Damn You, Darwin! Pt1. Cat & Mouse

In my last post, I described how tumours can become resistant to therapy by activating survival mechanisms, through a process known as Multidrug Resistance. I’m now going to talk about another way that therapy resistance can emerge, through the way that different tumour cell populations respond to therapy. And, specifically, how these responses can be explained by evolution. That’s right! Darwinian evolution!

Now, in order for me to explain how Darwinian evolution can be used to describe tumour responses and therapy resistance, I think it would help if you have an understanding of the basic concept. And while I’m sure that most people do understand the basic concepts behind Evolutionary Theory, I’m going to spend the rest of this post having a go at explaining it to those who don’t. I’ll then go on in the next post to relate it to cancer.

So.  Here we go. Darwinian Evolution 101:

Evolutionary theory, as first described by Darwin and Wallace, explains how new species emerge. Evolution happens through what is known as Selective Pressure. This term used to describe the forces that shape how populations change over time after, for example, a change in the environment. So, basically, it could be said that Selective Pressure is just a fancy way of saying “Chances Of Staying Alive After Some Bad Shit Happens.”

Let me use an example to try and explain. Imagine that there is a very big plain with a river running through the middle. On one side of the river (the East side), there is a population of wildcats. On the other side (the West side), there is a population of field mice.
Now, these two species have never met. The river is so wide, that the cats have never been able to cross over to mouse side, and the mice have never crossed over to the cat side.

And so, for generation after ageneration, the cats and mice have lived on their own side of the plain (their own specific environment), without any idea that the other species is there. But then, the environment changes.


Some Bad Shit Happens.

One day, there is an earthquake. This diverts the course of the river, splitting it in two. So now, instead of there being two environments, one with just cats and one with just mice, suddenly there are three environments: one in the East with just cats, one in the West with just mice and, in the middle, a new environment that contains cats and mice.


So what happens next? Well, in the case of the first two (cat-only and mouse-only), nothing much. These two populations will continue on exactly as before. Oh, the newly formed rivers will mean that there will be less space in each, but there will also be fewer animals taking up that space (as the rest got stuck in the new middle bit). So, for each, the environment is the same and therefore life will go on much as before.

But what about the cats & mice who now find themselves stuck together in the middle? Well, for the cats, there is Good News and Bad News. The Bad News is that the river has cut them off from their food supply, so they are likely to starve. But the Good News is that they are now surrounded by mice. Scrum-diddly-umptious mice! Hooray! And for the mice…..? Well….take a guess!

And so, the obvious happens. The cats start to eat the mice. And so the numbers of mice start to fall. Now, if this went on indefinitely, eventually the cats would eat all the mice and would then begin to starve. But that’s not what happens. Actually, the cats are only able to eat some of the mice.

Why? Well, it’s because the mice are not all alike. Within any population of animals you get some variation. Some individuals are bigger, some are smaller. Some are fatter, some are thinner. Some may be light coloured, some darker. And so on. This is just as true for mice (or cats or zebras or amoeba or plankton or whales) as it is for humans. So, in our example, there is some variation in the population of mice. Specifically, some have lighter fur and some have darker fur. And that is why the cats don’t eat them all. The cats find it easier to spot the lighter coloured mice, but find it slightly harder to see the darker ones. This means that the lighter coloured mice are more likely to be eaten and the darker coloured ones are more likely to escape (and therefore survive).

Now, as this continues, the darker coloured mice will be the ones more likely to survive long enough to mate and produce offspring. And those offspring are therefore also more likely to have dark fur (although there may also be some light coloured offspring but, again, they are less likely to survive being eaten). And, so the generations go by, the likelihood of finding a light-coloured mouse will get less and less until eventually the only mice you’ll find are dark.

And this is what is known as Selective Pressure. Basically the “pressure” comes from the chances of being eaten, which “selects” the traits within the population (dark fur in this case) that have increased chances of survival.

So that is what is happening with the mice. But what is happening to the cats in the meantime? Well, initially, they will be having a Whale of a time, eating lots of light-coloured mice and getting nice, full bellies. And this increases their chances of surviving and breeding, so the population will increase. However, over time, this will begin to change. As the Selective Pressure on the mouse population starts to make numbers of light-coloured mice fall and the (harder to spot) darker-coloured ones increase, the cats will find it harder and harder to catch their prey. And so they will start to starve and their numbers will start to fall.

