Three take home chemistry Nobel for harnessing protein ‘evolution’ | Science News for Students

Three take home chemistry Nobel for harnessing protein ‘evolution’

The scientists created bio-based techniques to speed up the development of drugs, fuels and more
Oct 3, 2018 — 7:02 pm EST
chemistry nobel

This year’s Nobel Prize in chemistry went to Frances Arnold (left), George P. Smith (middle) and Gregory P. Winter (right) for research on proteins, including enzymes and antibodies.

CalTech; University of Missouri; Aga Machaj/Wikimedia Commons (CC BY-SA 4.0)

Biologists often refer to evolution as the way living things adapt, genetically, to their environment. But scientists sometimes harness “evolution” to help out in other fields of science. Three who did were today awarded the 2018 Nobel Prize in chemistry. They developed ways to build proteins in the lab through the use of evolution.

The proteins that can be fashioned this way are suitable for a broad range of uses. These range from new drugs to biofuels.

Frances Arnold works at the California Institute of Technology in Pasadena. She will take home half of this year’s prize of 9 million Swedish kronor (about $1 million). She worked on enzymes. These are materials that cells create to speed up chemical reactions. Arnold learned how to make new enzymes from old ones. These new enzymes can be used to make biofuels, environmentally friendly detergents and other products.

Arnold is only the fifth woman over the past 117 years to win a Nobel Prize in chemistry.

Gregory Winter works in England at the University of Cambridge. George Smith is at the University of Missouri in Columbia. They will split the other half of this year’s chemistry prize. They found a way to build peptides (short strings of amino acids) using viruses. Some of the peptides are used to make antibodies and other medicines.

“Wow, well-deserved!” says Paul Dalby of this year’s prize winners. “Protein engineering as a field is absolutely founded upon their work,” he notes. Dalby is a biochemical engineer. He works in England at University College London.

All three winners will collect a medal and their shares of the prize money at a ceremony in Stockholm, Sweden on December 10. That’s the date in 1896 on which Alfred Nobel died.

Mining the chemical know-how of living organisms

In the late 1980s, Arnold wanted to make an enzyme to break down a milk protein, casein, in a solvent other than water. She could try to manually link up the amino-acid building blocks of that enzyme to give it the right properties. That would require knowing which amino acids to change. Instead, she opted for a more hands-off approach.

Arnold’s insight, says Jesse Bloom, “was to recognize that the most amazing molecules in the world weren’t created by chemists.” He is a microbiologist at the Fred Hutchinson Cancer Research Center in Seattle, Wash. Those cool molecules are made in the cells of living things. What’s more, he notes, “Biology didn’t make these chemicals using the methods we might learn in an organic chemistry class. Rather, it worked by evolution.”

Arnold first made many copies of the DNA that contains instructions for making the original enzyme. She put that DNA into bacteria. As the bacteria grew, genetic differences — changes known as mutations — arose by accident. 

Each batch of bacteria could have many different versions of the mutant enzyme-making genes. The bacteria also acted like living factories. They churned out many copies of each mutant enzyme. Arnold picked the version of that enzyme that did the best job at breaking down casein in a particular solvent. Then she repeated the mutation process, starting the best-working enzyme.

Her bacteria went through rounds of mutation-making. Each time she selected the best-working enzyme that some new mutant bacterium had made. In the end, Arnold was left with an extremely efficient, custom-made molecule. The technique she used is now known as “directed evolution.” It allows scientists to fine-tune the chemistry of their proteins in much the same way that Mother Nature does it. The difference: Arnold’s technique is thousands of times faster.

Researchers have used directed evolution to create enzymes that jump-start chemical reactions for creating new drugs and eco-friendly biofuels. Arnold’s lab has used this process to also create enzymes that help forge chemical connections not found in nature.

