Susan Sontag survived uterine and breast cancer, but as sometimes happens, the treatment that cured her eventually caused the MDS that killed her (“therapy-related MDS” or t-MDS). Her son David Rieff gives some insight into her illness in his bookSwimming in a Sea of Death: A Son’s Memoir (Granta). After a bone marrow transplant, her disease became full-blown leukaemia. (Not all cases of MDS are this severe.)
Chromosome analysis of the MDS cells is one of the tests used to predict the patient’s outlook. “The spectacularly difficult cytogenetics of her specific case” (very abnormal chromosomes), as Rieff puts it, means she had a poor chance of survival.
Sontag stands out as a patient because she wrote about illness, in her philosophical book Illness as Metaphor. I came across the story of her treatment and one of her quotes about illness in Siddhartha Mukherjee’s very readable book, The Emperor of All Maladies: A Biography of Cancer.
“Illness is the night-side of life, a more onerous citizenship. Everyone who is born holds dual citizenship, in the kingdom of the well, and in the kingdom of the sick. Although we all prefer to use only the good passport, sooner or later each of us is obliged, at least for a spell, to identify ourselves as citizens of that other place.”
Susan Sontag, Illness as Metaphor. Published by Farrar, Straus and Giroux (1978)
25th October is World MDS Awareness Day. This article is part of a series about high-profile MDS patients.
There are ever more DNA tests to work out whether a patient has MDS, what type and what treatment is suitable, and the outlook or prognosis. Here is an article and a video from the MDS UK Patient Support Group that explains how a myeloid gene panel is helping patients in the UK. One big benefit that the panellists talk about is that this test can generally be done on blood, which means the patient might avoid having a bone marrow biopsy.
Myeloid Gene panels – how are they used in MDS? from MDS UK Patient Support Group on Vimeo.
The Leukaemia Foundation of Australia established National MDS Day on 14th July a few years back and I’ve put together a post on this day over the past few years. The MDS Foundation’s MDS World Awareness Day is now marked on the 25th October, so I’ll be moving my posts to that date in the future. I hope they’re informative!!
The Leukaemia Foundation of Australia’s National MDS Day has just passed (14th July… but I was busy eating croissants so this post is a little late).
This time I thought I would tell you about a discovery that was made with the help of MDS.
How do healthy cells turn cancerous? Their DNA gradually accumulates errors. Most of these errors aren’t important, but occasionally they stop the cell from working properly. They might cause a cell to grow out of control – and this can lead to cancer.
Myelodysplastic syndromes, or MDS, are a range of blood disorders caused by such errors in the genes. Some types of MDS are relatively mild, but about a third go on to become acute myeloid leukaemia (AML). Thanks to research on MDS we understand its causes a lot better than we did ten or fifteen years ago.
My lab recently published a paper describing three cases of poor prognosis MDS and one case of AML with unusual but remarkably similar changes to the DNA. This complicated structure could not have been predicted by the standard methods of analysing cancer DNA or chromosomes. These features showed us the likely steps that led to these diseases.
Each long string of DNA is folded up neatly to make a chromosome. This is a Claymation that shows how Barbara McClintock’s classic breakage-fusion-bridge cycle causes chromosome abnormalities. The video shows one way that chromosomes (packages of DNA) can become disorganised.
The telomeres (that cap and protect the ends of the chromosomes) are shown falling off, making sticky chromosome ends which join together (see NOTE 2). It’s well accepted that these changes greatly increase the chance of cancerous gene changes. This process has reproduced many, many times in the lab. The problem is that it’s not often been demonstrated in actual cancers. But we did that.
Sometimes only part of the telomere erodes away – enough is lost that it no longer protects the chromosomes from sticking together. But there can be enough telomere DNA left to be a molecular signature of the telomere.
The arrow points to green dots in the middle of a chromosome. This is the left-over telomere signature that tells us that this abnormal chromosome was made by the joining together of sticky chromosome ends that had their telomeres eroded away. The other green dots are at the chromosome ends. The left and right photos show the same cell but in the right one the abnormal chromosome is identified by its red and blue label.
In our four cases we found that there was a small but non-functional piece of telomere DNA left behind where the two chromosomes joined. Because the telomeres didn’t function, the two chromosome ends could stick together. These caused breakage-fusion-bridge events that caused a protective tumour suppressor gene to be lost, and may have also caused cancer-causing genes to multiply.
MDS and AML have similar genetic causes, so if we learn about the causes of one of them it can help us understand the other. This is often the case with cancer research in a broader sense – if we understand the basic mechanisms in one cancer it can help us understand the mechanisms at work in other cancers better. Telomere fusion could potentially play a role in any cancer, so our MDS research is relevant to cancer research in general.
