1960s: silicon chips
It is hard to imagine life without
the now-ubiquitous silicon chip.
Chemists might not be the first band
of researchers to get the credit for
its development, but in fact many
chemical breakthroughs were needed
before the electrical engineers could
take over to produce silicon-based
integrated circuits.
‘Many of the initial developments
in the field were made by chemists
learning about silicon and its
material properties,’ says Ali Javey,
who researches nanomaterials for
technological applications at the
University of California, Berkeley,
US. From finding ways to make ultrapure semiconductor-grade silicon,
to doping the material by infusing in
atoms of other elements to tune its
semiconducting properties, chemists
initially played a leading role.
‘Developing reactions to chemically
etch the silicon and ways to pattern
the integrated circuit – that’s all
chemistry,’ Javey adds.
It was in the 1960s that all these
developments finally came together
to produce the first practical silicon
Texas Instruments’
‘Molecular Electronic
Computer’ of 1961 on
the left, dwarfed by a
conventional computer
with the same
electronic function
chips. In 1961, US company Texas
Instruments, one of the pioneers of
integrated circuit silicon technology,
demonstrated their ‘Molecular
Electronic Computer’ to the US
Air Force, which was ‘150 times
smaller and 48 times lighter’ than a
conventional computer of the time
with the same processing power. The
technology really took off thanks to
interest from the US military and
the space race. Some of the earliest
chips were used in the first guidance
computers to be fitted inside missiles,
and for the Apollo moon missions.
In the intervening years, silicon
became the domain of engineers
rather than scientists. But today the
input of chemists is becoming crucial
again, says Javey. ‘All of a sudden, the
dimensions of silicon chips have come
down to a size that chemists have been
working at for decades – at the level
of macromolecules. So chemists have
become involved again, developing
new nanoscale materials, fabrication
techniques, and doping with control
down to a few atomic layers.’
This is one of the areas where Javey
himself works. ‘We need to be able
to place dopants within 1–2nm thick
layers. Conventional techniques are
no good for that.’
However, it could be in fundamental
materials chemistry that the next
big chip technology breakthrough
comes. ‘The coming direction –
where chemists are playing a major
role – is in developing new types
of architecture based on flexible
substrates rather than on rigid silicon
wafers,’ says Javey
biosynthesis, and the link between
high cholesterol levels and coronary
heart disease. Today, cardiovascular
disease is the leading cause of death
worldwide, in countries rich
and poor, but at the time it
was primarily a disease of the
western world.
Cholesterol is taken up from
the diet, but can also be produced
in the liver if dietary sources are
lacking. Endo hypothesised that,
rather than blocking cholesterol
uptake from food, the best way
to reduce cholesterol levels in the
blood would be to inhibit the body’s
cholesterol-producing pathway.
Endo started by looking in
microbes, reasoning that they might
have evolved metabolites to block
steroid biosynthesis for self-defence.
Two years and 6000 microbes later,
Endo had a hit – the fungus Penicillium
citrinum was producing a compound,
dubbed ML-236B, which blocked
lipid synthesis. That compound is now
known as mevastatin.
By the end of the decade, the
first clinical trials of the drug were
underway – by which time other
medicinal chemistry groups were
also working in the area. In 1987,
lovastatin, developed by scientists at
Merck and Co, became the first statin
to receive regulatory approval by the
US Food and Drug Administration
(FDA). Pfizer’s Lipitor (atorvastatin)
has become the biggest selling
pharmaceutical of all time.
‘The challenge now is moving
statins from treatment to prevention,’
says Wald, who in 2000 along with
colleague Malcolm Law first proposed
the idea of a cardiovascular ‘polypill’,
a combination of cheap, safe and
effective drugs proven to lower
cholesterol and blood pressure.
Currently, statins are prescribed
based on various risk factors. But Wald
argues that reaching the age of 55 is
sufficient risk alone, and is about to
start a polypill trial to test the theory.
‘The problem is that beyond middle
age, everyone’s blood pressure and
cholesterol are high – certainly higher
than when that person was 20. That
increase is the driver behind the high
rates of stroke and heart disease.’
Whatever the next step in the
statin story, it is clear that Akira Endo
deserves greater recognition for his
leading role in its development.
1970s: the statins
In 1971, Japanese pharmaceutical
chemist Akira Endo set himself an
ambitious challenge: to identify
compounds that could lower
cholesterol levels in the blood,
a then-recently discovered risk
factor linked to coronary heart
disease. Forty years later, tens of
millions of people have benefited
from the family of drugs that Endo
discovered, known as the statins.
In the future, many millions
more could be taking these
medicines, as their use
increasingly shifts from
treatment to prevention.
‘I think the discovery of the statins
is comparable in importance to the
discovery of antibiotics,’ says Nicholas
Wald, director of the Wolfson Institute
of Preventive Medicine at Queen Mary
University of London, UK. ‘The story
of penicillin is well known – everyone
has heard of Alexander Fleming. But
not of Akira Endo – he’s an unsung
hero of pharmaceutical chemistry.’
