The Story of Our Science
Part of Our "Essays" Series
Getting from point A to our current status took about a decade and a half, several different countries in a couple of continents, and a large number of scientists. You'd think the effort would seem fragmented and, perhaps, even unfocussed, but the "red line" has been so red throughout the years that telling the story sounds like reading from a pre-prepared script.
It's what happens when your eyes are constantly focused on the same goal. And this is not one of those, "hindsight is 20/20" cases.
The First Head-Scratching Observation
Let’s define a stem cell. Please note the word ‘define’. It is the scientific community, not nature, that sets definitions. We define as stem cells those cells that can both produce more of their own kind, through division (‘self-renewal’) and, when conditions are right, mature into cell types that have specific functions in the tissue they reside (‘differentiation’).
Many cells can self-renew. Examples are cells called astrocytes. They are located in the brain and have functions in helping other cells in the brain, such as neurons, to function properly. But these are not stem cells because an astrocyte divides to generate additional astrocytes but will not change into any other kind of cell.
Other cells cannot self-renew. Neurons, for example, cannot divide, so they cannot generate other neurons. So, they are not stem cells. If you think about it, because neurons have such complicated shapes and oftentimes are really long, it would be extremely difficult for them to be able to divide (How do you split in half a cell that is centimeters long and with all sorts of complicated appendages and processes, and it already performing important functions connecting brain areas that must be constantly maintained for the organism to operate properly?).
Enter the stem cells. These are found in embryos, developing tissues, and in the adult tissues. Most probably, all adult tissues have a stem cell population. The ones in the brain have been extensively studied. And we know they can solve a big problem: Since neurons cannot generate new neurons, they can do it for us. But to be able to do so, they need two properties (the ones we described above): First, they need to divide (self-renewal) in order to give rise to more stem cells, avoiding their depletion, and then they must be able to change their fate and ‘differentiate’ into neurons. Stem cells can divide quite easily; after all, they are pretty small (no need for them to be big). They can also, depending on conditions, differentiate into astrocytes (although astrocytes can give rise to other astrocytes themselves, so we don't fully understand how important this ability is). They can also differentiate into the third main category of cells in the brain, oligodendrocytes (These wrap around neurons, insulating them and helping them propagate electrical signals efficiently, while at the same time protecting them from different insults).
Well, then, we have discovered the role of stem cells in adult tissues! It is to be a source of new cells and especially those that have difficulties in dividing.
Not so fast. Says who? Couldn’t they have additional roles, maybe really, really important roles outside the obvious one? Indeed, research has shown that stem cells residing in the adult brain are able to protect neurons in trouble and rescue them from certain death. Stem cells respond to tissue state as they receive signals from the bloodstream, cells of the blood vessels, immune system cells, and other cells of the nervous tissue and, accordingly, respond by producing their own signals that affect the survival and function of neurons and other cells. It makes sense, too, if you think about it and if you consider our evolutionary history:
Lower animals like some salamanders and fish exhibit amazing regenerative abilities, completely beyond what we (mammals, in general) can hope for. In these lower animals that represent earlier evolutionary states, stem cells in adult tissues are extremely good at producing new replacement cells. It is evidently a good deal for these – relatively – simple animals. Imagine a salamander getting bit on the head, escaping its predator, and hiding under a rock. Say it just had a nice meal. Its slow metabolism allows it to stay under that rock for many days, even weeks, possibly, waiting for its brain to regenerate. Done!
Now, imagine an early human getting bit on the head by a sabertooth cat. And, imagine, he survives and runs to his cave. His fast metabolism means that even if he had just eaten a meal, within a day or two, he needs to be back out and searching for new food and water. It is quite possible that as our more immediate ancestors developed a fast metabolism, the advantage of high-level regeneration became less relevant and it eventually got weeded out. That resulted in a more rigid brain.
That sounds bad but it’s not all bad: A rigid brain allows the long-term storage of information and this enables the process of learning. So that’s the turn we took. And it may be a one-way turn because, as you may imagine, once your survival is intricately connected to your ability to learn (your ‘smarts’), then too much regenerative ability may not give you much of a survival advantage. What if, miraculously, the sabretooth victim managed to regenerate his badly damaged brain? Great, now he lives! But he doesn’t remember any more how to carve a wheel, make clothes, hunt, start a fire, and he is dead anyway.
All the salamander needs to know is genetically encoded in its neural circuitry that is re-established after regeneration. That is called instinct. It is amazing that genetics provide this but it is also limited: It can tell you what smells good, what may take care of your urges, what may make you feel safe if you crawl under it. But it cannot encode much more, nothing like the complex techniques your tribespeople taught you, nothing you learned during your University classes.
