Boosting Your Bones

"Self-healing" is not a word that people usually associate with cancer. But researchers studying a very unusual and rare form of skin cancer that can clear up by itself have learned some lessons that could potentially lead to new treatments for the disease in the future.

It's a rare hereditary cancer called multiple self-healing squamous epithelioma, or MSSE for short - it only affects a handful of people every year in the UK, and most of them can trace their ancestry to a single family from Scotland. The disease causes large flat tumours on the skin which heal up of their own accord, leaving disfiguring scars but no other lasting effects.

Because of the inheritance pattern of the disease, scientists know that it must be caused by a fault in a single gene,  but the identity of this gene has been a mystery for more than 40 years. But now an international team of researchers led by Cancer Research UK's Dr David Goudie in Dundee have found the culprit. The team have published their findings in the journal Nature Genetics this week,  and their discovery could shed light on more common types of cancer as well.

The researchers looked at DNA samples from around 60 people with MSSE, and compared them with DNA from more than a hundred of their relative who were unaffected. They focused in particular on a region of DNA that had previously been shown to harbour the likely gene, narrowing down their search until they found the gene TGFBR1.

This gene encodes a receptor protein, which receive signals from a protein called TGF beta. These signals tell cells to divide, or to stop dividing, and the researchers were able to prove that carrying a faulty version of TGFBR1 caused people to develop MSSE tumours. Intriguingly, faults in TGF beta signalling have been found in many types of cancer.

TGF beta signalling is very interesting to cancer researchers, because it can be both a 'goodie' and a 'baddie' in the disease. In the early stages of more normal cancers, it tells cells to stop dividing, acting as a brake on   tumour growth. But after a while, it switches sides, and TGF beta signals tell cells to divide and grow faster, fuelling the growth of cancer.

But in the case of MSSE, the opposite seems to happen. Cells start off growing out of control, forming the characteristic skin tumour, but then they stop growing and go into reverse.

TGFBR1 is just one of a family of receptors that are involved in receiving TGF beta signals. The researchers think that the pattern of signals must be changing as the tumours grow and then heal, allowing the 'good' side to come forward.

Although MSSE is a very rare and unusual cancer, this discovery  could shed light on other, more common, types of cancer, because we know that TGF beta signalling is involved in many types of cancer. If researchers could figure out exactly how the changes in TGF beta signalling make MSSE tumours heal up, then maybe it could pave the way for future treatments for more common types of cancer.  So this is a nice example of how research into a very unusual disease could have a much wider relevance.

Goudie, D. et al (2011). Multiple self-healing squamous epithelioma is caused by a disease-specific spectrum of mutations in TGFBR1 Nature Genetics DOI:
10.1038/ng.780

Kat -   Also in the news this week, scientists have been using old bones to develop new treatments for chronic back pain.  [It's estimated that] 80% of us will suffer from a bad back at some time in our lives, but the condition is hard to treat because the causes of it are so varied.  Now, researchers have come up with a new way of testing out new treatments with a little help from our ancestors, as Jane Reck has been finding out...

Ruth -   The data that we need, we can derive from these older bones.  So, although the bones are old, what we end up with in the model is a simulation of a living spine.

Kate -   I, as an anthropologist, am providing access to data and providing access to analytical techniques which are going back, into bio-mechanical engineering.

Jane -   The unlikely combination of old human bones and the latest computer modelling techniques, are being used to develop new ways of treating chronic back pain.  Spines from around 40 skeletons, housed in various museums and anatomy collections are being analysed in the research, which is taking place at the Universities of Leeds and Bristol.  The computer modelling side of the work is led by Dr. Ruth Wilcox at Leeds.

Ruth -   We're using computer models, the same kinds of modelling processes we'd use in aeronautical engineering or in civil engineering to analyse structures, but using those types of principles to model the spine, and to simulate how a treatment would work within a spine.

Jane -   Ruth says, they're carrying out the work using the latest imaging techniques.

