Innate Repair - The Story
Complicated things make more sense in context. Let us explain, then, here, how and why we have been developing our concepts, from nitty-gritty molecular observations all the way to stopping disease progression in models of disease.
The Early Years at the NIH
If you study the "insides" of a cell you will find an enormously complex circuit of molecules and chemical reactions between those molecules and genes that are regulated as a result. We call this "signal transduction" and when you draw it out on paper, you would be forgiven to think it is a complex electrical circuitry.
Back in the early 2000s, it was widely understood that a particular molecule called STAT3 was really important to the vast majority of cells within the body. Without it they died. So, it was widely studied. Questions addressed included:
What regulates its activity?
Is it over-active in cancer?
Research performed on this molecule had provided important information:
This molecule was particularly active when a precise chemical modification (induced by various components of the signal transduction circuity of a cell) occurred on a particular component of this molecule.
STAT3 is a protein and proteins are made up of amino acids. In the case of STAT3, the chemical modification was the phosphorylation (i.e., the addition of a phosphate onto a particular amino acid: the tyrosine amino acid at position 705).
[Amino acid numbering is for the mouse version of STAT3. The human STAT3 is a bit different].
At that time, a lot of scientists were studying STAT3 in neural stem cells. These cells were really interesting as they were capable of dividing and generating new neurons, giving new hope in our quest to fight neurodegenerative disease.
That research demonstrated that in neural stem cells, STAT3 phosphorylation on the tyrosine forced them to differentiate into a particular mature cell type of the brain we call a glial cell. By doing so, neural stem cells stopped being neural stem cells.
While working at the National Institutes of Health (NIH) in the lab of Ron McKay, we realized the repercussions of these observations: Neural stem cells, unlike most cells in the body, don't use STAT3 for survival.
Actually, there was an alternative possibility: Just like STAT3 can be phosphorylated on the tyrosine amino acid at position 705, it can also be phosphorylated on the serine amino acid at position 727. But, few people studied the serine amino acid because many experiments (using common experimental cell types but not neural stem cells) showed that phosphorylation of the serine amino acid was not important.
Thus, our hypothesis became as such:
Either neural stem cells just don't care about STAT3 in general, or,
Neural stem cells, unlike most other cells, don't use the tyrosine amino acid for survival (as they use it for differentiation), but they use the serine amino acid for survival, instead.
We went on to prove it, showing that neural stem cells follow their own rules for survival. We posited that this is necessary as they need to allocate some of the signal transduction circuitry to their survival, and some to their differentiation. Therefore, they are a bit more complicated and nuanced.
Once we had this basic understanding, we were to identify many other components of the signal transduction machinery of the cell that regulated serine phosphorylation and not tyrosine phosphorylation. In this way, we elucidated a fairly complex molecular mechanism that was particularly important to neural stem cells.
Having such detailed understanding allowed us to come up with treatments that we could test in vivo. We proceeded to show that, just like in vitro, these treatments were able to increase the number of neural stem cells in the brain.
We now had a tremendous tool with which to ask an important fundamental question at the heart of regenerative medicine: What happens to the diseased brain when we increase the number of neural stem cells? Using models of ischemic stroke and Parkinson's disease, we demonstrated that these treatments greatly opposed the progression of disease, providing a blueprint that, in principle, could lead to new-generation therapies.
Our work also suggested that the improvements were not due to the generation of new neurons but by opposing the death of neurons that would normally die in these disorders.
We were keeping the bath tub full not so much by "turning the faucet on" but primarily by "capping the drain".
How About Cancer?
This all took several years to work out. By that time, it was understood that tumors contain a cell population that shares many characteristics with normal stem cells from the same tissue. Only that tumors grow uncontrollably.
Career moves found us in Dresden, Germany, where we asked if cancer stem cells also used this particular signal transduction circuitry. The answer was a big Yes, providing new opportunities for fighting this disease.
But cancer is sly, and we understood that many cancer cells exhibit extraordinary molecular flexibility. They can grow utilizing more "traditional" circuitry, or our newly found one. There are ways to block the first one - shouldn't we look for ways to block the new one, in manners consistent with clinical implementation?
Beyond the Brain
How widely used is this new circuitry? How about we look outside the normal or cancerous brain?
By some accounts, one of the closest tissues to the brain in the body is the adrenal medulla (that's where adrenaline is made), because they arise from common ancestral cells. We saw many similarities.
We started realizing that, perhaps, this new circuitry was not confined to a particular tissue of organ, but to "plastic" cells across many different tissues and organs. "Plastic" cells are those that can make particularly big decisions, for example, to divide or not, to differentiate or not.
Stem cells are plastic cells but there are others, too. An intriguing one is the pancreatic islet cells. These cells make insulin and when they die or malfunction, you have diabetes. They are plastic because when you gain weight and need more insulin, these cells are able to divide, thus increasing their number and producing more insulin. In certain paradigms of damage, they can divide and differentiate to help you regenerate. In many respects, they behave like stem cells.
So we looked and we spent a lot of time studying them and we discovered that they, too use this circuitry.
Where Next? ALS and GBM
Fifteen years or so into this line of research, we have identified a new molecular machinery that is key in neurodegenerative disease, cancer, and diabetes. We have validated our findings in multiple models of disease. Colleagues in the US, Canada, Europe, and Japan have confirmed the main tenets of our work.
Where to, now? How do we get these findings to the clinic and see patients benefit? We are focusing on three avenues:
1. Neurodegenerative disease. The novel circuitry is involved in the general protection of the brain. It is validated in ischemic stroke and Parkinson's disease and, more recently, in multiple sclerosis. To implement highly novel (and thus, risky) work to the patient, it is common to begin with patients suffering from particularly devastating neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS). Therefore, we seek partnerships to do so.
2. Cancer. Work from our lab and colleagues has shown the relevance of this new circuitry to different types of tumors. We are farther ahead, however, in aggressive brain tumors such as glioblastoma multiforme (GBM) where we have performed extensive characterizations of this circuitry. We seek partnerships to direct this work to the patient.
3. Diabetes. Our published and unpublished work demonstrated the importance of this circuitry to both type 1 and type 2 diabetes. This brings a completely new molecular and cellular concept in these diseases. We seek to work with experts in diabetes to extend this work.