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

ResearchBlogging.org

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

Best Laid Plans

Best Laid PlansWant to hear a joke?  A really, really good one?  Well I’ve got one for you, and it’s a cracker.  It’s one of those jokes that’s a bit dark.  A bit sick, if I’m honest.  And it’ll both tickle your funny bone, and leave you outraged.  Hopping mad, even.

Believe me.  When I heard it, the first thing I did was laugh out loud.  And then I got angry.  Really, REALLY bloody angry.  And the best of it is, that I am the butt of this particular joke.  Me, personally.  I’m the punchline.  Still want to hear it?  Well, here goes.  I just saw this headline in the Guardian:

Revealed: cancer scientists’ pensions invested in tobacco

Yup.  You read that right.  Like most other workplaces, researchers who work in UK universities – researchers like me – have a pension scheme.  Ours is called USS (University Superannuation Scheme) and it is used by the majority of universities in the UK.  So, every cancer researcher based in a UK university uses this scheme.

And, unknown to us, it seems that our scheme has been investing in the tobacco industry for years.  So, every university-based cancer researcher in the UK has, unwittingly, been indirectly profiting from cigarette sales.

Good joke, eh?  Isn’t that a doozy?

Now to say that I am unhappy about this particular state of affairs would be an understatement.  I’m not so much unhappy, as hopping bloody mad.  I’ve spent 20-odd years trying to develop new treatment options for cancer.  So, it’s more than a little galling to discover that I’ve actually, in all that time, been a total hypocrite.

When I retire and start to claim my pension, some of that money will be derived from the World’s most infamous cause of the very diseases I spent a career trying to treat.

I. Am. Not. Happy.

How could this have happened?  What were the directors of the pension scheme THINKING?  Well.  It’s pretty obvious, really.  They were thinking about one thing, and one thing only.  Profit.

We live in an age of Free Market Capitalism, where the only important consideration in any business, in any industry, is The Bottom Line.  Are you in the Red, or in the Black?  And how much are you in the Red or Black?  Profit is King.  It trumps all other considerations.  Morals?  Ethics?  Workers’ rights?  Pah!  As long as you’ve got a nice, fat number in the Plus column, then you’re laughing, right?  Job done.

And if you’ve gotten that number using methods that go against the fundamental principles of your stakeholders?  Who cares?  Screw ’em!  What are they going to do?  Give the money BACK?

So.  Was I surprised by the discovery that USS profits from tobacco?  Yes I was, naive fool that I am.  But was I shocked to the core of my being??  No.  It’s repugnant, but not shocking.  I know how the world works.

But that doesn’t make it RIGHT.  And it doesn’t mean that I just have to shrug and accept it.  This is wrong.  Plain wrong.  And I need to try and change it.  I don’t know how.  I don’t know if I can.  But I have to try, at least.

This is not over.

 

………………………….

ResearchBlogging.org

AG McCluskey (2016). Best Laid Plans Zongo’s Cancer Diaries

Patent-ly Obvious…?

Patent-ly ObviousSomething important happened a few months back.  Something which you probably don’t know anything about, because it wasn’t given the prominence it deserved.  But you should know about it, because it could, potentially, impact every single one of us.

An Australian grandmother won a landmark legal case, which has major ramifications for scientific research.  And what did she win?

She won the right for Australians to own their own bodies……..

Say……….WHAT????  What the hell does THAT mean??  Of course Australians own their own bodies!  They’re not slaves!

Ah……but that’s the thing.  Up until she won that case, there were people in Australia who didn’t own their own body….at least, not all of it.  There were teeny weeny bits of every Australian that actually, legally, belonged to someone else.  And it’s not just Australians….there are literally billions of people in the same situation.  Even YOU, sitting there, reading this may not legally own all of yourself.  Maybe even ME, as I write this, may not own all of myself…..

Let me explain.  In my last post, I spoke about the way that scientists are starting to identify and characterise tumour-specific genes and gene mutations, which they will use to develop new therapies and improve treatment planning.  Which is all very well and good, obviously, but it raises an interesting question.  One which has probably never occurred to most people before.

Who owns these genes?

“Huh?” I here you ask, “What do you mean, who OWNS them?  How can anyone “own” a gene?”  Well, that’s a good question.  And it takes us into a very tricky, and VERY controversial area:  Gene Patenting.

