The science behind the comic

When is it going to happen?

In chapter 9, the skin cell team are integrating the dopamine service. But is this actually possible today?

As our ability to make authentic dopaminergic neurons from skin cell sources improves, so does the reality of a first in human clinical trial.
Before actual transplants in humans, the regulatory authorities and the PD patients’ community want to see that trials on human are safe. This, of course, requires high quality pre-clinical evidence to support its use, which is being acquired today.
The first-in-human clinical trials are on the horizon (Barker et al., 2017).

Watch Malin Parmar describe her research in this 2-minutes video:

It is possible! But how?

In this chapter, we witness Jojo’s reprogramming from skin cell to neuron! You read the fiction, now you can discover how it is actually done.

Malin’s (and Fanny’s) work is characterised by many novelties.

The first and central one is that in the past, reprogramming could only be performed starting from embryos or foetuses, and not from skin cells. This had of course many ethical and availability problems; furthermore, the foetal therapy also has disappointing results.

The other one is that you see Jojo becoming smaller, but he doesn’t goes back to the state of pluripotency (that age when a cell can become anything). There is no need to go back to that stage in Malin’s research.

At the end, you see Fanny looking at the pool where the reprogramming is taking place. This process used to take around 50 days, but very recently scientists discovered some molecules that can speed up the conversion to 25 days[1].

And now that you’ve seen Jojo’s transformation in the story, you can see the video of how it works for real!

The embryo method is still carried out in China, where at this very moment a mass experiment is taking place[2]. New born neurons have been injected into the brains of humans. These clinical trials have caused concern all around the world as they are still considered as premature elsewhere, but as Malin said to Nature, we “are all rapidly moving towards clinical trials, and this field will be very exciting in the coming years”.

In the next chapter, we will look into the integration process of the new born neurons in the dopamine department!

1. Constitutively Active SMAD2/3 Are Broad-Scope Potentiators of Transcription-Factor-Mediated Cellular Reprogramming. Cell Stem Cell, 2017
2. https://www.nature.com/news/trials-of-embryonic-stem-cells-to-launch-in-china-1.22068

Fanny’s therapy: is it possible?

As advanced as it may sound, replacing dopamine cells in patients affected by Parkinson disease is not a new idea: studies have been carried out since the 80s!
But the results have been somewhat disappointing. Luckily, the research in this field has undergone a big change, also thanks to Malin Parmar’s research.

Why Parkinson disease?

Parkinson’s disease is a good candidate for cell therapy because only one cell type is affected, dopamine neurons, and degeneration is local. So there has been increasing interest in cell therapies to locally replace lost dopamine neurons. Also, Parkinson disease symptoms can be alleviated with other therapies but the disease cannot be cured otherwise, so there is a lot of need for this kind of research.

How is it possible?

One of the many advances is that while at the beginning, embryonic cells coming from fetal tissue were turned into neurons, nowadays Malin Parmar uses three new methods: she makes neurons out of stem cells made in the lab and skin cells from the patient’s body, and she also studies how to inject healthy genes into the brain.

All these methods are more effective and controllable than the embryonic cells method, and they do not have ethical implications.

You will find out how the skin cell reprogramming is done in chapter 8!

Let’s find out what is happening in Chapter 6 and how our story matches with scientific findings.

Jojo’s mum dies

Our skin is made from 90% of keratinocytes. They are the physical barrier which protects us from everything which is dangerous in the outside world: heat, UV, bacteria, viruses and much else.
A keratinocyte lifespan is about 50 days. The death of a cell leads to desquamation of our skin, which is at the same time replaced by new cells.
So actually, everything goes very fast in a cell’s life: Jojo’s mum couldn’t live longer that two months!

Neurons do not reproduce

As far as we know, this is generally true: our body can’t replace damaged nerve cells. In other words, neurons do not reproduce. But is it that sad, as Jojo’s mum thinks?
In reality, neurons having children would be more harm than good. They have a very complicated job and there are connected to other neurons as well all the other cells. Adding new neurons would mess up these connections.

