Archives for posts with tag: AML

Dahl - bedtime stories

Roald Dahl had anything but a boring life. I would say he followed his dreams. He told stories that have been loved by children all over the world, like Charlie and the Chocolate Factory and Matilda. He wrote the screenplay for a James Bond movieChitty Chitty Bang Bang and other movies. During World War II he was a fighter pilot and sent intelligence to the spy agency MI6. He died in 1990 from MDS when he was 74. MDS is short for myelodysplastic syndromes, which are a rare group of related diseases in which the blood doesn’t function properly.

Today, the 14th of July, is the third National MDS Day in Australia. A year ago I wrote about Carl Sagan and MDS. Sagan was a very well-known scientist who took quite an interest in his disease, and we can hear him speak about his illness and his fight with it in the media (there’s a link to an interview at the end of this post).

But there’s not much detail, on the internet at least. about Dahl’s illness. One biography just says he went into hospital with an unknown infection in November 1990 and died 11 days later. (Interestingly for me this was the John Radcliffe Hospital in Oxford, UK, and I was working there at the time.) Twenty percent of MDS patients do have infections that are serious enough to need a hospital stay, in fact that’s what finally killed Sagan too.

Organisers of a charity event for MDS in the UK this year took the trouble to explain what MDS is in their advertising material. MDS has a public image problem – almost no public image that is.

  • “Unfortunately (!) the only ‘celebrities’ that have had MDS are all dead (Carl Sagan, Roald Dahl, Susan Sonntag) – if we had a few living ones then maybe this would be a disease with more public profile and hence money for research.”

Myelodysplastic syndromes (MDS for short) can be mild, severe, or anything in between. About a third of people with MDS will get leukaemia (acute myeloid leukaemia or AML).

I’d like to think Mr Dahl would have made a good scientist. Apparently his mother wanted to pay for him to get a good university education but he passed up the offer because he would rather go exploring. He also had a wildly creative imagination, which is always good for investigating things. Indeed, whe did help invent a medical device – the Wade-Dahl-Till valve – that was used to save children with brain injury.

Roald Dahl knew about the importance of vaccination first-hand. His daughter Olivia died from Measles when she was seven. He wrote  a passionate letter pleading with parents to get their children vaccinated.

His widow Felicity set up the Roald Dahl Foundation, which is now known as the Marvellous Children’s Charity. It continues the work he started, helping seriously sick children. I think the Marvellous Mr Dahl would have approved.

SOME LINKS

More about MDS

Carl Sagan talking about his illness:

The Leukaemia Foundation of Australia has information for patients and carers, and supports research in Australia.

There’s also the MDS Beacon, the MDS Foundation, and information available through several other leukaemia and health-related organisations on the net.

More about Roald Dahl

Official website: http://roalddahl.com/

https://en.wikipedia.org/wiki/Roald_Dahl

Biographies

http://www.biographyonline.net/writers/roald-dahl.html

http://www.biography.com/people/roald-dahl-9264648

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As we’ve seen in previous posts, cancer is caused by some sort of error in the DNA of the cancer. Human DNA comes in 46 long strings called chromosomes and it sometimes breaks, but luckily the break is usually repaired. However, sometimes the repair process gets it wrong – for example two DNA ends are joined together that aren’t meant to be together.

This post is about a fairly recent discovery called chromothripsis. I’m going to describe it in terms of language, because after all, DNA is a language, and I think it will help picture what’s going on.

Anagrams are made by rearranging all the letters of a phrase or word to make another phrase or word, and it’s best if the new has a similar meaning to the old. Some examples are:

astronomer —-> moon starer
the meaning of life —-> the fine game of nil.

The rule for “perfect” anagrams is that all the letters are re-used in the new sentence.

Setting up printing originally involved arranging individual letters in a particular order on a plate. If the letters were dropped it wouldn’t be easy to get the letters back in the right order. If you had to put them back together in a hurry they’d be jumbled up and you wouldn’t get a meaningful anagram. In fact you’d probably have some missing letters left on the floor in a corner somewhere. Ok it’s starting to get complicated, but something similar can happen to DNA!

A printer inspecting a large form of type on a cylinder press. Each of the islands of text represents a single page, the darker blocks are images. The whole bed of type is printed on a single sheet of paper, which is then folded and cut to form many individual pages of a book.

At the beginning of 2011 Joshua Stephens and his colleagues published a paper that got a lot of cancer biologists excited. They noticed that the DNA of some cancers was very messed up. They even said that they’d found this in 10% of the cancers where they looked for it. Not only that, but they thought this had happened all at once by shattering of the chromosomes and rejoining of the broken pieces in a random and totally incorrect order.

Scientists love to make complicated words out of Greek roots. The Stephens paper called this process, this shattering and stitching back together of the chromosomes, “chromothripsis“. (An aside: The chromo- in chromothripsis is short for chromosome, or coloured thing. The authors say that thripsis means shattering into pieces.)

I had a couple of nice examples of chromothripsis acute myeloid leukaemia, but as someone who’s interested in chromosomes I wanted to talk about the chromosomes that were made by this whole chromothripsis process. There was no word for these new chromosomes so I came up with the term “anachromosome“. I like it because it has connotations of “new”, “remade”, and my favourite, “anagrams”. Although the anagram rule says all the letters have to be reused, there are apparently imperfect” anagrams which can leave out some letters to make the anagram work. This is more like an anachromosome. Inevitably lots of bits of chromosome don’t make it into the anachromosome and so are lost. Such wholesale shuffling and loss of large sections of DNA will probably kill the cell in most cases, but just occasionally it will produce a cell that can outgrow its neighbours – and turn cancerous.

This shows how the chromosome shatters and rejoins in a random order. Note that the two ends of the chromosome and the centromere (represented by a circle) are preserved. These are essential features of a functioning linear chromosome. From MacKinnon and Campbell 2013. Cancer Genetics 206:238-251.

This shows how the chromosome shatters and rejoins in a random order. Note that the two ends of the chromosome and the centromere (represented by a circle) are preserved. These are essential features of a functioning linear chromosome. From MacKinnon and Campbell 2013. Cancer Genetics 206:238-251.

References:

MacKinnon RN and Campbell LJ 2013. Chromothripsis under the microscope: a cytogenetic perspective of two cases of AML with catastrophic chromosome rearrangement. Cancer Genetics 206:238-251

Stephens PJ et al. 2011. Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development. Cell 144:27-40

This is the opening title of Paper Thin. Yesterday was the last day of filming and I got a look at some of the Director/Producer Elizabeth Duong‘s work. It’s exciting – this will be a touching but beautiful film. It’s based on a true story of a girl called Sadako who developed leukaemia after exposure to radiation in Hiroshima.

One of the hallmarks of leukaemia that’s caused by radiation or toxic chemicals is very rearranged chromosomes. I’m working on unravelling the patterns and causes of the very disorganised genetics of this type of leukaemia (known as therapy-related acute myeloid leukaemia).

Sadako hoped for a cure. My hope is that with the help of this film this research can continue and realise her dream for future leukaemia patients. A big thank-you to Elizabeth and all her helpers, who have given their time freely. A special mention also to Daniel Hernandez who composed the original soundtrack. It’s awesome. Here we have Essendon Symphony playing the opening theme and I think that’s Daniel playing over the stings.