In one sense, it sounds like madness.  How can you patent a human gene?  After all, these tumour-specific genes are present in cancer patients, aren’t they?  They aren’t artificial or synthetic.  They are part of the patients’ genetic makeup.  They are entirely natural.  So, how could it be possible for another person or business to OWN them?  It would mean that a cancer patient’s genome didn’t belong to them.  Part of their genome would actually belong to some other person or persons.  How the hell could that be possible?

Well, as mad as it sounds, this is EXACTLY what happens.  Many of the genes which have been identified – genes which are an entirely natural part of the human genome – are currently under patent.  They are owned by Biotech companies who are able to profit from their commercial exploitation.

But….how can this be??  How can you patent a naturally occurring gene?  And how can you make money from it?

Well……technically you can’t.  A patent only covers a new, novel concept or invention.  Therefore, any organism which is found in nature cannot be patented.  And this is why you cannot patent a plant or animal which is found in the wild.

So, surely this means that anyone who tried to patent a human gene would be laughed out of the building, right?  Nope.  This is because, in order to identify a gene in the first place, you have to use some sophisticated scientific techniques, which require specialised Hi-tech equipment.  Both of which had to be thought of.  Both of which had to be created.  And both of which can be PATENTED.  This is the loophole in the patenting laws which Biotech companies can exploit.  While the GENE cannot be patented because it’s natural, the METHOD used to identify it can.  And therefore, anything found by using that method comes under the terms of the patent and can be exploited commercially.  And has been.  Oh boy…..has it ever!  The numbers are a little unclear, but one recent study suggested that as much as 41% of the genes in the human genome have been patented in this fashion!

Now, to say that this had been controversial is a bit of an understatement.  Research scientists object because it stifles their work.  If their research identifies new genes then their work – their effort – will become the property of someone else, so why bother?  Other biotech companies object because it eats into any potential profits from their own products.  Clinicians object because it increases the costs of new diagnostic tests & treatments.  And lots of people across the board (scientists, doctors, patients, politicians, lawyers), they object for ethical reasons and question the legality of a gene – a naturally occurring object – being under patent.

The legal wrangles have been rumbling on for years.  The U.S. Supreme Court ruled against the gene patenting in 2013.  Which is great, obviously, but if the company holds patents in different countries, then the rules need changing in every one.  So the U.S. decision is not enforceable anywhere else.

Which brings us to the Australian case.  In a nutshell, a breast cancer patient called Yvonne D’Arcy brought a case against a Biotech company called Myriad Genetics which holds a patent for the BRCA1 gene.  BRCA1 is involved in DNA repair processes, and BRCA1 mutation has long been known to be associated with an increased risk of hereditary breast and ovarian cancers.    Now, an important point here is that Mrs D’Arcy didn’t have a BRCA1 mutation herself, so her decision wasn’t based on self-interest.  Instead, Mrs D’Arcy objected to this patent on the basis that it increased the costs of genetic screening and could, therefore, mean lower identification rates for women with a predisposition for breast and ovarian cancers.

Initially, the Australian Federal Court ruled in the company’s favour, but Mrs D’Arcy appealed and, at the end of 2015, the Appeal Court ruled that the BRCA1 protein, both the normal active form and the mutant which indicates of susceptibility to breast and ovarian cancer, was not a “patentable invention”.

Success!…and it seems as if the tide is turning.  Already, there are cases being brought in Canada against the patenting of genes and it looks as if the number of patents being filed for genetic sequences is falling worldwide.  So hopefully, one day, private businesses will no longer be able to claim ownership of naturally occurring genes and genetic material.

But until then, the fight goes on….

………………………………..

Rosenfeld, J., & Mason, C. (2013). Pervasive sequence patents cover the entire human genome Genome Medicine, 5 (3) DOI: 10.1186/gm431

Liddicoat J, Whitton T, & Nicol D (2015). Are the gene-patent storm clouds dissipating? A global snapshot. Nature biotechnology, 33 (4), 347-52 PMID: 25850055

ResearchBlogging.org
AG McCluskey (2016). Patent-ly Obvious…? Zongo’s Cancer Diaries

The One And Only

Marginal Gains 2We are living in an age of transition.  Things are changing in the world of oncology, and these changes are going to have major ramifications for the clinical experiences of future cancer patients.  In the last 30 years, there has been a huge improvement in cancer survival, as shown in the figure.  Now, there are multiple reasons for these improvements.