Ruth -   Microcomputer tomography scanning is imaging a specimen in three dimensions.  So it's similar to the type of techniques that we have in a hospital called a CAT scan.  In a hospital, a patient is imaged by basically being x-rayed from different angles and then using that to build up a 3D image of the patients.  This works in the same kind of way, but we're doing it at much higher resolution so that we can see the individual strands or struts of bone within the vertebra.  And that data, we then put into our computer models so that our computer model simulates this variation in bone across an individual vertebra but also from one patient to another.

Jane -   The bone remains are being gathered and scanned at the University of Bristol's Department of Archaeology and Anthropology by Dr. Kate Robson Brown.  Kate explains why they're using such old human remains.

Kate -   Most of the time at the moment, we get material from the more elderly sections of the population.  And in order to understand the range of variation within a normal population, we need to have information from younger adult age groups.  By using older collections of dry bone; these are macerated, which means cleaned, dry skeletons from those collections, it allows us to investigate bone morphology in age groups which are not accessible using recently donated material.  One of the skeletons we're looking at is that of an adult female.  She was quite little.  She was around 5'2" when she died.  She was probably in her late 20s or early 30s.  We have her complete skeleton.  This was a skeleton that made it's way into the collection we think in the 1930s, and this particular individual has a very clean, dry skeleton, so there's no evidence of osteoarthritis, there's no evidence of bone cancer, anything like that.  We can't tell from her skeleton what she died of, but it was certainly nothing that is represented on the bones itself.

Jane -   Ruth says, the new computer software will speed up the process of clinical trials, for testing out new treatments for chronic back pain.

Ruth -   The idea by the end of this project is that we'll have these models up and running.  A company could come in with a design for a new product and we could simulate how it would work across this population of different spines, so we could reduce the risk when it does go into the clinic, and prove beforehand that in our computer models, that it's behaving as it should.  The good thing about the computer models is that we can use them over and over again, so we could test lots of different products on the same computer model whereas if we're doing this in the laboratory, then we'd need a new spine, a new donated spine each time we wanted to test the new treatments out.

Jane -   Kate says the work could lead to tailor-made medical treatments and even provide new insights into how our ancestors evolved.

Kate -   It would surely be great if we could be in a position where surgical interventions could be assessed for us as an individual against a model of our own bones.  We're moving in that direction, but research like this is helping to provide the baseline data on which those developments can be made.  One of the really exciting developments that's arising out of this, for me as a Biologic Anthropologist, is being able to apply this type of modelling technique to fossil bones, for which there is no other way of testing them.  So for example, we could take a fossil skeleton that's 3 million years old, scan a vertebra, make a model of it, and actually test some locomotory strategies to see whether that individual in life walked around on two feet or four feet.  That's a major development for evolutionary anthropology.

Jane -   The research is funded by the Engineering in Physical Sciences Research Council, the computer modelling software is the first of it's kind for back conditions.  It should be available for testing out newly developed products and treatments in the next few years.

Kat -   Well, that's making me want to sit up straight with just listening to that.  That was Jane Reck from the Engineering and Physical Sciences Research Council.

Kat -   Planet Earth podcast presenter Richard Hollingham has been asking what have the Romans ever done for us?  Well, apart from building baths, sewers in cities and education, it turns out they were also into recycling.  And to hear how, he met up with Sheffield University's Caroline Jackson and Harriet Foster from the Norfolk Museums and Archaeology Service...

Caroline -   What we've got are six vessels.  Three drinking vessels, there's two jugs and a bottle, and they're all late 4th century.

Richard -   Now we've got here a modern glass which I am allowed to touch.  Actually, you look at this mass-produced modern glass and you compare it with these from almost 2000 years ago, Caroline.

Caroline -   That's right.

Richard -   These glasses could almost be mass-produced because those three glasses, pretty much identical.  You can imagine those in a box at a supermarket or something.

Caroline -   Well that's right.  They actually were mass-produced in a way.  Glass production, certainly by the 4th century was something which was prolific.  Glass is found in most archaeological contexts.  It's all blown glass, this is something which came in certainly in the Roman period.  The Romans invented glass blowing, something that perhaps wasn't around in earlier periods.  So, to produce the glass by blowing is very rapid.  It's a very easy technique once you've mastered it.  So you can produce many, many vessels from a small amount of glass, and this is why these have such thin walls as well - because they're blown.