Now, if this went on indefinitely, then eventually the cats would all starve to death. But, as before, this doesn’t happen. Because just as there is variation in the mouse population (colour of fur), there is also variation in the cat population: some of them find it slightly easier to spot the darker mice! Therefore the cats with slightly better eyesight will find it easier to catch the darker mice and are therefore more likely to survive long enough to produce offspring – offspring who are more likely to have the “good eyesight” trait. And, so the generations go by, the likelihood of finding cats with poorer eyesight will get less and less until eventually the only cats you’ll find have better eyesight.

And so, just as there is Selective Pressure on the mouse population which makes the darker fur more likely, there will also be Selective Pressure on the cat population which makes better eyesight more likely!

And this is just the start of it. Once this process gets started, it just keeps on going. So, over many, many generations, the Selective Pressures on the mouse and cat populations will keep pushing them to change. For the mice, over successive generations, you’d start to see the emergence of better and better forms of camouflage. For the cats, over successive generations, you’d start to see the emergence of better and more sophisticated eyesight. (But remember that not every member of the population will display these traits – the populations will still show variability and only certain individuals will be “selected” for survival – so it’s not every single member of the population that changes).

Now, if this went on long enough, eventually the populations of cats and mice would have changed so much that they would be completely different to the original cats & mice who found themselves stranded by the earthquake. They would be new species! And you could easily spot this be comparing them to the population of cats in the far East of the plain and the population of mice in the far West, neither of which were subject to the Selective Pressures and therefore remain much as they have always done. And so, while the plain initially only had a single species of cats and a single species of mice, after enough generations have passed you end up with two species of cats and two species of mice!


So that basically (very basically!), is Darwinian evolution. “But how does this relate to cancer??” I hear you cry. Well…..I’ll explain all in my next post…….

To Be Continued……


Darwin, Charles (1876). The Origin of Species
By Means of Natural Selection, or the Preservation of Favoured Races in the Struggle for Life Cambridge University Press DOI: 10.1017/CBO9780511694295


AG McCluskey (2016). Damn You Darwin! Pt1: Cat & Mouse Zongo’s Cancer Diaries

Nae Trainers!

nae-trainersSo, in my last post, I described how different cell populations within an individual tumour can respond differently to specific treatments, and how this combated with combination therapy.  In this post, I’m going to describe how tumours respond to these attacks, and why this can be very, very bad news for the patient.

One of the big things that people tend to forget is that cancer cells are derived from a patient’s own body.  Essentially, it is part of them.  And like any other cell in your body, it has built-in survival mechanisms that it uses to keep itself alive.  In one sense, that is what causes cancer – in normal cells, the survival mechanisms are tightly controlled, but in cancer cells the survival mechanisms are out of control (see No Bootees).

Now, if you think of survival from the perspective of the body as a whole, then some of these survival mechanisms are pretty well known about.  Eating.  Drinking.  Breathing.  Sleep.  And even when you zoom in to look just at an individual cell, there are equivalent mechanisms in place.  Now, obviously cells are much, much simpler than whole bodies (naturally!), so the equivalent cell-based mechanisms are simpler, but they work on the same basic principles.   So, cells need nutrients in order to survive, therefore the food you eat gets broken down and then distributed to every cell.  Same with water.   That’s how cells “eat” and “drink”.  Oxygen is extracted from the air you breathe and is transported around your body by your red blood cells where it is passed to every cell.  The cells use the oxygen & nutrients to make energy.  This releases carbon dioxide, which is returned by the blood cells to the lungs, where you breathe it out.   That’s how cells “breathe”.  Cells even have their own growth and rest rhythms.

Likewise, if we zoom out again to look at the whole-body situation, what happens if our body comes under attack from, say, a virus or bacterial infection?  Again, survival mechanisms kick in – namely our immune system.  The immune system is primed to recognise things that shouldn’t be in your body – things that could be harmful – and get rid of them.  And, once again, if we zoom in to the level of an individual cell, the individual cell also has defence systems that recognise things that shouldn’t be there – things that could be harmful – and get rid of them.

Again, I’m not saying that these cellular defences are the same as immune responses.  Your immune response is a very (very!) complicated system of different cell types and agents working together in a myriad of different ways.  And as cells are much simpler than whole bodies, the types of defences you’ll find inside a cell are also much simpler.

You can think of the cellular defences as working a bit like Bouncers in a Nightclub.  Their job is to patrol the cell looking for trouble.  If they see anything that looks dodgy, they grab it and throw it out.  This type of activity is important in normal cells, as it helps to protect against the actions of toxins that may have been ingested accidentally in food.  But the problem is, these survival mechanisms are only trying to protect the individual cell, not the body as a whole.  So, in cancer cells, the defence mechanisms will act to try and keep the cancer cells alive, even if this would be bad for a patient’s overall survival.  And this is what gives rise to therapy resistance.

