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The 2018 Nobel Laureates for Science

Source: Royal Swedish Academy of Sciences

The internationally acclaimed Nobel Prize is bestowed annually on people who have conferred “the greatest benefit on mankind” in six categories: Physiology or Medicine, Physics, Peace, Chemistry, Literature, and Economic Sciences (not technically a Nobel prize, but awarded with the other prizes). The Nobel prizes are awarded by institutes in Sweden in Norway—the Royal Swedish Academy of Sciences awards the Physics, Chemistry, and Economic Sciences prizes, the Swedish Academy awards the prize in Literature, the Nobel Assembly at the Karolinska Institute awards the prize in Physiology or Medicine, and the Norwegian Nobel Committee awards the Peace prize.

Receiving the Nobel prize is considered the most prestigious honor available in all of the six fields it awards a prize in. Nobel laureates are given a Nobel medal, a Nobel diploma, and a cash prize of 9 million Swedish koronas (about $1,001,000 USD). The Nobel prizes for 2018 were awarded starting on Monday, October 1st and continued through the week, with one prize being awarded each day.

Prize in Physiology or Medicine

              The Nobel Prize in Physiology or Medicine was awarded on the 1st of October jointly to James Allison of the United States and Tasuku Honjo of Japan for “their discovery of cancer therapy by inhibition of negative immune regulation”, according to a press release by the Nobel Assembly at the Karolinska Institute. Honjo discovered PD-1, a T-cell surface protein that blocks T-cell function, including attacking cancer cells. Honjo developed an antibody protein to inhibit the function of PD-1, allowing T-cells to attack cancer cells.

Allison studied another T-cell surface protein, CTLA-4. During the 1990s, when Allison was conducting his experiments, CTLA-4 was known to inhibit T-cell accelerators, causing T-cells to be inactivated and thus fail to attack cancer cells. Like Honjo, Allison developed an antibody that could bind to and block the function of CTLA-4, resulting in the termination of the T-cell block.

CTLA-4 and PD-1 are immune checkpoints, or regulators of the immune system that stop immune cells from attacking cells randomly. Without proteins like CTLA-4 and PD-1, autoimmune diseases, where the immune system attacks regular body parts, would more easily develop. However, cancer cells can disguise as regular body cells, avoiding the immune system. The method of targetting CTLA-4 and PD-1 in cancer treatment is called immune checkpoint therapy. Over the past decade, numerous monoclonal antibodies have been developed as drugs to target CTLA-4 and PD-1 to battle cancer, such as Keytruda, Bavencio, and Libtayo. The work of Allison and Honjo has made these advancements in the field of cancer therapy possible.

Diagram of Allison’s and Honjo’s methods to inhibit CTLA-4 and PD-1 (Source: Karolinska Institute)

In the upper two scenarios, a T-cell is receiving an antigen, a molecule from the cancer cell that induces an immune response. However, CTLA-4 and PD-1 are preventing the T-cells from being activated by the antigens. The green “Y” shapes are the antibodies that Allison and Honjo used to inhibit CTLA-4 and PD-1. Removal of CTLA-4 and PD-1 activates T-cell accelerators, allowing the T-cells to attack the cancer cells.

Prize in Physics

On the 2nd of October, The Royal Swedish Academy of Sciences awarded the Nobel Prize in Physics with one half to Arthur Ashkin of Bell Laboratories in Holmdel, New Jersey, for the development of “optical tweezers and their application to biological systems”, and the other half jointly to Gérard Mourou of École Polytechnique in Palaiseau, France and Donna Strickland of the University of Waterloo in Canada for “their method of generating high-intensity, ultra-short optical pulses”.

              Ashkin’s optical tweezers use the radiation pressure of light to move physical objects. In 1970, he first demonstrated that narrowly focused laser beams could accelerate dielectric particles in the direction of the propagation of the beam. Ashkin discovered that two counter-propagating laser beams could trap a particle in place. He constructed a three-dimensional trap using a single laser beam, using gravity to balance the force of the single vertical laser beam. However, this model was not effective when gravitational force was weak, so Ashkin and his colleagues developed the optical tweezers, another single-beam trap, but using only light. These optical tweezers beam laser light through a lens, creating a force opposite to the direction of propagation of the beam, allowing for trapping of a particle.

Ashkin realized that he could study biological systems effectively using the optical tweezers. He was able to capture viruses and living cells without damaging them. Later applications of optical tweezers to biology included manipulation of plant cell organelles, folding RNA molecules, and investigating the mechanics of bacterial flagellum, kinesin, the interactions of myosin and actin, DNA polymerase and other molecular motors.