Richard -   How do you know they recycled the glass?

Harriet -   We've known for a long time that the Romans recycled glass.  We've got evidence from a late 1st century AD source that talks about broken glass in Rome being collected up in exchange for items of small worth.  There's archaeological evidence for glass recycling.  So we find the equivalent of bottle banks.

Richard -   So what did you do then?

Caroline -   We took a lot of material from about 20 sites in Britain and analysed them chemically to see if we could see anything within their compositions which might give us an indication that recycling was taking place.  And the results of that were quite surprising.  

Harriet -   They were surprising because of the amount of recycling that we found that was going on.  A significant proportion of the assemblage that we looked at which was over 500 samples suggested to us that the glass was being recycled in quite large amounts and that was interesting because it throws out more questions about, what does that mean about the supply of glass to the province at that time?  Was glass being recycled because there weren't fresh supplies available or is it something else?

Richard -   Have you got any ideas why this might be going on?

Caroline -   By the late 3rd and 4th century, the Roman Empire is starting to change.  The large industrial complexes that you see are starting to decline, trade is starting to contract.  Now, we don't know exactly what was happening with supplies of glass because we don't have any archaeological evidence at this point that is published, where we know glass was being produced.  So we can't say this factory stopped and maybe that factory started, but we can say that it looks as though that supply of raw glass is starting to decline, because there is a greater proportion of recycled glass that you can see in the chemical fingerprint.  We've got elements in there which can only come from mixing that can't have come from the raw materials.  That's not just for the common forms and the common colours, even this more high status colourless glass, which is always thought of as something which is reserved perhaps for more specialised vessels, even that is showing evidence of large scale recycling.  So it's going on throughout the glass industry.

Richard -   Okay, so you're learning about the glass, but you can also, by using the glass, tell a lot about how the society was changing as well.

Caroline -   Well that's archaeology.  That's what we do.  The glass is a really interesting material, but only interesting in what it tells us about the people who were making it and consuming it.  In the same way as we look at any archaeological material, it's there for a purpose.  It's there to tell us about people, the individual, and society.

Kat -   That was Caroline Jackson and Harriet Foster, talking to there to Planet Earth podcast presenter Richard Hollingham.  You can hear the latest edition of the Planet Earth podcast as well as links to other Planet Earth Online resources at thenakedscientists.com/planetearth.

Chris -   Every year, about 75,000 people suffer a hip fracture in the UK and a majority of those will be down to the condition osteoporosis, that's the underlying cause of their bones being too weak.  This is basically bone thinning as we age.  Dr. Ken Poole is with us now.  He's a rheumatologist at the University of Cambridge where he's studying how bones weaken and change with age, and then some new ways that we can try to use to combat the problem.  Hello, Ken.

Ken -   Hello, Chris.

Chris -   Thanks for joining us on the Naked Scientists.  First of all, just fill us in, what actually is osteoporosis?

Ken -   Well, exactly as you say.  They're porous thin bones that fracture when they shouldn't.  So, a lady walking along, falling over from a standing height shouldn't break a wrist, but in osteoporosis, you might, bending to tie the shoelaces fracturing a vertebra.  So the little old lady, why is she little?  Because of vertebral fractures, the bones collapsing.  In the case of hip fracture, a trip or a stumble, or a fall, enough to break a hip.

Chris -   If you were to take a piece of bone from someone who has got osteoporosis, how would it compare if you looked at it both macroscopically, just by eye, and then microscopically down a microscope with someone who's got normal bone?

Ken -   Well, we do things like this in the clinic.  So, when we take a piece of bone normally from people's pelvis, the bone has a thick outer shell and an inner honeycomb which is a mesh full of struts.  In a young person, the outer shell is nice and thick and the honeycomb mesh is also thick, providing lots of support, like the inside of a Crunchy bar.  If you have an osteoporotic patient, then the outer shell is very much thinner and the mesh of struts may not even be there at all or where they're there, they're thinned and they don't connect properly.