The development of, and the advances in, diagnostic testing methods has led to earlier disease detection – and earlier diagnosis improves the likelihood of survival.  Also, improvements in scanning machinery coupled to the huge advances in computer technology has led to the development of precise, real time 3D imaging of tumours which has improved the targeting of radiotherapy beams and surgical excision – which has, itself also been proved by advances in keyhole surgery techniques.  Finally, the ongoing development of new chemotherapy drugs has increased the front-line and post-operative treatment options available to clinicians.

Now, all of this has made a difference.  A massive difference.  But more needs to be done.  And one big change that is coming – one that is being mentioned more and more – is the future potential of Personalised Medicine.

And this, Personalised Medicine, is the transition I started this post with.  Clinicians are starting to change the way they think about cancer – about what it is.  Or, to be more accurate, what they are – not a single disease, remember!  And this is leading to changes in how clinicians appraise the different treatment options available.

Now, I’ve mentioned before, cancer is an umbrella term for multiple diseases (see No Cure For Cancer…?).  So, breast cancer is different from colorectal cancer, which is different from lung cancer….etc, etc.  And I also mentioned in No Cure For Cancer…? that lung cancer is not one, single disease either, but can be subdivided into a variety of different cancers, which may require a variety of different treatments.

This type of thinking isn’t new, it’s how clinicians have thought about cancer for many years, and has, therefore, influenced both disease diagnosis and treatment scheduling.  But this is now changing.  It’s becoming more and more obvious that even this myriad of subdivisions is actually overly simplistic and the reality of each patient’s individual disease is much more complicated.

The reason for this is actually very simple.  Each of us is a unique individual.  We have our own unique genetic makeup.  Also, our own individual life experiences mean that the environmental factors we are exposed to, while not completely specific to each individual, are not going to be exactly identical to anybody else’s either.

And, as I’ve mentioned previously, cancer derived from a patient’s own cells.  Therefore, logically, if each patient is unique and their disease arises from themselves then this must mean that each patient’s disease is unique too!  The specific environmental factors each person is exposed to, coupled to the distinct genetic makeup of every individual, means that the risk of developing cancer (in any form) is likely to be different from person to person.  But, also, the way a cancer grows and spreads will likely be different from person to person too, as will the way the tumour responds to treatment, even if the tumours themselves appear to be similar at first.

So, consider the situation where two patients get diagnosed with the same disease, at the same stage, on the same day.  They may appear to be identical and, up till now, this has been the criteria used by clinicians to plan treatment options.  Oh, there will certainly be a whole lot of tests done to look at tumour markers, but on the whole the treatment options that are chosen will be based on size, position & stage of disease.

But actually, there is no guarantee that these two patients will respond to the same treatment in the same way.  This is because their tumours, despite the outward similarity, will actually be very different at an intracellular level.  They will have different genetic backgrounds, different metabolic rates and will be exposed to different environmental factors.  All because of the differences between the patients themselves.

And it is this – the fundamental differences between the tumours – that influence the success of different forms of treatment.  Different chemotherapy drugs target different proteins inside cells (the “Bills” from my Drug Discovery posts).  So, in the example above, the two patients with outwardly similar tumour will be treated with the same chemotherapy drug.  But, if one patient lacks the protein that drug targets, or has a mutation in the gene that makes it (which in turn changes the way it is put together), then the drug won’t work in this patient.  And the tumour will progress in that patient.

But this is starting to change.  Scientists are starting to investigate the tumours from individual patients, in order to identify the specific genes and other tumour-specific markers that can influence drug activity, tumour growth, disease progression etc, etc.  Recently, a major study in Breast cancer identified 93 different genes which could influence Breast cancer growth and development.  Now, these 93 genes don’t all do the same things, they are all different.  And not all 93 have to be present to get the disease.

But the presence or absence of these specific genes can influence how a tumour grows.  So, patient 1 might have, say, 5 of them.  If so, which 5?  What do those individual genes control?  Patient 2, however, has 10 of them – a different subset, with no overlap to patient 1’s markers.  What do these 10 genes control?  How will they influence tumour growth, treatment efficacy, etc?

And this is just the beginning.  Similar genotyping studies are being carried out for other types of cancer.  And it will be the results of these studies that will change treatment planning.  In future, when a patient is first diagnosed, as well as assessing the position, placement and stage of the disease, clinicians will also assess the specific genetic makeup of that individual patent’s individual tumour.  And then they will tailor the treatments they offer, in order to meet that patient’s specific requirements.

