Oct 07
Posted by: colinhockings  

Telomere Caps

Most denizens of the interwebs (at least of this corner of the interwebs) will have heard the announcement that the 2009 Nobel Prize in Physiology or Medicine will be given to Elizabeth Blackburn, Carol Greider and Jack Szostak for their work on telomeres – the structures found at the ends of human chromosomes. You may already have read a little about the research behind it (if not, the NobelPrize.org press release is a very good place to start) so I’ll try to keep the background as short as possible. What I would like to do here is to explain the assertions that “cancer research has also benefited from the Nobel-winning trio’s work”.

Telomeres are necessary for several reasons, among them to act as ‘padding’ during cell duplication. Every time a linear DNA molecule is replicated it loses a few base pairs from the ends (the reason why is quite interesting, see this description of the end replication problem). The telomeric sequence is simply “TTAGGG” (in vertebrates) repeated several thousand times so it doesn’t matter when some sequence is deleted. But, I hear you cry, how is this important for cancer?

Most cells in the body do not replicate. A typical tissue, such as skin, has a thin layer of stem cells that divide to produce more stem cells, as well as cells that will differentiate into skin cells. These cells divide a few more times until they are ‘terminally differentiated’. In the case of skin that means that they are filled with keratin and die, and when they reach the surface they are sloughed off. In other tissues the non-replicating terminally differentiated cells have different functions, for example as nerve cells or muscle cells. Thus the only cells that need to replicate infinitely are stem cells (and germ line cells, the cells that become sperm and eggs), so they express a protein called telomerase which adds extra copies of the repetitive sequences to the ends of chromosomes.

Those of you who’ve read my first ‘Understanding Cancer’ post – and anyone who knows a little bit about cancer biology – will see why this system is a major inhibitor of carcinogenesis: when a cell starts to over-proliferate it can only divide a certain number of times before the telomeres are fully eroded. In order to continue dividing it has to accumulate further mutations that render it immortal. These mutations have to be very specific, making them rarer: there are thousands of ways to make a cell grow faster, but only very few ways to lengthen its telomeres. Around 90% of cancers (remember: a cancer is, by definition, a collection of cells that have jumped this hurdle) have mutations that cause them to produce telomerase. Most of the remaining cases of cancer have recruited a normal DNA repair mechanism to lengthen the chromosomes by a process called ALT (Alternative Lengthening of Telomeres).

On a short side note: when telomeres were first elucidated it was thought by some that we’d found the key to aging. Unfortunately upregulating telomerase in an attempt to stay young only leads to more cancer, because you’ve removed one of the hurdles that a nascent tumour has to surmount.

Does anyone see the further significance here? All cancers have to overcome a certain problem, and most of them do it in exactly the same way. This makes telomerase a very attractive target for new chemotherapeutic drugs or other types of intervention, and the field is bustling with new ideas. A few clinical trials are showing progress, using gene therapy and small molecule inhibitors (a.k.a. drugs): for a fuller account read this nice open-access review. The approach that strikes me as the most fascinating – and promising – is the idea of vaccinating against telomerase. Almost all cells in the body constantly chew up a sample of their own proteins and display them to the cells of the immune system as a defence against viruses. If you can tell the immune system to attack cells that express telomerase (not quite as straightforward as one might think) it will specifically attack cancer cells. This should be more specific (read: cause less side effects) than most anti-cancer therapies because most drugs attack all rapidly-replicating cells, whereas this would only target immortal cells, and just like you may have learnt from comic books: immortality is a very rare privilege.

ResearchBlogging.orgShay, J., & Keith, W. (2008). Targeting telomerase for cancer therapeutics British Journal of Cancer, 98 (4), 677-683 DOI: 10.1038/sj.bjc.6604209

Jul 13
Posted by: colinhockings  

The Nuffield Council on Bioethics sent this email to Daniel MacArthur over at Genetic Future. Please think about the questions at hand and make your voice heard by sending your views to the Council. The deadline is the 21st of July (according to their website). Visit this page to respond.

Medical profiling and online medicine: the ethics of ‘personalised’ healthcare in a consumer age

The Nuffield Council on Bioethics is currently running a consultation on Medical profiling and online medicine: the ethics of ‘personalised’ healthcare in a consumer age. The paper provides background information and asks questions on a number of different issues relating to medical profiling and online medicine. We are also inviting respondents to inform us about any other areas that we should consider. We are seeking the views of people including those who have used medical profiling and online medicine services, people working in the area and other stakeholders, academics, policy makers and members of the public. To this end, we would greatly value your contribution given your interest and expertise in genetics generally and personal genomics specifically.

We should be most grateful if you would also include a notice about this consultation on your website, to inform your readers that we are seeking their views. All documents can be downloaded from the Council’s website or obtained by contacting us.