Chris -   Do we actually know why this happens?  I mean, are some people pre-destined to get this because of family reasons?  Is there a genetic cause or is it purely just down to how much exercise you have or haven't had, or what your diet's been like earlier in your life?

Ken -   Well those are all good points and fractures are multifactorial.  So you have the low bone strength from the osteoporosis, but you also have falls, you also have genetic factors.  One interesting factor is that if your parents have had a hip fracture, a mother or father, then your own risk of a hip fracture is higher as well.  And coming into that, things like reflexes as well, so your ability to deal with the fall which gets worse as you get older.

Chris -   What can we do about it?  So someone is diagnosed with osteoporosis.  They have a fracture of a wrist or something, they slip on the ice, what can we do once you've picked it up?

Ken -   Part of that job is greater awareness and things like the National Osteoporosis Society is great at doing that.  A risk fracture in an older woman is not something that you can leave, and you can ask some questions of that person and find out whether they've got very low bone density that can be improved by drugs.  And we've got plenty of drugs now that actually help and as we've discussed earlier, the exercise will help too.  And it's also dietary and even sunlight, things that can help with your bone strength.

Chris -   Okay.  Well, talk us through then, when you put someone on therapy, how are you monitoring them and taking this forward in the research domain, what are you actually doing to try to work out how to optimise therapy for this?

Ken -   So, one of the things that we use at the moment is DEXA scanning.  A lot of people have heard of this bone density scanning.  That is where we put people onto a bed, look at their spines and hips, and work out how dense the bone is and compare it to a normal range.  But we also know that half of people with hip fractures have a normal bone density result or one that doesn't come up as the osteoporosis threshold.  So, one of the things we need is better ways of picking people up, and also, monitoring their treatments.

Chris -   And how are you doing that?

Osteoclast:

Osteoblasts:

Ken -   Together with some of the engineers at the University of Cambridge, we've developed a technique which is
based on the CT scans that Ruth dealt with earlier.  It was actually interesting to hear that because we're using CT which is computer tomography scans of patients.  We can now map the outer shell of femurs, the femoral bone, and produce a colour map of how thick the bones are, and it's very interesting to see that in older people, they're often as thin as an eggshell.  My wife says that when you get old, your hips go pink because we use pink for less than 0.3 mm which is eggshell thin.  We've done a recent study that shows that one of the commonly used osteoporosis drugs called teriparatide which actually makes bone grow, that's actually able to put bone in places, just like Tim described where you have peak strain in the femur which is a good thing because that's where they often tend to break.

Chris -   Because that's where you want the bone to grow.

Ken -   That's right.

Chris -   Yeah.  So, I mean, that was going to be my next point, which is - people who've got osteoporosis have lost bone mass, have actually lost bone substance.  You want to put it back.  How do drugs and doctors attempt to make people who've got thin bones grow new bone, and why don't people just do that anyway?

Ken -   Well, there's drugs called bisphosphonates which are a lot of people are on, which are once weekly drugs usually, and they actually don't make new bone grow.  They're the most commonly used drugs, but then you actually stop it being broken down. 
As Tim said earlier, there's a process going on all the time of cells called osteoclasts, digging pits in bone, and osteoblasts, filling those pits back up.  In osteoporosis, that's out of sync and we called drugs called bisphosphonates which actually stop the osteoclasts from digging pits, and allows the bone that's there to harden off, and that actually prevents fracture, and they're very effective.  But right down on the other end of the spectrum, the osteoblasts that cause the bone to grow, there's a drug called teriparatide which is given to patients who are really in a bad way with osteoporosis at the moment.  So they've got multiple fractures and our studies showed that when you give this teriparatide, a daily injection, it causes bone to grow in these particular sites of interest.

Chris -   One of the stories I mentioned at the beginning was making hearts regrow and scientists are trying to make a heart that's in an adult, think it's in an embryo again because then it will regrow lost tissue.  Could we do the same thing for bones and fool bones into thinking that they're back in a baby so they begin to grow new bone, and thereby, get rid of the osteoporosis problem?

