Nobel Prize History
The Nobel Prize is the most prestigious award in the scientific world. It was created according to Mr. Alfred Nobel’s will to give a prize “to those who, during the preceding year, have conferred the greatest benefit to humankind” in physics, chemistry, physiology or medicine, literature, and peace. A sixth prize would be later on created for economic sciences by the Swedish central bank.
The decision of who to attribute the prize to belongs to multiple Swedish academic institutions.
Legacy Concerns
The decision to create the Nobel Prize came to Alfred Nobel after he read his own obituary, following a mistake by a French newspaper that misunderstood the news of his brother’s death. Titled “The Merchant of Death Is Dead”, the French article hammered Nobel for his invention of smokeless explosives, of which dynamite was the most famous one.
His inventions were very influential in shaping modern warfare, and Nobel purchased a massive iron and steel mill to turn it into a major armaments manufacturer. As he was first a chemist, engineer, and inventor, Nobel realized that he did not want his legacy to be one of a man remembered to have made a fortune over war and the death of others.
Nobel Prize
These days, Nobel’s Fortune is stored in a fund invested to generate income to finance the Nobel Foundation and the gold-plated green gold medal, diploma, and monetary award of 11 million SEK (around $1M) attributed to the winners.
Source: Britannica
Often, the Nobel Prize money is divided between several winners, especially in scientific fields where it is common for 2 or 3 leading figures to contribute together or in parallel to a groundbreaking discovery.
Over the years, the Nobel Prize became THE scientific prize, trying to strike a balance between theoretical and very practical discoveries. It has rewarded achievements that built the foundations of the modern world like radioactivity, antibiotics, X-rays, or PCR, as well as fundamental science like the power source of the sun, the electron charge, atomic structure, or superfluidity.
Evolution As A Tool
Since the landmark publication of “On the Origin of Species” by Charles Darwin in 1859, evolution has been at the center of biological sciences. In it, Darwin made public the key insight that life evolves over time when exposed to pressure from the environment.
Source: By John Murray, Publisher – Wikipedia
Since Darwin, biologists have realized evolution can be a very complex force, with not only mere survival impacting evolution, but also many other effects adding nuance to the idea, such as:
Overall, evolution works by selecting the most beneficial mutations among random mutations in a given situation. The important part is that this is a “blind” phenomenon, relying on millions of mutations instead of a conscious intent.
Far from just a theoretical concept, evolution has been a key part of human civilization. First, the artificial selection of valuable (for humans) traits appearing randomly is what made the domestication of crops and animals possible.
Without these more productive food sources, we might have never exited the stone age. So much before we knew about evolution or directed evolution, we leveraged it through a mix of guesses and approximations.
Source: Cell
Evolution can also be a mortal threat. Pathogens keep mutating, and the “winner” is able to evade our immune system and spread better. This is also the mechanism that allows bacteria to develop resistance to antibiotics, with each generation slowly getting better at evading the drugs.
Understanding evolution is a powerful tool for most scientists; some have pushed this concept further, winning the 2018 Nobel Prize in Chemistry.
Frances H. Arnold, who won half of that year’s Nobel Prize, leveraged evolution’s forces to develop greener processes for the chemical industry. Meanwhile, George P. Smith and Sir Gregory P. Winter used evolution at play in viruses to create new life-saving therapies.
Source: Nobel Prize
The Power Of Enzymes
Most of the biochemical processes that sustain life are driven by specialized proteins called enzymes.
Thanks to extremely complex 3D structures, as well as the frequent incorporation of elements like rare metals in the protein, they can accelerate chemical reactions that otherwise would never happen. This acceleration of chemical reaction is called catalysis.
Source: Ducksters
This is how life can perform chemical reactions like turning atmospheric nitrogen into ammonia (bacterial nitrogen fixation).
Replicating this process industrially requires extreme temperatures in the hundreds of degrees as well as a lot of energy and complex machinery.
Source: Essential Chemical Industry
Due to this astonishing capacity of enzymes to perform chemical transformation with less energy, industries have been using them for decades.
At first, this was done by utilizing microorganisms, such as yeast, for fermentation. Then, the industry started to use the isolated enzymes themselves. But Frances Arnold had another idea: to modify natural enzymes to make them more useful for humans.
Using Evolution To Create New Enzymes
Her first project was to modify an enzyme called subtilisin, used in detergent, food processing, packaging, and waste management applications. Instead of the natural subtilisin working in water, she wanted it to function in the organic solvent, dimethylformamide (DMF). DMF would normally degrade most proteins, making the enzyme non-functional.
