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(Image: Chris Brown)

IN THE corner of the lab, a machine the size of a coffee shop espresso maker quietly whirs and hums. It is dispensing not drinks, but complex chemicals. Everything is automated. Syringes tighten imperceptibly, sending solutions dribbling through a tangle of spaghetti-thin tubes into reaction vessels. Between loading the raw starting materials and collecting the final result, not a hand touches the set-up. Yet this nondescript machine could be the first step to banishing one of chemistry鈥檚 biggest demons.

The fact is, fabricating molecules takes a lot of time. at the University of Illinois, the machine鈥檚 inventor, encountered the problem while working as a doctor in the late 1990s. He talks of his hospital days when he saw the agony of incurable disease. It was then that Burke recognised the problem was partly down to the lack of drugs pouring out of research labs, so he decided to change tack and become a chemist. He quickly saw for himself how making molecules that could enter drug trials could be a painfully slow process. Done the traditional way, this involves trying out one reaction after another, building upwards from small molecules to larger, more complex ones. Every failed reaction was another day without concrete medical progress.

Burke and his machine are now part of a mission to change that by automating and rationalising chemical synthesis, and fashioning a science out of what was previously considered more of an art. If this crusade is successful, the time it takes to create a new drug could go from years to months or days. The age of chemistry as bottleneck in the drug discovery process could be entering its twilight.

Step into any lab working at the border between chemistry and biology and you鈥檒l probably already see a fridge-sized unit in the corner chugging away. It could be stitching together amino acids into proteins or nucleotides into DNA. If you slot vials of the four different nucleotides that make up DNA, or the amino acids that constitute proteins, into place, the machine will take a careful slurp from each in succession and build the biomolecule you programmed in.

Crafty carbon

Proteins and DNA are special types of molecule, though. They are normally composed of a finite set of building blocks joined one after the other in a line. Automated 鈥� or even particularly logical 鈥� ways to make other types of molecule have remained much harder nuts to crack.

The problem comes in the shape of what chemists call 鈥渟mall molecules鈥� or sometimes 鈥渘atural products鈥�, reflecting the fact that many of these compounds are made by living organisms. These molecules are the scents that flowers produce and the toxins on the backs of poisonous frogs 鈥� along with many of the drugs used in modern medicine.

But the term 鈥渟mall molecules鈥� hides a devilish complexity. A team led by chemist of the University of Bern in Switzerland recently put some figures on their variety. They looked at molecules with up to 17 atoms, containing any mixture of carbon, nitrogen, oxygen, sulphur and halogens such as iodine or chlorine. These elements, all common in medicinal chemicals, can combine to form a , the team calculated.

It is carbon that鈥檚 behind all this complexity. Its ability to form bonds with up to four other atoms at once rapidly leads to a dizzyingly large tree of diverse molecular structures. Things get even worse with chiral molecules. These come in two mirror-image forms that behave almost identically, except when it comes to interacting with biological machinery. One may be toxic, the other a wonder drug. For this and other reasons, labs attempting to make useful small molecules face an immense challenge (see 鈥�Chemical warfare鈥�). Burke calls it the synthesis barrier.

Many chemists have come to relish a difficult 鈥渢otal synthesis鈥� 鈥� making a molecule from scratch using basic starting materials 鈥� in the way mountaineers enjoy testing themselves on challenging peaks. The north face of the Eiger has been scaled many times over the years (see 鈥�Synthetic landmarks鈥�) but perhaps the time for indulging such heroics is over. After all, our search for the next generation of antibiotics is pushing us to the ends of the Earth and it isn鈥檛 getting any easier to discover new types of drugs.

鈥淐hemistry鈥檚 Eiger has been scaled many times, but is the time for such heroics over?鈥�

Enter Burke鈥檚 machine. It aims to turn 200 years of synthetic chemistry鈥檚 struggles into a push-button, computer-controlled exercise. To do this it relies on a type of reaction known as carbon coupling, which garnered a Nobel prize in 2010. This uses tiny amounts of elaborate catalysts based on metal atoms like palladium to allow precise joining of one carbon atom to another.

The reaction can work at room temperature and without other disruptive additives, which means even rather complex molecules can be methodically stitched together without damaging sensitive chemical groups in the process. Even better, the reactions can be run one after another with solvents and catalysts filtered out automatically, allowing many fragments to be joined in series. By varying the initial fragments, Burke鈥檚 device allows a mass of complex substances to be made from simple, widely available starting materials. Little human labour is needed.

