Discoveries of the last six decades 60 of innovation To celebrate the international of chemistry, James Mitchell Crow looks back at some of the discoveries and developments made by over the past six decades that have made the biggest difference to our lives, and to understanding the world around us

1950s: Where do we come from? What that the first historical date of any was life like for our ancestors? real certainty has been established.’ Such questions have long played The laborious early techniques on the mind of humans, and thanks for measuring the amount of to chemistry – and the action of radiocarbon in a sample required cosmic rays – we now have a good literally counting the slow decay part of the answer. of radiocarbon atoms in a sample Shortly before the second world using a gieger counter. ‘Today, using @ LIFE PICTURES / GETTY IMAGES GETTY / PICTURES LIFE @ TIME war, researchers studying Earth’s accelerator upper atmosphere made a discovery [AMS] we actually measure the that would revolutionise our ability to -14 atoms individually, peer into the past, allowing us to date and not the decay that comes off ancient sites and artefacts produced of them, so we can now measure by people as much as 50 000 years much older samples in a much ago. Cosmic rays colliding with the shorter amount of time – instead top of the atmosphere were found of months, something in the order to be generating , which of tens of minutes,’ says Stewart react with -14 to form Fallon, head of the radiocarbon carbon-14, ejecting a in the dating laboratory at the Australian process. This produces a steady National University in Canberra. input of radioactive carbon into the AMS needs so little material , which decays with a half- that specific compounds can be life of about 5600 years. chromatographically extracted from It was and his a sample for dating individually. colleagues at the University of Thanks to Libby’s work, Chicago, US, that turned this now extends far further back observation into a tool to accurately Willard Libby received During his work to establish in time. The technique has also date objects from our distant past – a the 1960 the technique’s reliability, Libby proved to be useful in fields outside discovery that won Libby the 1960 in chemistry for his discovered how challenging . Fallon uses it to study . pioneering work on archaeology had been up to that the uptake of radiocarbon by giant All organisms absorb carbon-14 carbon-14 dating point. ‘The first shock we had was in the sea since the burst during their lives, through when our advisors informed us of carbon-14 released into our or by consuming that history extended back only atmosphere during the of nuclear food, but stop absorbing any more 5000 years,’ Libby recalled during weapons testing. This data gives an at the point of death. From that his Nobel acceptance speech. ‘We accurate picture of ocean circulation point onwards, their radiocarbon had thought initially that we would over the past 50 years, information component slowly falls as it decays be able to get samples all along the that can be used to test ocean current back to nitrogen-14. Libby showed curve back to 30 000 years. In fact, models, which are being developed that this steady decline in carbon-14 it is at about the time of the First in part to help predict the impact of reveals any organic object’s age. Dynasty in Egypt (around BC3100) climate change. 38 | Chemistry World | March 2011 www.chemistryworld.org 1960s: silicon chips It is hard to imagine life without computers to be fitted inside missiles, the now-ubiquitous silicon chip. and for the Apollo moon missions. Chemists might not be the first band In the intervening years, silicon of researchers to get the credit for became the domain of engineers

TEXAS INSTRUMENTS TEXAS its development, but in fact many rather than scientists. But today the chemical breakthroughs were needed input of chemists is becoming crucial before the electrical engineers could again, says Javey. ‘All of a sudden, the take over to produce silicon-based dimensions of silicon chips have come integrated circuits. down to a size that chemists have been ‘Many of the initial developments working at for decades – at the level in the field were made by chemists of macromolecules. So chemists have learning about silicon and its become involved again, developing material properties,’ says Ali Javey, new nanoscale materials, fabrication who researches nanomaterials for techniques, and doping with control technological applications at the down to a few atomic layers.’ , Berkeley, This is one of the areas where Javey US. From finding ways to make ultra- Texas Instruments’ chips. In 1961, US company Texas himself works. ‘We need to be able pure semiconductor-grade silicon, ‘Molecular Electronic Instruments, one of the pioneers of to place dopants within 1–2nm thick to doping the material by infusing in Computer’ of 1961 on integrated circuit silicon technology, layers. Conventional techniques are atoms of other elements to tune its the left, dwarfed by a demonstrated their ‘Molecular no good for that.’ semiconducting properties, chemists conventional computer Electronic Computer’ to the US However, it could be in fundamental initially played a leading role. with the same Air Force, which was ‘150 materials chemistry that the next ‘Developing reactions to chemically electronic function smaller and 48 times lighter’ than a big chip technology breakthrough etch the silicon and ways to pattern conventional computer of the time comes. ‘The coming direction – the integrated circuit – that’s all with the same processing power. The where chemists are playing a major chemistry,’ Javey adds. technology really took off thanks to role – is in developing new types It was in the 1960s that all these interest from the US military and of architecture based on flexible developments finally came together the space race. Some of the earliest substrates rather than on rigid silicon to produce the first practical silicon chips were used in the first guidance wafers,’ says Javey 1970s: the statins In 1971, Japanese pharmaceutical biosynthesis, and the link between also working in the area. In 1987, Akira Endo set himself an high cholesterol levels and coronary lovastatin, developed by scientists at ambitious challenge: to identify heart disease. Today, cardiovascular Merck and Co, became the first statin compounds that could lower disease is the leading cause of death to receive regulatory approval by the cholesterol levels in the blood, worldwide, in countries rich US Food and Drug Administration a then-recently discovered risk and poor, but at the time it (FDA). Pfizer’s Lipitor (atorvastatin) factor linked to coronary heart was primarily a disease of the has become the biggest selling disease. Forty years later, tens of western world. pharmaceutical of all time. millions of people have benefited Cholesterol is taken up from ‘The challenge now is moving from the family of drugs that Endo the diet, but can also be produced statins from treatment to prevention,’ discovered, known as the statins. in the liver if dietary sources are says Wald, who in 2000 along with In the future, many millions lacking. Endo hypothesised that, colleague Malcolm Law first proposed more could be taking these rather than blocking cholesterol the idea of a cardiovascular ‘polypill’, medicines, as their use uptake from food, the best way a combination of cheap, safe and increasingly shifts from to reduce cholesterol levels in the effective drugs proven to lower treatment to prevention. Mevastatin – isolated blood would be to inhibit the body’s cholesterol and blood pressure. ‘I think the discovery of the statins in the 1970s – is cholesterol-producing pathway. Currently, statins are prescribed is comparable in importance to the considered the first Endo started by looking in based on various risk factors. But Wald discovery of antibiotics,’ says Nicholas statin microbes, reasoning that they might argues that reaching the age of 55 is Wald, director of the Wolfson Institute have evolved metabolites to block sufficient risk alone, and is about to of Preventive Medicine at Queen Mary steroid biosynthesis for self-defence. start a polypill trial to test the theory. University of London, UK. ‘The story Two years and 6000 microbes later, ‘The problem is that beyond middle of penicillin is well known – everyone Endo had a hit – the fungus Penicillium age, everyone’s blood pressure and has heard of Alexander Fleming. But citrinum was producing a compound, cholesterol are high – certainly higher not of Akira Endo – he’s an unsung dubbed ML-236B, which blocked than when that person was 20. That hero of pharmaceutical chemistry.’ lipid synthesis. That compound is now increase is the driver behind the high In 1968, Endo returned to Japan to known as mevastatin. rates of stroke and heart disease.’ work for the Sankyo pharmaceutical By the end of the decade, the Whatever the next step in the company, after a two year postdoctoral first clinical trials of the drug were statin story, it is clear that Akira Endo stint in the US. While abroad he underway – by which time other deserves greater recognition for his had learned about cholesterol medicinal chemistry groups were leading role in its development.

