Of mice and men: research gone awry
The title of John Steinbeck’s novella “Of Mice and Men” was inspired by Robert Burns’ well-known poem, “To a Mouse.” In it, the poet notes that the best laid plans of mice and men often go awry (or “gang aft agley,” in the original Scottish). As readers who follow medical research news well know, this relationship between mice and men (or, potentially, the lack) is often suggested in media reports. We've all heard of new “medical advances” based on studies done on laboratory mice.
If research experiments work in mice, readers may ask, does that mean the results can be applied to human or routine clinical research? The answer is a decisive no.
To underscore the questionable value of these mice studies for human subjects, James Heathers, a methodology and data scientist at Northeastern University in Boston, has launched a Twitter account called @justsaysinmice. In less than a week, it has garnered 40,000 followers.
The problem of conflating findings in mice to takeaways in humans is something that has annoyed Heathers for a while. As he told STAT, “When you say patients when you mean mice, or when you say women when you mean female mice, you are conflating a Phase 0 study with a Phase 3 study. When you mesh the two, the difference between one versus the other is five years and a billion dollars.”
When the media report on these mice studies, it would be helpful for patients if they pointed out that while they may be “of mice,” they are NOT “of men.” As I have stressed for many years: be cautious about early laboratory results. No matter how exciting, they might not apply in the clinic.
Results that come with a caution label
Researcher Michael Potter conducted the most famous experiments to understand what causes myeloma in mice. He showed that injecting mineral oil into the belly (or peritoneal) cavity of mice triggered chronic inflammation. This led to plasmacytosis and then myeloma. Although the results were reliable, the interpretation has been difficult. Nothing similar happens to myeloma patients.
Subsequently, pristane, a chemical present in mineral oil, has been linked to the causation of myeloma. This chemical is present in gasoline and other volatile hydrocarbons. Epidemiological studies have correlated myeloma with, for example, exposure to benzene mixtures, including pristane.
Of note, myeloma did not develop in germ-free mice. It seemed that the presence of unidentified infectious agents was necessary. The mineral oil contained viral particles. Again, much evidence suggests that a chronic triggering by an infectious agent can be important in causing myeloma in patients.
THE BOTTOM LINE: More than 50 years after the original mice research, we are still trying to figure out how different factors interact and lead to the causation of myeloma.
Cautions about “precision medicine”
In addition to hype about research in mice, there is a tendency to hype the potential of so-called precision medicine strategies. Identifying a single gene mutation is attractive as a target for new therapy. In isolation, this does indeed appear very attractive. However, myeloma cells have innumerable mutations. Thus, targeting one mutation leaves all the others unattended. This has led, for example, to a very brief response with anti-BRAF therapy in patients whose myeloma cells contain the BRAF (B-raf) mutation. Other mutations, such as K and N ras, take over and cause resistant cell growth. One must look at the full situation, considering both:
- Is a particular therapy effective against its precise target?
- Can this therapy help the patient in the big picture?
What to watch for in myeloma research
When I review the abstracts for the annual the American Society of Hematology (ASH) meeting, what do I look for? I am looking for results in patients—clinical trial results. Phase I and phase II results are the early results, which, again, must be viewed with caution. But some early results are so striking that future patient benefit is highly likely. For example, at ASH in 2018, we had the early results of the anti-BCMA CAR T trial from Legend Biotech (China). These results were presented as an oral presentation. They indicated a response rate of 88% in relapse patients with patients achieving MRD negative status and remissions of over one year. Obviously, further work is required, but optimism is a very reasonable assessment. Researchers must conduct phase III trials comparing a newer therapy with a standard approach. Such trial results will be able to document the true value of a promising therapy.
Robert Burns was fascinated by how both mice and men could gather effectively in the harvest fields of Scotland. Resilience was essential to gather and survive. So, indeed, we can learn and be thrilled by the success of a mouse. But in the big picture, due caution is required before we translate everything to our own lives!
Dr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.