How Long are your Telomeres?

The telomere is a DNA/protein complex that caps the ends of chromosomes. Everyone has seen the X shaped chromosomes but few people think about why our DNA is split into chromosomes rather than one large circular plasmid or set of plasmids like with bacteria. Furthermore, few people think about why chromosomes form that X shape and what stops the lengthening of the p and q arms. We'll be looking at the latter in this post.

One can think of the telomere as the aglet on the end of a shoe lace, the cap on the end of a length of DNA to stop it getting any longer - it's what stops chromosome legs linking up end to end. The region of DNA on either end of a chromosome is actually a length of G-rich DNA with the pattern TTAGGG repeating over and over again for a length of 5-15kb, then finishing off with a long G tail of 50 - 300b. A protein complex, sheltrin, binds to this section of DNA and helps the legth of DNA form a T loop which is a bit like a knot at the end of a shoe lace.

It is generally well known in the scientific community that the length of the telomere is related to the life span of a cell or multicellular organisms - regulating how many times cells can replicate before they stop dividing, go into senescence and eventually die. Generally a human cell will go through 40-60 cycles or thereabouts (the Hayflick limit). The length of telomeres reduces with every-other revolution of the cell cycle and it gets to critical length before the cell stops dividing.

This year's (2009) nobel prize in phyisology/medicine was awarded to Elizabeth H. Blackburn, Carol W. Greider and Jack W. Szostak for discovering how chromosomes are protected by telomeres and the enzyme telomerase. One of their key findings was that telomeres are not shortened with every cell cycle.

It is not known exactly to what level the length of telomeres or the rate of erosion affects people's life expectancy. The general rule is that if you start off with long telomeres and/or telomere shortening is slow, then your life expectancy will be longer. But life expectancy and longevity has multiple factors governing it.

Telomerase is the enzyme that keeps the telomere long. Some species even produce enough to lengthen their telomeres with every-other cycle so they live longer lives but they still die eventually. Telomerase and long telomeres may play a larger role in slowing the ageing process rather than extending life.

Because telomere erosion occurs consistantly during the cell cycle it can be used as a measurement of age of a species where it is difficult to predict the age of an animal. And intraspecies, the telomere lengths and rate of erosion is quite different. Compared to many animals the homo sapien has a really long life considering that human telomeres are only 8–12 kb in length or less at birth and reduce 2 - 4kb in a lifetime. The rate of change of telomere erosion plays a role but looking at the graph below it is not so clear cut if long telomere lengths extend life, especially when compared with our closest living relative, (Pan) the chimpanzee. And also, one wonders about trees - some trees are thousands of years old and still going! (see B.E. Falanary paper below)

Graph showing the relationship between rate of change in mean telomere length (TROC) (base pairs lost [negative numbers] or gained [positive numbers] per year) in various tissues and maximum life span for five birds shown in Table 1 (circles) and eight mammals (boxes) (see C.M. Vleck paper). Common names are: Mus spretus, western wild mouse; Ovis aries, domesticated sheep, Canis familiaris, dog; Macaca nemestrina, pigtailed macaque; Bos taurus, cattle; Macaca fascicularis, cynomolgus monkey; Pan troglodytes, chimpanzee; Homo sapiens, human. Taken from C.M. Vleck et al., The natural history of telomeres: tools for aging animals and exploring the aging process.

The role of telomeres is to maintain the chromosome package. In bacteria mutations are not a big deal but in higher organisms they can cause serious harm and even lead to cancer. The hayflick limit governed by telomere length is seen as a safety mechanism which limits the number of cycles a cell goes through in order to make sure the quality of the DNA does not deteriorate, because with age comes an increased risk of mutation and cancer development.

Recommended papers:
C.M. Vleck et al., 2003, The natural history of telomeres: tools for aging animals and exploring the aging process.
Y. Deng et al., 2008, Telomere dysfunction and tumour suppression: the senescence connection
P.M. Lansdorp, 2009, Telomeres and disease
B.E. Flanary, 2005, Analysis of telomere length and telomerase activity in tree species of various
life-spans, and with age in the bristlecone pine Pinus longaeva
T.J. Vulliami, 2009, Premature Aging
C. Auriche et al., 2007, Budding yeast with human telomeres: A puzzling structure

Cancer protein 'can be disarmed'

Scientists have found a way to disarm a protein thought to play a key role in leukaemia and other cancers.

The breakthrough raises hopes of a new type of therapy that could treat cancer and other diseases.

Previous attempts to neutralise the protein had failed, leading experts to conclude it was effectively "undruggable".