www.chemistryworld.org Chemistry World | March 2011 | 39 Discoveries of the last six decades 1980s:the polymerase chain reaction (PCR) As with many of the great scientific The oligonucleotides added to the discoveries, there’s a story behind mixture act as primers for each new the discovery of the polymerase strand, which are extended into chain reaction (PCR). a new full-length strand by DNA was driving through California, US, polymerase enzymes. late one Friday evening in April 1983 Every time this cycle takes place, when the technique that became the amount of DNA doubles. After 30 PCR first occurred to him. Ten years cycles, that first pair of strands have later, Mullis was awarded the Nobel become a billion strands. B. BOISSONNET / SCIENCE PHOTO LIBRARY LIBRARY PHOTO SCIENCE / BOISSONNET B. prize in chemistry for his discovery. The impact of the discovery of At the time of PCR’s invention, PCR on DNA research is hard to much of the work involving DNA overstate. As Carl-Ivar Brändén was rather a messy business, with of the Royal Swedish Academy of researchers trying to pick out the Sciences said when presenting small amount of DNA of interest Mullis the Nobel prize: ‘Cloning from the mass of strands isolated and sequencing of genes as well from any biological sample. As as site-directed mutagenesis he drove along Route 128, Mullis The development of Somehow, I thought, it had to be an have been facilitated and made wasn’t pondering a way to solve this PCR revolutionised illusion. Otherwise it would change more efficient. Genetic and fundamental problem, but a way DNA research DNA chemistry forever.’ evolutionary relationships are easily to identify an unknown base next PCR relies on the fact that base- studied, even from ancient to a known sequence. However, he pairing means double strands containing only fragments of DNA. suddenly realised that he had hit of DNA can act as a template Biotechnology applications of PCR upon something rather bigger. for themselves – and, as Mullis are numerous. In addition to being ‘I had solved the most annoying discovered, it also relies on an indispensable research tool in problems in DNA chemistry in temperature cycling. It took until drug design, the PCR method is a single lightning bolt,’ Mullis December 1983 for Mullis to finally now used in diagnosis of viral and recalled during his Nobel speech. achieve the first successful reaction. bacterial infections including HIV. ‘With two oligonucleotides, DNA By repeatedly raising and then The method is so sensitive that it is polymerase, and the four nucleoside lowering the temperature, the two used in forensic medicine to analyse triphosphates I could make as much strands separate and then grow the DNA content of a drop of blood of a DNA sequence as I wanted. complementary second strands. or a strand of hair.’ 1990s: antiretroviral drugs The sudden emergence of HIV–Aids transcriptase. This is the enzyme in the early 1980s, and its shocking targeted by the first successful subsequent global spread, is perhaps HIV–Aids drug, azidothymidine the greatest challenge ever to have (AZT). In 1987, AZT became the first faced medicinal and biological drug approved by the US Food and WELLCOME FOUNDATION WELLCOME chemists. In the intervening 30 years, Drug Administration to extend the the Joint United Nations Programme lives of Aids patients, and in 1990 on HIV–Aids (UNAIDS) estimates the drug was approved to delay the that more than 60 million people development of HIV into Aids. have been infected with HIV and However, it is in blocking a nearly 30 million people have died as later step in the HIV lifecycle that a result of this global pandemic. chemical scientists have played a However, the number of people particularly important role.1 Once dying from the disease now seems the viral DNA has been produced to be slowing. In 2009 there were 1.8 by the reverse transcriptase, it is million Aids-related deaths, down incorporated into the DNA of the from 2.1 million in 2004, according to host cell, where it gets copied. Once UNAIDS. That fall is in no small part this DNA has been transcribed by the a result of the now-broad range of infected cell into long polyproteins, drugs that have been developed. an enzyme called a protease chops HIV has proven vulnerable to it up to release the active viral drug treatment at several points in proteins, which go on to form new its lifecycle. As a retrovirus, HIV virions ready to infect more cells. carries its genetic information The drugs developed to inhibit the as RNA rather than DNA. To protease are one of the great success reproduce, the virus transcribes its stories of rational drug design. HIV RNA into DNA, a process involving Wellcome’s Retrovir (zidovudine) – more commonly known as protease was validated as a drug a viral enzyme called reverse azidothymidine or AZT – was the first successful HIV–Aids drug target in mid-1980s, and by the end 40 | Chemistry World | March 2011 www.chemistryworld.org of the decade x-ray crystal structures ‘Retroviruses protease inhibitor to be approved 1990s, and worked on the problem of the