Fertility Linked To The Packaging Of Sperm New research suggests that the packaging of human sperm using proteins called histones plays a bigger role in fertility than once thought. Professor of oncological sciences Bradley Cairns explains how sperm get their shape, and how that shape can affect embryonic development.
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Fertility Linked To The Packaging Of Sperm

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Fertility Linked To The Packaging Of Sperm

Fertility Linked To The Packaging Of Sperm

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From NPR News, this is TALK OF THE NATION SCIENCE FRIDAY. I'm Paul Raeburn. Up next, its Father's Day this summer, as well as the beginning of - this Sunday, as well as the beginning of summer. So what better time to consider what it takes to be a dad. And no, we don't mean changing diapers or reading books at bedtime. We're talking about something on a real micro-scale here - a molecular scale, actually.

For years, researchers studying infertility have known that you can tell a good sperm by its shape. Before a sperm sets out in search of an egg to fertilize, it packages its DNA as tightly as possible so it can swim fast and outrace its competitors. The fastest swimmer, after all, gets the DNA into the next generation if all goes well.

So new research suggests, however, that DNA packaging plays a much bigger role than scientists had thought. Tied up with all that packaging is information vital to the subsequent development of the fertilized egg.

Joining me now to explain this is one of the authors of the new research.

Bradley R. Cairns is an investigator at the Howard Hughes Medical Institute. He is also a professor in the Department of Oncological Sciences at the Huntsman Cancer Institute at the University of Utah School of Medicine. He joins us by phone from Salt Lake City. Thanks for talking with us today, Dr. Cairns.

Dr. BRADLEY CAIRNS (Investigator, Howard Hughes Medical Institute; Professor, Department of Ontological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine): It's great to be with you, Paul.

RAEBURN: If you have questions for Dr. Cairns, give us a call. Our number is 1-800-989-8255. That's 1-800-989-TALK. And if you want more information about what we're talking about this hour, go to our Web site at www.sciencefriday.com, where you will find links to our topics.

So the shape of the sperm, it turns out, Dr. Cairns, is very important in the job it has to do with the embryo. Tell us about what you found and why this was so surprising.

RAEBURN: Yeah, so basically we examined the packaging status of all the known genes in the genome in mature sperm from fertile men. And what we showed is that many of the genes that are important for the development of the human embryo, we call them developmental genes, are packaged in a special manner in the father's sperm, and this was neither known nor anticipated. And we think it has potential implications for developmental biology, for inheritance and as well for fertility, and they include the notion that the father may prepare his genome to help with embryo development all the way back in the sperm.

There's a possible program going on there for the future, preparing his genome for the future. And then also the idea of inheritance, that the embryo is going to inherit this special packaging on these genes, which we think might affect their expression in the embryo, helping to ensure that those genes come on at the right time and perhaps at the right strength.

And then there, as you mentioned in the opening piece, there are also clinical implications. Because you know about this new, special packaging that's inside the sperm, it raises the possibility that defects in this packaging, on these developmental genes, could lead either to infertility problems, inability to conceive or possibly developmental problems in the embryo.

RAEBURN: So let's break this down a bit now, take it step by step. The packaging inside the sperm, which compresses the DNA, is that the right term to use, compresses the DNA?

Dr. CAIRNS: Yes.

RAEBURN: The way that packaging is arranged sends some information to the embryo.

Dr. CAIRNS: Well, there are sort of - there are two packaging aspects that the sperm has to undergo. The first one is this condensation reaction that you were talking about, and what we know is that about 90, 95 percent of the genome is associated with this packaging protein called protamine. And it's special because it wraps the DNA very, very tightly and condenses the genome much more than it would be condensed in a normal cell.

And as you mentioned, this is very important for condensing the sperm head and making the sperm very fast because it's a race for fertilization. However, not the entire genome is packaged in this protamine molecule, this tight packager. They leave about five percent of the genome in another packaging protein called modified histones, and that is the special protein that is attached to these developmental genes.

RAEBURN: So the protamine replaces or gets rid of some of the histones.

Dr. CAIRNS: That's exactly right.

RAEBURN: And the histones that remain, which you said is only about five percent of the total, is - that's where the information lies.

Dr. CAIRNS: That's right. And those - we call them modified histones because they have these chemical tags on them, and those chemical tags are informative. They can influence whether that gene is activated or shut off. And we call these histone modifications, but you can sort of think of them as sort of red lights and green lights. And the modifications that have green lights are going to help those genes be activated, and those with red lights are going to delay or silence those genes in the embryo.

RAEBURN: Some genes you want on, and some you want off in the embryo to make things work right.

Dr. CAIRNS: That's exactly right.

