By Dona Suri
Mysterious ‘inscriptions’ ? … Yes! But first, a quick review of the basics of diabetes:
Nearly 500 million people all over the world suffer from diabetes. It is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation. According to the World Health Organisation, the annual deathtoll from diabetes comes to 1.5 million and most of these deaths are reported from low- and middle-income countries. Those who survive with diabetes are alive because they take medication or insulin shots every day. Both the number of cases and the prevalence of diabetes have been steadily increasing over the past few decades.
The problem of diabetes is the problem of insulin and the problem of insulin is the problem of the insulin secreting beta (β) cells. Get enough properly functioning βcells on the job and diabetes is gone.
Suppose a way could be found to generate β cells, or to “wake them up” if they stopped functioning?
That idea has been glimmering in the minds of medical researchers since the early 20th century when Nobel Prizes went to discoveries of β cells and their function. The search for ways to achieve that goal has driven research and advances in medical technology for a hundred years. The great leap forward came with advances in three areas:
Genetics: the discovery of stem cells and ways to modify them
Molecular biochemistry and
Medical technology: devices that enable researchers to see and measure.
Two epigeneticists* at the Baker Heart and Diabetes Institute, Melbourne, are on the 21st century frontier of β cell research
* Epigenetics is the study of how behaviors and environment can cause changes that affect the way genes work. Unlike genetic changes, epigenetic changes are reversible and do not change DNA sequence, but they can change how the body reads a DNA sequence.
One of them started out in Iran and one started out in Iraq, but it is in Australia that their genius has bloomed. If the Land of Oz has adopted them, so have they adopted Oz. To find Dr Ghaith Al-Hasani, you will have to ask for Dr Keith Al-Hasani. Similarly, Dr Assam El-Osta is known as Dr Sam El-Osta.
Their academic careers have taken many twists and turns but ultimately converged in the epigenetics lab at the Baker Institute. When it comes to βcells and all the processes surrounding them, nobody knows more than these two.
Common knowledge: The body repairs itself slowly and sometimes not at all. When β cells are disabled/destroyed, that’s it. The more β cells we lose, the less insulin we have. When insulin vanishes completely, we’re dead.
What stands in the way of regeneration? That question brought Al-Hasani and El-Osta together. Thanks to these two researchers, here’s what we know now:
After birth, the genes involved in development are switched off which means that, except for the ever-renewing liver, the body has limited capacity to regenerate new cells. The blocker is DNA methylation.
Methane is one carbon atom bonded to four hydrogen atoms (CH4). Methyl is derived from methane; it loses one hydrogen atom to become CH3. Methylation is the name for a process in which a small methyl group molecule gets added to DNA.
A tiny methyl molecule silences genes of progenitor cells (early descendants of stem cells).The gene just switches off. It hibernates. Get rid of the methyl molecule and the gene switches on again; the progenitor cells can be awakened. If the gene has the instructions for β cells, this means functional β cells can be generated.
That’s an explanation in seven sentences. A complete, scientifically acceptable, explanation takes pages and pages of dense, difficult, minutely detailed description with charts and diagrams.
Knowing why genes “hibernate” is Step 1. Figuring out how to wake them up again is Step 2. Al-Hasani and El-Osta have made huge progress in this direction too,
For 14 years Dr Al-Hasani has been working on stem cells and how they can be reprogrammed to perform the function of other cells in the body.
The breakthingrough when he was researching gamma-aminobutyric acid (GABA) and its astounding effect on pancreatic cells. (Results published in 2017). Before Al-Hasani’s study, GABA was known as a non-protein amino acid neurotransmitter, a chemical messenger that blocked specific signals in the central nervous system. It was an anti-stress mechanism because it slowed and calmed the brain.
Al-Hasani figured out that GABA could do something else too. Long-term GABA administration made pancreatic α cells less sensitive to the Arx gene, with the result that the α cells morphed to resemble β cells. These newly formed cells could secrete insulin.
Here was the means to achieve a long-sought goal: the generation of β cells, and that too in quantities sufficient to pump out enough insulin to bring blood sugar to normal level. Restoring functioning β cell numbers would transform the lives of diabetics.
Three years later, in 2021, Al-Hasani and his colleage, Ishant Khurana, were analyzing the intricacies of DNA methylation in terms of β-cells. This is where the work of Dr El-Osta and Dr Al-Hasani flowed together. Methylation is the focus of Dr El-Osta’s research.