To put it to the test, he took 12 readily available chemical building blocks and set about making a class of natural antimicrobials known as polyenes. In a paper published in May he showed he could synthesise 75 per cent of all the known polyene motifs present in natural products and achieved several first-time syntheses in short order (). In all, Burke has demonstrated his machine can make 14 classes of small molecule using just a limited array of raw materials.

Organic chemist at Stanford University is impressed with the work. It鈥檚 a 鈥減owerful approach鈥�, he says. But it still has limits. The machine鈥檚 reliance on just one type of carbon coupling reaction narrows its scope, says Bartosz Grzybowski, a chemist at Ulsan National Institute of Science and Technology in South Korea. Wender echoes that. 鈥淭here is going to be a need, as there always has been in synthetic organic chemistry, to expand the lexicon of reactions,鈥� he says.

But even just using carbon coupling could allow the synthesis of many more small molecules. Burke is now working to develop extra building blocks for that purpose. The bigger vision is that one day anyone could make any small molecule at the click of a mouse, and such next-generation machines are the objective of Burke鈥檚 spin-off company, , which is backed by $45 million of venture capital.

Others are trying to breach the synthesis barrier in different ways. Grzybowski is behind one computer-driven approach called , which has been dubbed the 鈥渃hemical internet鈥�. This software is limited to a few research groups at the moment, but talks to commercialise it are under way. Users key in a molecule they want to make and Chematica defines all possible ways of getting there using sequences of known reactions. For Grzybowski, it is a way of getting round the problem of chemists tending to stick to their own tried and trusted recipes, perhaps missing easier, quicker ways to make small molecules 鈥� or failing to see a route altogether.

, a chemist at the University of Southampton, UK, also speaks of a need to convince people there are better ways of doing things. He leads , an umbrella project set up to encourage collaboration on a synthesis machine capable of making any molecule. Swift progress is, he says, 鈥渉eld back by culture, including the culture of funding people rather than equipment鈥�.

Another thing that鈥檚 lacking is good data on how well any given reaction works. This is particularly true of failed reactions. Researchers know crossing off dead-end chemical reactions is a valuable exercise, but they鈥檙e loath to publicise their misfires 鈥� and few journals want to publish them, regardless. Dial-a-Molecule is encouraging as many labs as possible to switch from paper to electronic notebooks to record their reactions. This would help provide data way beyond the limited scope of published research.

Medicine machine: the first set-up to rapidly churn out potential new drugs (Image: L. Brian Stauffer/University of Illinois News Bureau)

In the meantime, the first synthesis machine is bubbling away back in the Illinois lab. Burke is using it to make better versions of a complex polyene called amphotericin. It is the only treatment for certain types of fungal infection, such as fungal meningitis, that kill 1.5 million people every year. The problem is that while amphotericin kills the fungus, it is also toxic to humans. Burke has been working on making variants that are fungicidal, but do not harm people. Promising candidates are already in preclinical trials 鈥� an advance that, done the traditional way, would have taken years, but which has taken just months.

Making bonds

The old ways are not ready to die yet though. Kyriacos Nicolaou is a specialist in total synthesis at Rice University in Texas. He agrees that automation is long overdue, but he still sees value in the conventional approach. His team has recently been working on one of the most complex natural compounds known, a neurotoxin found in marine animals called maitotoxin. Even if this molecule were accessible to a machine like Burke鈥檚 鈥� which it isn鈥檛 鈥� pursuing problems like this the old-fashioned way is useful, he says, because it yields new ways of reacting carbon and helps train each generation of chemists.

Burke鈥檚 machine has arrived at a good time. Chemists are getting better at predicting what shape and type of molecule they need for many applications, be it a new drug or as a component in solar panels. Many will welcome the chance to build those hypothetical molecules for real more quickly.

But perhaps the real promise of automatic chemistry lies in democratising the power to make and break chemical bonds. Synthesis machines will eventually mean anyone, scientist or layperson, can make a new molecule.

When it comes to automation and its power to unleash collaboration, 鈥渙ur field lags others鈥�, says Nicolaou. Engineers, for instance, might help chemists build better machines to begin with. But before long they might also ask what sort of molecules they would like to make themselves.

History shows us that putting technology into the hands of non-experts can have tremendous impacts, says Burke. 鈥淭hese are exciting times.鈥�

This article appeared in print under the headline 鈥淒ial M for molecule鈥