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subtilisin E
Arnold’s lab put an enzyme, named subtilisin E, through directed evolution. That led to their finding a more active form of this enzyme, which is now used in laundry detergents. The changes to create the first variant are shown here in yellow. The molecule was then allowed to evolve further to include the additional mutations. They show up in blue. Molecules and ions bound to the enzyme are pictured in grey.
L. You and F.H. Arnold/Protein Engineering 1996

Going viral

The other half of the Nobel prize honors work on a procedure to make chemicals using viruses. Certain viruses kill bacteria. Those viruses are known as phages (FAYZH-es). That’s short for bacteriophages. These are simple microbes. They’re just bundles of genetic material enclosed inside protein shells.

Smith and Winter created phage programmed with genes to build various proteins (or enzymes). Then they injected the phage into bacteria and let the phage reproduce inside them. Sometimes they mutated, making new versions of the target proteins. Those proteins would show up on the phage’s outer shells, earning the name “phage display.”

In the 1980s, Smith started work on this process by inserting certain genes into the DNA of phages. Those genes told cells how to make various proteins. Their gene-tweaking created phages that displayed the target proteins on their surface.

Smith’s goal had been to figure out which genes created which proteins. He essentially went fishing around a phage soup with a molecule known to hook a particular protein. This let him to pull out only the phages armed with that particular surface protein.

In 1985, Smith created a phage that held on its surface a piece of protein known as a peptide. He then used a peptide-binding chemical to glom onto this phage and pull it out of the crowd.

Other researchers have gone on to use his method to breed phage that wear antibodies and other biological molecules on their surfaces.

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phage display
George Smith developed a method of farming biomolecules called phage display. (1) The researcher inserts a gene for making a certain molecule (here, a piece of protein called a peptide) into a phage’s genetic code. (2) That creates a phage programmed to produce that peptide on its surface. (3) Using an antibody that binds to that peptide, a researcher can harvest the peptide-carrying phage from a soup of many phages.
©Johan Jarnestad/The Royal Swedish Academy of Sciences

On to antibodies

The human body naturally makes hundreds of thousands of antibodies. They are designed to latch onto viruses and bacteria. Their presence puts a bullseye on these microbes, marking them for destruction by immune cells. But researchers had long wanted to create antibodies in the lab to tackle various diseases. These could work as new drugs. In 1990, Winter used his phage-display method to create a phage armed with part of an antibody.

The antibody he used binds to a molecule known as phOx. Winter then used phOx to latch onto a phage wearing that antibody. It pulled the right phage out of a soup of four million other types of phage.

Winter then started using directed evolution, much as Arnold had been. He first created a pool of phage whose genes programmed them to produce billions of different antibodies. From that group, Winter now used a target molecule like phOx to serve as a hook. It would collect only those phage that were best at binding to it. From those phage, Winter bred a whole new generation of antibody-bearing phage. Then again, he used the target molecule to pick out the best of this newer bunch.

Using this survival-of-the-fittest-phage technique, Winter’s team created a drug based on an antibody. It treats the source of inflammation in people with autoimmune diseases. Such ailments hijack the immune system to attack a patient’s body. In 2002, a drug made this way, called Humira, was cleared to treat rheumatoid arthritis (RU-muh-toid Arth-RY-tis). Today, doctors use this drug to also treat two other autoimmune diseases.

Phage display “is an extremely versatile technology,” says Jonathan Lai. He’s a biochemist at the Albert Einstein College of Medicine in New York City. His lab uses the technique to make new vaccines. Other researchers have used phage display to produce antibodies that fight cancer or treat lupus (LOO-puhs).

Jon Lorsch directs the National Institute of General Medical Sciences in Bethesda, Md. He says that the discoveries by this year’s Nobel winners are “a great demonstration of how studying fundamental biological questions like the natural process of evolution can lead to great breakthroughs in technology and medicine.”

