Archives for posts with tag: DNA

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.

Cross-posted to Fireside Science on the SciFund Challenge network.

In the 21st century we have an amazing amount of knowledge at our fingertips. This includes the human genome sequence – (most of) the 3,381,944,086 letters of DNA code for a human, known as the human genome sequence. It’s publicly available and you can look it up or download it if you have a computer with internet. Maybe some of us in the developed world are even starting to take it for granted.

The downloadable sequence is just a reference – each one of us has our own unique variation of this standard. Many of us now have reason to find out the sequence of one of our own genes, for example to see if we have inherited a higher than average risk of cancer, or if we carry a gene for a genetic disease. It’s even possible to get your own whole, unique, genome sequenced (at a cost).

In the 1980s the human genome sequence was a dream. Using the technologies available at the time we’d still be sequencing by hand. The Human Genome Project led to a lot of automated sequencing methods being developed – and they’re still being improved, which is still bringing the cost of DNA sequencing down.

This huge project was undertaken by many laboratories across the world. It was intended to be, and has been, a resource for improving health care. It’s not the only sequenced genome. Simpler organisms like viruses and yeasts, which have much smaller genomes, were sequenced before the human genome, and as time goes on we’re getting genome sequences for more and more living things.

So how was the human genome sequenced? There are a range of basic techniques and tools that allow DNA to be manipulated and  read. I’ve put together a Prezi which gives a visual overview of these tools.

Prezi: Tools for DNA discovery and innovation

DNA tools

To see this Prezi with more detailed explanations click on the link above.

DNA can be thought of as a long string of “letters” (nucleotide molecules) strung together. This makes up the code of life and it’s translated into a different language that can make any of the huge variety of proteins, like collagen, haemoglobin, insulin or botox. DNA can be cut, rearranged and joined back together. This makes it very versatile – it can be manipulated. It can be cut up and pasted into different organisms and the host organism will treat it like its own DNA – because the code of life is universal.

Another useful feature of the DNA molecule is that it’s made of two strands which pair together and each one can be made anew from its partner. Thus we can make new DNA in the test tube. One DNA strand can also find its partner so we can find or pick up a whole piece of DNA if we have a  just a small section of its partner.

So these tools for DNA analysis can also be used for our own purposes – for example. to make proteins such as human insulin in massive amounts. You can even make a gene from scratch if you know the code of the protein you want to make. But you’ll still need a live organism to process it into protein for you. Amazing! Diabetics used to rely on pig and cattle insulin, but the human version is better for us!

Cross posted from Fireside Science at SciFund Challenge

Further reading:

The Wellcome Trust’s Sanger Centre has a lot of information, videos and interactive tools that help explain DNA analysis and how the Human Genome was broken down into sections and sequenced.

Telomeres. Apparently that’s the new buzz word in cosmetics . They come in different sizes – as we age they shorten. It’s been suggested that we could lengthen them to cancel the effects of ageing, or shorten them to cure cancer. But what are they?

They’re an integral part of our chromosomes. The 46 long strings of genes in each human cell are folded up to form chromosomes, which we can see down the microscope. The telomeres are at both ends of each chromosome. They protect the ends of the chromosomes, and stop the chromosomes from sticking to each other. Chromosomes joining together can be a cause of cancer – more about how that works when we look at the promised breakage-fusion-bridge clay model (in stop motion hopefully!).

The green spots are telomeres on the blue chromosomes from a leukaemia cell. Spot the two abnormal "ring" chromosomes - no ends, no telomeres.

The green spots mark the telomeres on the chromosomes from a leukaemia cell. Spot the two abnormal “ring” chromosomes – no ends, no telomeres (answer next time).

As we age our telomeres get shorter. Telomere shortening has also been associated with other factors such as extreme psychological stress and toxins, including chemotherapy. As well as cancer, short telomeres have been associated with diabetes, cardiovascular disease, osteoarthritis and other diseases. But it also seems that measures like reducing stress, improving diet and exercise may stop or even reverse this premature telomere shortening.

Here’s the paradox – short telomeres can help trigger cancer, but once established the cancer switches on a telomere-lengthening mechanism (usually an enzyme called telomerase) to survive.

And so different researchers are trying contrasting approaches to manipulating telomeres for improved health.

On the one hand, some researchers are looking at the possibility of using the telomere-activating enzyme telomerase to reverse the effects of ageing. Some cosmetics are already available that contain a chemical that’s been reported to activate telomerase. This same chemical is being tested for use as a treatment for some diseases associated with ageing and short telomeres.

