Tag Archives: mutation

Turning the tables: using genetic mutations to fix nature’s problems

The Conversation

Merlin Crossley, UNSW Australia

Everyone is different. That’s a simple truism, but it’s is also true when it comes to how people respond to diseases; some people are laid low and others shrug off the same ailment.

And it’s true of genetic diseases. Even when two individuals carry the same mutation, the severity of the disease may vary between them.

Sometimes this is due to environmental variation, but in other cases it reflects additional genetic changes that also influence how the disease affects that person. Some people will have other harmful mutations that combine with the main disease gene to make the condition worse, while more fortunate people may have inherited other variations, actual beneficial mutations, that reduce or even eliminate symptoms.

One of the best known illustrations of this phenomenon centres around the inherited blood disorder sickle cell anaemia. This lifelong condition is due to mutations in the adult globin gene – a point mutation in that gene renders it defective and patients suffer from anaemia throughout their lives. The symptoms can be severe. Damaged blood cells can block blood vessels leading to intense pain and even loss of life.

In the blood

But, as mentioned above, symptoms vary between individuals. Environmental variability also influences symptoms, so affected individuals may be advised to avoid high altitude and oxygen stress, for example. But genetic variations also exist. Some individuals carry a second mutation in the regulatory region of another globin gene that alleviates symptoms of sickle cell anaemia.

These individuals have a benign condition called Hereditary Persistence of Foetal Haemoglobin (HPFH). They have an “up-mutation” in the control region of a separate globin, the foetal globin gene, which boosts expression of that gene. The extra foetal globin can replace the defective beta globin.

I realise that is fairly complicated. But, put simply: humans have several globin genes. The foetal globins are turned on before birth and have a high affinity for oxygen; they enable the baby to snatch oxygen from its mother’s blood. After we are born the adult, or beta globin, gene comes on and the foetal globin gene is shut off.

But in a few people with HPFH the foetal globin gene stays on throughout life. Interestingly, this doesn’t seem to cause any health problems. Individuals with HPFH can even have normal pregnancies. They just have extra foetal globin in their blood.

The crux of the matter is this: if an individual inherits the sickle cell mutation and an HPFH mutation, they have few if any symptoms, because the extra foetal globin does the work of the defective adult globin gene.

So could one effectively “cure” sickle cell anaemia by introducing the HPFH mutation into blood cells affected by the defective adult globin gene?

Switching on the backup

Well, this is precisely the approach we have taken. Using the new technique of “genome editing”, we have introduced one of the best characterised HPFH mutations, and we find that we can successfully turn on the sleeping foetal globin gene.

At this stage we have only done this in cell lines in the laboratory. To turn this into a therapy, one would have to do it in haematopoietic stem cells – i.e. blood-forming stem cells – from the patient. It would be necessary to achieve a high frequency of editing in enough stem cells to enable repopulation of the patient’s blood with genetically enhanced cells.

Gene repair

But if it is so easy to edit the genome now, why don’t we just correct the sickle cell mutation rather than introducing a new mutation, albeit a beneficial and benign mutation?

Well, that is certainly a good strategy in the case of sickle cell anaemia, and many people are working on just that. But it may be a less ideal strategy for other blood diseases and various genetic diseases where large genes or regions of the genome are deleted.

In the case of the thalassaemias, for example, many different gene deletions occur. It may not be practical to edit in large gene replacement cassettes, and one would have to design a different insert for each mutation. In contrast, building in the foetal globin activating mutation should provide additional globin and work to compensate in many of these conditions.

Towards gene therapy using genome editing

A new age of genetic engineering is beginning, due to the ability to edit the genome using new DNA-cutting tools, with the technical names: CRISPRs, TALENs and ZFNs.

Gene correction or the introduction of beneficial mutations may be important in treatments in the future.

In agriculture they may also be important. Many genome wide association studies have identified beneficial mutations associated with particular prised qualities. Genome editing can also be used to introduce beneficial mutations in this context and may give rise to a new generation of crops and livestock.

The techniques are also interesting because no new or artificial material need be introduced. All one is doing is mimicking a naturally occurring beneficial mutation. The introduction of artificial transgenes has alarmed some parts of society.

Additionally, transgenes are recognised as foreign by some organisms and are shut down by epigenetic silencing, just as computer viruses are recognised and shut down by anti-virus software.

Beneficial mutations are unlikely to be subject to the same limitations. They are already known to work in nature and introducing them to improve human health or in agriculture may have many advantages.

The ConversationMerlin Crossley is Dean of Science and Professor of Molecular Biology at UNSW Australia.

This article was originally published on The Conversation. (Reblogged by permission). Read the original article.