The study, carried out by the US Dana-Farber Cancer Institute, features in the journal Nature.

The protein is one of the body's transcription factors, which turn genes on or off and set in motion genetic cascades that control how cells grow and develop. They also help fuel the growth of tumours.

The transcription factor targeted in the latest study is a protein called Notch.

The gene responsible for manufacturing the protein is often damaged or mutated in patients with a form of blood cancer known as T-cell acute lymphoblastic leukaemia (ALL).

Stapled peptides promise to significantly expand the range of what's considered 'druggable' Professor Greg Verdine Dana-Farber Cancer Institute

As a result the gene is switched on all the time, driving the uncontrolled cell growth characteristic of cancer.

Similar abnormalities in Notch also underlie other cancers, including lung, ovarian, pancreatic and gastrointestinal tumours.

Examining the structure of Notch closely, the researchers isolated a potential weak spot in its structure.

They employed a state-of-the-art technique using chemical braces to mould protein snippets called peptides into specific three dimensional shapes.

These "stapled" peptides are readily absorbed by cells, and are so tiny they can be deployed to alter gene regulation at specific sites.

After designing and testing several synthetic stapled peptides, the researchers identified one that was able to disrupt Notch's function.

When tested in mice it was found to limit the growth of cancer cells.

It may lead to alternative drugs and better treatments for this kind of leukaemia and maybe other cancers Dr David Ish-Horowicz Cancer Research UK

Analysis showed that activity was depressed in genes both directly and indirectly controlled by Notch.

The researchers hope the technique could also be used to target other transcription factors with a similar structure.

Researcher Professor Greg Verdine said: "Stapled peptides promise to significantly expand the range of what's considered 'druggable'.

"With our discovery, we've declared open season on transcription factors and other intractable drug targets."

Dr David Ish-Horowicz, head of developmental genetics at Cancer Research UK's London Research Institute, described the research as "very interesting".

He said: "There is already considerable work by scientists into ways to block Notch to try and reverse the effects of ALL, but the current drugs have some serious side-effects.

"This study describes the design of a new chemical that blocks the mechanism in a different way.

"The new chemical has only been tested in mice so far, and so we don't know how it will behave in humans.

"But, long term, it may lead to alternative drugs and better treatments for this kind of leukaemia and maybe other cancers."

http://news.bbc.co.uk/1/hi/health/8353229.stm

Master-switch Gene FOXP2 is the reason why we can speak and chimps can't

(* speak the same way)

One gene 'prevents chimps talking'

A single gene that is dramatically different in chimpanzees and humans may explain why apes cannot talk.

The FOXP2 gene underwent rapid changes around the time that language emerged in people.

Scientists in the US have now learned that human and chimp versions of the gene not only look different but also function in very different ways. FOXP2 acts as a "master switch" for other genes, turning them on or off.

Scientists at the University of California at Los Angeles (UCLA) scoured human DNA to see which areas are targeted by the gene. They then looked at what effect human and chimp forms of FOXP2 had on human cell lines. To their surprise, the two FOXP2 versions triggered different patterns of activity in the human genes.

"We found that a significant number of the newly-identified targets are expressed differently in human and chimpanzee brains," said study leader Dr Daniel Geschwind. "This suggests that FOXP2 drives these genes to behave differently in the two species."

Previous research has shown a close link between FOXP2 and the power of speech. The amino acid composition of the human version of the gene mutated and changed rapidly around the time language first developed.

The findings, reported in the journal Nature, may also help scientists understand how certain brain disorders such as autism and schizophrenia disrupt speech.

Co-author Dr Genevieve Konopka, also from UCLA, said: "Genetic changes between the human and chimp species hold the clues for how our brains developed their capacity for language.

"By pinpointing the genes influenced by FOXP2, we have identified a new set of tools for studying how human speech could be regulated at the molecular level."

http://uk.news.yahoo.com/21/20091111/tsc-one-gene-prevents-chimps-talking-4b158bc.html

Software: Bounded Queue, a PHP Class

I wrote a PHP class called the Bounded Queue that might be of use to people. It is released under the New BSD license so go ahead and use it freely if you want.

The guys at PHPClasses.org gave it this description: This class can be used to manage a queue with a limited number of elements. It can push and pop items of any type into a queue array. If the queue already contains the limit number of items when a new item is pushed, the item at the bottom of the queue is popped (shifted) out.

Technically, this queue is bidirectional and you can even insert or remove items from the middle of the queue and even change its size dynamically. Here it is:

http://www.phpclasses.org/bounded-queue

PHPClasses.org have considered the class to be "Noteable". "This means that the site users interested in packages that have something special, are being notified to pay special attention to your package." Cool :)

If you do decide to use it then please tell me what for and warn me about any bugs. Thanks.

