How to build a pancreas

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To cure type 1 diabetes we need to do 2 things. Firstly, since the patient has no more pancreatic beta cells to produce insulin we need to make new beta cells. This is what we are going to discuss here. Additionally, we will need to somehow get the immune system to stop attacking beta cells but this is a topic for another article.

How do we make pancreatic beta cells? The principle involves transcription factors and their regulation of the genes that make a beta cell a beta cell. Remember that genes encode proteins and the genetic code is transcribed into RNA which is then translated into protein. Proteins are the infrastructure of the cell. They are the machines that build things through directed chemical reactions (enzymes). They are the components of the vast information network that detects transfers, integrates, and ultimately acts on environmental information (receptors and signal transduction proteins). They give the cell its shape (cytoskeletal proteins), handle its waste (transporters), and do at least 100 other things.

Think about all the different cells in your body. Kidney cells are different from brain cells, which, in turn, are different from pancreatic beta cells etc. Now, all of these cells have exactly the same DNA. Keep in mind that the DNA encodes your genes and your genes are the blueprints for all of the proteins that are going to get made. Your pancreatic cells do pancreatic type stuff because of the proteins present in those cells. This means that the pancreatic beta cell somehow knows which blueprints to read (i.e. which genes to transcribe).

Genes, being long stretches of DNA, have parts that code for protein and other parts that serve to regulate when the gene will be transcribed. We call these regulatory parts of a gene the “promoter”. Ultimately, an enzyme called RNA polymerase has to physically sit down at the right spot on the DNA and start copying the DNA sequence into RNA. Before that can happen, a special landing pad needs to be constructed to guide the polymerase to the right spot. This is accomplished by a special class of proteins that have the ability to recognize and bind to a specific sequence of DNA in the promoter. These proteins are called transcription factors.

Going back to the pancreatic beta cell, all of the blueprints for making and operating a beta cell have promoter sequences that beta cell transcription factors will bind to, thus activating those genes. As you might imagine, some genes are needed in all cells and these will have somewhat more general promoters while other genes may be needed in some combination of specific tissues (say in the brain and in the pancreas) and these will have appropriate promoter sequences to make this happen.

Pancreatic beta cells are beta cells cells, in part, because of the collection of transcription factors found there. Think about what is unique about a beta cell. It makes and secretes insulin for one thing. This means it needs all of the genes turned on (including the insulin gene) to make insulin, package it into secretory vesicles, and construct docking sites on the cell membrane so that those vesicles can fuse and release their contents. In addition, it needs to somehow detect the need for insulin and respond with an appropriate amount of vesicular fusions. The things that it will need to detect are surprisingly many; including glucose levels as well as a variety of hormones that are secreted by the gut and by the nervous system. These hormones are secreted in anticipation of a need for changing the status quo. For example, you decide to eat lunch. Even before the food hits your stomach, the beta cells know due to hormone secretions and are busily preparing. So, all of these capabilities require a complement of genes. What would make a lot of sense is for many of these genes to have similar promoters such that they are transcribed as functional groups. Satisfyingly, this is the case. Promoter sequences allow genes to be organized into overlapping groups based on function. Indeed many proteins fit together to make larger machines (like the transcription complex) so it makes quite a bit of sense to have them transcribed together.

And yet…… this seems unsatisfying in a way because we have simply pushed back the big question one level. Where did those transcription factors come from? Of course, since they are proteins, they came from genes which encoded those proteins and, in turn, there must have been other transcription factors which activated the genes for those beta cell specific transcription factors to be made in some sort of proto-beta cell during development. How circular. It is beginning to smack of the chicken and egg problem. Now we have a special name for these sorts of transcription factors. We think of them as master regulatory switches. As we move backwards through development we move through a lineage of different transcription factor genes, each of which, turns on different groups of genes to build the embryo.

There is one final concept needed to complete the picture. The egg and many of the subsequent cells of the early embryo physically store RNA encoding transcription factors in different parts of the cell. When that cell divides, the two daughter cells will have different transcription factor RNAs and thus will each go in a separate developmental direction as those RNAs are translated into proteins and those different transcription factor proteins will promote the transcription of different genes. Thus do we get different tissues.

Now enters that contentious cell – the human embryonic stem cell. If we know what master switches to activate, we can guide the stem cell to become a pancreas. If the stem cell comes from your body, then the pancreas will be identical to your tissues and this will decrease the likelihood of immune attack. This is the fundamental concept. Introduce the right transcription factors and voila…a pancreas is made!

I am off climbing some mountain or other in a remote part of Canada and will return Feb 14 (weather permitting). This article was originally published on my Examiner.com page and I have republished it here for your reading pleasure.

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