Ask yourself:  What are cancer treatments for?  Answer: to kill cancer cells.  Next question:  How do they do this?  Answer:  they act like toxins, or poisons which kill the cancer cells.  Now, since cells, both normal and cancer, have defence mechanisms to protect against toxins, how do you think the cancer cells will react to chemotherapy drugs which act like toxins?  That’s right.  They activate their defences.

They send out the Bouncers.

And this is another way that cancer cells resist chemo drugs.  So, while the last post I explained that some cancer cells can resist drugs because they lack the thing the drug targets, you can see that another way they do it is by attacking the drug itself.

The Bouncers grab the chemotherapy drug and “disarm” it by altering its chemical structure so it can’t work anymore (the biological equivalent of twisting its arm up its back).  Then, they frog-march the drug to the edge of the cell and throw it out.

So, even if the cancer cell contains the drug’s target and is susceptible to its action, it doesn’t matter because the drug doesn’t get anywhere near the target.  It gets disarmed & booted out before it can work.

And it gets worse.  Because there is a nasty little twist to the tale.  The way that the Bouncers recognise the chemo drug is by its chemical structure. Chemo drugs, like a lot of toxins, tend to be big, bulky, complicated molecules.  So, when they get switched on, the Bouncers will grab any big, bulky, complicated molecule and get rid of it.

Again, to go back to the Nightclub analogy, think of it like a dress code.  A Nightclub Bouncer spots that some of the clientele are wearing trainers and chucks them out.  It doesn’t matter if they are causing trouble or not.  It doesn’t matter if they are splashing the cash.  The Nightclub has a “No Trainers” rule, so the trainer-wearers get the boot.

“Nae trainers mate,” the Bouncers say, “Beat it!”

And this is also what happens in cancer cells.  A doctor gives a cancer patient a drug.  The patient’s cancer cells activate the Bouncers.  The Bouncers recognise the drug’s big, bulky, complicated structure – its trainers!  So the Bouncers chuck it out.  Therefore the drug doesn’t work.

So, the doctor prescribes another drug.  But!  That drug also has a big, bulky, complicated structure – it also has trainers!  So the cancer cell Bouncers get rid of that one too.  Same with the third drug prescribed.  And the fourth.  And the fifth. And so on…..

…And that is what can be so nasty about this process.  Any cancer cell which activates its defences to become resistant to ONE drug, is ALSO IMMEDIATELY RESISTANT TO LOTS OF OTHER DRUGS AS WELL!

This process is called Multidrug Resistance and while it is not found in every cancer type (thankfully!), it is a hallmark of aggressive cancers.  In fact, you could say that it is why these diseases are aggressive in the first place – they grow and spread so much because standard chemo simply doesn’t work on them.  Their Bouncers are too good.

Now, as you would expect, this is something that attracts a lot of research.  Some groups are trying to develop new drugs which don’t get targeted (ie. without trainers).  Others are investigating the defence systems to try and find ways of deactivating them – of getting rid of the Bouncers. If either approach can be made to work, it would be a big step forward in the treatment of aggressive disease.  Until then…..the Bouncers will keep on working.  And the cancers will keep on growing.

Review article (2000). Cancer multidrug resistance Nature Biotechnology, 18 (Supp) DOI: 10.1038/80051

AG McCluskey (2016). Nae Trainers! Zongo’s Cancer Diaries

Strength In Numbers

strength-in-numbersThis post is going to be about combination therapies.  Why are they needed?  And how are they used?

Whenever someone is diagnosed with cancer, the clinicians will think carefully about what treatment, or treatments, to use.  If the tumour is early-stage, then fairly straightforward treatments can be used – maybe surgery, or a course of either radiotherapy or chemotherapy.  But, if the tumour is more advanced, or is inaccessible, then the medical team might decide on using two or more different types of treatment together.  And one of the reasons behind this, is down to the make-up of the tumours themselves.

If you go by media reporting, you would think cancer is a single thing, with a single cause.  But, as I’ve mentioned before, this is overly simplistic.  The word “cancer” is an umbrella term which describes a wide range of different diseases which induce similar symptoms – uncontrolled cell growth.  So, you shouldn’t think of cancer as a single disease, with a single cause, requiring a single cure.