She first creates thousands of variant versions of the enzyme by creating mutations in the corresponding gene. She then inserts that mutated enzyme-coding gene into bacteria. Checking the activity of the mutated subtilisin in a 35% DMF solution, she selected the version that worked the best. She then performed a series of mutations on the selected sequences and checked their activity again.
Astonishingly, after only 2 “generations” of such artificial evolution, she had already found a new version of subtilisin that worked better in DMF than in water.
She repeated the process a third time by mutating this latest version of subtilisin again. She discovered a variant that worked 256 times better in DMF than the original enzyme.
Source: Nobel Prize
It is worth putting an emphasis that no researcher could have predicted which mutation would yield such a result. Checking it manually one by one would have been extremely expensive and time-consuming.
Instead, replicating the mechanics of evolution in a microcosm allowed new solutions to be found in record time. This method would become the basis of an entire field of biochemical engineering, creating custom enzymes for a myriad of applications in pharmaceutical, chemical, and biological production.
Creating New Enzymatic Catalysts
Arnold did not stop at boosting or modifying the preexisting activity of enzymes. She also looked at how to create entirely new chemical activity that did not exist in nature. The problem with this is her method would not work, as you need at least some initial level of the desired activity to be selected and improved upon by evolution.
For this, she and her team went on to randomly modify enzymes with catalytic activity that theoretically could work on other chemical reactions not happening in nature, but useful for the chemical industry.
They would find a “promiscuous enzyme with at least low activity for the intended reaction” among the modified enzymes, even if it was a low-efficiency one. Once this starting point was established, directed evolution could take over to achieve high efficiency after enough generations of selection.
Source: Nobel Prize
New Biochemistry
If entirely new catalytic activity were not enough, Arnold’s team even invented whole new classes of biochemical reactions.
Using the same method of starting from a low-efficiency enzyme, they found that the enzyme Cytochrome C, from Rhodothermus marinus, could create carbon-silicon bonds with very low efficiency, essentially just by accident rather than per design.
Carbon-silicon bonds, or organosilicon, are common in human-driven chemistry but not used by any biological organism. They are useful in pharmaceuticals as well as in many other products, including agricultural chemicals, paints, semiconductors, computers, and TV screens.
Several rounds of directed evolution yielded a mutated Cytochrome C that catalyzes silicon-carbon bond formation 40x better than the starting enzyme. The evolved enzyme also had a 15x higher turnover number than the best non-enzyme catalyst known for the same reaction.
Similar results were also obtained in producing chemicals with only one enantiomer (one among many possible 3D configurations of the same molecule).
Advantages Of Directed Evolution Enzymes
When only one enantiomer among all configurations is useful, enantio-selectivity enzymes can drastically improve productivity and reduce waste.
Because these enzymes are catalysts made of proteins, they also remove the need for polluting toxic metals and, often, massive amounts of organic solvents.
Boosting Genetic Research
Meanwhile, other researchers were studying the genome in the 1980s, when genetic sciences were still young.
A key issue they struggled with was to identify the specific gene that would produce a known protein, as we were decades before the human genome was decoded in the early 2000s.
George P. Smith’s team started working with bacteriophages, viruses specialized in infecting only bacteria, and with a knack for replicating genetic sequences quickly.
Smith started with a large library of unidentified genes or fragments of genes. He then inserted them unidentified into the virus’ DNA coding for a protein on the capsule, leading to the foreign proteins to be displayed at the surface of the virus.
Source: Nobel Prize
He would then use antibodies to “fish” for the protein of interest, picking the right phage out of millions. As a bycatch, they would, therefore, also fish out the DNA contained in the phage, allowing them to match the previously unknown gene to the protein of interest.
They called this technique “phage display”.
In itself, this was a breakthrough in molecular biology and contributed greatly to a better understanding of the genome. However, it is from the contribution of the third winner of this Nobel Prize that the most important contribution of phage display to humankind would come.
Antibodies Evolution
Evolutive forces are not only a play with entire species or for specific enzymes, but also in our immune system.
Thanks to random variations of their genetic sequence, our immune cells can produce hundreds of thousands of different kinds of antibodies. To avoid auto-immune disease, a selection process removes the antibodies that would react to the body’s cells. The still enormous diversity of the leftover allows. Theoretically, any new virus or bacteria can be matched by at least one antibody type.
In true evolutive fashion, such effective antibodies would be selected and multiplied, creating immunity against the disease. This property of antibodies to “evolve” to match specific proteins linked to diseases was already leveraged by injecting mice with them and collecting the resulting antibodies produced in response to be used as a therapy.