On the other hand, because cancers need telomerase to be able to divide indefinitely, other researchers are looking into the possibility of destroying telomerase as a cancer treatment.

These potential treatments will need extensive testing to see if they work and make sure they don’t have unwanted side effects.

From the search for eternal youth to understanding and curing cancer, we haven’t heard the end of telomeres.


A single fertilised egg cell becomes a mature human by growing and dividing into two, many times over. Each time a chromosome makes a copy of itself the telomeres lose a little bit off their ends. The older we get the shorter our telomeres become, so there’s a limited number of times a cell can divide.

That is, unless an enzyme called telomerase is turned on. This enzyme lengthens the telomeres. If you think about it, although most cells in our bodies are programmed to divide a limited number of times, some cells have been dividing for millenia – germ cells – eggs and sperm. It’s cells like these that need telomerase.

Most cancer cells are also able to divide indefinitely by switching on telomerase.

Once the telomeres are dangerously short the chromosomes can start sticking together and becoming abnormal. This stage is called crisis.  The cells don’t function properly, and are a cancer risk, and they stop dividing or self-destruct. There are “tumour suppressors” that look after this self-destruction, but occasionally a cell will bypass this (for example by having a mutated tumour suppressor gene), survive and divide. If the cells divide, these abnormal chromosomes can become more abnormal and turn on cancer genes or lose tumour suppressor genes.


This process has mostly been studied in lab animals or cells grown in the laboratory in artificial conditions. So we can extrapolate and suggest that chromosomes with short telomeres can join together and cause cancer. Unfortunately chemotherapy is associated with shortened telomeres, and is a risk factor for leukaemia. These therapy-related leukaemias are usually marked by very abnormal chromosomes.  In my own research I’ve identified some abnormal leukaemia chromosomes that have been made by chromosomes joining together at the telomeres. This was done by identifying which chromosomes are joined together, AND by looking at the molecular content of the chromosomes. End-to-end joining of the chromosomes is actually a lot more common than it’s thought, at least for the abnormal chromosomes I’ve looked at. The similarity between risk factors for very abnormal leukaemia chromosomes and shortened telomeres is interesting.

One thing I’d like to do is find out how common this joining together of the chromosome ends is, in other types of abnormal chromosomes in leukaemia (AML), and eventually look at other cancers. It would help understand how these cancers are caused and possibly identify ways to prevent this. Other information from this type of study could identify more genes with a role in cancer. This opens up new possibilities for developing treatments.

“Abnormal chromosomes made by the end-to-end joining of two chromosomes….” – that sounds like a segue into the breakage-fusion-bridge cycle. More on that later.


E. Blackburn and E. Epel 2012. Too toxic to ignore. Nature 490:169-171 (about stress, disease and telomere shortening). Note, Elizabeth Blackburn is Australia’s only female Nobel Prize winner (in science at least) – she shared the prize for Physiology or Medicine in 2009 for her discovery of telomeres.

C. Buseman 2012. Is telomerase a viable target in cancer? Mutation Research 730:90-97

E. Callaway 2010. Telomerase reverses ageing process. Dramatic rejuvenation of prematurely aged mice hints at potential therapy. Nature 28th November 2010 (published online).

B. de Jesus et al. 2013. Telomerase at the intersection of cancer and aging. Trends in Genetics (available online 19th July 2013)

C. Harley et al 2011. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Research 14:45-56.

R. MacKinnon and L. Campbell 2011. The role of dicentric chromosome formation and secondary centromere deletion in the evolution of myeloid malignancy. Genetics Research International Article ID 643628

R. MacKinnon et al 2011. Unbalanced translocation of 20q in AML and MDS often involves interstitial rather than terminal deletion of 20q. Cancer Genetics 204:153-161.

T. Morin. A balanced article on telomeres in Dayspa Magazine online.

What makes a cell become cancerous?

This can happen if the chromosomes are incorrectly distributed to a new cell. The cell could get too many copies of a cancer-promoting gene, or too few copies of a cancer-protecting gene.

The breakage-fusion-bridge cycle is one way that this can happen. This  week I was asked to provide a cartoon showing the breakage-fusion-bridge cycle and how it relates to a chromosome abnormality I was describing.