And it is also overly-simplistic to subdivide “cancer” into separate diseases, each of which has a single, initial cause.  As I mentioned back in The One And Only, cancer is a complex, multifactorial condition which does not have a single cause, but instead arises from lots of different mistakes, errors and damaging factors – some genetic, some environmental.  That is what has started the movement towards Personalised Medicine.  The idea that there is going to be ONE approach that will work as a one-size-fits-all cancer treatment against every tumour is wrong-headed.

But actually, the situation is even worse than that, because even within a single tumour, not all of the individual cancer cells are the same.  As the tumour grows, different parts of it will start to behave differently.  This could be because some regions of the tumour are nearer the blood vessels and so have better access to oxygen and nutrients.

Or, as cancer is caused in the first place by changes inside the cells, further changes can occur in some cells that alters their characteristics, while different changes happen in other tumour cells, so they start to behave differently.  But, whichever way it happens, the upshot is that you end up with lots of cells behaving in different ways, even within an individual tumour.

Now, if you bear that in mind, it should be obvious why using a single type of treatment might not be a good idea.  Every drug is developed to hit a specific cancer-related target.  But, if different cancer cells inside the tumour change in different ways as the tumour grows, then you might find that one of these changes is to the target you are trying to hit.  So, the treatment won’t kill those cells anymore.

This is why single treatments can fail.  It’s not that the treatments themselves don’t work, is that they don’t always work.  Therefore:

Targeting specific gene mutations is a valid approach, but it cannot be the ONLY approach, because not every cancer cell carries the specific mutation, therefore targeting it exclusively will not work in all cases.

Targeting an aberrant signalling pathway is a valid approach, but it cannot be the ONLY approach, because not every cancer cell displays errors in this signalling cascade, therefore targeting it exclusively will not work in all cases.

Targeting aberrant production of a specific growth factor is a valid approach, but it cannot be the ONLY approach, because not every cancer cell exhibits deregulation of this particular growth factor, therefore targeting it exclusively will not work in all cases.

Targeting aberrant metabolic regulation is a valid approach, but it cannot be the ONLY approach, because not every cancer cell exhibits aberrant metabolism, therefore targeting it exclusively will not work in all cases.

……..Complicated, innit?

So that is why, in a lot of cases, a combination of different treatments is used.  The tumour contains different populations of cells which behave in different ways.  But, while one of these subpopulations might be resistant to one type of treatment, it might still be susceptible to a second.  Another subpopulation might be resistant to both treatments, but susceptible to a third.  And so on…

So, by using 2-way, 3-way combinations, you hope to hit lots of cancer-specific targets at once and get a double- or triple-whammy that kills all of the different tumour cell subpopulation sat once.

So, that’s the theory.  Now, obviously, it doesn’t always work.  Partly, this is because there’s a limit to how much treatment a patient can handle.  Individual chemotherapy treatments can have pretty severe side effects, so if you are giving 2 or 3 of them, you obviously multiple these side effects – and there’s only so much the patient can take.

But another reason these treatments can fail is in the way that tumour cells respond to them.

….And I’ll talk about this in my next post.

Komarova, N., & Boland, C. (2013). Cancer: Calculated treatment Nature, 499 (7458), 291-292 DOI: 10.1038/499291a

AG McCluskey (2016). Strength in Numbers Zongo’s Cancer Diaries

The Angry Silence

Angry SilenceMy last post discussed the findings outlined in the recent report from MacMillan Cancer Support, Cancer: Then and Now.  Previously, I concentrated on the improvements in cancer survival rates over the last 40 years and described how this was due to improvements in diagnosis and treatment options.

But in this post I’m going to talk about another thing that the MacMillan report highlighted as having changed dramatically since the 1970’s.  Something which also has a major impact on the quality of life for cancer patients and can also, as we are now beginning to understand, contribute to increased chances of survival.


30-40 years ago, cancer was a taboo subject.  People didn’t talk about it.  In those days, cancer was seen as a Bogey man, a terrifying spectre that shouldn’t be mentioned in case it tempted fate.  A diagnosis of cancer was seen as an automatic death sentence, so the very mention of the word struck terror in the hearts and minds of even the strongest and most courageous.

So someone diagnosed with cancer 30 years ago would suddenly find the world a dark, terrifying place.  Not only were survival rates poor, but they would often find themselves isolated, unable to speak to anyone about their fears.  One patient is quoted as saying, “In the 1980s there was no one to help or advise.  I felt very alone and frightened, and thought I was going to die.”