NOTES
The paper: The dicentric chromosome dic(20;22) is a recurrent abnormality in myelodysplastic syndromes and is a product of telomere fusion. Ruth MacKinnon, Hendrika Duivenvoorden, Lynda Campbell and Meaghan Wall, 2016. Cytogenetic and Genome Research 150(3-4):262-272
The gene errors discussed here usually occur in the body cells rather than the reproductive cells, so they’re not inherited.
For simplicity the Claymation shows telomere fusion in chromosomes that are dividing. In fact it probably occurs when the DNA is unravelled in the interphase nucleus.
This is cross-posted to Fireside Science on the SciFund Challenge network.
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.
There’s also the MDS Beacon, the MDS Foundation, and information available through several other leukaemia and health-related organisations on the net.
Carl Sagan was an astronomer and academic, best known for popularising astronomy. He hosted and co-produced the original hugely popular series Cosmos: A Personal Voyage. Its sequel Cosmos: A Spacetime Odyssey was released this year. Even though I’m a biologist at heart I was fascinated by the original Cosmos.
Sagan was diagnosed with a myelodysplastic syndrome (MDS) and died at the age of 62, in 1996. In interviews near the end of his life he discussed myelodysplasia and said he was hopeful he’d been cured. He died at the Fred Hutchinson Cancer Research Center of pneumonia after his third bone marrow transplant, a complication of this illness.
Most people with a diagnosis of MDS won’t have heard of it before. MDS is a group of bone marrow diseases. It’s at least as common as or more common than leukaemia but older people have a higher risk – perhaps one in 2,000 over the age of 60. A third of people with MDS will develop leukaemia. The 14th July, 2014, is the Leukaemia Foundation of Australia‘s second National MDS Day . One of the aims of MDS Day is to raise awareness of MDS.
Sagan’s illness was an opportunity to popularise MDS, but look how the cause of his death was described in these TV news reports.
In these news stories he was said to have died from a complication of “a rare blood disorder that led to cancer”, or “a blood disease”, “a bone marrow disease”, and even a” bone cancer” – the name of his disease was avoided.
Myelodysplasia literally means abnormal bone marrow cells. Blood cells are made in the bone marrow. In MDS the immature bone marow cells are abnormal and don’t mature properly. So the blood doesn’t have enough normal blood cells to do its job effectively. The blood is made of a number of different types of cells and the different types of MDS relate to the type of abnormal cell. MDS is often associated with a recognised chromosome abnormality, and identifying these chromosome abnormalities can help with diagnosis, treatment and prognosis. Therapy-related MDS is a specific type of MDS caused by treatment for a previous unrelated cancer and it usually has a poor outcome and very abnormal chromosomes.
MDS research has been neglected but has picked up recently. Some of the recent progress includes work by Carl Walkley and Louise Purton at St Vincent’s Institute in Melbourne, Australia.
MDS has had a history of name changes that seems to have made the meaning of its name less clear, except to medically trained people. This hasn’t helped improve public awareness of MDS. It was first named Di Guglielmo Syndrome in 1923 after its discoverer, then became refractory anaemia, then preleukaemic anaemia, preleukaemic acute human leukaemia, preleukaemia, and finally in 1976 the French-American-British Co-Operative Group of haematologists named it myelodysplastic syndromes. This recognised that it’s a group of related diseases and that not all cases will go on to develop into leukaemia.
Pathologist Ed Uthman, thinks Sagan’s Disease would be a better name for myelodysplastic syndromes – both as a tribute to Carl Sagan and a name that would mean more to most people than myelodysplastic syndromes. Maybe he has something. Plenty of syndromes and diseases are named after people who studied them. Down Syndrome would have to be the best known example. Have you heard of amyotrophic lateral sclerosis? Motor neurone disease? Lou Gehrig’s disease? The first name is probably a nice technical description of the disease, but I’m guessing you’re more likely to have an idea of what the disease is from one of the last two names, because they’re used in popular media and are connected in the public eye with famous sufferers – Stephen Hawking and Lou Gehrig. (Ed Uthman also think’s Lou Gehrig’s Disease should be “Hawking’s Disease”.)
I’ll let Carl Sagan have the last words on popular (mis)understanding of science (extract from Wikiquote).
We live in a society absolutely dependent on science and technology and yet have cleverly arranged things so that almost no one understands science and technology. That’s a clear prescription for disaster.
Every kid starts out as a natural-born scientist, and then we beat it out of them. A few trickle through the system with their wonder and enthusiasm for science intact.
Chromosomes and Cancer 
