By 1878, Louis Pasteur had formulated his germ theory of disease and had turned his attention to chicken cholera, a problem that plagued the French poultry industry. He managed to isolate a microbe from sick chickens he believed caused the disease and showed that injecting it into healthy birds led to their demise within a day. Scientific evidence requires repetition of an experiment, but a summer vacation intervened. No problem, Pasteur thought, he would just store his bacterial culture. To his astonishment, injecting the culture that had been stored for three months had no effect on the chickens!
He tried again with a fresh culture, and the chickens remained disease-free. While many would have concluded that in the original experiment the chickens must have been affected by something other than the suspect bacteria, Pasteur hypothesized that perhaps storage for three months had altered the microbes in a way that resulted in offering protection against infection by fresh bacteria. As it turned out, Pasteur had managed to immunize the chickens with an attenuated microbe! It didn鈥檛 take long to prove that a weakened form of an infectious organism could impart immunity against the disease normally caused by a more vibrant version.
This discovery paved the way for the development of 鈥渓ive, attenuated vaccines鈥� which are still very much in practice. A leading example is the triple vaccine against DTP (diphtheria, tetanus, and pertussis).
The message here is far from a simple 鈥渟cientists need a little R & R鈥�. Rather, scientific inspiration often comes from keeping a keen eye on anomalies, instances that deviate from the comfortable norm. This is also echoed in a story that was shunned for more than a century before finally being embraced as the new paradigm to dissect and tackle cancer.
It all started in Manhattan, New York, in 1891, a decade after Dr. Pasteur鈥檚 landmark cholera vaccine. The protagonist, this time, is Dr. William B. Coley, an accomplished bone surgeon. The loss of a young patient to sarcoma (malignant tumours in bones and soft tissues) struck Dr. Coley who was determined to find a cure. Browsing through case histories, he noticed something out of the ordinary: some cancer patients experienced spontaneous shrinkage of tumours (some even complete remission) following a nasty bacterial skin infection (called erysipelas) that induced symptoms including high fevers.
Dr. Coley hypothesized that the infection most likely triggered an immune reaction by the body, potent enough to shrink the tumour. He then experimented by injecting live erysipelas bacteria directly into the tumour and later refined the meds as a combination of two different bacteria, dubbed as 鈥淐oley鈥檚 toxins.鈥�
Akin to Dr. Pasteur鈥檚 chicken cholera vaccine, production of 鈥淐oley鈥檚 toxin鈥� involved treatment of the bacteria with heat to reduce their virulence without affecting their ability to induce a robust stimulation of immune cells to fight and shrink tumors. There were, of course, areas in need of improvement with 鈥淐oley鈥檚 toxins,鈥� but the timing was inopportune because the discovery of radioactivity at the turn of the 20th century rendered radiation therapy center stage for cancer treatment.
Although pushed to the back burner, Coley had laid the foundation for the immunotherapy of cancer. Starting from the late 1920s, other scientists continued to tread the path initiated by Dr. Coley and today he is lauded as the 鈥淔ather of Tumor Immunology.鈥� Although Coley鈥檚 toxins are no longer used, save for a variant of the strategy to treat bladder cancer, Dr. Coley gets credit for the idea of stimulating the immune system to fight cancer.
In 2018, the Nobel Prize in Physiology and Medicine was awarded to Drs. James Allison and Tasuku Honjo for finding a way to allow T cells, an important component of the immune system, to attack cancer cells without harming normal cells.
Former President Jimmy Carter presents a stunning example of the effectiveness of immunotherapy. In 2015 he was diagnosed with melanoma that had spread to his liver and brain. Death seemed imminent. But his doctors suggested treatment with pembrolizumab, a revolutionary new drug that blocks a protein called PD-1 on the surface of T-cells, important components of the immune system. PD-1 acts as a 鈥渂rake鈥� on the ability of these cells to attack invaders and blocking it allows the T-cells to find and kill cancer cells. President Carter is still with us, his cancer gone!
Take-home message:
- Accumulations of anomalies can lead to a fundamental paradigm shift
- Timely noticing such anomalies (and subsequent follow-up and follow-through) requires a ready mind
Dr. Nancy Liu-Sullivan holds a Ph.D. in Molecular and Cellular Pharmacology and served as a senior research scientist at Memorial Sloan Kettering Cancer Center. She currently teaches biology at the College of Staten Island, City University of New York.