But, also, not only did cancer patients find it hard to talk to friends and loved ones, there was also very little information available to them from medical professionals.  This is backed up by the medical staff involved, as one oncology nurse who worked in the 1980’s explains, “Cancer was hush, hush.  Our job was to explain what cancer was in the kindliest way as there were no story lines in television soaps, no magazine features about people with cancer to relate to.”

So, up until the ‘80’s, being a cancer patient must have been utterly terrifying.  They had no information.  They wouldn’t have gotten any from medics or nurses.  They wouldn’t be able to share their experiences to anyone outside of their immediate families or close friends – and that’s assuming their friends & families would want to talk about it at all.

And even if they did survive, there was nothing, nothing in the way of aftercare or psychological support to help them cope and process the extremely traumatic experiences they had been through.

Think about that for a minute.  A diagnosis of cancer is incredibly stressful. Undergoing treatment is incredibly stressful.  And even surviving is incredibly stressful.  Imagine doing all of that with virtually no support, no help, no one to turn to.

No one to talk to.

But that has changed in the last 30 years. Oh, don’t get me wrong, a cancer diagnosis is still a stressful experience.  And treatment and recovery is no picnic either.  But one big difference (other than the improvements in diagnosis and planning I’ve already spoken about) is that cancer is not a dirty word anymore.  There’s not anywhere near the same level of secrecy and taboo associated with cancer diagnosis as there was back then, so current cancer patients won’t be as isolated as they would have been in the past.

The information available for patients nowadays is vast.  MacMillan themselves offer advice and support and CRUK’s webpage is a huge resource.  Also, the number of personal testimonies out there, in the form of books, movies, blogs etc. mean that there are plenty of reassuring voices.  And all of this can make the experience for patients less stressful.  Not stress-free, you understand, but infinitely better than it used to be.

And this can be important for another reason.  One which is remarkable, but still not well understood.  It can help improve survival.

Studies through the years have found that a patient’s psychological state can influence the success or failure of their treatment.  Generally speaking, patients who experienced depression, distress or a lack of social support had poorer outcomes.  In contrast, those patients who had large, supportive social networks had a lower relative risk of cancer mortality of between 12-25%.

But what could be causing this?  Well, according to this review, stress can induce the production of mood-altering hormones, which can affect normal bodily functions such as the immune system, inflammation and blood-flow.  And these alterations in bodily function can make the environment more favourable for tumour growth and spread.

So, if anyone reading this has cancer or if you know someone who does, make sure you keep talking.  Not only will the patient feel better, it might actually help make them better too.
Lutgendorf, S., & Andersen, B. (2015). Biobehavioral approaches to cancer progression and survival: Mechanisms and interventions. American Psychologist, 70 (2), 186-197 DOI: 10.1037/a0035730

MacMillan Cancer Support (2016). Cancer: Then and Now. Diagnosis, treatment and aftercare from 1970–2016 MacMillan Cancer Support

AG McCluskey (2016). The Angry Silence Zongo’s Cancer Diaries

Live Long & Prosper!

A bit of good news today.

Macmillan Cancer Support have released a report, Cancer: Then and Now, which shows that people diagnosed with cancer are twice as likely to survive for at least a decade they were in the early 1970s.

Cancer incidence rates UK 1979-2013Now this is a great thing to see.  Quite often, I’ve heard people complaining about the fact that cancer incidence rates have risen since the 1970s.  And it’s true, more people are diagnosed with cancer nowadays, as you can see in this graph from CRUK.  For both men and women, while the lines may wobble a bit, the overall trend is an increase in cancer incidence.  On average, the incidence rate in 1979 was 450 per 100,000.  By 2013, this had risen to 600 per 100,000.  Or, to express it as the relative risk so popular in the media, cancer incidence rose by 33.3% in that timeframe.  Now this can seem down-heartening.  Depressing, even.  And Scary.  But what does this increase actually mean?

I’ve heard complaints that this increase is down to our lifestyles.  E numbers in food….GMOs….poor diets…..pollution…..you name it.  And, in one sense, these people are right.  In a sense, increased cancer incidence is down to our lifestyles.  Just not in the way that they imagine.

UK Life expectancy 1980-2012As I’ve mentioned before – waaaaay back in Chinese Whispers – cancer is, generally, a disease of aging.  The longer you live, the bigger the probability that you’ll get cancer.  And that’s the point.  Yes, it’s true that cancer incidence has increased since the 1970s, but so has life expectancy.  This figure from UK National Statistics, and it covers, more or less, the same timeframe as the cancer incidence figure above.  Now, what you can see right away is that life expectancy is also increasing on average, from 71 & 77 for men and women respectively in 1980, to 78.7 & 82.6 in 2010-12.  And this equates to a rise of approx 11% for men and 7% for women.

