The Young Sperm, Poised for GreatnessMay 22, 2014
In the body, a skin cell will always be skin, and a heart cell will always be heart. But the first hours of life, cells in the nascent embryo are totipotent: they have the incredible flexibility to mature into skin, heart, gut, or any type of cell. New research by University of Utah professor of oncology, Brad Cairns, Ph.D., provides surprising insights into how, and when, cells acquire this magical ability. His work was published on May 15 in the journal, Cell Stem Cell. Dr. Cairns explains his findings and their implications in understanding mechanisms that drive cancer, and the beginnings of life.
Recording: Examining the latest research and telling you about the latest news, the science and research show is on The Scope.
Interviewer: In the first hours of life cells in the embryo have the incredible flexibility to become skin, gut, heart, or any type of cell in the body. New research by my guest, Dr. Brad Cairns, provides new insights into how and when cells acquire this ability. His work has implications for understanding cancer, fertility, and the beginnings of life.
Dr. Cairns, you research adult germ line stem cells. Can you explain why they are interesting to study?
Dr. Brad Cairns: So they share with other stem cells the ability to become sort of any type of cell in principle, but these are special cells in that in practice they only become sperm. Okay? So they're called unipone [SP], they become one thing.
When most people usually think about stem cells they think that they can become many, many different types of cells. So blood stem cells can become many different types of blood cells. Embryonic stem cells can become many types of tissues.
These germ line stem cells can only become one type of cell which is sperm. However, one of the interesting insights that we've had is that they have sort of embedded in them the possibility to become very easily any type of cell.
And in fact, that fact is shown in the cancer biology of these cells. So normally they only make sperm, but when signaling within them or their genome goes awry, they can become essentially any type of cell. They can form what are called teratomas which are special types of tumors which come from what are called all three germ layers and they're the only type of cell that can become really any type of germ layer, and any type of tissue once it goes towards cancer.
So our work is trying to understand how that cell can have embedded within it the ability to become any type of cell, but normally stick only to the course of making one cell type and that is sperm.
Interviewer: Why is that interesting to know?
Dr. Brad Cairns: After fertilization one cell has to make all cells and that's a fundamentally interesting question, right, that literally thousands of labs across the world work on. Right? So we're not solving that question by ourselves. Right? But I think we're adding an important set of information to that which is how much of that ability to make every type of cell has to be established at the time of fertilization versus already being pre-programmed into the two cells that are coming to it, the sperm and egg.
And that has been the subject of a lot of debate in the past and it's been very hard to address it, but modern molecular biology and genomics has allowed us to begin to answer that question, and we think we've made a lot of progress to that.
The previous view was that probably those changes that occurred after fertilization were probably the dominant set of manipulations of the genome that needed to happen for totipotency. And our results are strongly supporting the idea that a very large amount of the ability to become any type of cell is actually established in the gametes, in the sperm and egg before fertilization even happens.
Interviewer: Much of what you're looking at in this study is whether genes and these cell types are accessible or not. So can you first talk about the biology of this and what exactly you're looking at?
Dr. Brad Cairns: It turns out that whether a gene is turned on or not depends first on whether it is what's called transcribed or made from DNA into RNA. And for that, there's an enzyme called RNA polymerase that has to sit on that gene and make the DNA into RNA. But not all genes in the genome are actually accessible to RNA polymerase just coming and sitting on them.
It turns out that a lot of the genes in the genome are actually packaged or wrapped up in such a way that they're inaccessible to that transcription [inaudible 00:04:13] machinery, that RNA polymerase.
And one of the things that we found which I think is quite interesting is that there are a key set of genes in the adult germ line stem cell that are important for the cell to become any type of cell to have this totipotency potential for it. And actually those genes have this special type of packaging which is to keep the gene open per se, so it's poised essentially.
So it is packaged, but it's sort of hair triggered. RNA polymerase can't come in right now, but if it just flipped a little switch, RNA polymerase could come into all of those genes and allow that cell to become any type of cell to be totipotent.
Interviewer: To be very simplistic in an analogy, maybe one way to think of it is that the DNA are words in a book and there are different tags on the DNA that can either say that the book is closed, and so then you can't read those words, or the book is open and you're saying there is actually an in between state where the book is half way open.
Dr. Brad Cairns: Yeah, I think that's one way to put it. Yeah, the book is half way open. And then if you just push it a little bit more, the light would fall and you could read it. So that comes, I think, with . . . You see that in systems where you don't really have the time to, let's say, find all of the pages that you need to open and open them.
So the cell basically puts bookmarks at all of the important places where it knows it needs to open and it opens them partially so that if you had to read those 12 particular passages, you didn't have to find them. And actually when fertilization occurs, you can go through very, very rapid divisions and those cells have to become totipotent very quickly.
So I think it's an engineering principle where because it has to be done rapidly and it has to be done accurately, you don't leave it either up to chance or up to the large amounts of labor you would need to use after fertilization. You basically bookmark everything, open it up halfway, and then when the sperm and egg come together you sort of just complete the job that you had already started.
Interviewer: Where are these bookmarks? What are the important things that the cell needs to bookmark?
Dr. Brad Cairns: So there are a set of key factors and what they're called is transcription factors. They're a set of about four to six of them. And what they do is they essentially place bookmarks, so they're important to identifying basically all of the pages in the book that are sort of the recipe creators for this totipotency, this ability to become any type of cell.
Among those factors are also signaling factors and they are receptors, and ligands, and other types of molecules that are needed for these cells to have a conversation with each other as well during the developmental process.
Interviewer: And what fascinates you about this work?
Dr. Brad Cairns: Everything I've told you about, I think, the thing I like the most is the embedding of totipotency. What is the engineering of becoming any type of cell? I think the key is to find that cell that can become anything and study it. And for, I think, both technical and ethical reasons, we can't work on fertilized human eggs. Right?
Dr. Brad Cairns: So you have to have a surrogate that is technically feasible and ethically available for you to do that kind of research. Right? And if we've found that totipotency is actually embedded into the germ line stem cell and we can figure out how to culture it in a way that can maintain that totipotency, then I think we can go very deep in understanding what is the molecular wiring diagram and conversation that needs to go on to keep it totipotent. And then what are the risks and liabilities to a deviation from that in terms of cancer cell biology?
Recording: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences Radio.