In 1968, Endo returned to Japan to
work for the Sankyo pharmaceutical
company, after a two year postdoctoral
stint in the US. While abroad he
had learned about cholesterol
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Mevastatin – isolated
in the 1970s – is
considered the first
statin
Chemistry World | March 2011 | 39
Discoveries of the last six decades
B. BOISSONNET / SCIENCE PHOTO LIBRARY
1980s:the polymerase chain reaction (PCR)
As with many of the great scientific
discoveries, there’s a story behind
the discovery of the polymerase
chain reaction (PCR). Kary Mullis
was driving through California, US,
late one Friday evening in April 1983
when the technique that became
PCR first occurred to him. Ten years
later, Mullis was awarded the Nobel
prize in chemistry for his discovery.
At the time of PCR’s invention,
much of the work involving DNA
was rather a messy business, with
researchers trying to pick out the
small amount of DNA of interest
from the mass of strands isolated
from any biological sample. As
he drove along Route 128, Mullis
wasn’t pondering a way to solve this
fundamental problem, but a way
to identify an unknown base next
to a known sequence. However, he
suddenly realised that he had hit
upon something rather bigger.
‘I had solved the most annoying
problems in DNA chemistry in
a single lightning bolt,’ Mullis
recalled during his Nobel speech.
‘With two oligonucleotides, DNA
polymerase, and the four nucleoside
triphosphates I could make as much
of a DNA sequence as I wanted.
The development of
PCR revolutionised
DNA research
Somehow, I thought, it had to be an
illusion. Otherwise it would change
DNA chemistry forever.’
PCR relies on the fact that basepairing means double strands
of DNA can act as a template
for themselves – and, as Mullis
discovered, it also relies on
temperature cycling. It took until
December 1983 for Mullis to finally
achieve the first successful reaction.
By repeatedly raising and then
lowering the temperature, the two
strands separate and then grow
complementary second strands.
The oligonucleotides added to the
mixture act as primers for each new
strand, which are extended into
a new full-length strand by DNA
polymerase enzymes.
Every time this cycle takes place,
the amount of DNA doubles. After 30
cycles, that first pair of strands have
become a billion strands.
The impact of the discovery of
PCR on DNA research is hard to
overstate. As Carl-Ivar Brändén
of the Royal Swedish Academy of
Sciences said when presenting
Mullis the Nobel prize: ‘Cloning
and sequencing of genes as well
as site-directed mutagenesis
have been facilitated and made
more efficient. Genetic and
evolutionary relationships are easily
studied, even from ancient fossils
containing only fragments of DNA.
Biotechnology applications of PCR
are numerous. In addition to being
an indispensable research tool in
drug design, the PCR method is
now used in diagnosis of viral and
bacterial infections including HIV.
The method is so sensitive that it is
used in forensic medicine to analyse
the DNA content of a drop of blood
or a strand of hair.’
WELLCOME FOUNDATION
1990s: antiretroviral drugs
The sudden emergence of HIV–Aids
in the early 1980s, and its shocking
subsequent global spread, is perhaps
the greatest challenge ever to have
faced medicinal and biological
chemists. In the intervening 30 years,
the Joint United Nations Programme
on HIV–Aids (UNAIDS) estimates
that more than 60 million people
have been infected with HIV and
nearly 30 million people have died as
a result of this global pandemic.
However, the number of people
dying from the disease now seems
to be slowing. In 2009 there were 1.8
million Aids-related deaths, down
from 2.1 million in 2004, according to
UNAIDS. That fall is in no small part
a result of the now-broad range of
drugs that have been developed.
HIV has proven vulnerable to
drug treatment at several points in
its lifecycle. As a retrovirus, HIV
carries its genetic information
as RNA rather than DNA. To
reproduce, the virus transcribes its
RNA into DNA, a process involving
Wellcome’s Retrovir (zidovudine) – more commonly known as
a viral enzyme called reverse
azidothymidine or AZT – was the first successful HIV–Aids drug
40 | Chemistry World | March 2011
transcriptase. This is the enzyme
targeted by the first successful
HIV–Aids drug, azidothymidine
(AZT). In 1987, AZT became the first
drug approved by the US Food and
Drug Administration to extend the
lives of Aids patients, and in 1990
the drug was approved to delay the
development of HIV into Aids.
However, it is in blocking a
later step in the HIV lifecycle that
chemical scientists have played a
particularly important role.1 Once
the viral DNA has been produced
by the reverse transcriptase, it is
incorporated into the DNA of the
host cell, where it gets copied. Once
this DNA has been transcribed by the
infected cell into long polyproteins,
an enzyme called a protease chops
it up to release the active viral
proteins, which go on to form new
virions ready to infect more cells.