This dogma has been challenged[1] in the 90s by a Princeton scientist, and today many researchers are working on this issue.

Jojo works for the thymus service

The thymus is located in our chest, and it is associated with our immune system: it is a barrier which protects us, just like the skin, but in a different way. Indeed, the thymus helps us to elaborate a type of white blood cells, called T cells, which defend our body from invaders.
Some kind of skin cells do live in the thymus and filter T cells, making sure that they won’t attack our body’s own cells: even researchers call them working class heroes[2]!

1. Does your brain produce new cells?, Mo Costandi, The Guardian, February 2012
2. Thymic epithelial cells: working class heroes for T cell development and repertoire selection, Graham Anderson, Yousuke Takahama, Trends in Immunology, May 2012

The skin and its connections

In this episode our heroes are trying to hack the nervous system. They find themselves tangled in cables, since the skin/brain connection is a complex one, and it is a two-way road.
Indeed, not only the skin transmits information to the brain: the skin can reveal our thoughts and feelings, and it's affected by them[1]!
Think of blushing, short and long-term effects of stress and anxiety , and even skin conditions and aging[2].
As the older cell Jake gets arrested, the skin police gets him to the head of the immune system. Such a connection exists too: the skin is our interface between our organs and an hostile environment. And the skin is not just a barrier: it is a fully fledged immune organ!

Glossary:

Telomeres:

Discovered in the 30s by the Nobel prize winner Barbara McClintock, they protect our chromosomes from deterioration and when they get shorter, cells get older.

But you can do something about it: studies demonstrate that a healthy lifestyle, yoga and meditation can increase their length of 10%[3]!

Apoptosis:

Apoptosis is a process of programmed cell death. It is a process that cannot be stopped once it has begun.
It goes on in our body since we are embryos: but it cannot be neither inhibited nor boosted without major consequences as serious diseases.

Axons:

The axons that Jojo and his friends are trying to hack are projections of neurons. They are transmissions lines, as their function is to pass information (for instance touch and warmth) to different neurons.
They look like very tails – they can even be longer than one meter, but one axon is composed by only one cell!

1. Y. Chen and J. Lyga, Brain-skin connection: stress, inflammation and skin aging. Allergy Drug Targets. 2014;13(3):177-90.
2. J. Salmon, C. Armstrong, and J. Ansel, The skin as an immune organ. West J Med. 1994 Feb; 160(2): 146–152.
3. D. Ornish, J. Lin, J;. Daubenmier, J. Weidner, G. Epel, E. Kemp, M. Magbanua, R. Marlin, L. Yglecias, P. Carroll, E. Blackburn, EH (Nov 2008). "Increased telomerase activity and comprehensive lifestyle changes: a pilot study". Lancet Oncol. 9 (11): 1048–57.

What is dopamine?

Dopamine is a neurotransmitter, it means that it acts as a messenger between brain cells. This chemical is created in various parts of the brain and is critical in all sorts of brain functions, including thinking, moving, sleeping, mood, attention, motivation, seeking and reward.

Reward and reinforcement help us learn where to find things that make us feel enjoyment, pleasure, and therefore motivates us to seek out certain behaviors, such as food, sex, and drugs.

But dopamine has a more sinister side. Drugs such as cocaine, nicotine and heroin cause huge boosts in dopamine. The “high” people feel when they use drugs comes partly from that dopamine spike. And that prompts people to seek out those drugs again and again — even though they are harmful. Indeed, the brain “reward” associated with that high can lead to drug abuse and eventually to addiction.

An improper level of dopamine is the common factor in drug addiction and Parkinson’s disease.

What is a Merkel cell?

Merkel cells like Lisa and Jojo are essential for sensation and found in the skin. We have a lot of Merkel cells in our highest sensitive spots like, for example, in our fingertips.

They are called after The German anatomist Friedrich Sigmund Merkel but even after their discovery their role has been debated and their function described as "enigmatic".

Merkel cells often make synaptic contacts with sensory nerve endings, meaning that they are an indispensable part of the somatorysensory system. So, they are actually in touch with the neural system: could they hack it like Jojo and Lisa?