However, the problem was that, being mice antibodies, the human bodies often reacted poorly to the foreign antibodies.
Mixing Phage Display & Direct Evolution
This was where Gregory Winter had the idea to use Smith’s phage display method.
First, he demonstrated a new method so that phages would display the active part of the antibody on the surface of the virus capsule. He then built up a library of phages with billions of varieties of antibodies on their surfaces.
From this library, specific phages whose antibodies would match at least somewhat a target protein were fished out. He then applied the directed evolution method from Arnold to randomly change the sequence of the antibody and create a new phage/antibody fragment library.
From this new library, only the antibody fragments with the strongest match would be kept, and the process repeated until a very high affinity to the target protein was achieved.
Through this method, he would by 1994 develop antibodies that attached to cancer cells with a high level of specificity.
New Therapeutic Options
Winter would go on and found Cambridge Antibody Technology, turning this technology into therapies.
In 2002, the first approved fully human therapeutic antibody created by using phage display was commercialized, under the name Adalimumab and the brand name HUMIRA, commercialized by AbbVie. The drug binds to TNF-α, a cytokine responsible for triggering inflammation. Adalimumab is used in the treatment of rheumatoid arthritis, psoriasis, inflammatory bowel disease, and other inflammation-related diseases.
Adalimumab would go on to make $20.7B for AbbVie in 2021 and seems to hold on even with the appearance of biosimilars (generic drugs for biologics). In 2006, Cambridge Antibody Technology was acquired by AstraZeneca for £702m.
Phage display is currently used to create many other new antibody-based therapies, including inflammatory syndromes, toxin neutralization, counteracting autoimmune diseases, and treating metastatic cancer.
Investing In Directed Evolution
Currently, antibody therapies developed with phage therapy are by far the largest market created by the development of methods leveraging directed evolution, followed closely by enzyme-based catalysts.
You can invest in related companies through many brokers, and you can find here, on securities.io, our recommendations for the best brokers in the USA, Canada, Australia, the UK, as well as many other countries.
If you are not interested in picking specific companies, you can also look into biotech ETFs like WisdomTree BioRevolution UCITS ETF (WBIO), VanEck Biotech ETF (BBH), or First Trust NYSE Arca Biotechnology Index Fund (FBT), which will provide a more diversified exposure to capitalize on the growing biotech economy.
Enzymes and Antibodies Companies
1. Codexis
The company focuses on enzymes. As explained above, these proteins can “make happen” (catalyzed) chemical reactions that otherwise would not be possible or very slow.
The goal of Codexis is to replace chemical processes with enzyme-driven biochemical processes instead.
It uses machine learning to create thousands of variants of enzymes to optimize their performance, which can be productivity, specificity, stability, or concentration in the host organism.
These enzymes are selected through directed evolution using the company’s CodeEvolver platform.
Source: Nature
It can then offer custom enzymes to industrial and pharmaceutical companies.
It focuses on 3 applications:
- Biotherapeutics to treat genetic diseases, with 24 candidates in the research pipeline
- Life sciences research, especially genomics and DNA & RNA synthesis.
- Pharmaceutical manufacturing, for example, optimizing existing production facilities.
The company is also looking to grow into the RNAi and siRNA manufacturing market. These technologies are becoming a focus of the biotech and pharmaceutical industry, with currently 6 approved siRNA therapies and, globally, more than 450 RNAi pipeline assets in development today, of which 42 are in Phase 2 & 3 clinical trials.
Source: Codexis
For now, 90% of revenues come from enzymes, not biotherapeutics. The focus is to grow with mid-sized pharmaceutical companies while maintaining relations with existing large pharmaceutical companies.
2. Ginkgo Bioworks
The company is producing on-demand organisms for specific applications, including biomedical applications and industrial and material sciences programs.
It also has a large biosecurity segment, which was booming during the pandemic.
In most cases, some form of directed evolution is used in the production and selection of Gingko’s products.
Ginkgo Bioworks has diversified its applications widely with many research programs and partnerships:
It makes money by being first paid upfront for the development process and then through royalties on the finished product.
Gingko’s partnerships are constantly expanding, with:
Ginkgo Bioworks also partners with all the major agricultural corporations, most of which have some interests in biofuel production and microbiology. A few of these include Bayer, Cargill, Syngenta, Corteva, ADM, Exacta, and more.
Source: Gingko Bioworks
Gingko’s experience in custom designs of genetic sequences, organisms, and selection, as well as in biosecurity monitoring, makes it a key provider to every industry looking to leverage enzymes and antibodies for their specific application.
As a service provider, Gingko is well-positioned to capitalize on the growth of the industry as a whole.
