Mr N’s last wish



How are you feeling today?”

“You know, they are always telling me to do stuff, all kinds of stuff, like I used to, but I just can’t. I don’t have the energy and I am less connected to others around me. I feel like I am dying, really [1].”

“What about the pharma-agents? Are they doing you any good?”

“Well, you know…they come and they try to help, and they do, but it is not like they really know me or really understand my problem. What they do eases my hardships for some time, but it does not really take me back to a healthy state.”

“What do you mean?”

“Tell me, if you were a throat with an infection, would you expect to be cured with paracetamol? Paracetamol eases the pain but does not kill the pathogen. You address the symptom but you don’t treat the cause. I am pretty sure that if they really understood how things work around here while we are healthy, myself and all the others, we would not be in this position right now.”

“When did you start to notice that you were unwell?”  

“A problem like this does not start overnight. Think about the following: it takes on the order of several dozens of minutes for a cell to generate new proteins. So, how long would you expect it to take for a given protein to accumulate inside us so that, where once it was vital, it is now toxic and harmful [2]? Analogously, lets consider the case of lipids. Lipids are a vital source of energy but if they over-accumulate inside the arteries they become toxic for the body…and we know it is not like an artery wakes up one day to find her walls covered with fat, right?”

“But don’t you think there must be a turning point, or in other terms, a point of no return?”

Well, maybe, I don’t know. But if there is one, we need to understand which events come before and after this point: before, while the system is still healthy, and after, when the system needs some kind of help to deal with the problem.”

And that would be the moment where the agents’ help would be most helpful?

Exactly! And it would not be that hard, they would just have to ride the wave!”

“Ride the wave?”

For example, when the skin suffers a lesion, a battalion of immune system cells run to the damaged area, helping with skin repair, while protecting the organism from pathogens. There is probably already some kind of mechanism to deal with a mild version of our problem, but there are limitations and at a certain point the process spins out of control. Maybe we would just need the agents to amplify a mechanism that is already there, therefore ‘riding the wave’. But that is currently not the case: the agents come and work like a crutch and then the leg is just leaning restfully, but not really adapting and reacting to the unbalance [3].”

“That’s what you would like the agents to do? To train you to regain balance, to recalibrate the state?”

“We as a whole are very adaptable, that’s our strength, our trump. For sure it can also be used to help us heal ourselves. Can you imagine that the agents’ action is to train us to correct the unbalance and make us ‘produce’ dopamine again like in the old days [4]? To be able to reconnect with other neurons and work full power again, watching the body doing all those amazing things like riding a bicycle or making love…Do you know what is the worst of all? To watch other neurons dying slowly in front of us, knowing that our turn will come too…”

“But how come so many of you die without notice?”

The brain has millions of millions of neurons and, in truth, neurons die every day like any other cell of the body. We can adjust our roles, take tasks from the ones that die. The brain was built for redundancy, it is robust to so many minor changes that only if a big, big portion of us starts to fail will it be noticed and then it will be too late, the damage will already be too overwhelming. For example, I was connected to a guy from the olfactory team and he started to be unreliable, sometimes he was just not reacting to my messages [5]. And I was not the only one complaining about this team. For me, it was an alarm call but we only started to have real problems many, many months later.”

“But you are aware that, as a ‘genetic convict’, sort of speak, you have very little chances of regaining health?”

I am not strictly convicted by my genes [6]. Yes, I know that my DNA may have something that makes me more vulnerable, but information contained in DNA is not carved in stone. It can be read and translated differently depending on many factors and maybe the agents could help there too…In conclusion, there must be different ways to help revert the situation, as many as there are factors implicated in generating the problem…”

“Do you have any last request?”

“I would just like to have the comfort of knowing that when I die there will be a scientific explanation for it…”

I don’t get that…

“If a brain suffers a stroke, neurons die because oxygen stops flowing, which in turn stops the cell obtaining nutrients that it needs to function. Now, if a brain suffers from Parkinson’s, scientists can’t yet say what the cause of death really is. Can they? [7]”

About Parkinson’s disease:
[1] Parkinson’s disease is a chronic and progressive movement disorder, meaning that symptoms persist and worsen over time.
[2] Researchers have discovered that the hallmark sign of Parkinson’s disease is the accumulation of certain proteins. These clumps are called Lewy bodies.
[3] Current therapeutics include pharmaceutical agents that are converted to dopamine when arriving at the brain, an approach equivalent to giving insulin to a diabetic patient; additionally, there are surgical alternatives that mostly rely on implanting a pacemaker in the brain that stimulates neurons electrically, very much like a heart pacemaker.
[4] Parkinson’s disease involves the malfunction and death of neurons that produce dopamine, a chemical that sends messages to the part of the brain that controls movement and coordination. These neurons are located in a brain area called substantia nigra. When approximately 60 to 80% of the dopamine-producing cells are damaged, and do not produce enough dopamine, the motor symptoms of Parkinson’s disease start to appear.
[5] Many experts think that the disease is caused by a combination of genetic and environmental factors, which may vary from person to person.
[6] Lewy bodies are found not only in the substantia nigra but also in the brain stem and the olfactory bulb. These areas of the brain are implicated in non-motor functions such as sleep regulation and the sense of smell. The presence of Lewy bodies in these areas accounts for the non-motor symptoms experienced by some people with Parkinson’s disease, before any motor symptoms of the disease appear.
[7] The chemical or genetic trigger that initiates the cell death process in dopamine neurons is the subject of intense scientific study. Many believe that by understanding the sequence of events that leads to the loss of dopamine cells, scientists will be able to develop treatments to stop or reverse the disease. To date, despite decades of intensive study, the causes of Parkinson’s remain unknown.
For more information:




Ana Rita Fonseca studied Engineering as an undergraduate and then moved to neuroscience where she is developing a PhD project in rodent decision ­making at the Systems Neuroscience lab, Champalimaud Neuroscience Programme.



Edited by: Ivo Marcelo (section editor), Clara Howcroft Ferreira (editor-in-chief)


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