Stage 2

Tuesday 23 January 2018

I notice a slight tremor in my hand.

Nothing unusual about that. From time to time my hand shakes but it is only occasional and it usually doesn’t last more than a few seconds.

But then I look again in abject horror.

My heart skips a beat.

It is my left hand that is tremoring. My Parkinson’s started on my right side.

Can it be true? Can the disease have spread so rapidly to the other side of my brain that I am now starting Stage 2 only a year after being diagnosed with Stage 1? (See my previous post on the five stages of Parkinson’s.)

I open and close my left fist a few times, like I am asked to do at my medical appointments. Sure enough, the movements are slow due some stiffness, the same as I used to have on my right side when the thing first started. This stiffness on the left side is new. Meanwhile the stiffness in my right hand is worse than it used to be.

I am due to see The Professor in March for my next check-up at which point he will almost certainly introduce some new drugs to my pharmaceutical regimen. I feel under-medicated at the moment on my 1.57mg/day of pramipexole and I can’t increase my dosage of that due to all the side effects I experienced last year. There is now rigidity in my right hand most of the time and it occasionally tremors. My sleep is still disturbed, though better than it was a few months ago. When I go running, the discomfort in my right foot now starts soon after the first kilometre rather than half way through my 5K.

The slow death of the dopaminergic cells in my substantia nigra has undoubtedly continued throughout the year since I was diagnosed, but the start of symptoms on the other side of my body is an unexpected development. I hadn’t given much thought to when Stage 2 might start but I suppose I assumed it would be at least three or four years.

The symptoms will be alleviated soon enough when my meds are adjusted, and I will once again be able to function almost normally.

However, it is a stark reminder that the high stakes game of chess against the Parkinson’s grandmaster continues.

After some opening sparring in which we exchanged a couple of pawns each, he has now pulled off a surprise attack and moved a piece up – I have lost a knight perhaps. I still have plenty options on my side, but my defences have been weakened.

Across the world, teams of scientists continue to beaver away so that I might have smarter strategies at my disposal, if not to turn the tide then at least to prolong the match.

In the meantime, I make my next move in the knowledge that my shadowy adversary remains undefeated.

The endgame just edged a little bit closer.

On and off

Monday 15 January 2018

People with Parkinson’s sometimes talk about being “on” or “off”.

On is when you are feeling good and able to function well, for example being able to walk or write (relatively) normally.

Off is when you are feeling crap and struggle with movement, either with tremor, slowness or outright inability to move (“freezing”). Or you may be experiencing significant non-motor symptoms like heavy fatigue.

As I have now heard many times from many different people, Parkinson’s is a highly individual condition with varied symptoms and varied progression. But most people experience on and off periods at some point.

The simple explanation for these on and off periods is that the level of dopamine is fluctuating in the brain. This is mainly due to the drugs not releasing their chemicals evenly, so sometimes there is too much dopamine and sometimes too little in the places that need it.

Though I suspect this is not the whole story and even with perfect medication that releases smoothly, there are other factors at play. One of these is the dopaminergic cells themselves which seem to ebb and flow in their production of the precious neurotransmitter. (Maybe, just maybe, the condition reverses its progression a little from time to time – if only we could find out how, that might lead to a cure…)

Although I take the same medication at the same time every morning, sometimes I feel dreadful all day. Other times I feel energised and able to function pretty much as if I don't have Parkinson’s at all.

And today?

Well, most of the day I was “on” but I’m starting to feel very much “off” now with stiffness in my right hand and general tiredness. Time to stop writing and get to bed.

As for tomorrow – a regular Tuesday in the office – I have no idea whether it will be an on day, or an off day, or a mixture of both.

Faulty DNA

Saturday 6 January 2018

I took Rosa to the Science Museum in London this week, but, if I’m honest, the trip was more for my benefit than for hers.

On the ground floor, in between the steam engines that powered the industrial revolution and the IMAX theatre that shows the latest wonders in 3D, is a small exhibit that most people walk straight past.

Yet it is one of the most seminal objects in all of science (perhaps in both senses of the word ‘seminal’...).

It is the original model of the double helix structure of deoxyribonucleic acid - better known as DNA - constructed by Francis Crick and James Watson in their Cambridge laboratory in 1953.

Compared to the molecular models built in labs or simulated on computers today it seems very antiquated - all clumsy steel rods, plates and bolts. It is not particularly beautiful but the elegance of nature’s design still shines through. You can clearly see how the four different bases pair with one another: A (Adenine) with T (Thymine) and G (Guanine) with C (Cytosine), this being the key to how the genetic code is replicated in all organisms.

It is one of my favourite museum pieces anywhere in the world. 