Power Words

(more about Power Words)

amino acids     Simple molecules that occur naturally in plant and animal tissues and that are the basic building blocks of proteins.

antibody     Any of a large number of proteins that the body produces from B cells and releases into the blood supply as part of its immune response. The production of antibodies is triggered when the body encounters an antigen, some foreign material. Antibodies then lock onto antigens as a first step in disabling the germs or other foreign substances that were the source of those antigens. 

arthritis     A disease that causes painful inflammation in the joints.

atom     The basic unit of a chemical element. Atoms are made up of a dense nucleus that contains positively charged protons and uncharged neutrons. The nucleus is orbited by a cloud of negatively charged electrons.

autoimmunity     (adj. autoimmune) A process whereby the immune system turns against its host. This inappropriate reaction can cause disease instead of curing it. Autoimmune diseases can be quite severe and hard for doctors to treat. They include rheumatoid arthritis (affecting joints, such as knees), multiple sclerosis (targeting nerves and muscles), Crohn’s disease (affecting the gut), psoriasis and lupus (affecting skin) and the type of diabetes that typically develops in young children. In all of these cases, the immune system generates out-of-control inflammation.

bacteria     (singular: bacterium) Single-celled organisms. These dwell nearly everywhere on Earth, from the bottom of the sea to inside other living organisms (such as plants and animals).

bacteriophage     Also known simply as a phage. This is a type of virus that infects — and ultimately kills — bacteria, but not before reproducing and spreading. The term is, like “deer” or “fish”, both singular and plural.

biochemical     (adj.) Referring to something made and used within living things.

biofuels     Energy sources derived from carbon stored in living organisms. Although wood is a biofuel, most people who support “green” sources of energy consider biofuels to be liquids that can substitute for gasoline. Examples include bioethanol, an alcohol derived from crops such as corn or sugarcane. Engineers are also developing ways to make biofuels from nonfood crops, such as trees and shrubs. Renewable biofuels are an alternative to nonrenewable fossil fuels.

biology     The study of living things. The scientists who study them are known as biologists.

cancer     Any of more than 100 different diseases, each characterized by the rapid, uncontrolled growth of abnormal cells. The development and growth of cancers, also known as malignancies, can lead to tumors, pain and death.

carbon     The chemical element having the atomic number 6. It is the physical basis of all life on Earth. Carbon exists freely as graphite and diamond. It is an important part of coal, limestone and petroleum, and is capable of self-bonding, chemically, to form an enormous number of chemically, biologically and commercially important molecules.

cell     The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. Depending on their size, animals are made of anywhere from thousands to trillions of cells. Most organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.

chemical     A substance formed from two or more atoms that unite (bond) in a fixed proportion and structure. For example, water is a chemical made when two hydrogen atoms bond to one oxygen atom. Its chemical formula is H2O. Chemical also can be an adjective to describe properties of materials that are the result of various reactions between different compounds.

chemical reaction     A process that involves the rearrangement of the molecules or structure of a substance, as opposed to a change in physical form (as from a solid to a gas).

chemistry     The field of science that deals with the composition, structure and properties of substances and how they interact. Scientists use this knowledge to study unfamiliar substances, to reproduce large quantities of useful substances or to design and create new and useful substances.

detergent     A compound derived from petroleum products, often used for cleaning. Detergents work by breaking up and surrounding dirt particles or oily substances, so that they can be washed away with water.

engineer     A person who uses science to solve problems. As a verb, to engineer means to design a device, material or process that will solve some problem or unmet need.

engineering     The field of research that uses math and science to solve practical problems.

environment     The sum of all of the things that exist around some organism or the process and the condition those things create. Environment may refer to the weather and ecosystem in which some animal lives, or, perhaps, the temperature and humidity (or even the placement of components in some electronics system or product).

enzymes     Molecules made by living things to speed up chemical reactions.

evolution     (v. to evolve) A process by which species undergo changes over time, usually through genetic variation and natural selection. These changes usually result in a new type of organism better suited for its environment than the earlier type. The newer type is not necessarily more “advanced,” just better adapted to the particular conditions in which it developed. 

fundamental     Something that is basic or serves as the foundation for another thing or idea.

gene     (adj. genetic) A segment of DNA that codes, or holds instructions, for a cell’s production of a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.

generation     A group of individuals (in any species) born at about the same time or that are regarded as a single group. Your parents belong to one generation of your family, for example, and your grandparents to another. Similarly, you and everyone within a few years of your age across the planet are referred to as belonging to a particular generation of humans. The term also is sometimes extended to year classes of other animals or to types of inanimate objects (such as electronics or automobiles).

