Friday May 25 2012
Male contraceptive: no pill, just tinkering with genes in mice
“Scientists are a step close to developing a contraceptive pill for men,” says The Daily Telegraph. The newspaper says that new research has found a gene the controls the final stages of sperm development and could result in temporary infertility if blocked.
Rather than being a clinical trial of a new drug or even an examination of human fertility, this news is based on an experimental study in mice. It aimed to identify new genes involved in male fertility, and discovered a genetic mutation that caused male mice to be infertile. It did this by altering a protein called KATNAL1, which plays a role in remodelling the ‘scaffolding’ structure present in cells that helps them divide and transport substances.
KATNAL1 protein was also found to be essential in the working of specialised cells that help sperm to mature, and using genetics to alter the protein was what caused infertility in the mice.
While this is interesting research, it is far too preliminary to say that it heralds a future male pill or potential treatments for male infertility. This is for a number of reasons including that it is yet to be shown that inhibiting or mutating this protein causes male infertility in humans. Also it would need to be established that we can safely interfere with or fix problems with this protein.
If developing this research towards a treatment does prove to be possible, any potential drug will have to undergo testing in animals followed by trials in humans to ensure that it is effective and safe. This new research is an essential first step in this long process, but such developments can take a great deal of time and are not always successful.
Where did the story come from?
This international study was carried out by researchers from a number of scientific and medical institutions in Bulgaria, Australia and the UK, including the University of Edinburgh, and the Mary Lyon Centre and Mammalian Genetics Unit at Harwell Science and Innovation Campus. It was funded by the UK Medical Research Council and the Australian National Health and Medical Research Council.
The study was published in the peer-reviewed journal PLoS Genetics.
Most newspaper headlines suggested that the findings of this research paper could lead to a male contraceptive pill. Although theoretically possible, this is likely to be a long way off.
What kind of research was this?
Over the years, there have been various attempts to produce male counterparts to contraceptive methods used by females. For example, there has long been a goal to produce a male pill and even human trials of a monthly male contraceptive jab.
This animal-based research aimed to identify genes that are involved in male fertility and how mutations in these genes might affect male fertility.
Animal research is a first step in understanding how different cells and biological processes work. By understanding these processes better, researchers aim to work out ways to stop or, harness them, or potentially fix them if they go wrong resulting in human disease. Carrying out this type of research is essential to the development of new drugs, but it is painstaking and lengthy process and is not always successful.
What did the research involve?
The researchers used a chemical treatment to cause random mutations in male mice, and then screened them for infertility. In the mice that were found to be infertile, the mutations that caused this infertility were then identified using standard methods of examining DNA.
Within DNA, certain sequences, known as genes, control specific functions in the body by producing proteins. Once the researchers identified the genes that were mutated in these mice, they looked at the function of the protein coded for by the gene, and confirmed that the mutation would result in a protein that did not perform its normal function. They then carried out other experiments to investigate how the mutation was affecting male fertility.
What were the basic results?
The screen identified one ‘family’ of mice that had a type of genetic mutation that caused some males to be infertile. To be infertile, male mice had to carry two copies of a particular mutated gene, one inherited from each parent. Male mice carrying only one mutated version of the gene were fertile, but could pass the gene on to their offspring, and potentially have infertile offspring if mated with a female carrying the mutated gene.
The researchers found that the mutation was in a gene called Katnal1 and was brought about by a change in a single DNA ‘base’ (that is, a single letter within a genetic code). Proteins are made of smaller ‘building blocks’ called amino acids, and this mutation was predicted to cause a different amino acid to be incorporated into the protein’s structure. This substitution was predicted to stop the protein from working normally.
The researchers then looked at the function of the protein produced by this gene, which is called KATNAL1. They found that KATNAL1 played a role in the remodelling of a cell’s cytoskeleton. The cytoskeleton is effectively a scaffold that maintains the structure of a cell and plays important roles in the movement of substances around the cell and in cell division. The mutated form of KATNAL1 could not perform this remodelling in cells grown in the laboratory.
The researchers then looked in more detail at the testes, since they had found that mice with this mutation were infertile but had no obvious effects on other body systems. The researchers found that the KATNAL1 protein is present in both human and mouse testes in specialised cells called Sertoli cells, which support the development of sperm. Mice carrying the mutated version of the Katnal1 gene had smaller testes and the researchers found that this was because immature sperm cells were released prematurely. In these mice, KATNAL1 protein was not found where it should be in the Sertoli cells, and the cells had a less stable cytoskeleton.
How did the researchers interpret the results?
The researchers conclude that they have identified the KATNAL1 protein ‘as an essential regulator of male fertility’. They say this information will aid understanding of how the Sertoli cells support sperm development and promote male fertility. They conclude that ‘such information will be of utility both for increasing our understanding of male infertility and the development of treatments and non-hormonal male contraceptives’.
This animal-based study has identified that a protein called KATNAL1 is essential in supporting the production of mature sperm, and therefore male fertility, in mice. The protein performs this key role through its actions in cells called Sertoli cells, which protect and support cell germ cells through their development cycle. This research also found that KATNAL1 plays a role in the dynamics of the cytoskeleton scaffolding of these cells, and that this role is essential for their function.
The specific mutation in the Katnal1 gene identified in the mice in this study causes the protein to be non-functional and mice with two copies of this mutation are sterile due to the release of immature sperm cells.
Turning their attention to humans, the researchers went on to show that the Katnal1 gene is also active in men’s testes. However, we do not yet know whether mutations in the gene could be contributing to cases of male infertility in humans, or even whether men carry mutations of this gene due to the mutation being chemically induced in mice.
This is interesting research but it does not follow that both a male pill and potential treatments for male infertility are just around the corner.
So far, the most significant finding is that a protein essential for male fertility in mice has been identified. However, more information is required before new treatments can be developed. For example, there is a need to establish whether the protein works in a similar way in human testis cells, and whether we can safely interfere with its function. It might also be helpful to observe whether the mutation occurs in humans, and what effect it actually produces.
Crucially, before a male pill could be developed, the researchers will have to identify a safe, reversible way of interfering with this protein’s function in the Sertoli cells. Any potential drug would then have to undergo testing through animal trials followed by trials in humans to show that it was effective and safe before it could be licensed for human use.
Overall, developing a ‘male pill based on these findings will take a lot of slow and painstaking research, which is not guaranteed to be successful or to produce a contraceptive as effective or safe as measures such as condoms.