Biology and Beagles: The Evolution of Computational Biology

Computational biology, although not new, has made major leaps and gains in recent years. AlphaFold 2, created by Deepmind, a Google subsidiary, was reported to have solved the protein folding issue. Now with an even more powerful AlphaFold 3 and other tools that can simulate how drugs dock and interact not only with target proteins, but other physiological structures, computational biology is at the forefront of a debate regarding animal testing and has even helped drive legislation through congress.

Structure Determines Function

“Structure Determines Function” is one of the first things an individual in a biochemistry or computational biology course would hear. Proteins (referenced here) are responsible for essentially all life processes and disease within the body. It is therefore obvious why researchers are so keen on determining protein structure in search for cures to diseases. With proteins consisting of sometimes thousands of Amino Acids, it can be difficult for researchers to accurately assess a protein structure and determine how a long branch of Amino Acids fold. In 2022, AlphaFold was able to predict the 3-D structure of almost every known protein, a number estimated to be 200 million. CASP, the Critical Assessment of Structure Prediction, is a protein folding competition in which various teams can test the efficacy of their computer models. When AlphaFold 2 entered CASP14 in 2020, there was no question, AlphaFold 2 absolutely dominated the competition to the point where the “protein folding problem” was solved. Through machine learning and a system that made protein folding predictions based upon previously known structures, determined by time consuming and expensive processes like X-ray crystallography, NMR, or cryogenic electron microscopy, AlphaFold 2 was able to take the gold. Although Deepmind did not participate in CASP15, all of the systems the top competitors in CASP15 used customized versions of AlphaFold 2 as Deepmind had released the source code for AlphaFold, making it accessible to anyone who wanted to try their hand in computational biology.

While AlphaFold 2 was revolutionary, its successor AlphaFold 3 offers to not only model, but also solve problems regarding how proteins interact with other compounds. Announced in May 2024, AlphaFold 3, which leverages AI, can not only predict the structure of proteins, DNA, RNA, and ligands, but also predict how biomolecular interactions would take place. While AlphaFold 2 only focused on protein, AlphaFold 3 pulled back the curtain on a broader range of biomolecules. With disruptions in protein structure often leading to disease, simulations of interactions between proteins and other biomolecules clue researchers in to how a disease can progress, and what can possibly be done to prevent it. Although only allowed for non-commercial research, the AlphaFold server allows individuals to access AlphaFold 3 for free and reduces the cost of protein-structure prediction, which can cost hundreds of thousands of dollars, to essentially zero.

A lesson in toxicity testing

In 2022, congress passed the FDA Modernization Act 2.0. This act in essence authorized the use of non-animal preclinical testing alternatives, including computer modeling, to obtain FDA approval in regard to the proliferation and development of new therapeutics. This act overruled the previous Federal Food, Drug, and Cosmetic Act which was passed in 1938 and required that all drugs must be tested on animals before human clinical trials.

The 1938 Federal Food, Drug, and Cosmetic Act was originally passed after Elixir Sulfanilamide, between the months of September and October of 1937, was responsible for the deaths of more than 100 people in 15 states. Sulfanilamide, originally produced by S.E. Massengill Co, is a drug used to treat bacterial infections and is still, safely, in use today. In the 1930s, the drug was known to have powerful effects and was used primarily in tablet and powder form. A salesman requested the drug in liquid form as was demanded by some in southern states and the company chemist discovered that the sulfanilamide dissolved well in diethylene glycol. Once tested by the company for appearance, flavor, and fragrance (but not toxicity) the drug was shipped out all over the country. In early October, the American Medical Association (AMA) began receiving reports of deaths linked to an unfamiliar sulfanilamide compound. After testing was performed on the compound by the AMA and diethylene glycol was determined to be the toxic ingredient, a warning was issued that Elixir Sulfanilamide was “toxic and deadly.” The FDA was notified and an inspector, confirming the deaths were linked to Elixir Sulfanilamide, required the manufacturing company to send telegrams informing salesmen, pharmacists, and doctors that it was “Imperative you take up immediately all elixir sulfanilamide dispenses, product may be dangerous to life. Return all stocks, our expense” (FDA). The FDA mobilized nearly their whole staff to track down the distributed medicine and there were some hiccups along the way. One instance resulted in the jailing of a salesman before he was willing to talk about the distribution information. Another instance resulted in a woman who “had thrown the bottle out the window into an alley. The inspector found the bottle still unbroken, still containing enough elixir to kill any child intrigued enough to swallow its sweet, raspberry-flavored contents.”

• Diethylene Glycol was the agent responsible for the high toxicity of Elixir Sulfanilamide. Diethylene Glycol is commonly used in antifreeze amongst various other industrial products. It is not suited for human consumption.

All in, elixir sulfanilamide killed 107 people, most of whom were children. Though tragic, this incident proved why stringent protocols and government oversight were necessary in the drug development process. The adoption of the Federal Food, Drug, and Cosmetic Act, along with the New Drug section, set out to prevent another tragedy like this from occurring – and it worked. In 1961, the act “saved the nation from an even greater drug tragedy– a thalidomide disaster– like that in Germany and England” (FDA).

New technologies mean new protocols

Evidently, stringent regulation and safety testing is critical for any new drug, or variation of a previous drug, that is to be marketed to the general public. The incidents involving elixir sulfanilamide and thalidomide should be viewed as the why for testing protocols - not the how. With new technologies like that of AlphaFold 3 and variations of, along with strict clinical testing requirements, non-clinical (preclinical included) toxicity studies can be modeled accurately and this has been acknowledged by the FDA. 

Prior to the passage of the FDA Modernization Act 2.0, animals had been required in preclinical testing. While most individuals would think of mice and “lab rats” as animals of choice, there is another extremely common animal used in testing: Beagle Dogs.

Often chosen due to their small size and passive nature, beagle dogs are used in animal testing quite frequently. While laws are in place to prevent unnecessary animal suffering, according to the USDA, 58,000 dogs were used in USDA research in 2019 alone, with 16,013 of the dogs likely experiencing pain as part of the research. One should note that research is not always pretty. Much of what is known about the human body in regard to extreme conditions is due to research performed by Nazi Germany and Imperial Japan on prisoners of war during WWII. While there is obviously a stark contrast between experimentation performed on animals to create life saving medicines and that undertaken during one of the darkest times in world history, an ethical dilemma remains. Should animal testing be required, especially when computational biology has made such massive gains in recent years? The FDA doesn’t seem to think so.

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