enzyme had been published by the FDA, sports a hydroxyl as a visiting scientist at SmithKline by several groups. (See Chemistry develop group in place of the amide usually Beecham Pharmaceuticals (now part World, November 2009, p50) resistance to cleaved by the protein. of GSK) in Philadelphia, US. By studying the structure and These HIV drugs have been ‘A huge amount of research effort mechanism of the enzyme, drugs drugs, so we particularly successful as it is their went into developing HIV protease designed to block it could be always need emergence that led to the rise of inhibitors – it’s a real chemistry developed. HIV protease works drug combination therapies known success story,’ says Abell. The benefits by inserting water molecules new ones to as highly active antiretroviral continue to be felt widely today, he into particular amide groups stay one step therapy (HAART). These cocktails adds. ‘The HIV protease inhibitor along the polyprotein backbone, allow doctors to hit HIV at multiple work really set the scene for chemists which cleaves the chain at those ahead’ points in its lifecycle at once, and to interact with other scientific points to release the functioning have dramatically extended the life disciplines to quickly drive forward viral proteins. The drugs that expectancy of HIV-positive people. medicinal chemistry projects.’ successfully target this enzyme ‘HIV protease inhibitors have The chemist’s job in the area isn’t mimic the tetrahedral intermediate had wide benefits for those who can done, he says. ‘Retroviruses develop of the hydrolysis reaction, and are access them,’ says Andrew Abell, resistance to drugs, so we always designed not to be cleaved in two by who studies enzyme inhibitors need to develop new ones to stay one the enzyme, so remain blocking the at the University of Adelaide in step ahead.’ active site. For example, saquinavir, Australia. Abell began working on Reference which in 1995 became the first HIV HIV protease inhibitors in the early 1 E De Clercq, Rev. Med. Virol., 2009, 19, 287

2000s: thin film solar cells As alternative energy rose example, has developed a solution- the first products might be rather inexorably up the political agenda based process for large scale niche, but that’s just the beginning, throughout the 2000s, so rose the manufacture of these cells. says Udo Bach, who researches performance of a new breed of However, other thin film dye-sensitised solar cells at Monash cheap, efficient solar cells that could technologies aren’t far behind. University in Melbourne, Australia. fill that gap – if the price is right. Amorphous silicon, organic ‘People like me who work in this ‘Solar cells are all about cost,’ Thin film solar cells dye-sensitised cells, and area wouldn’t put in all the effort says Ali Javey, who studies light- are now beginning to indium gallium selenide (CIS or if they thought that all we could harvesting nanomaterials at the compete with silicon in CIGS), are also beginning to be make is a solar-powered backpack University of California, Berkeley, efficiency and cost commercialised. In some cases that could charge a mobile phone. US. ‘Back in the 1950s, the first cells We have something much bigger cost around $1700 (£1060 at today’s in mind, and I definitely see the exchange rates) per watt. Today potential for these organic solar we’re at about $3 per watt, and it’s cells to be applied in large scale solar continuing to fall.’ farms,’ says Bach. The US government, which Javey is also looking ahead. invested heavily in solar technology ‘We’re trying to grow single crystal research as part of its economic materials using a cheap process on stimulus package, predicts that solar low cost substrates,’ he says. ‘We energy could reach grid parity with start with a cheap aluminium foil, fuel generated electricity by and anodise it, which generates 2015. Subsequent improvements an array of pores in the surface.

US DEPARTMENT OF ENERGY/ SCIENCE PHOTO LIBRARY PHOTO SCIENCE ENERGY/ OF DEPARTMENT US should see the costs fall still further. We use these pores like little test These developments are in no tubes to grow single crystals in. small part the result of emerging The test tube confines the growth thin film technologies, which in of the crystal, so acts as a template.’ 2009 dropped below the cost of The resulting material is an array traditional silicon panels for the first of light-absorbing nanopillars, all time. ‘Today, the installed cost of a single crystals. crystalline silicon solar panel is $5 ‘It is very difficult to say which per peak watt. For thin film cadmium technology will make it in 10 or 20 telluride it is $4.50,’ says Javey. years’ time – which is why we have The breakthrough for cadmium to work on all of them,’ says Bach. telluride cells has been finding ways ‘That’s why it’s such an exciting area to grow them uniformly, reliably to work in,’ says Javey. ‘One major and reproducibly over large areas at technological advance could change low cost. The US firm First Solar, for the story completely.’

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