El-Osta goes at the problem from a different angle. He’s interested in exactly how epigenetic changes hardwire specific genes. He found that methylation is central to a phenomenon called “metabolic memory”. His research links DNA methylation with diabetic kidney disease, and histone methylation with diabetic cardiovascular disease. The good news is that metabolic memory can be countered by detecting diabetes at the very outset and bringing it under control immediately. His study of a prototype drug that could erase histone methylation by affecting the action of SET7 resulted in a huge advance in understanding this process.
SET7 is a KMT* that methylates specific lysine residues of the histone and nonhistone proteins. KMTs catalyze the transfer of one to three methyl groups from S-adenosylmethionine (SAM) to specific lysine residues on histones.
*KMT:
K stands for lysine, an amino acid essential for warm-blooded animals; obtained from food because the body can’t make it. Many common proteins release lysine when water molecules break their chemical bond and join with the resulting molecular fragments.
M stands for methylation: a methyl group molecule gets added to DNA
T stands for transferase: an enzyme that adds phosphate groups (PO43−) to other molecules.
Al-Hasani and El-Osta teamed up and turned their attention to two newly developed epigenetic drugs: Tazemetostat and GSK126.
In January 2020, America’s Food and Drug Administration approved Tazemetostat. It treats certain forms of cancer and is described as an epigenetic regulator that inhibits EZH2
EZH2 stands for Enhancer of Zeste Homolog 2,
Homologue: something that matches something else in terms of position, structure, value, or purpose.
Zeste is a DNA binding protein; it activates genes by binding to regulatory regions and forming multi-protein complexes.
2: EZH2 is the second version of a substance that heightens the action of a protein that is the same as the zeste protein.
EZH2 prevents the expression of key anti-metastatic genes in cancer stem cells.
Tazemetostat is an inhibitor, so that means that Tazemetostat thwarts the action of EZH2.
All together, the meaning is that Tazemetostat doesn’t allow a cancerous tumour to spread.
The other drug was GSK126. (GSK stands for Glaxo Smith Kline, the manufacturer.) It’s another epigenetic drug that acts on EZH2. It inhibits cell migration and growth of blood vessels in solid tumors by shutting off the VEGF-A gene.
El-Osta, Al-Hasani and their other team members wanted to find out what effect the two small molecule inhibitors (Tazemetostat and GSK 126) would have on non-functional or newly made β cells. Exactly how did these small molecule inhibitors go to work on the DNA-organising proteins called histones?
If the EZH2 was not inhibited but given free rein, what happened to histone bivalency? Was it suppressed?
Did Tazemetostat remove the methyl group molecules from the gene? Did GSK126 have the same effect?
It turned out that both the new epigenetic drugs successfully stimulated β cells and the effect was clear in just 48 hours. The β cells started responding to glucose and they started producing insulin
Three individuals got to play a stellar role in this research after they were dead: a child, newly diagnosed with Type 1 diabetes, an adult Type 1 diabetes patient and a non-diabetic adult. Their pancreatic tissues — specifically, the exocrine duct cells — were used to observe and measure the effects of Tazemetostat and GSK126.
Here’s what they found:
When the exocrine cells were stimulated by either of the new drugs, the cells changed into cells with β characteristics which reacted to glucose and produced insulin. The ex vivo exocrine cells became capable of expressing insulin. The cells were “re-programmed”.
The researchers observed that when the genes were switched off through histone methylation, it was not an irreversible event. What prevented it from being irreversible was a condition called histone bivalency. In over-simple terms, this means that in the case of development-related genes, two functionally opposite histone marks exist at the same time in more or less same place.
[Here is a fuller explanation: https://genesdev.cshlp.org/content/27/12/1318]
Bottom line: The researchers saw that targeting EZH2 is fundamental to β-cell regeneration. Their conclusion: Reprogrammed pancreatic ductal cells exhibit insulin production and secretion in response to a physiological glucose challenge ex vivo.
To paraphrase the Baker Institute press release:
This novel therapeutic approach
Holds the potential to become the first disease modifying treatment for Type 1 diabetes.
It does so by harnessing the patient’s remaining pancreatic cells and facilitating glucose responsive insulin production.
This treatment can enable people living with diabetes to potentially achieve independence from round-the-clock insulin injections
This treatment could cure people with Type 2 diabetes
This treatment addresses the stark reality of donor organ shortages. Until now pancreas transplant was the only means to restore pancreas function.
Of course, the findings of Drs El-Osta and Al-Hasani don’t mean that endrocrinologists are going to be writing prescriptions for Tazemetostat and GSK 126 tomorrow. Much work remains to be done before patients can actually get treatment based on these new epigenetic drugs.