How a failed psoriasis study pushed a whole field forward

Scientists have made some of the biggest strides in various fields after being directed by past failures

Over 90 percent of experimental medical treatments that enter clinical trials fail. But that doesn’t necessarily mean that those trials were a waste of time. Scientists have made some of the biggest strides in various fields after being directed by past failures. Entering the murky realm of speculation, one could argue that today’s understanding of the nature of the immune cell group known as T cells, which travel throughout the body helping to regulate the efficiency of immune responses, would be vastly different if a drug trail in the early 2000s hadn’t failed.

The drug was anti E-selectin, which was being tested as a potential treatment of the symptoms of psoriasis, a skin disease identifiable by characteristic red, itchy patches of skin called psoriatic plaques. While it is a relatively common disease, its underlying causes remain obscure. What has been known for years, however, is that T cells play an important role in the disease.

An elusive mechanism doesn’t preclude the ability to treat a disease, as famously illustrated in managing neurodegenerative diseases such as Alzheimer’s. In a similar spirit, researchers seeking to connect the dots between T cells and psoriatic plaques devised a simple treatment: They reasoned that since psoriasis only appears in patches, then the T cell must have to physically reach those areas to cause plaques. Aiming to disrupt this process they settled on anti E-selectin, designed to block T cells from leaving the blood and migrating to the skin.

Anti E-selectin passed through the preliminary requirements with flying colors and proceeded to human clinical trials — where it failed completely. After weeks of treatments, trial subjects showed no change in the size or severity of psoriatic plaques. The results were baffling. Anti E-selectin was an established treatment that had seen success in lab experiments, the logic was sound, there was no obvious reason as to why the trial failed.

While scientists sat scratching their head over the failure of anti E-selectin, another group of scientists in Switzerland went back to the drawing board and decided to approach the problem from a different direction. Using a transgenic mouse, which lacked its own T cells, scientists grafted non-psoriatic skin from psoriasis patients onto the mice. Shockingly, despite the complete lack of native T cells, the mice developed psoriasis. By taking a skin biopsy from the mouse and looking more closely at the psoriatic plaques under a microscope, scientists noticed that the few T cells that had been transplanted into the mouse via the human skin — subsequently termed “tissue-resident memory T cells” due to their location in tissue instead of blood — had grown into a large population of cells. These cells had then spread throughout the skin and caused the development of psoriatic plaques on the mice.

The findings flipped the established understanding of psoriasis on its head, showing that the development of the disease was completely independent of the recruitment of circulating T cells. Armed with this knowledge, scientists headed back to the clinic. Tailoring treatments to focus on T cells in the skin, these clinical trials, conducted more than a decade after the first failed psoriasis trials, met with great success at resolving cases of psoriatic plaques.

Revisiting the failure of the of the anti E-selectin trial with the clarity of hindsight, and the knowledge of the existence of a substantial population of resident T cells, scientists could now reevaluate the results of the trial. The prevailing dogma of T cells was that all T cells were part of one large, circulating group that traveled throughout the body, out of the blood into tissue as needed, and then drained back into the blood. Resident T cells were thought to be a temporary state, a small subset of the larger group, and not as a particularly large or distinctive one. It was with this concept that scientists had planned the trial.

They had thought that blocking the process of T cell cycling would stop the T cells responsible for psoriatic plaques from ever reaching the skin. After the mouse experiment it became clear, however, that the T cells responsible for psoriasis weren’t mobile at all. They had been underneath the skin, and the psoriatic plaques, the entire time. Armed with this knowledge the scientists could then move forward to more specific treatments aimed at the correct group of cells.

While explaining the failure of the clinical trial was satisfying in and of itself, returning to the failure offered something else — something that scientists could only begin to appreciate by considering the implications of the detailed results of the mouse experiment in the context of the outcome of the clinical trial.

Scientists began to realize that the traditional way of approaching T cells, of treating them as one large group, wasn’t working. There wasn’t going to be a general, systematic approach to researching or treating T cell diseases. Instead, researchers and physicians would have to think of T cells as a dynamic, variable group of cells with unique features in unique cases, requiring specialized treatments.

This was a poignant example of the direction medicine had to, and still has to, head. In many cases, broad, generalized treatments and system-wide approaches alone aren’t going to do the trick. The devil is in the details — in fine-toothed, deliberate, personalized approaches taken in context. Fully appreciating the reasons behind the failed anti E-selectin was also one of the first signs leading scientist down a path they continue to travel today, one investigating the many subtypes of T cells, their locations, and their roles in disease. An avenue that might not have been taken if researchers had been content to shelf their failures and move on to the next treatment.

Considering, or in some cases even dwelling, on failure isn’t always pleasant. But we can learn as much from our failures in science as we can from our successes.

Link Original: https://www.salon.com/2018/10/01/how-a-failed-psoriasis-study-pushed-a-whole-field-forward_partner/

 

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