So remember:  You are an individual.  Your disease is also individual.  And, in future, your treatment will be individual too.

Welcome to the age of Personalised Medicine.

 

…………………………………….

Nik-Zainal, S., Davies, H., Staaf, J., Ramakrishna, M., Glodzik, D., Zou, X., Martincorena, I., Alexandrov, L., Martin, S., Wedge, D., Van Loo, P., Ju, Y., Smid, M., Brinkman, A., Morganella, S., Aure, M., Lingjærde, O., Langerød, A., Ringnér, M., Ahn, S., Boyault, S., Brock, J., Broeks, A., Butler, A., Desmedt, C., Dirix, L., Dronov, S., Fatima, A., Foekens, J., Gerstung, M., Hooijer, G., Jang, S., Jones, D., Kim, H., King, T., Krishnamurthy, S., Lee, H., Lee, J., Li, Y., McLaren, S., Menzies, A., Mustonen, V., O’Meara, S., Pauporté, I., Pivot, X., Purdie, C., Raine, K., Ramakrishnan, K., Rodríguez-González, F., Romieu, G., Sieuwerts, A., Simpson, P., Shepherd, R., Stebbings, L., Stefansson, O., Teague, J., Tommasi, S., Treilleux, I., Van den Eynden, G., Vermeulen, P., Vincent-Salomon, A., Yates, L., Caldas, C., Veer, L., Tutt, A., Knappskog, S., Tan, B., Jonkers, J., Borg, �., Ueno, N., Sotiriou, C., Viari, A., Futreal, P., Campbell, P., Span, P., Van Laere, S., Lakhani, S., Eyfjord, J., Thompson, A., Birney, E., Stunnenberg, H., van de Vijver, M., Martens, J., Børresen-Dale, A., Richardson, A., Kong, G., Thomas, G., & Stratton, M. (2016). Landscape of somatic mutations in 560 breast cancer whole-genome sequences Nature DOI: 10.1038/nature17676

Morganella, S., Alexandrov, L., Glodzik, D., Zou, X., Davies, H., Staaf, J., Sieuwerts, A., Brinkman, A., Martin, S., Ramakrishna, M., Butler, A., Kim, H., Borg, �., Sotiriou, C., Futreal, P., Campbell, P., Span, P., Van Laere, S., Lakhani, S., Eyfjord, J., Thompson, A., Stunnenberg, H., van de Vijver, M., Martens, J., Børresen-Dale, A., Richardson, A., Kong, G., Thomas, G., Sale, J., Rada, C., Stratton, M., Birney, E., & Nik-Zainal, S. (2016). The topography of mutational processes in breast cancer genomes Nature Communications, 7 DOI: 10.1038/ncomms11383

ResearchBlogging.org
AG McCluskey (2016). The One And Only Zongo’s Cancer Diaries

Fight The Good Fight?

 

Fight the good fightInteresting story in the Guardian last week.  “CRUK defends use of amateur boxing events for fundraising.”

Basically, CRUK have been working with a company called Ultra White Collar Boxing (UWCB) who organise amateur boxing matches in order to raise funds for cancer research.  This has drawn criticism from boxing’s governing bodies, Boxing Scotland and England Boxing, both of which highlight the potentially serious health risks to the participants.  In response, a CRUK spokesman replied, “….UWCB adhere to all necessary health and safety procedures….(and) has raised an incredible £3.7m for the charity.  Cancer Research UK receives no government funding, so we rely solely on the money we receive from our supporters.”

Now, this raises an interesting question about how charity fundraising is carried out.

There are a helluva lot of charities out there, all trying to raise money and increase public awareness about their chosen area.  When it comes to cancer, the best known of these is obviously CRUK, which has an interest in cancer as a whole, ie. in ALL forms of cancer and in all types of treatment & care provision.  But, as well as CRUK, there are many, many other cancer charities out there.

These tend to be smaller organisations, with a more focused remit.  Often they will be interested in specific types of cancer, eg. Prostate Cancer UK, Breast Cancer Now, Neuroblastoma UK (who have funded a lot of my work through the years) and many, many others.

Also, there are other organisations out there, who are less interested in particular diseases, but are more interested in the specific patients who are affected (eg. Children With Cancer), or in patient care provision (eg. MacMillan Cancer Support).  Others are interested in funding specific types of study (eg. the Hadwen Trust).