So we are living longer.  And as cancer is more likely the longer you live, cancer rates would be expected to rise.  “But!” I hear you cry, “Surely cancer incidence is rising faster than life expectancy!”  Why would that be??”

Well, for a start, this is a logical fallacy.  There’s no direct connection between the two sets of statistics, so there’s no reason to expect that they will go up or go down by exactly the same amount.  And people do die from other things, so this will lower life expectancy.

But it is also down to one of the factors highlighted in the MacMillan report.  We are getting better at diagnosing cancer – and in early diagnosis.  So, 40 years ago, people might have cancer for a long time before diagnosis.  Some may even have died from undiagnosed diseases.  But improvements in scanning technology and in the development of tests for cancer-specific markers mean that this is less likely.  So we can spot these things earlier.  And the earlier a disease is found, the more treatable it is.

Marginal Gains 2I’ve shown this figure from CRUK before – and I’m more than happy to show it again!  This one shows how the survival rates for the commonly found cancers in the UK have changed from the early 70s until 2010.  And, as you can see, all the arrows are pointing to the right.  Survival is increasing across the board.  So, yes, cancer incidence rates are increasing.  But detection & survival rates are increasing too.

Better chemotherapy treatments are available.  Cancer patients are fast-tracked to ensure their treatment starts earlier.  The improvements in scanning technology which allow better diagnoses also give surgeons a better view of tumours – where they are, how big they are, whether they’ve spread.  And that makes successful surgery more likely and also increases the potential for other treatments such as radiotherapy.

Does this mean everything is Okay-Dokay-Fine?  No, of course not.  There’s still a lot to do.  But, in a time where it seems as if everything’s going down the crapper (Hi there, Brexit!  Yo, President Trump!), it’s nice to have a wee bit of good news for a change.  And if you are suffering from cancer, or know someone who is, then that’s what you’ll get today.  This is the (ahem) “best” time there’s ever been to be a cancer patient.  Your chances of surviving, of living a long & happy life are better now that they’ve ever, EVER been.  Might not seem like much, but that tiny sliver of light can mean a helluva lot, if all you see is darkness.

So have a good day, folks.  Live Long & Prosper.


MacMillan Cancer Support (2016). Cancer: Then and Now. Diagnosis, treatment and aftercare from 1970–2016 MacMillan Cancer Support

AG McCluskey (2016). Life Long & Prosper! Zongo’s Cancer Diaries

Computer Says No

Anti-cancer therapy and Autoimmune disease:  Part II

Computer Says NoSo, in my last post I gave a brief description of Autimmune conditions.  Now, I’m going to describe the ways that research into cancer treatments is impacting on these diseases.

There was a big splash in the Media last Friday about a potential new treatment for certain forms of Multiple Sclerosis (MS).  And the basis of that treatment?  Chemotherapy.  Yes, that’s right, cancer chemotherapy.  MS patients are being treated with high doses of chemotherapy drugs to try and alleviate their symptoms.  But why would you do this??  And how can it work?

I’ve spoken before about the common side-effects of cancer therapies such as chemotherapy and radiotherapy.  Back in Bullseye! I described how these treatments can damage the patients’ immune systems.  And this can be very bad for the patient, obviously.  But the thing is, something which is bad in one setting can actually be good in another.

Listen to me!  I sound like one of those self-help books.  Turn that frown upside down! Accentuate the positive, eliminate the negative!  Take a sad soooong and make it better…..  But this, in essence, is the basis of the new treatment for MS that is being investigated.

So MS, like other Autoimmune diseases, is caused by an out-of-control immune reaction.  So, what could you do to you fix it?  How could you get the immune response back under control?  Well, conventional treatments have tried to suppress the immune response in these patients.  This has only had limited success, unfortunately.  This led some researchers to consider something more drastic. They decided to treat the immune system like a computer.

Picture the scene:  You’re on your PC, and it stops working.  What do you do?  Easy.  Chances are, you switch it off, then switch it back on again.  And you hope that this’ll fix the problem.  But what if it doesn’t work?  What if you find that the program is corrupted?  Well, you can erase the corrupted version from your hard-disk and then re-install a clean version.  And this, essentially, is the concept behind the new treatment for MS.

