Awards for treating cancer, better lasers and evolving proteins
EARLY October is a nerve-racking period for the world’s top scientists. Though few will admit it, many who have done important work hope at this time of the year for a phone call, often in the middle of the night, that will tell them they are invited to an early Yuletide celebration in Stockholm. There are other, more lucrative, prizes around, and the trio of physics, chemistry and physiology or medicine that Alfred Nobel outlined in his will as suitable scientific subjects for reward is thought by some to be out of date. But the prestige of being a Nobel laureate remains undiminished.
This time around the physiology prize went to James Allison of the University of Texas and Tasuku Honjo of Kyoto University, in Japan, “for their discovery of cancer therapy by inhibition of negative immune regulation”. The fact that remissions from apparently terminal cancer, though rare, do happen from time to time had long led some to dream that it might be possible to harness the body’s immune system to attack malignancies. The immune system is a network of cells which defends against parasites and pathogens. Yet decades of effort to encourage it to assault cancer effectively as well, an idea called immunotherapy, led to nothing. These many failures had, by the 1990s, caused most people and firms to abandon the field.
Dr Allison was one of the few who never lost hope. He was particularly interested in a protein called CTLA-4. This is found on the surfaces of some T-cells, one of the main types of cell in the immune system. By 1994, when he was at the University of California, Berkeley, he and others had discovered that CTLA-4 puts a brake on T-cells’ ability to respond to cancer. In response he developed an antibody that blocks the protein, preventing this braking action. Thus unchained, T-cells can respond to tumours by attacking them. Tumours in mice vanished when they were given these CTLA-4-blocking antibodies.
On the other side of the Pacific, Dr Honjo had, since 1992, been researching a different immune-system protein. In 1999 he showed that this protein, PD-1, worked like CTLA-4 in that it seemed to damp down the immune system. When the gene encoding it was switched off, mice would develop autoimmune disease—a sign of an over-active immune system. Again, blocking the protein’s activity seemed a promising anti-cancer strategy. Dr Honjo was so convinced that he pushed until he found a biotechnology firm that would try to develop his work into a treatment.
Eventually, a trickle of research started on molecules that work as inhibitors of these two “checkpoint” proteins, and in 2010 the field came of age when Bristol-Myers Squibb, a drug company, released results from a trial of an anti-CTLA-4 antibody on patients with malignant melanoma. The results were astonishing. It was the first medicine able to improve survival from this disease.
Today, research into checkpoint inhibitors is booming. Molecules that affect PD-1 have proved more popular with drug companies, because the side-effects connected with CTLA-4 are trickier to handle. More than 1,100 PD-1-related trials are under way. Immunotherapy is now the hottest field in oncology and one that is likely, over the next five to ten years, to transform the way that many cancers are treated.
Dynamite with a laser beam
The physics prize was awarded to a trio of researchers for improvements to lasers. One share went to Arthur Ashkin, who worked at Bell Laboratories (though he is now retired), honouring his invention of optical tweezers. These are tiny laser beams that can be used to hold minuscule objects, such as biological cells, viruses or even individual atoms. They work because—as James Clerk Maxwell suggested in 1862 and Pyotr Lebedev proved in 1900—the photons that make up light carry momentum. This means they exert pressure on any surface exposed to them.
Dr Ashkin’s first invention was essentially the opposite of the tractor beams common in science fiction. Rather than pulling an object towards the laser emitter, he showed that he could use radiation pressure to push it away. Refinements soon followed. Laser beams are more intense in the middle. That generates a force which, counter-intuitively, tends to move the particle back towards the centre of the beam, trapping it there. The addition of a microscopic lens, to focus the laser light even further, generates a pull force to oppose the push. The result is a device that can hold an item steady, and even move it about in three dimensions.
It sounds complicated, and working through the maths is not for the faint-hearted. But the Nobel committee demonstrated the basic principle with the aid of a hair dryer and a ping-pong ball. Anyone who can remember physics from school will recall that a hair dryer can levitate such a ball by trapping it within the current of hot air. Dr Ashkin’s method has since been used in many areas of science, from probing the structure of tiny molecular machines in cells to assembling chemical compounds one atom at a time.
The other two shares of the physics prize honoured a different contribution. They were awarded to Donna Strickland (who thereby became only the third female physics laureate) and Gérard Mourou for their work on boosting the power that lasers can achieve.