But, whatever the specific organisation, you’ll often find that the people involved in setting up & running these charities have a very personal reason for doing so.  Either they have suffered from cancer themselves, or else a loved one has (and in the case of the people involved with Neuroblastoma UK – a childhood cancer, remember – I can tell you from personal experience that listening to their stories is utterly heartbreaking.)

And there is no doubt that the work these people do is good.  The money they raise – the money they distribute – makes a real difference.  The research they fund provides insight into the fundamental causes of cancer.  They help to find new targets for drug development and other new treatment methods.  They fund the clinical trials to test these new treatments.  They fund patient support groups.  They fund hospices.  These people work tirelessly, with total dedication, to try and improve cancer treatments and patient care, and I have nothing but the UTMOST respect for them.

But the Guardian story raises an interesting question.  One which I’m not sure I can answer.  How should money be raised?  What’s an appropriate way of fundraising?  And, crucially, what is not appropriate?  Now, it seems obvious that there are certain people that cancer charities shouldn’t be taking money from.  Criminal organisations, for instance.  Or Tobacco companies….Especially the latter.  So, not all donations are acceptable.

But where do you draw the line?  And do UWCB’s activities cross that line?  Is it right for cancer charities (or any charities) to take the money raised by these boxing events?  After all, the health risks of boxing have been debated repeatedly over the years.  So, should a health charity take money from an organisation whose activities might have serious health consequences?

It’s a tricky question.  But the thing is, if the answer is “No, they shouldn’t take that money”, well that just opens a can of worms, because there are plenty of other activities used for fundraising which could be considered dangerous too.  So, is it OK to take money from someone doing a sponsored marathon?  Or a hill climb?  Because both of these activities can also be incredibly dangerous if the participant is under prepared.  What about bungee jumping?  Or sky diving?  These could also be considered dangerous pursuits, but I’ve never seen any objections to the use of money raised from these activities either.

Now, certainly, it could be argued that boxing is different.  It involves acts of intentional harm.  Shouldn’t that be taken into account?  Well…..maybe so.  But then, surely, this brings up the subject of free will.  The participants in these events are not being forced into it, nor are they being hoodwinked.  On the contrary, the people involved are, in general, well aware of the potential risks and are still choosing to take part.  So, should their personal opinions and choices be dismissed?  Again, I’m not sure I can say Yay or Nay.

And remember, these activities have raised millions.  That should count for something, right?  Well, actually, we’re on firmer ground here.  The amount means nothing.  After all, as I said earlier, the tobacco companies would be more than happy to shovel gazillions into cancer charities (and possibly still do, in countries where they can get away with it).   But the good that money could do would be off-set massively by the validation the tobacco companies would gain from the gesture – and would then use to justify their activities.

So, the end does not always justify the means.  Those involved in running the charities have to decide, on a case by case basis, whether to accept a donation or not.  Most times, they’ll get it right.  But sometimes, they’ll get it wrong.  Whether this is one of those times….?  I don’t know.  But I do know that they’ll make the choices that seem correct to them at the time.

And what more could any of us ask?

 

PS.  The eagle-eyed will have noticed that I’ve provided links to the cancer charities mentioned in this post.  Just click on the name of the charity, and you’ll be taken to their website.  Please:  follow a link.  Make a donation.  However big or small an amount, any money you can give can make a difference.  Cheers.

…………….

O’Toole, L., Nurse, P., & Radda, G. (2003). An analysis of cancer research funding in the UK Nature Reviews Cancer, 3 (2), 139-143 DOI: 10.1038/nrc994

ResearchBlogging.org
AG McCluskey (2016). Fight The Good Fight? Zongo’s Cancer Diaries

Review, Refine, Redesign

Drug Discovery: Part III

Review, Refine, RedesignSo, this post follows on the story of how new drugs are discovered and developed.  Back in Kill “Bill” !!!, I explained how epidemiological techniques are used to try and identify new targets for Drug Development.  And then, in Blocks & Locks…, I described how compound libraries & natural products are used to try and find chemical agents that will bind to the target.  Now, in this post, I’m going to talk about what happens next.

…But why SHOULD there be a next step at all?  I mean, we’ve found a chemical agent that hits the target, right?  Job done, surely?

Um…no.  Sorry.  It aint that simple, I’m afraid.  In fact, the REAL work has only just started.