By lucky coincidence my colleague Lan Ta just this week published a paper with a neat breakage-fusion-bridge cartoon that was put together by Bruce Mercer. As well as being a scientist, Bruce is a graphic artist – a very handy combination. So I was trying to draw the modified cartoon for Bruce in two dimensions, without much success. Then modelling clay came to the rescue and I was able to show him what I meant.

So I would like to share the 3D modelling clay version, but before we look at the breakage-fusion-bridge cycle, which is an abnormal pattern of chromosome division, we had better look at normal chromosome division (or mitosis).


These are chromosomes in modelling clay. There are 23 pairs of chromosomes in a human cell but we will follow 3 chromosomes for simplicity.  The chromosomes only take on a recognisable shape when the cell is ready to divide. Each chromosome is made of two halves called chromatids, which are identical. These are held together at the centromere.

mitosis 1

In a cell the chromosomes are usually not recognisable – the DNA is unravelled in the nucleus. In a growing cell each unravelled  chromosome is producing a copy of itself so that there will be a chromosome for each of the two new daughter cells when the cell divides, or reproduces itself.


After the chromosomes take shape they line up together (at the metaphase plate) between two ends, or poles, of the cell. The centromere has another very important function in cell division. It attaches to fine fibres (microtubules) which stretch between the poles.



The two halves of the centromere separate and each draws its chromatid (which is now a new daughter chromosome) along these microtubules.




So when the cell divides in two to make two new cells, each chromatid becomes a chromosome in one of the new cells.


Cell division complete, the chromosomes unravel and copy themselves again ready for the next cell division.

This process happens successfully millions of times every day to create new cells in our bodies – amazing.

In the year 2000 the draft human genome sequence was announced by Tony Blair and Bill Clinton. It was said to be complete in 2003, in time for the 50th anniversary of the discovery of the structure of DNA. Well actually it wasn’t quite finished. Actually it’s still not finished. Besides the tweaking that still goes on here and there, there are still big gaps. And what’s in these gaps sometimes has a significant role in cancer.

The biggest gaps are centromeres. Centromeres and telomeres are made of what is known as repetitive DNA, and this is hard to sequence. There’s more detail below.

Cancer chromosomes often have centromere or telomere abnormalities. In fact these abnormalities can cause cancer or make it progress faster.

In cancer research there’s a big push to sequence the genomes of different types of cancer  to try and understand the many different DNA changes that can cause cancer. Some researchers try to understand telomeres and centromeres and their role in cancer, but in cancer sequencing projects, and also in diagnostics, centromeres and telomeres are pretty much ignored. Although they’re difficult to sequence, the repetitive DNA does make them easy to study by some other techniques.

One of the goals of personalised medicine is to be able to read a person’s complete genome. For cancer this would include the abnormal cancer genome. But at the moment these gaps mean that we can’t describe the abnormal cancer chromosomes from end to end by sequencing them. The approach I use allows me to work out what’s in each chromosome and discover telomere and centromere abnormalities.


By looking at things that most people don’t worry about I’ve overturned a few assumptions and made some unexpected discoveries, particularly about centromeres in leukaemia.

A normal chromosome has one centromere. I found that chromosomes with two centromeres are more common in  acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) than was thought. I found that most of these chromosomes with two centromeres were probably made by two chromosomes joining together.

Telomeres are at the ends of chromosomes and stop them from sticking to each other, so when the telomeres are eroded,  chromosomes can join together. They can be eroded by exposure to chemical toxins, cancer drugs and radiation. So it’s interesting that the leukaemias that are caused by these exposures have more of these two-centromered chromosomes than other leukaemias.

centromeres - dicentric

Fluorescent DNA probes can label up centromeres (blue) and genes (red). In this image there is also a chromosome 20 paint – the green regions are from chromosome 20.


Telomeres and centromeres are made of highly repetitive DNA and make up some of the gaps in the human genome sequence.

Sequencing a genome is like reading a story. But first we cut the book up into tiny fragments. We read them piece by piece, then try to join the pieces together to make the story, by matching the overlapping parts. Where this approach falls apart is that some sections are repetitive. Some pages are made up of a single word or phrase repeated over and over and over and over and over and over (I won’t repeat that hundreds of thousands of times, but you should get the picture). So if a lot of fragments just say the same thing “over and over and over”, it’s very hard to put them together meaningfully.