Strickland and Mourou created ultrashort high-intensity laser pulses using a method called chirped pulse amplification, or CPA. CPA is currently applied to various fields and industries such as corrective eye surgery, particle acceleration, strong-field physics, and film. Many more applications of CPA are yet to be explored.

Before the innovation of Strickland and Mourou, short laser pulses did not have a very large energy per pulse. Excessive amplification to the laser pulse could damage the amplifier and laser machinery. CPA consists of three steps: a) an ultra-short laser pulse is lengthened, resulting in a reduction in peak power, b) its power is amplified in a way that avoids damage to laser material, and c) the laser pulse is recompressed, resulting in a drastic increase in peak power.

A diagram depicting the mechanism of chirped pulse amplification (Source: Royal Swedish Academy of Sciences)

Prize in Chemistry

              The Nobel Prize in Chemistry was awarded on the 3rd of October with one half to Frances Arnold of Caltech for “the directed evolution of enzymes”, and the other half jointly to George Smith of the University of Missouri and Gregory Winter of the MRC Laboratory of Molecular Biology in Cambridge, UK, for “the phage display of peptides and antibodies”.

              Directed evolution of enzymes is an artificial process that mimics natural selection to produce enzymes with a specific function. In 1984, scientist Manfred Eigen described a procedure for direct evolution. His procedure is as follows:

  1. Produce mutant varieties of genes
  2. Separate and clone those mutant genes
  3. Amplify clones
  4. Express clones
  5. Test resulting proteins for wanted phenotype
  6. Test mutant genes for the genotype for corresponding wanted phenotype
  7. Repeat procedure with the optimal mutant genes

A decade after Eigen published his paper, Frances Arnold applied Eigen’s method to subtilisin E, a protease that breaks down the milk protein casein, that was obtained from the bacterium Bacillus subtilis. She wanted an enzyme that would work in the organic solvent dimethylformamide, instead of water. Using directed evolution, she was able to create an enzyme with a 256-fold higher activity in dimethylformamide than the original subtilisin E.

Later, Willem P. C. Stemmer, a Dutch scientist who died in 2013, developed a DNA recombination strategy dubbed “DNA shuffling”, where genes are randomly fragmented and reassembled. He showed that DNA shuffling can create variations more often than other methods and thus can improve the chance of producing an optimal gene. However, since Stemmer is deceased, he did not receive part of the Nobel Prize. Directed evolution of enzymes has had many practical uses, such as the production of sustainable biofuels, chemicals, laboratory reagents, drugs, and consumer products, the catalyzation of artificial chemical bonds, such as carbon-silicon and carbon-borane bonds, and the improvement of selectivity of enzymes.

The other half of the Chemistry prize was awarded jointly to George Smith and Gregory Winter. In 1985, George Smith developed the idea of phage display, where bacteriophages/phages (bacteria-infecting viruses) match a protein with the gene that encodes it. To do this, he obtained DNA into the genome of the phage. When the phage infected a bacterium, the phage inserted its genome into the genome of the bacterium. When the new phages were produced from the bacterium’s infected genome, the peptide produced by Smith’s inserted DNA was fused to the capsules of the phages. Smith selected an antibody that was attracted to a specific protein that might have been encoded by a part of the DNA he inserted. Using this antibody and a technique called affinity chromatography, Smith isolated some phages with the antibody’s corresponding peptide fused on the phages’ capsules. He reproduced the phages with the peptide by infecting bacteria with those phages and eliminated the other phages, resulting in the enrichment of the phage fused to the wanted peptide. When Smith looked at the genome of that phage, he could determine the gene that encoded the peptide fused to the phages.

Diagram of Smith’s method (Source: Royal Swedish Academy of Sciences)

              Around 1990, Gregory Winter used Smith’s technique to display a fully functional antibody fragment on a phage. Winter enriched the phages carrying the antibody fragment using affinity chromatography. In the next several years, Winter created a phage library storing billions of antibodies. He used directed evolution to develop antibodies that had higher affinities for their target molecules and “humanize” the antibodies to be used as drugs for humans. Later, Winter and his colleagues started a pharmaceutical, Cambridge Antibody Technology (CAT), that used phage display to develop drugs. CAT later developed adalimumab, sold under the name Humira, which treats rheumatoid arthritis, Chron’s disease, chronic psoriasis, and many other conditions. Phage display was later used on many other monoclonal antibody drugs.

              All the technologies and innovations created by the Medicine, Chemistry, and Physics prize recipients have been already put to use in a variety of fields, from pharmaceuticals to particle acceleration. Many more uses for these innovations will likely be used in the future. Allison, Honjo, Ashkin, Mourou, Strickland, Arnold, Smith, and Winter’s contributions to science have been extremely important. These individuals have truly deserved the prizes, since they have, per the will of Alfred Nobel, “conferred the greatest benefit to humankind”.

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