There are several issues that need to be fixed before your chemical agent (called the Initial Hit in the vernacular) can be turned into a drug that can progress to clinical trials.  The first issue has to do with the way that cells are put together.  The inside of every cell is full of stuff.  There are factories, powers stations, structural supports, transport systems, waste management systems… Just LOADS of stuff.  And all of it relies on proteins.  There are hundreds and hundreds of different types of proteins inside your cells, bumping into each other, reacting with each other, getting involved in cascades where one protein reacts with another & makes it go & react with a third, which goes & reacts with a fourth, which reacts with a fifth…..and so on and so on.

Now, the point is, the target you want to hit with your new drug – the “Bill” from the last couple of posts – it is just one of these proteins.  So you want your drug to hit the “Bill”.  And ONLY the “Bill”, because the “Bill” is specific to (or at least more commonly found in) cancer cells.

But!  The problem is that many of the proteins found in your cells look very similar. They have “common motifs”, as we say.  Back in Blocks & Locks…, I described the “Bill” as being like a lock, and the Initial Hit as being like a key for that lock.  So, when I say that the proteins have common motifs, what I mean is that the “locks” on the proteins all look so similar, that you need to find a very, very specific key – one that only fits the lock on your “Bill” and no other.

But, you might find that while the Initial Hit you’ve found – the one you hope to turn into a new drug – fits the “Bill” lock, it also fits the locks of other proteins too.  A lot of other proteins.  Potentially, it could fit HUNDREDS of other proteins.  And this is baaaaaaad.  The less specific your Initial Hit is, the more off-target effects you’ll get.  And if those off-target effects damage normal cells as well as cancer cells, not only will it be less effective against the cancer, it could cause very, VERY nasty side effects if you give it to patients.

The second main issue you have to consider is how sensitive your Initial Hit is.  Or, to put it another way, how much of it you need to give to show an effect.  What you need in a drug, is not just a chemical agent that hits the target, but one that shows its effects at very low concentrations, so that the amount that you need to give the patient isn’t too big.  There’s no point having a drug that hits the target perfectly, with no off-target effects, if you have to give it in a pill the size of a grand-size pizza.  Or an injection the size of a barrel.

The third main issue is the easiest to understand:  does it dissolve in water?  Lots of medical treatments are given through a drip, so your drug has to be soluble.  If it isn’t, then this is a MAJOR drawback for its clinical use.  In order to get to the tumour and have an effect, drugs have to travel through the bloodstream, so the most effect way is to put it in a drip, so it can be injected straight into a vein.  A drug that is delivered in pill form has to be digested.  Not only could the digestive enzymes affect the drug, making it ineffective, but there’s no guarantee that the drug will pass through the digestive system into the bloodstream at all, so it may not get anywhere near the tumour anyway.

So that’s your three main issues:

Specificity – Does your agent hit any other targets?

Sensitivity – What’s the lowest amount you need to show the desired effect?

Solubility – Can you put it into a solution, so it can be delivered through the bloodstream?

Now, chances are while your Initial Hit targets your “Bill”, unless you’re very VERY lucky, it’s likely to have low Specificity, low Sensitivity and low Solubility. So, your Initial Hit will have lots of off-target effects and you’d need bucket loads of it to have an effect.  Neither of which matters, as it isn’t soluble in water, so you’ll never be able to deliver it anyway.

So, this is where Medicinal Chemistry comes in.  This is the branch of science which aims to overcome these problems.  The chemists know the chemical structure of the Initial Hit.  So, they start to alter it by changing the chemical building blocks (see Blocks & Locks… again) – adding bits here, removing bits there – changing the structure, to try and improve its performance.  The aim is to increase the Specificity so that off-target effects are minimised, increase the Sensitivity so that lower doses produce maximum effects, and increase the Solubility, so that it can be delivered effectively.

This known in the trade as “Hit to Lead optimisation”.  Basically, this is where you try to turn your Initial Hit into a “Lead Compound”, ie. one which “leads the way”, and so has improved performance and is more drug-like.  Often, it is a balancing act.  Altering one bit of the chemistry might increase the Specificity, but changing that bit also decreases the Sensitivity.  Or, you might make a change that increases the Sensitivity, but the off-target effects increase.  And reduces the Solubility.

