Complete paradigm shifts in medicine are rare, but there have nevertheless been several major examples in the past hundred years. Treatments and approaches that seemed set in stone one decade can easily seem silly the next, as new information about the disease or underlying biology comes to light. Hindsight grants us clarity, but sometimes the factors that lead us down a particular treatment path can be as arbitrary as a feud between colleagues. Might there be paradigm shifts looming in oncology, neurology and more, triggered by a return to previous treatments?
This article was authored by Ward Capoen from V-Bio Ventures.
Ask anybody about the standard treatment for diabetes and they will tell you it is insulin. Certainly, since the discovery and purification of this miraculous substance a century ago, that has been the case. Dr Frederick G. Banting first isolated insulin in a series of experiments in 1921-23 and demonstrated that it was able to reduce blood sugar and ketoacidosis in a 14-year-old boy. The rest is history: initially obtained from animal cadavers and then famously produced at Eli Lilly and Genentech in 1982, insulin took over as the number-one treatment for diabetes.
However, diabetes has been recognized as a disease for millennia, well before insulin was first isolated. The first know references to the condition even date back to as early as 1500 BC. For all these years, the disease didn’t go completely untreated: the standard treatment recommended by doctors was essentially a low carb diet. In the 19th century medical bible, “The principles and practice of medicine”, Sir William Osler even prescribes a diet that would likely be identified today as an Atkins or ketogenic diet (depending on if you’re asking a baby boomer or a millennial).
A number of companies have been founded in the last few years, using ketogenic diets as an added treatment for diabetes. They have so far been very successful at treating the disease with significantly less need for medications. One hundred years after insulin was discovered, we are returning to a combination therapy using the original effective treatment for diabetes.
The feud that (nearly) killed cancer immunotherapy
Have there been other similar paradigm shifts in medicine recently? As with the diabetes diets, the rise in immuno-oncology could also be described as a return to earlier treatment methods. Until the early 2000s, a combination of surgery with chemotherapy or radiation therapy was overwhelmingly the standard in cancer treatments. This domination of chemo can partially be traced back to the work of a single pediatric pathologist: Dr Sidney Farber of the Children’s Hospital in Boston. Experimenting with different folate analogues in the 1940s, he was able to treat children with acute lymphoblastic leukemia (ALL), making this childhood leukemia the first cancer type to be successfully treated with chemotherapy. To this day, Dr Farber is acknowledged as the father of modern chemotherapy, but the standard treatment for cancer may have taken a different path if it hadn’t been for some coincidences and personal feuds half a century earlier.
These stories show us how treatment paradigms can take a particular route based on luck, timing, and even the (inter)personal relations of the scientists involved.
In 1891, New York oncologist Dr William Coley became intrigued by a patient case where a bacterial infection seemed to eliminate an untreatable neck tumor. Delving into the medical records for similar cases, Coley found more evidence of cancer regression linked to bacterial infections. He decided to explore the phenomenon to see if an immune response triggered by bacteria could purposefully be used as a cancer treatment.
In his early attempts, Coley injected ten patients with live streptococcus bacteria. Though the treatments seemed to work for the cancer, the unpredictable nature of the bacterial infection led to the deaths of two patients. Coley switched to using a formula of dead bacteria, later dubbed Coley’s toxins, which he used to treat hundreds of patients through his career with reasonable efficacy. However, the controversy of the initial deaths hounded his work, and another therapy had arisen that many doctors viewed as a safer alternative: radiation therapy.
One of Coley’s most outspoken detractors was his own boss, Dr James Ewing (who later would lend his name to Ewing’s sarcoma). As evidenced by their memos to one another, there was a strong interpersonal animosity between Coley and Ewing, with the latter being a passionate proponent of radiation therapy. Ewing eventually outlawed the use of the Coley’s bacteria-based method at the hospital altogether. If not for this personal feud and the coincidental concurrent rise in radiation therapy, cancer immunotherapies may have had an added 100 years of research and development.
Breakthroughs in the brain domain
We can find more modern examples of paradigm shifts in the fields of neurology. When pharmaceutical companies discovered the effect of selective serotonin reuptake inhibitors (SSRIs) on depression, it quickly led to the launch of the blockbuster drug Prozac in 1987. Since then, very little progress has been made in the treatment of depression; companies have developed marginally safer SSRIs, which have boosted sales but had little impact on patient outcomes.
Interestingly, around the time that the first SSRIs were being marketed, researchers were also starting to see the correlation between depression and inflammation. By the early nineties, the Macrophage Theory of Depression had formed, postulating that inflammatory cytokines released by macrophages can drive depression. The implication was that underlying, subchronic inflammation may be contributing to the mental illness. This theory has since been supported by the correlation between depression and certain auto-immune diseases, and the fact that using cytokines like interferon alfa or TNF to treat other diseases has led to depressive symptoms in patients.
The potential of anti-inflammatory drugs in the treatment of depression has now started gaining traction as a potential alternative for classic antidepressants. That the genericization of SSRIs has caused other treatment avenues to become more financially interesting has no doubt contributed to this renewed interest, but the discovery of novel pathways and druggable targets has doubtlessly contributed as well.
Medical standards can easily shift, causing controversy and disruption in the field but ultimately bringing value to the patients.
Other recent neuro-immunology approaches (with success in preclinical studies) include the use of inflammasome inhibitors in neurodegenerative diseases such as Alzheimer’s, and the discovery of innate immune cell involvement in the initiation and chronification of pain. Though still in early phases, these new methods may lead to treatment shifts of their own in the future.
These stories show us how treatment paradigms can take a particular route based on luck, timing, and even the (inter)personal relations of the scientists involved. Sometimes historical rejects can provide inspiration for new therapeutic pathways forward. For us at V-Bio Ventures, it is clear that medical standards can easily shift, causing controversy and disruption in the field but ultimately bringing value to the patients. These examples of new approaches seem to be particularly rich at the interface between different disciplines, like nutrition and endocrinology, or immunology and oncology/neurology. The exchange of expertise between disciplines can be a valuable source of innovation, and lateral thinking will bring better treatments to patients in the years to come.
