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Dr. Mary Ann Handel

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Dr. Mary Ann Handel, Ph.D.

Finding the Genes That Drive Male Fertility

NICHD grantee Dr. Mary Ann Handel, a senior research scientist at The Jackson LaboratoryExternal Web Site Policy in Bar Harbor, Maine, says her work on the genetics of male infertility has taken place during one of the most exciting times ever in genetics. She hopes that her work can help solve the complex puzzle of how genes affect human fertility and infertility.

Watch Dr. Handel discuss her research.

A text alternative is available at

Select a link below to read Dr. Handel’s extended comments from an interview held in Maryland in early 2014:

Understanding the Fundamentals of Egg and Sperm
Tracing Infertility to Its Genetic Causes
Infertility in Mice and Men
Infertility's Complex Causes
The Flip Side of the Infertility Coin
Mapping the Future of Infertility Research

Understanding the Fundamentals of Egg and Sperm

Q: How do you describe your work to neighbors and friends?

Dr. Handel:External Web Site Policy When I’m talking to my friends and neighbors, I say I study how sperm cells get made. And most of them can identify with that. And I tell them I am particularly interested in the genes that control how the male germ cells get made.

And the other thing that really drives my passion—this came a little bit later in my career—but I am interested in how the sperm cell precursors undergo the specialized division process that gets the right number of chromosomes into every sperm, so that when a sperm unites with an egg, when they join up, we now have the proper number of chromosomes, one member of each chromosome pair from each parent. So I am interested in that process, determining what we call chromosome segregation.

Q: Most of our cells have 23 pairs of chromosomes, for a total of 46. But the germ cells—and the egg and sperm they produce—have only 23 chromosomes, one chromosome from each pair?

Yes. And if there are errors in the process of reduction from the 46 chromosomes to the 23 that go into the germ cells, then the egg or the sperm can either lack a chromosome or have an extra chromosome. One example of this in humans is Down syndrome, which results from having one too many of the chromosome number 21. So Down syndrome is sometimes called trisomy 21.

I’m studying the genetics of that: how the chromosomes get together in the cell. Actually, the first thing that happens is the like chromosomes come together as a pair, and then in the division process they separate from each other. There is something about putting them in a pair where they can recognize each other that then allows them to separate in a very structured and mannerly way during the division process that makes the egg and sperm cells.

I am particularly interested in how these chromosomes recognize each other and how they form a specialized attachment that is actually a DNA recombination event.

Tracing Infertility to Its Genetic Causes

Q: How did you become interested in the genetics of male infertility?

I started out at Johns Hopkins University. My husband took a teaching position at Kansas State University, so I finished at Hopkins and did my research at Kansas State. Then I did postdoctoral work in molecular biology. It was then that I got interested in reproduction and male reproduction in particular, because I was using sperm cells as an example of specialized cell differentiation.

This was the late 1960s, early 1970s, and all of us in that generation wanted to be socially relevant. I was interested in the potential for dealing with population problems. And, of course, the flip side of the contraception coin is infertility.

Q: What are the most common causes of male infertility?

Male infertility is very interesting in the human population, mostly because we know so little about it. Roughly 15% of couples are infertile, and roughly half of all infertility is due to male infertility. We have this common phrase, “idiopathic male infertility,” and it means the male is infertile but we don’t really know why. A sizable proportion of all male infertility is idiopathic. We presume that some of these reasons are genetic, but we can’t really pinpoint any specific genes.

Infertility in Mice and Men

Q: Why do you study mice when you are interested in human infertility?

I study male infertility in the laboratory mouse because we understand the genetics of the laboratory mouse very well. And the genetic pathways that lead to both health and disease in the laboratory mouse are very similar, if not identical, to the pathways that lead to the same healthy or diseased conditions in humans.
There is another issue that we really appreciate in humans as well as in mice, which is that fertility is what we call a “complex trait.” And that means that there are many genes that determine the outcome.

A common example of a complex human trait is cardiovascular disease. There are many different ways you can get to the endpoint of cardiovascular disease. Many of those ways involve mutations in any number of different genes. But diet plays a role, too.

Similarly, male infertility is a complex trait. There are many different genes that contribute to fertility, and maybe a mutation in one gene in that pathway won’t cause infertility, but if you have a mutation in two or three different genes, then acting together, they might cause infertility.

So this makes it a difficult and exciting intellectual challenge to get at the causes of infertility. And now that many more people are having their genome sequenced as part of the analysis of complex diseases like cancer or heart disease, we are going to find out more about the mutations in those genes that we know from the mouse contribute to male fertility.

Q: You can create mutations in mice to find out about the genes involved in infertility—could you talk more about that?

One of the most exciting research projects that I have been involved in in the past decade is a project at the Jackson Laboratory where we deliberately create mutations. We don’t know at the outset which mutations cause infertility, but we screen all of these animals for fertility by mating them, and the ones that are infertile, then, we go through complex genetic and molecular processes to identify the gene that has been mutated, and then we can tick off another gene that contributes to fertility in both males and females. My primary job is to study the male infertility.

