Thalidomide: Can We Justify Discovery After Damage?

Research supports thalidomide’s ability to treat blood cancers, despite its controversial past.

In the world of scientific research and medical science, the “wonder” drug often depends on the failures and “dead ends” of another scientist or study. If Sir Alexander Fleming had not kept his laboratory so disorganized, would he have discovered the mold killing bacteria in a contaminated petri dish, leading to the discovery of Penicillin? Dr. Fleming’s “dirty” laboratory seems insignificant compared to Penicillin’s revolutionary treatment for bacterial infections (1). However, this idea raises an ethical dilemma for many scientists today. At what point are accidents and failures valuable to scientific research? When does the potential of discovery outweigh the potential for harm? 

From the late 1950s to early 1960s, the German pharmaceutical company Chemie Grüenthal created thalidomide as the newest wonder drug. Touted as a non-addictive and non-toxic sedative (2), thalidomide could treat numerous conditions, including colds, insomnia, anxiety, and nausea (2, 3). The drug was distributed in over 40 countries and specifically marketed towards pregnant women experiencing morning sickness (3, 4, 5). Despite extensive advertisements promoting the drug’s safety, thalidomide was never approved for distribution in the U.S. (3). Dr. Frances Oldham Kelsey, a pharmacologist at the Federal Drug Administration (FDA), continuously denied requests from thalidomide’s manufacturers with concerns about the applications’ dependence on testimonial evidence rather than clinical data. Not long thereafter, her insight would be recognized with the President’s Award for Distinguished Federal Civil Service (6).

The results of thalidomide-treated pregnancies challenged its “guaranteed” safety. In 1961, Australian obstetrician William McBride submitted a letter to the medical journal The Lancet concerning “multiple severe abnormalities” in babies born to women who took thalidomide during pregnancy (7). The same year, German pediatrician Widukind Lenz identified a link between thalidomide use and congenital abnormalities in the ears and limbs, prompting him to contact Chemie Gruenthal (8). The company formally withdrew the drug in late November 1961. By then, thalidomide exposure had resulted in an estimated 10,000 newborn babies worldwide with severe and often fatal birth defects (5, 9). 

The widespread harm caused by thalidomide prompted many scientists to reevaluate drug safety screening. During the 1950s, testing for teratogenic effects or fetal compromise, birth defects caused by exposure to a teratogen, was not formally implemented (10). Chemie Grüenthal reportedly tested thalidomide on rats and mice, but never tested the drug on pregnant animals. Later studies with rabbits, monkeys, and other small mammals found the drug’s fetal toxicity. Additionally, the harmful side effects of thalidomide vary depending on administration during the pregnancy timeline. These effects included malformation and shortening of the limbs and digits; eye and ear damage; facial disfigurement; and damage to the skeletal structure and internal organs (11, 12). The variation in birth defects made it challenging for scientists to identify thalidomide as the underlying cause. Furthermore, disabilities caused to the upper limbs by genetic conditions like Holt-Oram Syndrome and TARS Syndrome were similar to the profound limb abnormalities caused by thalidomide, complicating the drug’s linkage to congenital defects (11). 

Since the thalidomide tragedy in the 1960s, scientists have continued to research its molecular mechanisms and how it causes congenital defects. In 2010, Japanese scientists found that thalidomide binds to and alters cereblon (CRBN) protein function. CRBN proteins are an integral part of the protein complex E3 ubiquitin ligase. Protein complexes are groups of proteins that interact at the same time to carry out cellular processes, for instance, DNA replication or energy conversion. E3 ubiquitin ligase, vital to embryonic development, tags substrate cells (cells that need to be degraded to maintain cell health) for elimination. Thalidomide alters CRBN’s function, resulting in the targeting of new proteins and birth abnormalities (9). 

In 2018, scientists at Dana Farber Cancer Institute built on this research by identifying thalidomide’s teratogenic mechanism with limb malformations, one of thalidomide’s most severe side effects. Using human embryonic stem cells and a mass spectrometry workflow (which measures the mass-to-charge ratio of ions to identify molecules), scientists found the drug caused drastic reductions in an essential protein to limb development: SALL4 (13). Thalidomide hijacked CRBN cells and marked SALL4 as a substrate protein, causing the E3 ubiquitin ligase complex to target it for destruction (14). These studies, which provide a better understanding of thalidomide’s molecular mechanisms, have been instrumental in exploring thalidomide’s potential as a form of cancer treatment. In the 1990s, thalidomide’s anticancer properties were discovered as the drug inhibits blood vessel growth, which is necessary to support cancerous tumor growth. Its ability to target blood-related cancers like multiple myeloma led to its approval for cancer therapies. In 2013, a study found that when thalidomide and similar drugs bind to CRBN, they can trigger the destruction of transcription factors IKZF1 and IKZF3. Transcription factors regulate gene expression by turning genes “on” or “off.” In cancer cells, transcription factors are often mutated or deregulated, which drives tumor proliferation by abnormally turning the genes on or off (15). Transcription factors IKZF1 and IKZF3 are commonly overactive in multiple myeloma cells; the destruction of these transcription factors slows the progression of the cancer (16).

Despite thalidomide’s potential in cancer therapy, the drug’s tragedy in the 1960s continues to affect populations today. While organizations like The Thalidomide Trust provide aid to people born with disabilities because of thalidomide, the drug reminds one of the dangers within scientific experimentation. Today, survivors of thalidomide’s birth defects experience numerous health problems, including severe and often continuous pain, reduced mobility and strength, numbness, and poor emotional health. Many individuals require prosthetic limbs, hearing aids, electronic wheelchairs, and adapted vehicles. The Thalidomide Trust estimates that over 40% of individuals with thalidomide-caused disabilities are unable to work due to their disabilities and health problems. So, should scientists continue to reintegrate thalidomide treatments? Since the tragedy, many countries and research regulatory agencies have established new toxicity testing protocols intended to ensure drug safety (16). With these new policies and the rapid expansion of scientific knowledge, scientists must consider both the potential therapeutic benefits of thalidomide and the historical risks to prioritize patient safety (17)

Bibliography

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