This, basically, is what a large amount of Drug Discovery research comprises of.  The medicinal chemists take an Initial Hit and tweak the structure, then the biologists test it, to see if the change has improved it.  If it has, then the chemists take this new structure and tweak it again, to try and improve it further.  Maybe it will, maybe it won’t.  So, the biologists test this new version and give the results back to the chemists, who tweak the structure again to make another version…which the biologists test….which leads to another version…which the biologists test….etc, etc, etc.

This can go on for a loooong time, as the chemists try to improve the performance of each generation of compound.  But slowly – very slowly – subsequent iterations of the chemical will (hopefully!) show improvements until a Lead Compound is developed that can enter preclinical trials.

But that’s another story….

 

………….
Hughes, J., Rees, S., Kalindjian, S., & Philpott, K. (2011). Principles of early drug discovery British Journal of Pharmacology, 162 (6), 1239-1249 DOI: 10.1111/j.1476-5381.2010.01127.x

ResearchBlogging.org

AG McCluskey (2016). Review, Refine, Redesign Zongo’s Cancer Diaries

You Scratch My Back…

You scratch my backThere’s a stereotype that you often see in the movies or on TV.  The lone scientist working away in isolation on his (or her, but usually his) mad scheme.  Often they will be in an isolated location – maybe on an island, or even in a castle (looks dramatic, but the heating bills are horrendous) and usually with only one assistant (who might have some peculiar trait – maybe a deformity, maybe a questionable grip on sanity).

Now, obviously, Frankenstein is the most well known of this particular stereotype, but the same tropes pop up over and over in the media.  And you won’t be surprised to learn that it’s all bollocks.

For a start, scientists couldn’t conduct their work in the middle of nowhere.  Who would fund them?  (“You want this Research Council to fund your Foul, Unspeakable Study?  Yes that seems fine….But where will you do it?  On an island in the middle of the Atlantic?  Oh, I don’t think so – that’s outside our funding area.  We have some very nice facilities at a University near you, if that suits.  No?  Oh well”)

And how would they get the equipment?  You use a lot of consumable (plastic tubes, bags, disposable pipettes etc.)  How would they get them delivered? (“What’s the delivery address?  Oh, the “Secret Bunker” in the middle of the Sahara?  I think we may need to add an extra charge on that, Sir.”)

So, like I say:  Bollocks.

Also, another thing this stereotype gets wrong is the idea that scientists work in isolation.  Quite simply, that would never work.  Science is a communal thing.  Where do most scientists work?  Universities. And universities are communal and collegiate – they are about people working together collaboratively.

Collaboration is at the heart of the sciences, certainly the biological sciences.  Look at any research paper and you will (usually) see a long list of names, and more often than not, many of the authors will be based very far away geographically.

The reason for this is quite simple.  Over time, as the generations have passed, researchers have found that their work has become focused into ever more narrow areas of interest, so that an individual researcher may be an expert in one area, but be less knowledgeable about other areas – areas which, to an outsider, may seem to be very closely related.  So, I might have a lot of knowledge about certain biological pathways, eg. DNA damage responses, but that doesn’t mean I’m an expert in DNA replication (I might know the generalities, but not the specifics).

So, in the same way, when conducting a study, it’s quite common to find your work starting to move into another area – one which you might not know that much about.  Or, you might need access to some specialised equipment that is only found in a few places in the country.   And so, you will need to work with other researchers.  Now, these other researchers are not going to do this out of the goodness of their hearts, so there has do be something in it for them.  It could be that you can help them in their work, just as they are helping you with yours.  It could be that when you combine your separate sets of data together, it opens up new avenues of research (and therefore, potentially, new sources of funding).  And this is how scientific collaborations are formed.

This is why conferences are so useful.  You might go along to a conference in your area of research, but when you are there you will meet many other people, who may be working in a similar area, or they may be in your area, but coming from an angle you’ve never thought of.  Or, indeed, they might be in a totally unrelated area, but something they say makes a little lightbulb go “DING!” in the back of your head.

Either way, you’ll start to collaborate.  And that’s how science works.

 

…although, if anyone knows where I can find a deformed, psychotic minion to do my bidding, that would be great. They are waaaaay cheaper to employ than technicians…

…….

Brown, R., Deletic, A., & Wong, T. (2015). Interdisciplinarity: How to catalyse collaboration Nature, 525 (7569), 315-317 DOI: 10.1038/525315a

ResearchBlogging.org

AG McCluskey (2016). You Scratch My Back… Zongo’s Cancer Diaries