The role of the Council is to examine ethical issues raised by new developments in biological and medical research. It is an independent body, funded jointly by the Nuffield Foundation, the Medical Research Council and the Wellcome Trust. It works by considering topics in depth, publishing reports on its findings and making recommendations to policy makers.

In September 2008, the Council set up a Working Party to examine the ethical issues raised by medical profiling and online medicine, chaired by Christopher Hood, Gladstone Professor of Government at the University of Oxford. Further details about the Working Party, which also includes members with expertise in economics, genetics, law, medicine, philosophy, social science and telemedicine, can be found on the Council’s website.

In its work, the Working Party will consider the ramifications of different technologies, including:

The deadline for responses is 31st July 2009. The Working Party will consider all the consultation responses received and use them to inform its deliberations. A report with conclusions and recommendations is expected to be published in Spring 2010, and a copy of the final report will be sent to all consultation respondents.

+ electronic health records;
+ web enabled health information;
+ internet based drug purchasing;
+ telemedicine;
+ body imaging; and
+ DNA profiling.

The deadline for responses is 31st July 2009. The Working Party will consider all the consultation responses received and use them to inform its deliberations. A report with conclusions and recommendations is expected to be published in Spring 2010, and a copy of the final report will be sent to all consultation respondents.

Jul 09
Posted by: colinhockings  

 

What is cancer? Everyone knows that it is a terrifying disease and has some ideas about a mass of cells that grow uncontrollably but I get the feeling that many people don’t quite understand how it actually happens. I think that even from my biochemistry and cell biology lectures I’d still have a very woolly appreciation of what’s important when it comes to cancer. Before I start with the science, I have to recommend “The Hallmarks of Cancer” by Hanahan and Weinberg – it’s a very readable review that neatly organises cancer biology and was written to help usher in a new way of thinking about cancer. 

Cancer can be thought of as being evolution in action. Very simply put: if something replicates faster than its siblings it will dominate its environment, a fact that is as true of cells as it is of rabbits. However, in the human body, with its exquisite regulation of functional tissues and organs, replication is normally kept under control and almost all cells divide very slowly or not at all. Why is this? Because the somatic (i.e. body) cells do not contribute to the next generation, only the germ line cells (which make sperm and eggs) do. Thus there is no evolutionary competition between cells (c.f. ant colonies: the workers are sterile and do not contribute to the next generation, so there’s no evolutionary competition between them and they’ll willingly sacrifice themselves for the colony) – they don’t try to outgrow each other and dominate their organ, because that would be bad for the organism and their genetic material would not be passed on to the next generation. The problem is that evolution is blind so there’s no ‘trying to outgrow’ or foresight involved. If one cell looses the shackles that stop it from replicating it will replicate, causing cancer. It doesn’t ‘know’ that it will only be able to replicate until the organism dies, at which point all its progeny will die too. The effects of natural selection don’t stop there though: one mutation may allow a cell to ignore one signal to stop dividing, but if one of the group of dividing cells acquires another mutation that allows it to divide even faster, then its progeny will come to dominate the tumour.

So what are the changes that cause cancer, and why do they occur? As I’ve just alluded to, we’re talking about mutations – changes to the signal transduction pathways that tell the cells what to do. Mutations happen for all sorts of reasons, most commonly because DNA replication (required for every cell to divide) makes mistakes. Certain things, such as UV light (in sunshine) and many of the components of cigarette smoke also cause mutations and so can increase the likelihood of cancer developing. However, many of the other substances that have been touted as ‘causing cancer’ (c.f. the Daily Mail) have only very mild effects if any.

Simply replicating faster isn’t enough for a cell to become cancerous. Its progeny will still mature and eventually stop growing as they differentiate into skin cells or white blood cells or whatever. In addition, when the body notices the cancer, the immune system will tell the cells to “commit suicide” – i.e. undergo apoptosis. If it forms a lump of cells, there won’t be a blood supply so the ones in the centre will die. After a certain number of divisions, cells slow down and enter ‘senescence’. What I’m trying to say is that one mutation in a single pathway is not enough to create a tumour and kill you. There are several ‘hallmarks’, or characteristics that a potential cancer cell needs to acquire through different mutations in different pathways. These are: 

  • Self-sufficiency in growth signals
  • Insensitivity to anti-growth signals
  • Evading apoptosis (so the cells cannot “commit suicide”)
  • Limitless replicative potential (immortality – most cells can only divide a finite number of times)
  • Sustained angiogenesis (creating a blood supply to the tumour)
  • Tissue invasion and metastasis (this is what kills people, when the tumour invades surrounding areas, bits fall into the blood stream and grow in other parts of the body)

Only once some of the cells of a tumour acquire all these characteristics do you have a full-blown aggressive cancer.

In the following posts on this topic I’ll talk about cancer therapies, leukemia and other types of cancer, as well as the mechanisms of some of the more “popular” cancers (colon, breast, cervical and prostate) and what is meant by predisposition to certain cancers.