Club foot and thalidomide

16 December 2013

Interview with

Neil Vargesson, University of Aberdeen

A child with club footNeil -  Clubfoot is a limb defect that causes the failure in a foot to rotate correctly.  And so, the child is walking on their ankle joint as opposed to the base of the foot as you and I would.

Chris -   Why does that happen?

Neil -   The short answer is, we don't know.  But there's many ways that it's caused.  Bone malformations or muscle failure, or blood vessels.  We got interested because in Scotland, incidence is quite high.  And so, it's 1 in 500 births have clubfoot.  It can occur on one side or both sides, and we've made animal models.  We have a mouse model, and I've made a chicken embryo model.  Basically, we found in these particular models that it's due to neuromuscular failure.  So, if you block the nerves as it guides through the limbs and it fails to reach the muscles, the muscles don't form and then the muscles prevent this process called rotation occurring in the embryo which is a process by which the forming foot rotates around so that it can be walked upon.  That doesn't happen so that they stay where they were as an embryo which is sort of looking like a bit an arm almost and the result is clubfoot.

Chris -   You mentioned that the incidence is quite high in Scotland.  Do you know what the genes are then because if there's a high incidence, there must be families with it?

Neil -   It is familial and there are many genes linked to it.  But the ones that cause this are still unknown.  That's what we're doing - that's why we have these different models here, chicken and mice.  The idea is, is that we're going to hopefully going to find those genes that cause those particular clubfoot malformations and then that will hopefully give us some diagnostic or tools that we can then identify potential families at risk.

Chris -   If you look in the chickens, do you actually have a gene that you've mutated or changed in order to make the chick or the mouse have the problem or was this just, you got these animals by random selection?

Neil -   No.  With the chicken, it's pharmacologically induced.  We used drugs that blocks neuromuscular migration and that causes a very severe clubfoot.  The ankle joint is almost faced on the femur if you like, the upper part of the leg.  From that, we've looked at the muscles and the nerves and other tissues like the vessels and tendons and things to understand what's going on and what the process is.  Now, we're starting to screen some of the targets we've found in the mouse or potential targets in the mouse into the chick to see what they do and how they do it.

Chris -   Of course, one disorder which is very visibly manifested in people is the disorder caused by the drug thalidomide which was used in the 1950's and the 1960's.  Does that give us any clues because it produces these profound limb abnormalities and affected people?  Does that give us any clues as to how this problem can happen naturally?

Neil -   Clubfoot was seen in thalidomide embryomyopathy.  Yes, ultimately, when we worked out the genes involved in thalidomide, that should give us major insights of the normal and abnormal limb development.  That's what we're doing.  We use thalidomide in chicken embryos to induce these limb defects and then study molecular as well as physical changes.  Hopefully, if we understand the mechanisms by which thalidomide cause malformation, hopefully, we'll be able to understand more about normal development and why things go wrong in other conditions.

Chris -   It is also quite a good drug.  Thalidomide is still used, but not for what it was used when women were pregnant in the '50s and '60s.  It's used for various disorders, leprosy and even myeloma these days.

Neil -   That's correct.  Thalidomide is now used around the world.  It's the treatment for leprosy.  It's used in the UK, in the US, parts of Australia and other parts of Europe for the treatment of multiple myeloma where it prolongs life by up to 18 months.  It's also in clinical trials for things like Crohn's disease, HIV and other inflammatory disorders.  Very effective in those conditions.  Sadly, in some countries, we are still seeing birth defects. Particularly in brazil, t here was a story just this year around a new generation of thalidomide survivors out there.  This is due to drugs still being teratogenic.  If it's taken at the wrong period of the formation of the embryo, you'll have a birth defect.

Chris -   Do we know why it's so specific for the arms and legs, and other organs and other parts of the body don't appear to be affected in the same way?

Neil -   The drug affects many tissues.  The limbs obviously are the ones that you see the most of because you see them on the person.  But in fact, any organ can be affected by the drug.  In the majority of the survivors, they have a range of limb damage.  Of course, you can look at it and say, well, when the drug was taken, it was given to treat morning sickness, and at that particular time the limbs were rapidly forming and they're rapidly growing.  So, limbs were no doubt targeted at that time point.  And we've shown that blood vessels were destroyed and if you lose blood vessels, you induce cell death, you lose the gene expression pathways.  This results in a range of limb defects.  So, we can induce that in chicken, but other tissues can be affected as well. Our group at the moment are trying to find out how, what targets of the drug result in these range of defects.  We're also trying to make forms of the drug that don't cause birth defect, but it's still clinically relevant.

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