The story of the discovery of the structure of DNA is a classic tale of a frantic race to the finish in a rapidly evolving field. That Crick and Watson were first past the post was in no small part helped by the work of Rosalind Franklin, an X-ray crystallographer (a specialist in interpreting photographs of X-rays scattered by crystallised substances). The chauvinism of the time meant that her contribution was downplayed, but nowadays she is recognised properly, albeit posthumously, for her instrumental role.  

Uncovering the structure of DNA was only the starting point. It turned out that the far greater challenge was to understand how the code actually works. This is something with which contemporary genetics still has much further to go. 

In a human genome there are 3.2 billion individual base pairs which, in groups of three, form the 20 or so ‘letters’ of the genetic alphabet. These are organised into about 20,000 genes - sequences of genetic letters that tell the body how to create the proteins of which we are made*. The genes are spread across our 23 pairs of chromosomes.

99.7% of our DNA is the same as the person sitting next to us on the bus or the train. It’s what makes us human. The remaining 0.3% is what makes us unique (unless you happen to have an identical twin). As a species, we are far more alike than we are different. 

After Crick, Watson and Franklin’s discovery of the structure of DNA it would take a further 47 years before the entire genome of the average human was sequenced, also involving a race to the finish by rival research groups. You may remember the fanfare around the human genome project in 2000. 

Now that has been done, the individual genes can be identified, and the function of each gene painstakingly figured out.  

This is far from straightforward. In simple organisms, sometimes there are single genes that map directly to a physical characteristic (known as a phenotype).  For example, whether a tomato is red or yellow is determined by a single gene.  In humans, the vast majority of phenotypes, such as height or eye colour, are determined by a combination of genes which may interact in very complex ways. And of course, for most things such as the risk of developing a particular condition, many environmental factors are at play as well.  

The precise make up of each gene can vary through random mutations. When an egg is fertilised, the copying of the genes from parent to child is remarkably precise. But just occasionally there is an error in a single letter creating a variation of a gene that can be passed down through further generations. Mutations can also be introduced by things like excessive exposure to X-rays. 

A few of these variations (called alleles) are known give the carrier an increased risk of developing Parkinson’s. But carrying them does not guarantee that the disease will manifest itself. Again, it is the combination of multiple factors, both genetic and environmental, and perhaps a dose of pot luck, that leads to Parkinson’s. 

It is currently thought that around 10% of Parkinson’s cases have a genetic cause. Given my family history of Parkinson’s it is highly probable that I am in this group: my mother likely passed some faulty DNA to me, and her father to her, and his father to him.    

There are 24 genes listed by the 100,000 genomes project on their website as having alleles, some of them very rare, known to have a strong link to Parkinson’s.

Does my DNA carry one of these mutations? Or perhaps some new mutation never seen before? Whatever the case, as I was tested only a few weeks ago, it will be quite some time before I find out. But if I do have faulty DNA there is most likely an even chance that I have passed it on to my daughter.

I watch Rosa whilst she eats her margarita pizza for lunch in the museum café. We discuss how the exhibits we have seen that morning relate to what she has been learning at school in her physics and biology lessons. She is full of the inquisitiveness and earnestness of youth.

I look into her refulgent brown eyes, unmistakeably mine. I wonder what else she has inherited from me. Have I cursed her with this disease? She has a whole life ahead of her, but will her later years be blighted by this incurable neurological menace? 

Surprisingly, I don’t feel guilty about it.

Likewise, I don’t blame my mother for my own situation. 

The eternal paradox of being a parent is that we cannot** change our children, only strive to give them the best start in life so that they, we hope, will at least head off in the right direction. 

When the time is right, perhaps the best advice I will be able to give my beloved Rosa is this:

In life we can’t change the hand we are dealt with.

What matters is how we play our cards.

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* In fact, only about 2% of our genetic material is directly related to encoding proteins. Much of the other 98% is related to switching individual genes on and off in complex ways, for example controlling growth in childhood, and some of it is possibly “junk” DNA, serving no purpose other than to keep replicating itself. The truth is, geneticists are still trying to figure out what most of our DNA does.

** With genetics, nothing is simple. Nascent research areas like gene therapy raise the possibility of changing our DNA to ameliorate conditions with a genetic causal factor. Then there is the broader debate around neo-eugenics, giving individuals the freedom to make reproductive decisions based on genetic information (as opposed to state sponsored eugenics which has a very troubling history). I may try and tackle these topics, and their ethical implications, in a future post. 

For a great overview of the history and the future of genetics, I can highly recommend “The Gene, An Intimate History” by Siddhartha Mukherjee. Strangely prophetic that Rosa bought me this book for Christmas….