The centromere guides the chromosome to the two daughter cells during cell division. A normal chromosome has one centromere. When a chromosome has two centromeres (we call this a dicentric chromosome), the chromosome can be pulled in opposite directions, breaking the chromosome and causing more chromosome disorganisation.Telomeres cap the ends of normal healthy chromosomes. One of their functions is to stop the chromosomes from sticking to each other. So when the telomeres are lost or eroded the chromosomes can join together. That’s one way of creating a chromosome with two centromeres.

Telomere loss is a natural part of ageing. There are also many environmental and lifestyle factors that are thought to affect telomere length. Short telomeres are thought to be a cancer risk because dicentric chromosomes are more likely to arise.

Telomeres and centromeres are very important parts of a normal chromosome. You could say they hold the chromosome together. They have a lot of influence on whether chromosomes are normal and stay normal.


Murnane JP 2012. Telomere dysfunction and chromosome instability. Mutat Res. 2012 Feb 1;730(1-2):28-36. (Open access)

MacKinnon RN and Campbell, LJ. 2011. The role of dicentric chromosome formation and secondary centromere deletion in the evolution of myeloid malignancy. Genetics Research International. Article ID 643628. (Open access)

MacKinnon RN, Duivenvoorden HM and Campbell LJ. 2011. Unbalanced translocation of 20q in AML and MDS often involves interstitial rather than terminal deletion of 20q. Cancer Genet. 204(3):153-61.

Angelina Jolie decided to have a double mastectomy because she inherited a high risk of breast cancer. What’s remarkable is that all of a sudden people are questioning whether they should be investigating their own cancer risk. Cancer services are fielding many more queries about cancer testing than they were before her announcement. (20th June: I posted this ten days ago, and I’ve just updated the title in response to what has become known as the “Angelina effect”.  Cancer Council Victoria has just announced a 1033% increase in the number of calls to its helpline.)  This is despite the fact that what we know about breast cancer risk that led to Ms Jolie’s decision has already been publicly available for many years. Clearly it was not out there in a way that people took much notice of.

Better communication of science will prevent people from missing or misunderstanding  important information like that.

Is cancer the most common genetic disease? According to The Cancer Genome Project website it is. This might sound scary. Does it mean you have a high risk of cancer if one of your parent has had it? Not necessarily. “Cancer genetics” means one thing to most people and another to cancer scientists. To understand all this we need to understand something about genes and the the role they play.

Genetics is usually understood to mean the characteristics that you inherit from your parents. These characteristics are encoded in our genes,  which are instructions written in a special language called DNA. Every cell has a copy of the set of instructions, and can read them. Genes control our physical features, and the way our bodies’ function, for example how they grow. Genes in the germ cells (eggs and sperm) are passed on from parent to child. Genes in the embryo are passed on to every new cell as we grow. The new cells include eggs and sperm, and their genes are passed on again to the next generation.

The genes can get damaged – this can happen by chance, or it can be caused by environmental factors. Usually this damage is not a problem for a number of reasons. But sometimes the damage is a step in the development of cancer. Usually more than one of these cancerous genetic changes has to occur before cancer is triggered. For breast cancer to develop, these errors need to occur together in the same breast cell.  So cancer can arise in any part of the body, but one of these faulty genes is only inherited if it’s in a germ cell.

If the faulty cancer-promoting genes are inherited, cancer is more likely, because fewer additional gene errors are needed before cancer is triggered. Ms Jolie is reported to have a faulty or mutated BRCA gene. A mutation in a woman’s BRCA gene (BRCA1 or BRCA2) means a 60% lifetime risk of breast cancer, compared to a 12% risk in women without the mutation (National Cancer Institute).

What’s a genome anyway? Scientists studying the genes talk about the genome. This simply means all the genes in an organism – a plant, animal, microbe, you or me. And if you think small-scale, every cell has a genome. Genomics is the study of a genome, be it  the whole organism or a single cell. So “genomics” is really a less ambiguous term than “genetics” when you’re talking about cancer, but to most people it’s jargon. I think this will change as genomics becomes a much more prominent part of health care, including cancer treatment. So to answer the question posed above, yes, cancer is the most common genetic disease, but not in the generally understood sense.

There’s a huge amount of research behind our knowledge of BRCA genes and our ability to use this information to prevent or treat cancer. Cancer is a very diverse disease and we are nowhere near understanding all the gene errors behind all the various types of cancer. The more we discover the better equipped we will be to prevent, detect and cure cancer.

(With thanks to Qian Yu for helpful comments)