The drugs developed to inhibit the
protease are one of the great success
stories of rational drug design. HIV
protease was validated as a drug
target in mid-1980s, and by the end
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of the decade x-ray crystal structures
of the enzyme had been published
by several groups. (See Chemistry
World, November 2009, p50)
By studying the structure and
mechanism of the enzyme, drugs
designed to block it could be
developed. HIV protease works
by inserting water molecules
into particular amide groups
along the polyprotein backbone,
which cleaves the chain at those
points to release the functioning
viral proteins. The drugs that
successfully target this enzyme
mimic the tetrahedral intermediate
of the hydrolysis reaction, and are
designed not to be cleaved in two by
the enzyme, so remain blocking the
active site. For example, saquinavir,
which in 1995 became the first HIV
‘Retroviruses
develop
resistance to
drugs, so we
always need
new ones to
stay one step
ahead’
protease inhibitor to be approved
by the FDA, sports a hydroxyl
group in place of the amide usually
cleaved by the protein.
These HIV drugs have been
particularly successful as it is their
emergence that led to the rise of
drug combination therapies known
as highly active antiretroviral
therapy (HAART). These cocktails
allow doctors to hit HIV at multiple
points in its lifecycle at once, and
have dramatically extended the life
expectancy of HIV-positive people.
‘HIV protease inhibitors have
had wide benefits for those who can
access them,’ says Andrew Abell,
who studies enzyme inhibitors
at the University of Adelaide in
Australia. Abell began working on
HIV protease inhibitors in the early
1990s, and worked on the problem
as a visiting scientist at SmithKline
Beecham Pharmaceuticals (now part
of GSK) in Philadelphia, US.
‘A huge amount of research effort
went into developing HIV protease
inhibitors – it’s a real chemistry
success story,’ says Abell. The benefits
continue to be felt widely today, he
adds. ‘The HIV protease inhibitor
work really set the scene for chemists
to interact with other scientific
disciplines to quickly drive forward
medicinal chemistry projects.’
The chemist’s job in the area isn’t
done, he says. ‘Retroviruses develop
resistance to drugs, so we always
need to develop new ones to stay one
step ahead.’
Reference
1 E De Clercq, Rev. Med. Virol., 2009, 19, 287
US DEPARTMENT OF ENERGY/ SCIENCE PHOTO LIBRARY
2000s: thin film solar cells
As alternative energy rose
inexorably up the political agenda
throughout the 2000s, so rose the
performance of a new breed of
cheap, efficient solar cells that could
fill that gap – if the price is right.
‘Solar cells are all about cost,’
says Ali Javey, who studies lightharvesting nanomaterials at the
University of California, Berkeley,
US. ‘Back in the 1950s, the first cells
cost around $1700 (£1060 at today’s
exchange rates) per watt. Today
we’re at about $3 per watt, and it’s
continuing to fall.’
The US government, which
invested heavily in solar technology
research as part of its economic
stimulus package, predicts that solar
energy could reach grid parity with
fossil fuel generated electricity by
2015. Subsequent improvements
should see the costs fall still further.
These developments are in no
small part the result of emerging
thin film technologies, which in
2009 dropped below the cost of
traditional silicon panels for the first
time. ‘Today, the installed cost of a
crystalline silicon solar panel is $5
per peak watt. For thin film cadmium
telluride it is $4.50,’ says Javey.
The breakthrough for cadmium
telluride cells has been finding ways
to grow them uniformly, reliably
and reproducibly over large areas at
low cost. The US firm First Solar, for
Thin film solar cells
are now beginning to
compete with silicon in
efficiency and cost
example, has developed a solutionbased process for large scale
manufacture of these cells.
However, other thin film
technologies aren’t far behind.
Amorphous silicon, organic
dye-sensitised cells, and copper
indium gallium selenide (CIS or
CIGS), are also beginning to be
commercialised. In some cases
the first products might be rather
niche, but that’s just the beginning,
says Udo Bach, who researches
dye-sensitised solar cells at Monash
University in Melbourne, Australia.
‘People like me who work in this
area wouldn’t put in all the effort
if they thought that all we could
make is a solar-powered backpack
that could charge a mobile phone.
We have something much bigger
in mind, and I definitely see the
potential for these organic solar
cells to be applied in large scale solar
farms,’ says Bach.
Javey is also looking ahead.
‘We’re trying to grow single crystal
materials using a cheap process on
low cost substrates,’ he says. ‘We
start with a cheap aluminium foil,
and anodise it, which generates
an array of pores in the surface.
We use these pores like little test
tubes to grow single crystals in.
The test tube confines the growth
of the crystal, so acts as a template.’
The resulting material is an array
of light-absorbing nanopillars, all
single crystals.
‘It is very difficult to say which
technology will make it in 10 or 20
years’ time – which is why we have
to work on all of them,’ says Bach.
‘That’s why it’s such an exciting area
to work in,’ says Javey. ‘One major
technological advance could change
the story completely.’
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