Just a quick note to mark World MDS Day (the 25th October).
The MDS Foundation is holding a fundraising walk on 24th October this year (2021) – a Sunday. Find out about it here.
The great news is that they’ve already gone past the $200,000 goal. Well done everyone! It’s not too late and you can walk virtually from anywhere if you’re not in Boston.
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 book Swimming 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.
Other stories:
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
In the cells that make up your body, about 2 metres (6 feet) of DNA – strings of genes – are coiled up and packaged into a typically roundish nucleus. This nucleus is only about one hundred-thousandth of a metre wide. I’ve said before that the DNA packed into the nucleus “appears to be a tangled mess”. But looks can be deceptive.
In this great little video Carl Zimmer challenges the idea that DNA in the nucleus is arranged randomly. Job Dekker and his group are finding that the nucleus is actually very organised. Zimmer conjures up an image of tiny robots in the cell folding the DNA very precisely.
[From Science Happens! Episode 5: Everything you thought you knew about the shape of DNA is wrong]
Some genes control other genes. Dekker’s research suggests that the way DNA folds helps this process – by bringing controlling genes close to the genes they regulate. One cause of cancer could be bad folding that interferes with this control mechanism.
Dekker’s group is trying to work out which genes lie next to each other and how DNA is folded. The answer will be extremely complex. Dekker thinks that one day this knowledge will make it possible to fix badly folded DNA in cancer cells.
The 14th July is the Leukaemia Foundation of Australia’s annual National MDS Day.
Myelodysplastic Syndromes (MDS) make up a group of diseases that have abnormal blood cell production. MDS is sometimes called pre-leukemia because about a third of patients with MDS will develop leukemia.
MDS is caused by errors in the bone marrow’s genetic information. These errors can often be seen down the microscope as changes to the chromosomes. MDS patients typically have their bone marrow cells analysed to find chromosome abnormalities. Why?
These chromosome abnormalities can reveal important information about their disease, such as diagnosis, appropriate treatment and prognosis.
The IPSS-R is a system that’s used to work out prognosis for MDS patients – that is, how they will do – what their health outlook and risk of developing leukaemia are. A prognostic score is a number calculated from different aspects of the disease. A low score indicates low risk and risk increases as the score goes up. Cytogenetics, or chromosome analysis, is needed to calculate this score because “chromosome abnormalities” is one of the five categories used in the calculation.
For example, if the cells are missing a Y chromosome nothing is added to the IPSS-R prognostic score, whereas if four or more chromosome abnormalities are found, 4 points are added to the score, which can almost single-handedly take the disease into the high (4.5-6) or very high (over 6) risk category.
Normal chromosome 20 (left) and abnormal chromosome 20 missing most of the long arm (“del(20q)”).
The abnormal chromosome pictured on the right is a deleted chromosome 20 – it’s lost a big chunk carrying hundreds of genes. This is one of the well-known chromosome abnormalities in MDS. We can work out which genes have been lost using higher resolution molecular analysis, but this is not necessary for calculating the IPSS-R prognostic score. One point is added to the score if there’s a deleted chromosome 20 and it’s the only chromosome abnormality. It’s one of the chromosome abnormalities in the “good” cytogenetic category.
So chromosome analysis is an important piece of the puzzle in the care of MDS patients.
More information:
The IPSS-R – http://www.bloodjournal.org/content/120/12/2454?sso-checked=true
MDS Foundation – What is MDS? http://www.mds-foundation.org/what-is-mds/
The MDS Beacon – http://www.mdsbeacon.com/
Previous MDS Day posts:
Carl Sagan’s Lasts Project – Overcoming MDS
What does IPSS-R stand for? Revised International Prognostic Scoring System for Myelodysplastic Syndromes.
Cross-posted to Fireside Science on the SciFund Challenge network
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 movie, Chitty 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.
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
The Leukaemia Project has a new home on this blog. It features my research, and most particularly Elizabeth Duong’s short film about Sadako Sasaki and the thousand paper cranes. You can read about the making of the film on some of the earlier posts and watch it here:
and here:
Most cells in our bodies contain 46 separate long DNA strings that spend most of their time in what appears to be a tangled mess – in a sort of round shape we know as the nucleus. Then lo and behold, these long strings fold up and become chromosomes. Why do they do that?
Bill Earnshaw’s lab at Edinburgh University does some amazing work with chromosomes and cell division. He can explain very elegantly why we need chromosomes.
The DNA makes a copy of itself before the cell divides into two. The chromosomes help make sure each new daughter cell gets an identical copy of this DNA. It’s easier to divide tangled strings into two if you untangle them and roll them up into balls first
Here are some photos from the Earnshaw lab of the chromosomes during cell division.
In the photo above the chromosomes are lining up along the middle of the dividing cell (the “equator” or “metaphase plate”). When they’re all lined up correctly (this stage is “metaphase”) the next stage can start:
The photo above shows the blue chromosome halves (after the doubled-up chromosomes have split in two) separating along the green spindle fibres (this stage is “anaphase”). Each set of chromosomes will belong to one of the two new daughter cells. If this happens correctly both new cells have identical sets of DNA. This whole cycle of chromosome growth and division is called “mitosis”.
DNA carries genes that make up the blueprint that’s responsible for making every cell, every tissue, every organ work correctly. So it’s important we have the right set of genes.
Cells divide a lot – millions of our cells divide every minute so it’s important that the DNA is shared precisely each time. Mistakes can cause the new daughter cells to misfunction. These cells can become cancerous or produce babies with genetic disease. Usually the cell watches out for these mistakes and self-destructs. But not always. Research helps us understand these processes, how they can go wrong, and work out ways to prevent or fix these mistakes.
Cross-posted to Fireside Science at SciFund Challenge.
Images from http://earnshaw.bio.ed.ac.uk/.
Chromosomes and Cancer 