genetic     Having to do with chromosomes, DNA and the genes contained within DNA. The field of science dealing with these biological instructions is known as genetics. People who work in this field are geneticists.

germ     Any one-celled microorganism, such as a bacterium or fungal species, or a virus particle. Some germs cause disease. Others can promote the health of more complex organisms, including birds and mammals. The health effects of most germs, however, remain unknown.

immune     (adj.) Having to do with the immunity. (v.) Able to ward off a particular infection. Alternatively, this term can be used to mean an organism shows no impacts from exposure to a particular poison or process. More generally, the term may signal that something cannot be hurt by a particular drug, disease or chemical.

immune system     The collection of cells and their responses that help the body fight off infections and deal with foreign substances that may provoke allergies.

inflammation     (adj. inflammatory) The body’s response to cellular injury and obesity; it often involves swelling, redness, heat and pain. It also is an underlying feature responsible for the development and aggravation of many diseases, especially heart disease and diabetes.

insight     The ability to gain an accurate and deep understanding of a situation just by thinking about it, instead of working out a solution through experimentation.

link     A connection between two people or things.

manufacturing     The making of things, usually on a large scale.

microbiology     The study of microorganisms, principally bacteria, fungi and viruses. Scientists who study microbes and the infections they can cause or ways that they can interact with their environment are known as microbiologists.

molecule     An electrically neutral group of atoms that represents the smallest possible amount of a chemical compound. Molecules can be made of single types of atoms or of different types. For example, the oxygen in the air is made of two oxygen atoms (O2), but water is made of two hydrogen atoms and one oxygen atom (H2O).

mutation     (v. mutate) Some change that occurs to a gene in an organism’s DNA. Some mutations occur naturally. Others can be triggered by outside factors, such as pollution, radiation, medicines or something in the diet. A gene with this change is referred to as a mutant.

National Institute of General Medical Sciences     One of the 21 separate National Institutes of Health. This one both conducts internal research and finances research by others into basic biological processes and that may lead to better disease diagnosis, treatment and prevention.

Nobel Prize     A prestigious award named after Alfred Nobel. Best known as the inventor of dynamite, Nobel was a wealthy man when he died on December 10, 1896. In his will, Nobel left much of his fortune to create prizes to those who have done their best for humanity in the fields of physics, chemistry, physiology or medicine, literature and peace. Winners receive a medal and large cash award.

novel     Something that is clever or unusual and new, as in never seen before.

organic     (in chemistry) An adjective that indicates something is carbon-containing; a term that relates to the chemicals that make up living organisms. (in agriculture) Farm products grown without the use of non-natural and potentially toxic chemicals, such as pesticides.

organism     Any living thing, from elephants and plants to bacteria and other types of single-celled life.

peptide     A short chain of amino acids (usually fewer than 100).

phage     Short for bacteriophage. This is a type of virus that infects — and ultimately kills — bacteria, but not before reproducing and spreading. Phage is both singular and plural, like fish. (For instance, if you had many tuna, the plural would be fish. But if you had many tuna, mackerel, cod and halibut, you’d say there were many fishes. The same applies to phage.)

protein     A compound made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of living cells, muscle and tissues; they also do the work inside of cells. Among the better-known, stand-alone proteins are the hemoglobin (in blood) and the antibodies (also in blood) that attempt to fight infections. Medicines frequently work by latching onto proteins.

range     The full extent or distribution of something. For instance, a plant or animal’s range is the area over which it naturally exists. (in math or for measurements) The extent to which variation in values is possible. Also, the distance within which something can be reached or perceived.

silicon     A nonmetal, semiconducting element used in making electronic circuits. Pure silicon exists in a shiny, dark-gray crystalline form and as a shapeless powder.

solvent     A material (usually a liquid) used to dissolve some other material into a solution.

technology     The application of scientific knowledge for practical purposes, especially in industry — or the devices, processes and systems that result from those efforts.

vaccine     (v. vaccinate) A biological mixture that resembles a disease-causing agent. It is given to help the body create immunity to a particular disease. The injections used to administer most vaccines are known as vaccinations.