Brenner is a physician-scientist and president and chief executive officer of Sanford Burnham Prebys and lives in La Jolla.
In 1937, there was great demand for a new way to treat streptococcal infections, which range from mild tonsillitis to scarlet fever to toxic shock syndrome. A drug called sulfanilamide, when taken in tablet and powder form, had proven effective. Now a pharmaceutical company wanted to market a liquid form, which it tested for flavor, appearance and fragrance.
But not for toxicity. Back then, there were no laws requiring safety studies. Selling toxic drugs might be bad for business, but it was not necessarily illegal. Shipments of the liquid form of sulfanilamide went out nationwide in early September. By mid-October, there were reports of people dying.
By the time the drug was pulled from the market, more than a 100 people had died after taking liquid sulfanilamide, many of them children. “Elixir of Sulfanilamide” was poisonous to humans, but no one knew until it was too late. The pharmaceutical company claimed no responsibility, but the company chemist who had invented the elixir apparently did: He committed suicide.
A few months later, Congress ed the Federal Food, Drug and Cosmetic Act of 1938, which mandated that before any new drug for people could be sold, it must undergo animal testing.
Animal testing in drug development makes sense. No one advocates for the use of “human guinea pigs.” It is profoundly unethical. Animal models of human disease have a long history. More than 2,400 years ago, it was recognized that studying animals could provide powerful insights into ourselves. Over time, animal models have become extraordinarily sophisticated, with diverse species reimagined or re-engineered to mimic a host of human maladies.
But animal models of human disease have always been imperfect. A mouse is not a human. Modern medicine has “cured” a lot of ailments in animal models, from rodents (primarily) to rabbits, dogs, cats, sheep, goats, fish, chickens, horses, pigs and nonhuman primates in smaller percentages.
But the fact remains that in current drug development practice using animal testing, nine out of 10 drugs that enter clinical trials fail because they are ultimately unsafe or ineffective in people. From this perspective, the animal experiments upon which these drug efforts were based have proven to be largely a waste of time, money and animal lives.
In late 2022, the Food and Drug istration acknowledged the need for a better way and Congress ed the FDA Modernization Act 2.0, which recognized the limitations of animals in scientific research and encouraged the pursuit of novel, innovative, non-animal alternatives.
Researchers are ecstatic and motivated. Animal testing is expensive, difficult to do and, frankly, scientists do not want to experiment on animals unnecessarily. They do so only because that’s been the best way to get needed information.
But emerging alternatives abound, from testing human cells in cultures to miniaturized or bioprinted organs to non-invasive imaging to experiments using computational or mathematical models driven by artificial intelligence and machine learning.
These approaches are all works in progress. None fully capture the complexity of human biology (and maybe never will), but they are all human-derived and human-based and avoid the speculative pitfalls of a trans-species leap.
I am a practicing physician and researcher in gastroenterology. I treat and study the digestive system, with a particular focus on the liver, the body’s largest and arguably most complicated organ, with more than 300 functions.
Liver disease is among the most common conditions in the United States. More than 100 million Americans have some form, mostly fatty liver disease that can, if undetected and untreated, lead to cirrhosis and liver cancer. Chronic liver disease and cirrhosis are the ninth leading causes of death in the U.S., and rising.
In my own specialty, we are exploring a variety of alternatives to animal testing to find desperately needed new drugs for the treatment of liver diseases. These range from precision-cut liver slices kept alive in culture to organoids (clusters of developing cells that recreate in miniature the structure and functions of organs) to bioprinted cellular systems and sustainable 3D structures (liver on a chip).
Currently, there are limitations with all of these approaches. Precision-cut liver slices can only be kept functional for a handful of days before they degrade. Systems consisting of only one or a few types of liver cell may not capture the full complexity of the actual organ. And much work remains to show whether these models effectively and accurately do what we want them to do. That is, will investigational drugs or treatments tested in non-animal models prove as safe and effective in people?
Here’s what we do know: Working with actual human cells and tissues, whether from the liver or another organ, is far more likely to directly inform our research and efforts than working with cells from another species, whether in culture or in the actual animal.
Switching entirely to non-animal experimentation will take time. Progress will be slow and fitful, while the imperative to remedy our myriad ills is constant and accelerating. Physicians and scientists use the best tools available in the moment, but newer, better tools are coming.