RAEBURN: Now here's my - as I read the study and looked at this and thought about it a bit, here's my naive question. I can understand, I mean I get the idea that there's information encoded in these histones in the sperm, but my sense of when the sperm does fertilize the egg and that the chromosomes from the mother and father have to get arranged together to make a pair and start the process - you can correct me where I'm wrong here - but that that's sort of a, you know, a stormy event.

The sperm plunges in, and there has to be a lot of scrambling around, I would think. And how is that information preserved during that complicated process?

Dr. CAIRNS: Actually, you pointed out one of the major remaining questions that we have. So indeed, all of the protamine is stripped off of the male genome, and what we need to now - so we have evidence that this special packaging resides on these developmental genes. And the pattern of those modifications, those red and green lights, is highly suggestive that they are instructive in the early embryo, but we have not proven this. And the challenge is to be able to monitor those modified histones that comes from the father in the developing embryo.

Now, our work was all done in humans. And following up this work in humans is a real challenge because we would have to do that work in human embryos. And because of both technical and ethical challenges, we've elected to follow up on this work using a different model organism called the zebrafish. And there you can get literally tens of thousands of fertilized eggs to monitor this process. And although we haven't published this, we know that these same developmental genes are packaged in an almost identical manner in the mature sperm of zebrafish.

So it's in that organism that we're going to address the maintenance of those marks and also their impact on gene expression in the embryo.

RAEBURN: Who knew our cousins the zebrafish, in other words.

(Soundbite of laughter)

RAEBURN: It's interesting, actually, an interesting - I guess it's an evolutionary point that a species as different from us as zebrafish would share some of these important processes.

Let's take a question from Debbie(ph) in Denver. Debbie, you're on SCIENCE FRIDAY.

KATHY(ph): It's Kathy, actually, but I'll ask a question, anyway.

RAEBURN: I'm sorry Kathy, but you are in Denver.

KATHY: I just wondered if there's any practical fertility testing that has come out of this yet. I know now when they do semen analysis, they look at morphology and motility, but is this something you can (unintelligible) in a regular semen analysis, or is this not there yet?

Dr. CAIRNS: So that's a great question, Kathy. So we are definitely interested in extending this to fertility research. So what we would like to do is to develop a clinical diagnostic that can tell a healthy sperm packaging from defects in packaging. And then what we'll do is try to correlate defects in packaging with outcomes.

Now to do this, you actually need hundreds of patients. And you have to look at the sperm prospectively, at their packaging defects, and then connect that to outcomes data in terms of successful pregnancies. And the hope is that we'll be able to sort of do personalized fertility for men. And it turns out that actually the man is responsible for the fertility defect more often than people realize, and the hope is that then we can use that information to counsel couples on their odds at achieving a health pregnancy. And I think it'll be quite useful in the cases where you find the packaging is defective in almost every sperm, and then the couple might be counseled appropriately to consider other options. And knowing this up front might save the couple a lot of money and emotional and physical distress.

RAEBURN: Does that answer your question?

KATHY: Yeah, it does. And I just wondered, too, if you would be able then to choose like a particular sperm, and then would that only be useful with ICSI, or would it ever have anything wider beyond that?

RAEBURN: Tell us what ICSI is, as well.

KATHY: ICSI is when they basically, I don't know, drill the sperm into an egg…

(Soundbite of laughter)

Dr. CAIRNS: So I'll take that.

RAEBURN: Sounds awesome, yeah.

Dr. CAIRNS: ICSI is, it's an acronym for I-C-S-I for intracytoplasmic sperm injection. And what they do then, instead of allowing normal fertilization, they actually put the sperm into a needle, and they inject it into the egg. And the question is exactly right.

So what they're doing now is they're simply looking at sperm morphology, whether this transition from a round spermatid to a very tightly compacted, crescent spermatid has gone well. That test looks at the gross morphology but doesn't look at the second part of the packaging, whether those sperm have retained those important modified histones on those important developmental genes.

I think developing a test that will examine that individual sperm is a real challenge, but we are talking about how we might do that in order to select sperm that are packaged correctly.

RAEBURN: Thanks, Kathy.

KATHY: Thank you.

RAEBURN: So one of the questions that I had, looking at this as well, was all this talk about sperm and packaging, is there a similar thing going on in the egg? I guess the egg doesn't have to race anywhere, so it doesn't have to compress. But what's happening there?

Dr. CAIRNS: Well, I think - so that's an excellent question. And that is near the top of our list. And, again, we can't study this in human cells so we are going to rely on zebra fish again to look at this as our model organism.

I would speculate, actually, that the packaging is going to be similar both in the egg and in the sperm. And the reason is the parents have the same motivation, they want to make a healthy baby. They want everything to go perfectly. So they want to turn on all the important decision-making genes in the early embryo at the right time and the right strength.