Alas, that’s the path we took, for better or for worse. Our stem cells may have started gradually losing their super-regenerative powers over the eons. But it is very difficult for Biology to wipe a cell out. It is much easier for a cell to adopt new roles, bit-by-bit, until it can finally be distinguished from its great fore-parents. Today, our adult brain stem cells are so-so at producing new neurons. There are two small brain areas where conditions seem just right for them to do it quite efficiently. But, otherwise, not so much. They seem to be able to help other cells survive; we are still investigating this but early data are very strong. We should really understand this better and coax them to do much more of it. And, we must keep an open mind so that when we stumble upon their next trick we don’t miss it, even if we haven’t thought of it.
And now, for the hard part. The mechanics of the cell. All these signals that we mentioned above are sensed by cells and then they start an extraordinarily complicated series of changes inside the cell that result in the activation of proteins and genes, which, subsequently, result in all sorts of decisions: divide, stop dividing, divide faster/slower, die, release your own signals, differentiate into any of many cell types, etc.
If you want to find a new drug you need to (a) have a concept as to what precise part of this intimidatingly complex machinery you want to tweak, and then (b) find a way to do so. Let us say this is not easy, we obsess with this on a daily basis, and leave it at that, for now, for this pop-science account. But, as promised, let’s put down the rationale.
We need to find stem cell – specific drugs. In that way, the drugs will affect stem cells but will not inadvertently affect other cells, thus avoiding unwanted (and highly unpredictable) side-effects. This is simple to understand. It is also important to understand that perfection does not exist in Biology, so good enough will have to do.
The simplistic way to go about finding such drugs is to assume that stem cells, being somewhat different than other cells, and being the only cells able to self-renew and differentiate (by definition), have an extra ‘toolbox’ they use – maybe some extra genes or extra proteins. So, we should identify them and drug them!
But that is not the case. They have the same genes and proteins that other cells also have. So how can they be special and yet have the same tools as anybody else?
A Parable (We hope you like dogs)
Since we are sticking with the logic and leaving the nitty gritty molecular details a bit out of the argument, for now, let’s summon Stripe and Dot for some help. Stripe and Dot are two very likeable dogs that have been raised together. They both know the exact same ten commands [For example, one of them is “fetch”, by which they fetch whatever is closest to them and another is “come on”, etc.]. Beyond these ten commands, they don’t know any others.
Stripe knows these ten commands really well and as such, he knows how to perform ten tasks (one task per command). His owner is able to demonstrate these to his friends, amusing everyone who watches.
Dot also knows these ten commands really well. But, somehow, she and her owner can demonstrate fifteen tasks! How does she do this?
Her owner (and demonstration partner) knows the answer.
“She interprets the commands differently. She is better at sensing nuance and she has her own way of interpreting the commands, leading to different responses. For example, whereas ‘fetch’ to her is just that, like with Stripe, ‘come on’ is much more nuanced. Depending on my tone of voice, it may mean, ‘move and follow me’, in which case she follows me, or it may mean ‘oh my, that is great!’, in which case she jumps around in joy and then sits on all fours waiting for a pat on the head’.
So, without knowing more commands, without being given different commands, Dot is better at distinguishing minor differences in the presentation of these commands than Stripe, allowing her to perform more tasks.
Stem cells are a bit like that: Some signals make non-stem cells divide. The more you give, the more they divide. This may be similar with a stem cell. But if you give too much, instead of dividing even more, the signal now starts activating completely different molecules that activate its differentiation. In this way, without extra signals and without extra molecules within the cell, a stem cell can regulate both its self-renewal and ability to differentiate.
It is not a simple task to introduce this line of thought into Biological research. But when you do, you are faced with an entirely new world of opportunities, and we are elbows-deep in this, identifying new potential therapeutic targets and then drugs (and other types of manipulations such as interfering with genetic material that encodes these targets) to manipulate them.
So, then, are Stem Cells that Special?
Yes and no.
Yes because of everything we laid out so far. Stem cells can do special things and although they use the same ‘language’ as all other cells, they do have their own ‘dialect’ that makes them interpret signals very differently.
No because we see that other cells also use this ‘dialect’ and some of these cells are not really stem cells. They are just cells that, like stem cells, can make really big decisions, even if these don’t qualify as stem cells. Insulin-producing cells of the pancreas, for example, use this dialect. They can take big decisions because, if conditions require (for example, if one eats too much for too long and gains a lot of weight), they can divide much more to meet the new insulin requirements. But they don’t seem to differentiate into other cell types, so we cannot call them stem cells. But they are ‘plastic’ (i.e., they can undergo some really impressive changes), so they appear to have use for that dialect as well.
There will be many more dialects to discover and learn and utilize. It remains to be seen if these will make stem cells stand out even more or less from other types of cell. That may not matter so much at all. What matters is to work out all the dialects and use them to communicate what we need to a multitude of cell types with specificity at the same time.
It is a bit as if you have a stadium that you need to evacuate, full of people speaking different dialects and you use the different dialects to convey different messages to different groups of people, orchestrating the perfect evacuation (fast, effective, and no one gets hurt).
[Below is the diagram of the STAT3-Ser/Hes3 Signaling Axis, a molecular pathway that we have elucidated and is a central focus in our lab. You can read more about it in the Wikipedia link by clicking on the diagram].