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Why the causes of cancer are more than just random bad luck

The Conversation

By Darren Saunders, Garvan Institute

What causes cancer? This deceptively simple question has a devilishly complex answer. So when US researchers proposed a relatively simple mathematical formula to explain a long-standing conundrum in cancer earlier this year, it was bound to get a lot of attention.

The study published in the journal Science suggested a correlation between the variation in cancer occurrence between different tissues and the number of stem cell divisions in each tissue. In other words, it said the tissues most vulnerable to cancer are those with the greatest number of stem cell divisions.

Most of the reporting about the research ran with the line that “cancer is all down to bad luck”, implying that developing the disease is out of our hands and that preventative efforts might be useless. But is that really the case?

Much of the misunderstanding seems to have arisen from the authors’ statement that a third of the variation in cancer risk among tissues is attributable to environmental or inherited factors, with the majority due to random mutations during DNA replication in normal cells. This statement about relative risk was overblown into blanket conclusions about the underlying causes of cancer.

The wonder of replication

Cancer emerges when one of the cells that make up your tissues (and organs) grows and divides without control, losing its specialised function and invading other tissue. This happens when normal control of cell growth and division is compromised through changes, or mutations, in your genome (the chemical instruction book for life).

Mutations lie at the heart of cancer biology.

The genome is made from a chemical alphabet of just four letters (A,T,G, and C) “written” into DNA. It works like a kind of computer software for our cells, with strict instructions for growth and function.

Each of the 100 trillion cells in your body contains roughly six billion letters (called nucleotides) of this code, condensed into a thin strand of DNA about two metres long. To put this into perspective, if you stretched out all the DNA in a human body it would reach around the moon and back several times.

Every time a cell divides, the genome must be copied accurately and quickly. This synthesis of new DNA is called replication, and the numbers behind it are staggering. UK researcher John Diffley has calculated that you will have synthesised the equivalent of a light-year of DNA (10 trillion kilometres) by the time you’re 50.

Words simply cannot do this amazing process justice, but this short video by award-winning animator Drew Berry will blow your mind:


DNA replication has evolved to be incredibly efficient and reliable, but random mistakes (mutations) occasionally happen. Still, they occur at a rate of less than once per genome per cell division, thanks to some impressive molecular proofreading machines, which constantly survey the newly copied DNA and correct errors.

But with so many cells dividing so often, DNA replication still represents a major source of mutations. And every cell division increases the chance of accumulating mutations in important genes, increasing the likelihood of cancer.

Other sources of mutation

Mutations can take many forms and can emerge in a number of ways – not just through replication errors. We inherit between 50 and 100 mutations from our parents at birth, for instance, and any new or de novo mutations act on this inherited genetic background.

Even normal cellular metabolism damages DNA through the production of reactive oxygen. And, in a sinister twist, many of the inherited mutations that predispose people to cancer hit genes that control the DNA proofreading and repair systems (such as the breast cancer genes BRCA1 and BRCA2). This has the effect of amplifying the rate of new mutations.

The other major causes of DNA mutation are lifestyle or environmental factors. We are exposed to a range of these in our everyday lives, such as UV radiation from sunshine, and chemicals including asbestos or from smoking cigarettes.

Lifestyle factors including diet and alcohol consumption may also contribute. Some viruses and bacteria are known to cause DNA damage leading to cancer. They include the human papillomavirus (HPV) for cervical cancer and H. pylori for gastric cancer.

Not off the hook: alcohol and diet can contribute to DNA mutations. Source: Erik/Flickr, CC BY-NC

Although these different agents leave unique chemical signatures in the DNA, they are still essentially random events. Random mutations are, in fact, the raw material driving evolution. And the processes of mutation and evolution are accelerated in cancer. Indeed, we are only now starting to understand the importance of evolution in driving cancer emergence and spread, as well as its resistance to therapy.

Minimising risk

Where does this leave the idea that cancer is all down to bad luck? Is modifying your lifestyle to minimise exposure to risk factors futile?

As usual, reality lies somewhere in the middle of competing narratives. Life is a kind of genetic gamble. We have to play the cards dealt us, but we can stack the odds in either direction by altering our exposure to environmental and lifestyle factors. Suggesting cancer is all down to bad luck dilutes the important message that risk can be modified by behaviour.

The cancer lexicon is littered with notions of guilt and blame. Death is often framed as “losing the battle with cancer”, for instance. And patients and their families are bombarded by gurus profiteering from various diet and lifestyle interventions. Their implicit messages can often leave people feeling that their cancer is all their own fault and wondering if there was something they could have done differently.

The fact remains that, in many cases, there isn’t.

The ConversationThis article was originally published on The Conversation. (Reblogged by permission). Read the original article.


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