In cancer patients, there is an extreme form of treatment that is sometimes used which involves very high doses of chemotherapy or radiotherapy.  Now, this may, or may not, destroy the patient’s tumour.  Obviously, it’s hoped that it’ll be the former!  But one thing it definitely will do, as a side-effect, is destroy the patient’s immune system.  This is obviously not great, so in order to mitigate these unwanted side-effects, clinicians will repair the damage to the patient’s immune response by restoring the immune system after treatment.  They do this using a technique called haemopoietic stem cell transplantation.

The haemopoietic stem cells live in your bone marrow and are the cells which give rise to all the different types of immune system cells.  These are destroyed by the high dose therapy and this is what damages the patient’s immune system irreparably.  So, knowing this is going to happen, clinicians remove some of the haemopoietic stem cells from the patient and store them before the high dose treatment is administered.  After the treatment has finished, the clinicians can then put the patient’s haemopoietic stem cells back into their body, where they will grow and divide, and recreate the patient’s immune system.

So, that is what happens in cancer.  But how does this apply to MS? Well, clinicians realised that what was a negative in a cancer setting – the destruction of & replacement of the immune system – could be a positive in the case of Autoimmune diseases.  Autoimmune conditions are caused by aberrant immune responses, and high-dose chemotherapy or radiotherapy destroys the immune response.

So clinicians theorised that, like a computer, the use of high dose anti-cancer therapies, coupled with haemopoietic stem cell recovery & transplantation might erase the corrupted version of the patients’ immune systems and replace them with a rebooted, correctly functioning version.

So, a trial was conducted where haemopoietic stem cells were isolated from 24 MS patients.  The 24 patients were then dosed with very high doses of chemotherapy drugs, which destroyed their immune systems.  Then, the haemopoietic stem cells were put back.

Now.  Sounds easy, yeah?  Well…..no.  This treatment is not straightforward.  Far from it.  It is incredibly tricky.  And, it is incredibly risky. Chemotherapy drugs can have very, VERY nasty side-effects – and not just against the immune system.  Indeed, one of the patients actually died during the course of this treatment, and all of the others suffered from a variety of pretty serious side-effects.  So, not a walk in the park, by any means.

But, in the 23 patients who survived the treatment, the early results seem to be very promising.  Their rebooted immune systems appear, so far, to be functioning normally, with no evidence of MS-related activity.  Some of them have reported that their symptoms have stabilised.  Others have actually seen an improvement in their conditions, recovering their mobility and quality of life.

So, all good, so far.  And, as well as MS, similar studies are ongoing in patients with other Autoimmune conditions, such as Scleroderma.  Now it’s still early days.  There’s no way of knowing how long the rebooted immune systems in these patients will maintain their normal function.  Hopefully, their immune systems will remain normal for a very, very long time.  But, it’s possible that their rebooted immunity might contain the same flaws as the original, so that the Autoimmune conditions re-emerge.  But even if this is the case, when could this happen?  Dunno.  There’s no way to tell yet.

Also, there is no way of knowing what other long-term effects will be caused by the high dose treatments.  This approach is basically using a sledge-hammer to crack a nut – it hits the immune system, certainly, but it hits a lot of other things too.  Studies of cancer survivors have shown that these high dose treatments can damage the digestive system, liver, kidneys, cardiovascular system and many others.  And a lot of this damage may not become apparent for many years after the treatment has ended.  So, it’s likely that similar side-effects will also be observed in the follow-up studies of the MS & Scleroderma patients taking part in these trials.  So, a lot (and I mean, a LOT) of extra study will be needed to work out the long-term health risks of this approach.

But remember, this is just the early stages of this type of approach.  If it can be shown to have real long-term benefits, then it will help drive research into finding more immune-specific treatments that can avoid potential off target side-effects.  That still needs to be determined though.  All we can say is that for now, for right now, we have a therapy which has the potential to be a major breakthrough in the treatment of MS, Scleroderma and other Autoimmune diseases.

Dr Harold L Atkins, MDcorrespondenceemail, Marjorie Bowman, MScN, David Allan, MD, Grizel Anstee, MD, Prof Douglas L Arnold, MD, Prof Amit Bar-Or, MD, Isabelle Bence-Bruckler, MD, Paul Birch, MLT, Prof Christopher Bredeson, MD, Jacqueline Chen, PhD, Prof (2016). Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial The Lancet : http://dx.doi.org/10.1016/S0140-6736(16)30169-6