So I would think the two would be in complete alignment. But it is an excellent untested question that we are definitely pursuing.

RAEBURN: There's a funny thing here, the sperm is packaging itself in order to beat its competitors to the egg.

Dr. CAIRNS: Yes.

RAEBURN: Except that all the competitors have the same genes. So why is it so essential - how did that happen? In other words, it doesn't matter. As long as one gets there, the father has contributed his genes to the embryo, right?

Dr. CAIRNS: Well, that's true. But the - you have to think about it on an evolutionary scale, right? So if you think back in evolution when people had multiple partners, which father would be most likely to have a successful conception. And each time you try for natural conception, there's a certain percentage odds that you're going to fertilize that egg. And if you have faster swimmers, then you have a better chance of getting the job done.

RAEBURN: Right. So I guess the process, in other words, is that the group, as a whole, of sperm that's released all have this kind of packaging and it is not important which one gets there. It's important that that individual sperm gets there…

Dr. CAIRNS: Yes.

RAEBURN: …from an evolutionary standpoint. Okay, I'll drop that before I get more confused than I want to get. So the - it's very interesting to me that this is very basic research, I think, if you're talking about molecules on DNA. Yet, it sort of has - as the caller pointed out - it has sort of immediate clinical implications. That's not always the case.

Dr. CAIRNS: That's definitely true. So I mean, I work on gene packaging and expression at the Huntsman Cancer Institute. And gene packaging and expression has overlap, great overlap with cancer biology. But we also recognize the opportunity to look at this question in other areas such as developmental biology and fertility. And we just feel fortunate to have arranged a collaboration with Doug Carrell's lab who runs the Utah In Vitro Fertilization Clinic here in Utah. And we have a joint graduate student, Sue Hammoud, who just did a great job on this project.

RAEBURN: Let me pause for a moment to say that I'm Paul Raeburn and this is TALK OF THE NATION from NPR News.

Now, you just raised another question for me. You work at a cancer center.

Dr. CAIRNS: Yes.

RAEBURN: And we're not really talking about cancer here.

(Soundbite of laughter)

RAEBURN: So what - did you lose your job? Is this the time you want to announce it, or take a wrong turn? What happened?

Dr. CAIRNS: No, absolutely not. So, that's a very good question. So I talked about this just briefly, but I'll tell you a little bit more about it. So cancer is a problem in cell growth and development. And the problem in cancer is that these cells will stop developing and grow out of control. And that defect is related to their over-expression of genes that control cell growth. And their under-expression of genes that restrict growth.

And what we and many others in the field of chromatin structure have found out over decades of research is that gene packaging plays a critical role in regulating those genes that control growth and development. So understanding the relationship between gene packaging and gene expression is important for understanding normal growth and development as well as cancer.

Basically, you have to know how a process normally happens to understand how to fix it when it's broken. And so, we're trying to find out the fundamental mechanisms that control gene regulation at the packaging level.

RAEBURN: So this happens in all kinds of, in all cells in the human body or most cells?

Dr. CAIRNS: Absolutely. Absolutely.

RAEBURN: In all cells. Now, this is - I don't know whether this speaks directly to in vitro fertilization, but there is an opportunity where clinicians have a chance to look at the sperm before it's selected and so forth. Is this something that could help improve the outlook for that process or is the outlook for that process fine as it is?

Dr. CAIRNS: Well, as I mentioned before in answer to Karen's question, we're hopeful that we'll be able to improve on sperm selection. That we will be able to tell a sperm that has proper packaging of these developmental genes, not just the correct morphology. And we are also developing some more sophisticated tests to analyze packaging because there are many cases where a patient will have apparently fine morphology but they won't be able to conceive. And there we think there might be problems at particular genes in their genome.

And we have these very sophisticated techniques now where we can look at packaging and other attributes of individual genes in the genome essentially by looking at all genome - all genes in the genome at the same time. So, the technology has really come a tremendous way and we're taking advantage of it to look at these problems.

RAEBURN: Well, thanks so much for taking the time to be with us. I'd like to thank Bradley R. Cairns, an investigator at the Howard Hughes Medical Institute. He's also a professor in the Department of Oncological Sciences at the Huntsman Cancer Institute, where I'm relieved to know he belongs, even though he also works on fertility.

(Soundbite of laughter)

RAEBURN: And he's at the University of Utah School of Medicine. Thanks for talking with us today.

Dr. CAIRNS: It's been a real pleasure, Paul. Thank you.

(Soundbite of music)

RAEBURN: We'll be right back after this short break.

This is TALK OF THE NATION from NPR News.

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