Ken -   Well, Tim said earlier about the vast amounts of material that might be unnecessary to carry around if you had, say a gene;  And in fact, there is a gene, the sclerostin protein which is a funny name, but it's from a disease called sclerosteosis, and by examining that disease, scientists have been able to find just that, the off switch for forming bone.  By giving people a monoclonal antibody against this protein, you can actually make bone form at amazing rates in all sorts of places, and that seems to be the most likely approach to make new bone in all sorts of situations where it's needed.

Chris -   But that sounds a bit dangerous because you could end up growing bone where you don't want to grow bone, as in where you don't need it.

Ken -   And that is actually one of the features of the condition, sclerosteosis, so bone is beautifully regulated and held back from doing silly things, and one of the silly things that it can do is, if it closes off the inside holes called foramen inside the skull, that's a bad place to have bone.  The patients who have this disease actually close off things like their facial nerve cavity, their ear canals, and even the very large foramen magnum that carries the nerves, and they can die from this condition.  So, it's all things in moderation and a lot of work has to be done to make those safe.

Chris -   And just to finish off briefly, Ken.  I suppose if you've got systems now that are enabling us to track where new bone is being laid down, if you could work out what the signals are that are active in that site, and then tell this gene which is the bone growth off switch to activate just in that site, then you'd have a way of thickening up the bone where it needs to be thicker, and leaving other sites like the sensitive ones you mentioned unharmed.

Ken -   Working out those processes is absolutely key.

Chris -   Ken, thank you very much.  That was Ken Poole.  He is an arthritis research UK clinician scientist at the NIHR Biomedical Research Centre in Cambridge. 

We put this to Dr Ken Poole and Professor Tim Skerry... Ken - Diet and nutrition is very important, and the one that people think about most is vitamin D. Calcium is also very important. We have not enough vitamin D from sunlight at these sorts of northern latitudes, so those are important. In order to work out how important, you can look at the body mass index and a low body mass index is a risk factor for fracture. That's one of the things that we plug-in to the World Health Organisation Frax tool which is a thing that predicts what your own fracture risk is. You can run this on an Apple, on an iPhone, or even just on the web from the Frax website and that will tell you what your own risk is over the next 10 years. So yeah, nutrients and diet are very important.

Chris - Sounds good. Anything to add to that, Tim?

Tim - I don't think so. I think generally, western diets have reasonably good levels of calcium, but yes, as Ken says, vitamin D could be something that people need to worry about.

We put this to Dr Ken Poole...

Ken - Yes. The steroids are one of the classic "bad for bone" drugs. It's normally steroid tablets that are worse than the inhalers, but there is a smaller effect of the inhalers. It's important that if someone is on a steroid inhaler like that, that they do all the lifestyle things like the diet and the exercise, and nutrition to ensure that they get the most out of their bones.

We put this to Dr Ken Poole...

Ken - Normally, it's thought of in terms of the amount of energy available in a fall; and it's a surprisingly little amount of the energy: about a fifth to a tenth of the amount of energy in a fall is enough to break that femur.

With a hip fracture, there's such a thing as the perfect force. If you are unlucky and fall backwards and to the side - even if you're young - you can snap your femur.

We put this to Dr Ken Poole...

Ken - Yes, it is true. The fat cells are part of the same lineage as the bone cells. So when we get older, we start making more fat cells and less bone forming cells, and that's an inevitable consequence within the bones.

We put this to Professor Tim Skerry and Dr Ken Poole...

Tim - Well there's certainly some basis for that. Black people do have stronger bones than white people but I think there's more to it than that and I think Ken, probably, as a clinician has some additional thoughts about that.

Chris - Ken?

Ken - Well that's very interesting. The MRC Human Nutrition Team in Cambridge often work in the Gambia and the bones of people there may look like they're osteoporotic on the scan, but actually they're stronger, and that's one of the paradoxes. But it's one of those things that when using the Frax tool, which is a new way of finding out people's risk of a fracture, you have to make sure you're in the right ethnicity group because it's calibrated by a different nation.

Chris - That's interesting. So if you don't make an account or take it into account where someone comes from, you could end up with the scan, giving you a misleading result for the very reason Tim just mentioned.

Ken - That's absolutely right and there are numbers available for each of the countries that they've got data available at the moment.