In the complex company that is the human body, Jojo, our protagonist who just reached the level of maturity allowing him become specialised, is still convinced that to become a neuron you just to have the study a lot and work hard! Unfortunately, this idea not correspond to reality.

Many cells in the human body can divide and reproduce – a process called mitosis - and this is what make the process of healing possible.
For instant, after a cut, new skin cells multiply to repair the wound, and many other kind of cells for example “glue like cells” called platelets stick together to prevent blood and other liquids to leak out, while white blood cells attack germs that may have gotten into the wound. At the end of all this extra working hours that would displease Jojo’s father working that would displease the working union of Jojo’s father colleagues, a new layer ok skin is ready and the scab falls off.

Skin Cell (left) vs neurons (right)

However, neurons cannot reproduce, and this make diseases affecting the brain particularly destructive (the good news is that neurons live a pretty long time, the bad news is that is really harmful to damage your neurons with drugs). This means that if you are a neuron you can’t reproduce, and that you cannot become a neuron once you are a specialised cell. Probably, this is because adding new neurons would mess up very specific connection in a very complex system, so until now we have to cope with a trade-off between the ability to repair our neurons, that would lead to possible healing from degenerative diseases like Alzheimer and Parkinson, and messing up already established connection.
Actually, this is not completely true: we got a small number of new neurons cells every ten years – making young people’s brain particularly challenged to adjust to new neurons. So, think about those new neurons cells when your 15 year old kid starts to smoke and stop clean up her room!

But: new neurons would make possible to heal from brain disease, which is now a day almost impossible, and is the very much ambitious goal of our project In-Brain lled by Malin Parmar, researcher at the Lund University: “normal” cells will be finally able to replace damaged neurons! The European Research Council is determined to winning this war with a European approach[1].

1. Agnete Kirkeby, Malin Parmar, Roger A Barker, Strategies for bringing stem cell-derived dopamine neurons to the clinic: A European approach (STEM-PD)

IN VIVO REPROGRAMMING: A NOVEL ROUTE TO BRAIN REPAIR by Malin Parmar (Lund University)

Jojo badly desires to become a neuron, but it's not studying or working hard that he will succeed!

To explain this to him, the Hormonal Resources Manager describes to Jojo the "fundamental dogma of biology".

The fundamental dogma of biology (sometimes “central dogma” or “Crick’s dogma” who coined the term) states that genetic information flows from DNA to RNA to protein. Then as a final step DNA is (in theory) replicated faithfully, because, as a Nature paper[1] stated in 1970, such information cannot be transferred back once arrived to protein.

Here’s an analogy[2]: you want to learn how to make a dress, but nobody among your acquaintances knows how to do that. You don’t have internet access, but you have some fabric and a library. What do you do? You go to the library, find a book containing instructions about making a dress, and you write down the instructions on a notebook. At home you grab your fabric (= amino acids, used to build proteins), follow the instructions (= a gene) noted on the notebook (= the RNA) and make a dress (= the protein product).

So, the “children” of a cell are a copy of the cell… except for the totipotent cells that the Manager will describe you if you read the second chapter of “A Cell’s Life”!

1. Crick, F (August 1970). "Central dogma of molecular biology." (PDF). Nature. 227 (5258): 561–3. Bibcode:1970Natur.227..561C. PMID 4913914. doi:10.1038/227561a0.
2. The analogy is inspired by a course on www.study.com

IN VIVO REPROGRAMMING: A NOVEL ROUTE TO BRAIN REPAIR by Malin Parmar (Lund University)

Until recently, once a cell became specialised, its fate was sealed: the cell was unable to become any other cell type. For example, just like Jojo, once a skin cell, always a skin cell.

However, in 2006, scientists succeeded to reverse this process. They turned a specialised cell back into a stem cell: a cell which is not specialised yet and has the potential to become any type of cell in the body.

Malin Parmar, the leading researcher of the ERC project InBrain (In Vivo Reprogramming: a Novel Route to Brain Repair) is bringing this research even further forward: she is directly reprogramming cells into functional neurons, without passing by the stem-cell phase…