In our mutagenesis program, we determine animals that are infertile in much the same way that people discover they are infertile. And that is, we mate the animals, and if they don’t produce any offspring, then we bring these animals to what we call our mouse infertility clinics. And we do a lot of the same analyses on these infertile mice that humans have when they go to an infertility clinic.

So, for instance, when males go to an infertility clinic, they find out if their sperm count is normal. Do their sperm look normal? Do their sperm have normal motility?

Infertility’s Complex Causes

Q: What have you found from the mutagenesis program?

So in our program, we’ve done random mutagenesis, and interestingly enough, we find we get many more “hits,” or genes that cause infertility, in males than in females. So roughly 75% to 80% of our mutations cause male infertility only. About 16% cause male and female infertility. And the remaining, which is less than 10%, cause female infertility only.

We don’t really know why this is, but it could be because there is more built-in redundancy in the female reproductive system, in the genetic pathways that are involved. And so we infer that in humans, there are genes that affect only male fertility and genes that affect only female infertility. But some genes—the ones that we have discovered affect chromosome behavior—will affect both male and female fertility.

The Flip Side of the Infertility Coin

Q: It is very complex. There could be almost as many causes as people, yes?

Right, I don’t think there is going to be a common cause for male infertility. There are many ways in which it could go wrong, the end result of which is infertility. So I think we are going to find many causes for infertility, and that gives us many different ways of trying to tackle it. And if we go back to using this information for contraception, what we know is that as a human population, we need different contraceptives acting in different ways and utilized at different times in the life history of us as human beings. We might be using one kind of contraception before we start families and another kind of contraception after we have had the children that we want. So family planning requires a flexibility of options. Just like not every drug works for every person, not every contraception [method] is going to fit into the lifestyle of every person, so we want that many different alternatives. So from that perspective, maybe it is good there are many routes to infertility.

Q: Are we going to move beyond the usefulness of the mouse?

I think that is an excellent question. I would say no, we are not going to move beyond the usefulness of the mouse—at least not in the foreseeable future, because as we discover genes in humans and we say, “Aha, okay, this gene contributes to this disease or this infertility in the male,” well, then the next thing that we want to do for humans is say, “Okay, how can we mitigate this? How can we cure the disease?” Or, “Oh, maybe we can use this gene as a target for a novel contraceptive method if it interferes with fertility.” So we are going to need the mouse to test our hypotheses. Can we use a pharmaceutical agent, a chemical, to alleviate the infertility? Or can we use an agent to exploit what we know and develop a contraceptive that will be useful?

Mapping the Future of Infertility Research

Q: What brings you to the Washington area?

I am in Washington for evaluation and a forward look for some NIH programs that we call SCCPIRs. These are the Specialized Cooperative Centers Program in Reproduction and Infertility Research. We have been taking a broad view of the future of reproduction and infertility research. There are eight existing programs. This is a very exciting program of the NIH: There are centers at universities across the country, where there is a mix of basic research—the kind of research that I do—and also clinical translational research—taking that new knowledge from experimental analysis of organisms like mice and applying it to human infertility and human conditions, such as endometriosis or premature ovarian failure. These programs have been a great opportunity and have spawned a lot of collaborative research that would not necessarily have happened through the traditional R01 individual grant program. Both kinds of programs are vitally important, but these SCCPIR programs have actually promoted and facilitated collaborative research, and several important diagnostic and therapeutic advances have come out of these programs, so it has been exciting to look at their progress.

Q: Your work also includes something called epigenetics. Can you explain what epigenetics is and how it is connected to your work?

The focus of my research is on infertility, but I am interested in the behavior of chromosomes in the early stages of germ cell development. I am interested, by extension, in other areas that impact on chromosome structure and chromosome behavior. And one of the hottest topics these days is epigenetics—that is, modifications to chromosomes that are not inherited mutations in the DNA, but that may be due to extra chemical groups stuck onto the DNA or modifications to the proteins that associate the DNA. These epigenetic effects may result from environmental factors, including exposure to diet, chemicals, or exercise.
The chemical modifications to the DNA can determine whether a gene is on or off, whether it is active or silent. So these epigenetic modifications can change the outcome, even though they are not changing the basic genetic code. We are probably going to find that these epigenetic effects are important to male and female fertility.

Q: Are you hopeful that you will be able to uncover some of the mysteries of infertility?

I think, if I and the other people in other laboratories can solve some of those basic mysteries, that this will give us a lot of insight into a very important step in fertility, namely the making of the gamete—the egg or the sperm cell.

I think the hope for male reproduction and reproductive biology, in general, is that we are going to be able to understand the very complicated network of biological, biochemical, molecular processes that are contributing, not only at the level of making the germ cells, which is my specialty, but at the level of the hormonal signals that set that process in motion.

We are in an era of big biology—systems biology and systems genetics. Everything that we study in human physiology is very complex and requires the interaction of a large number of genes and molecular systems.

I think we are going to make tremendous progress in the next 10 years. I don’t think we are going to unravel it all. We know enough now to know that every problem that we solve opens a Pandora’s box of problems in behind it that we have to solve. But I think we are going to make tremendous progress in the interaction of environment and physiology in reproduction.

More Information

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Last Updated Date: 06/23/2014
Last Reviewed Date: 06/23/2014
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