by John Aitken

I am the typical absent-minded scientist. I have never been able to focus on the task in hand, as there are too many distractions in the laboratory. What should be a logical progression becomes diverted by interesting observations and unexpected findings. My memory has never been particularly polished. I always remember faces but forget the names behind them. In my laboratory, the back of my hand resembles a tattooed mosaic of letters –washed off every day and replenished as the need arises. Lately, I have replaced this reliable system with paper lists. There is something incredibly empowering about crossing each task off as it is completed. The smart phone is a lifesaver. I can schedule events and give myself some warning before they occur. This is particularly useful for birthdays, especially my wife’s!

My memory is not as polished as it was at age 30. I can still recite entire speeches from Shakespeare, but I sometimes forget to pick up the dry cleaning. When I go to the supermarket, I carry a list with me. The list is a document added to by family members until I go down to do the shopping. “If it’s not on the list, then I’m not interested.” I assume that this is part of the process of growing old; some events are important, while others are less attractive. It’s the latter I am prone to forgetting.

All of this begs a question: If I have a large brain and many neurons to assist my powers of recall, how does the immune system get along? My immune system has been “primed” to recognize threats to my health, and also to keep my body in generally good shape over a lifetime. In order to properly fight infections, the immune system needs to distinguish between the invaders and the beneficial bacteria, which reside on and in us as part and parcel of life.

Mycobacteria are often seen as invaders. T cell macrophages patrol the blood for signs of mycobacteria and direct the fight against these organisms. This army needs to be briefed, and the ongoing briefing is undertaken by macrophages previously exposed to the mycobacteria. This sensitization, or prior exposure, takes place in the normal course of childhood. Mycobacteria are well distributed in the environment; in food, in water, and in the good earth. Once exposed, this protection can last a lifetime.

Immunity against Mycobacterium tuberculosis (the mycobacterium that causes TB) also requires a prior contact–either through vaccine or through actual infection. The vaccine is known as BCG, which stands for Bacille Calmette Guerin. BCG is a thoroughly timid version of Mycobacterium bovis, a type of TB once found in cattle, and a close relative of M. tuberculosis. BCG is a “domesticated” (attenuated) form of TB that is unlikely to cause an infection, but stimulates the immune system to recognize TB and contain the pathogen before the TB can set up a life-threatening infection.

Immunity to TB after vaccination with BCG can last a lifetime. The prevalent explanation for this longevity of immunity is a phenomenon known as “immune memory.” The theory of immune memory is that the immune system, including the macrophage, retains a memory of TB and any subsequent exposure to TB will trigger macrophages to come to the site of infection and neutralize the TB bacilli. Immune memory is a great concept, but the way in which the macrophages retain a memory of the pathogen is unclear. Macrophages have a lifespan of 1-2 years, then they die. However, immunity to TB will continue for decades after the BCG vaccination.

I recently read a paper by a group of software designers who were attempting to produce a software model of immune memory. It had quickly become obvious to the authors that the mechanisms involved in immune memory were poorly understood. As the authors put it, “the definition of immunological memory is not straightforward.” Indeed, the reader can sense despair leaking from the text as the authors realize the writing of the software program was not going to be straight forward either.

Why is it important to understand the mechanisms behind immune memory? One reason is the growing possibility of immunotherapy via vaccination. If BCG protects against tuberculosis, can a similar vaccine protect against the onset of Crohn’s disease or other “autoimmune” diseases? There is another reason why we should understand immune memory and the BCG vaccination. Evidence suggests that the immune memory involved in the BCG vaccine is not a result of exposure to remnants of dead Mycobacterium bovis. The macrophages may not be carrying a “shopping list” when on patrol.

A better, and more efficient model might be to carry a sample of the Mycobacterium species instead. Like a trophy, the microorganism is paraded around the body to educate the immune system, safely locked within the macrophage. When the parasitized macrophage dies, a newly minted macrophage takes over the task; and so it goes on. This sort of idea is heresy. The idea that “human blood contains no bacteria and is sterile” is sacrosanct. In reality, that statement is under close review these days, as is the theory of immune memory.

For our purposes, let’s imagine that the BCG vaccine maintains long-term immunity in the host by in fact co-existing and living inside the bloodstream. That feat is beneficial for the mycobacterium, surrounded by a moving feast of amino acids and proteins. It is also beneficial to the host, as the subdued mycobacterial villain is paraded around the body, stimulating the immune system. An elegant and efficient example of evolution. Symbiosis in action.

Evolution is a random process, not always directed at benefits to both parties. One thought that has been occupying my mind is: What if a new pathogen was introduced into this well-balanced system, which then evolved to mimic a beneficial mycobacteria species, but with a sinister intent?  Like the story of the Trojan Horse, such an invader would dodge the immune system and go straight to the heart of the host. Immune memory would be of no help at all.