After their invention in 1960, lasers’ maximum intensities rose quickly, increasing almost 100,000-fold by 1970. At that point, though, progress stalled (see chart). It only got going again when Dr Strickland (who worked on the problem for her PhD thesis at the University of Rochester, in New York state) and Dr Mourou (who was her supervisor) came up with the idea of chirped-pulse amplification.
The difficulty with generating high-intensity laser beams was that they damaged the machines used to make them. Once again, the details of the solution are fiendish. But its essence is simple—take a short-duration laser beam and make it last longer. The same amount of energy spread over a longer time leads to a lower maximum power. The resulting beam can then be amplified further without frying any sensitive components. The final stage is to compress the amplified beam back to its initial, short duration. That gives it an extremely high power. Modern lasers can, very briefly, reach a peak power of a petawatt. That is about 1m times more than is generated by a nuclear power station.
High-power, short-duration lasers have all sorts of uses. The Nobel committee chose to focus on the familiar example of eye surgery, in which a laser beam is used to sculpt the surface of the eye in order to correct short-sightedness. Other uses include everything from industrial machining, via new types of particle accelerator, to the ability to probe the behaviour of matter on ultra-short timescales. Not bad for a PhD thesis.
The chemistry prize, too, was divided. Half went to Frances Arnold of the California Institute of Technology, “for the directed evolution of enzymes”. The other half is shared by George Smith of the University of Missouri and Sir Gregory Winter of the Laboratory of Molecular Biology, in Cambridge, “for the phage display of peptides and antibodies”. But the real winner is evolution, for all three laureates harnessed its power to make proteins more useful for medicine and chemistry.
A revolution through evolution
Dr Arnold, who studied mechanical and aerospace engineering as an undergraduate, won her half for making synthetic enzymes (proteins that catalyse chemical reactions) by “directed evolution”. She started, as any engineer would, by attempting to redesign enzymes—making changes that, she reasoned, should improve their catalytic powers. This proved too difficult.
Like all proteins, enzymes are chainlike molecules made up of hundreds or, often, thousands of links called amino acids—a type of molecule that comes in 20 varieties in living things. In the 1990s Dr Arnold, faced with the bewildering number of possibilities this generates for top-down redesign, decided to abandon her approach and turned instead to evolution.
She had been trying to modify subtilisin, an enzyme that chops up other proteins, so that it would work in dimethylformamide (DMF), a solvent. That is an environment far removed from the watery cytoplasm of a cell. She set about introducing, at random, various mutations into the gene that encodes subtilisin, to produce thousands of different versions of that gene. Next, she inserted these modified genes into bacteria to produce thousands of tweaked forms of subtilisin.
She then assessed which of these enzymes were able to break down casein, a milk protein, in DMF. Then she selected the best for a further round of random mutation and screening. And so on. After the third round of this process, she found a variant of subtilisin with ten amino-acid substitutions that worked 256 times better in the solvent than the original enzyme did. Since her breakthrough, researchers (including Dr Arnold herself) have used this “directed evolution” to tailor enzymes to make drugs and biofuels.
Directed evolution was also behind Dr Smith’s and Sir Gregory’s contributions. Dr Smith invented phage display, a technique that can be used to drive the evolution of new proteins. It works by adding an extra gene to a bacteriophage (a virus that infects bacteria). Bacteriophages reproduce by hijacking the bacterial protein-making machinery. The infected bacteria then churn out thousands of copies of the original virus—with the addition, in this case, of the protein encoded by the extra gene.
Dr Winter (as he then was) soon realised that phage display could be used to direct the evolution of antibodies, which are proteins tailored to attach specifically to other proteins (usually belonging to parasites and pathogens) in order to gum those proteins up and mark the cells they are part of for destruction by the immune system. He created bacteriophages with billions of different antibodies on their surfaces and searched for those that liked to stick in this way to TNF-alpha, a protein which causes inflammation in autoimmune diseases. The best candidates were then recycled into another round of such “fishing” and the result, after several rounds, was an antibody that binds tightly to TNF-alpha.
In 1989 Dr Winter and his colleagues founded a firm called Cambridge Antibody Technology to produce this protein, which they called adalimumab. It is now marketed by Abbott Laboratories, a large drug company, as a treatment for rheumatoid arthritis and inflammatory bowel disease. Dr Winter’s knighthood followed in 2004. Adalimumab’s success has spurred efforts to make antibodies to attack tumours, Alzheimer’s disease and lupus. Alfred Nobel’s will specified that the prizes were to be given for work that was “for the greatest benefit to mankind”. This year the awarding committees seem to have got that right.