Craciunescu, O., Steffey, B., Kelsey, C., Larrier, N., Paarz-Largay, C., Prosnitz, R., Chao, N., Chute, J., Gasparetto, C., Horwitz, M., Long, G., Rizzieri, D., & Sullivan, K. (2011). Renal Shielding and Dosimetry for Patients With Severe Systemic Sclerosis Receiving Immunoablation With Total Body Irradiation in the Scleroderma: Cyclophosphamide or Transplantation Trial International Journal of Radiation Oncology*Biology*Physics, 79 (4), 1248-1255 DOI: 10.1016/j.ijrobp.2010.05.036


AG McCluskey (2016). Computer Says No Zongo’s Cancer Diaries

Collateral Damage

Anti-cancer therapy and Autoimmune disease:  Part I

Collateral DamageBit of a detour in this post, as I’m going to be talking about Autoimmune diseases.  There is a cancer connection though, which is the current trials into the use of anti-cancer therapy to treat these Autoimmune conditions.  But, in order to explain how this works, I need to explain what Autoimmune diseases are.  So, that will be the subject of this post.  In the next one I’ll go on to discuss the current attempts to treat these diseases with chemotherapy and radiotherapy.

So.  Here we go.  Autoimmune disease 101:

Autoimmune diseases are caused by errors in the patient’s immune system.  Now, your immune system is there to do a very specific, very important job.  It’s there to protect you against infection.  The cells of your immune system circulate through your body, looking for anything that doesn’t belong.  If they find anything, they attack & destroy it.  This is how you fight off viruses, bacteria, fungal infections, etc.

So that’s what the immune system does.  It wanders about, looking for a fight.  But why doesn’t it start a fight with your own cells?  Well, as I described back in No Cure For Cancer…? every cell in your body has a protein on the outside called MHC, which acts like an “identity card” for the immune system.  So, normally, the immune system will ignore any cell which has the correct “identity card”, which is why it’s so hard to activate an immune response to cancer cells.

But, unfortunately, in some people this system breaks down.  Their immune systems stop recognising the “identity card” on some of their cells, which leads to them being incorrectly labelled as foreign invaders.  It’s a bit like the reports we’ve all heard from Iraq & Afghanistan, where innocent civilians are incorrectly identified as Enemy Combatants and blown to bits.  “Collateral Damage” is the oddly benign euphemism for this.  And the same thing happens in an Autoimmune disease.  So, the immune system goes on the offensive and starts to attack the supposed “foreign invaders”.

Different cell types come under attack in different Autoimmune diseases. In Rheumatoid Arthritis it is the joints. In Scleroderma it is the connective tissue that surrounds your blood vessels & major organs. And in MS it is a specialised cell type called oligodendrocytes.  I’m now going to describe the situation in MS, but similar events occur in Rheumatoid Arthritis, Scleroderma and other Autoimmine conditions.

So, in MS, the cells that comes under attack are the oligodendrocytes, which are part of your Central Nervous System (CNS).  The CNS is how information moves from your brain to your body and vice versa.  So, if you feel hot or cold, hurt yourself or feel hungry etc, then the information travels up the CNS to the brain.  If you decide to move your arms & legs, pick your nose or whatever, then your brain sends the appropriate signals to your body via the CNS.  Now, the signals work like electrical currents travelling through your nerves, in much the same way as the electricity running through the wires that power appliances like your TV, tablet, PC, etc.  In these appliances, the electrical wires  are covered in plastic insulation to prevent short circuits, which can damage the appliance, possibly irreparably.

And, in exactly the same way, your nerves are also covered in insulation to prevent “short circuits” in your CNS.  This biological insulator is called Myelin, and it is made by the oligodendrocytes.  So, in people with MS, the out-of-control immune response attacks & destroys the oligodendrocytes.  This means that their bodies can no longer make the insulating Myelin which protects the nerves in their CNS.  Therefore, their nerves become exposed, and this results in “short circuits” in their CNS.  And this is what causes the symptoms of MS.

In other Autoimmune conditions, the same thing happens.  In Rheumatoid arthritis, the painful swelling and deformation in the patients’ joints is caused by damage to the cartilage and bone.  In Scleroderma, damage to the connective tissue under the skin and around internal organs and blood vessels, leads to hard, painful swelling on the skin, circulatory problems and organ failure.  But in each case, like MS, the real issue in the aberrant, out-of-control immune response.

Right!  Now you have a (very!) brief description of Autoimmune diseases in general and MS in particular.  In the next post, I’ll go on to describe the potential of anti-cancer therapies for treating these conditions.

Bell, E., & Bird, L. (2005). Autoimmunity Nature, 435 (7042), 583-583 DOI: 10.1038/435583a


AG McCluskey (2016). Collateral Damage Zongo’s Cancer Diaries