Higgs’s bosuns

WILL he or won’t he? That was the question on the mind of anyone with a passing interest in the topic as representatives of Sweden’s Royal Academy of Science prepared to announce the winner of this year’s Nobel physics prize. Well, he did. Half a century after predicting the existence of the particle which bears his name Peter Higgs, of Edinburgh University, was awarded science’s highest accolade. Another, even bigger mystery was who would share the honour—and the cheque for SKr8m ($1.2m). In the event, after postponing the announcement twice (rare for the punctual Swedes) the prize-givers plumped for François Englert of the Free University of Brussels.

Unusually for Nobel laureates in science, Dr Higgs is already a household name. The search for his boson, which theory predicts gives other particles their masses, started in earnest, and with immense publicity, in 2008. That was when CERN—Europe’s (and the world’s) leading particle-physics laboratory—switched on the Large Hadron Collider, a particle accelerator whose first task was to find it. When the boson’s existence was confirmed, in 2012, Dr Higgs became the bookies’ favourite for an early Nobel prize.

Who would share it with him, though, was bound to cause trouble. The experimenters at CERN had a good claim, and there was talk of the whole organisation being named as joint prize-winner. There were also Tom Kibble, Gerald Guralnik and Carl Hagen, who published what is widely regarded as a more complete theoretical explanation of the particle, but did so a few weeks after Dr Higgs’s paper. And there were Dr Englert and his colleague Robert Brout, who anticipated Dr Higgs’s mechanism by a similar amount of time, but failed, explicitly, to predict the existence of the boson.

Brout having died in 2011, and tradition dictating that the prize cannot be split more than three ways, the Academy took what looks like the simplest course in picking Dr Higgs and Dr Englert. That is bound to rankle with the others. But no one ever said that life is fair.

Blowing bubbles

Less predictably, and less controversially, the prize for physiology or medicine went to James Rothman of Yale, Randy Schekman of the University of California, Berkeley, and Thomas Südhof of Stanford University, for their work on vesicles. These are small, bubble-like structures, surrounded by fatty membranes, which ship hormones, enzymes and various other molecules around a cell, and sometimes export them to the outside world.

Dr Schekman’s work in the late 1970s explored the mechanisms which control vesicle transport. He used genetic screening—newfangled at the time—to spot yeast cells whose transport systems were failing, causing jams in some parts of the cell and supply shortages in others. By comparing defective cells with properly functioning ones, Dr Schekman was able to isolate three different classes of genes in which mutations caused the chaos.

Knowing how a piece of machinery can break down is important in understanding it. But so is knowing how it is meant to work. Dr Rothman discovered the molecular mechanism by which individual vesicles discharge their cargoes where they are needed, whether to other structures within a cell or through the cell wall to the outside. He identified a pair of protein complexes, one on the vesicles and the second on their specific targets, that bind to each other like the two halves of a zip. If the proteins match, the vesicle opens and disgorges its cargo. If they do not, the loading bay remains shut.

Dr Südhof applied these insights to the specific question of how nerve cells communicate. When such a cell fires, an electrical impulse travels down its length until it reaches a synapse—a point at which one nerve cell abuts another. There, the electric signal stimulates the release of neurotransmitters. These are specialised molecules that cross the synaptic gap and stimulate the second nerve cell. Dr Südhof described exactly how an arriving electrical impulse causes a rush of calcium ions into a cell, and how these subsequently cause vesicles loaded with neurotransmitters to bind to the cell wall and disgorge their contents across the gap.

Many of the journalists attending the prize ceremony seemed baffled by the details of the announcement. “You’re like Swedish undergrad students,” chided the committee, miffed by the lack of questions. An alternative explanation is that the hacks actually understood the science for once. After all, the vesicle-transport system described by the three laureates now features in cell-biology textbooks the world over. It is vital for everything from cell division to the regulation of bodily systems by hormones. Diabetes, botulism and several neurological illnesses are at least partly a consequence of its malfunctioning. Knowing how it works is therefore a step towards treatment.

Familiarity from school cannot, however, have been the explanation of a similar lack of questions after the announcement of the chemistry prize. This went to Martin Karplus, Michael Levitt and Arieh Warshel, a trio who have collectively helped tame the daunting mathematical complexity involved in simulating chemical reactions.

A good way to think about chemistry is that it is applied physics. Chemical reactions involve the gyrations of electrons, whose behaviour is well understood thanks to quantum mechanics. But physicists have the luxury of dealing with particles in isolation, which keeps the maths simple. Chemists must deal with the complexity of the real world, with multiple electrons swirling around in several different substances. And applying quantum mechanics to the real world—even with powerful computers—turns out to be a pig of a problem.

Fortunately, there is an alternative. The old physics of Isaac Newton is simpler than the modern quantum stuff. Complicated molecules such as enzymes and drugs can be modelled fairly easily. But Newtonian models tell you only how a chemical is built. They cannot say anything about how it will react in the presence of something else.

Model behaviour

In the early 1970s Dr Karplus led a research group at Harvard that built some of the early quantum-mechanical computer simulations. Drs Levitt and Warshel, meanwhile, had been working on a Newtonian program at the Weizmann Institute of Science, in Israel. This was capable of handling even large biological molecules such as enzymes.

When Dr Warshel arrived at Harvard in 1970, after finishing his PhD, he and Dr Karplus began to collaborate. Their crucial insight was that it is not necessary to simulate the entire chemical with great accuracy. Although many biological molecules are big, their active sites—the bits which actually perform the exciting reactions—are small. So the two researchers came up with a hybrid approach that used quantum mechanics to model the interesting parts of a molecule, but simulated the rest with faster, more rough-and-ready Newtonian methods.

Their first program suffered from limitations which meant it could be applied only in certain cases. But over the next few years the pair, who were now joined by Dr Levitt, broadened the model so that it could accommodate virtually anything. They tweaked its performance, too, to make it more computationally tractable. They worked out, for instance, that it was possible to treat large parts of a molecule not merely in a Newtonian way, but as a single, homogeneous lump, without compromising accuracy.

As with any model, the result is not a full-blown simulation of reality. That would miss the point. Instead, the newly minted laureates have created something that focuses on what researchers are interested in, and abstracts away the rest. It is, to quote Albert Einstein, as simple as possible—but no simpler. And in so doing, they have brought chemistry fully into the computer age./economist