Update of news

Here's a few things of interest that happened lately:

A critically ill Turkish boy has had his life saved after scientists were able to read his genome quickly and work out that he had a wrong diagnosis. http://news.bbc.co.uk/1/hi/health/8315258.stm (I want to see much more of this sort of thing)

Twitter has signed deals to put messages sent via the microblogging service into the Microsoft and Google search indexes. http://news.bbc.co.uk/1/hi/technology/8310716.stm (This is highly important because it means that flash trends and spreading of diseases/viruses (biological & Comutational) can be identified globally within a very short period of time and without overburdening twitter - they're infamous for crashing regularly... data mining ftw)

Scientists say they have discovered an antibody that could minimise the major internal bleeding seen in traumas like bullet wounds and car crashes. http://news.bbc.co.uk/1/hi/health/8322454.stm

A South Korean court has convicted the disgraced cloning scientist Hwang Woo-suk of embezzlement over his stem cell research. He was given a two-year sentence suspended for three years. The 56-year-old scientist's work had raised hopes of finding cures for diseases such as Alzheimer's. But his research was declared bogus in 2005, and he was put on trial the following year for embezzlement and accepting money under false pretences. Hwang's research made him a South Korean hero until revelations that it was false shocked the nation. http://news.bbc.co.uk/1/hi/world/asia-pacific/8325377.stm (I know this is old news but it's interesting how long it's taken them to finally convict him... but NOT jail him!)

I like bears :) http://news.bbc.co.uk/earth/hi/earth_news/newsid_8321000/8321102.stm

Tiny metal particles have been shown to cause changes to DNA across a cellular barrier - without having to cross it. The nanometre and micrometre scale particles resulted in an increase of damage to DNA across the barrier via a never-before-seen cell signal process. http://news.bbc.co.uk/1/hi/sci/tech/8344815.stm (Be afraid, be VERY afraid!)

The man who pioneered life-saving treatment for tuberculosis sufferers has died in Edinburgh at the age of 97. http://news.bbc.co.uk/1/hi/scotland/edinburgh_and_east/8342593.stm

Nearly 40% of breast cancer tumours change form when they spread, a UK study shows... AND ...Women treated for breast cancer are at a higher risk of a relapse if they have "dense" breasts, say researchers. http://news.bbc.co.uk/1/hi/health/8337795.stm http://news.bbc.co.uk/1/hi/health/8345245.stm (You could imagine a doctor talking to his patient one day: You're dense! Just like your breasts.)

Hundreds of experts from 50 nations are set to agree on a "DNA barcode" system that gives every plant on Earth a unique genetic fingerprint. http://news.bbc.co.uk/1/hi/sci/tech/8346635.stm

Scientists have identified a drug which may offer hope to patients with a particularly lethal form of lung cancer. The drug eliminated small cell lung cancer tumours in 50% of mice, and blocked the cells' ability to resist standard chemotherapy treatment. http://news.bbc.co.uk/1/hi/health/8350220.stm

Cancer can spread to foetus from the mother

Scientists have established beyond doubt that in rare cases cancer can be transmitted in the womb, following the birth of a baby to a woman with leukaemia.

A team at the Institute of Cancer Research, a college of the University of London, working with colleagues in Japan, found that the cancer had defied accepted theories of biology. Leukaemia cells had crossed the placenta and spread from the 28-year-old mother to her unborn baby.

Dr Tony Ford on how cancer can pass from the woman to foetus in the womb Link to this audio

There have been suspicions for years that cancer could be passed on in the womb. About 17 cases of suspected mother-to-child transmission have been noted – usually leukaemia or melanoma. But until now researchers have been unable to establish whether it had happened and, if so, how.

If the cells did cross the placental barrier, the child's immune system should have recognised them as foreign invaders and destroyed them.

In the latest case no one knew the mother, who was Japanese, had cancer during her pregnancy. She had a normal delivery in hospital, giving birth to an apparently healthy baby girl.

But just over a month later the mother developed vaginal bleeding, which became uncontrollable. She was diagnosed with an advanced stage of leukaemia and died.

When the baby was 11 months old she was brought to hospital with a swollen right cheek. Tests showed she had a tumour in her jaw and the cancer had spread to her lungs.

Although the cancers were not the same – the baby had a lymphoma and is now in remission – the Japanese doctors suspected a link to the leukaemia that had killed her mother.

They called in the team at the Institute of Cancer Research, which has done a lot of work in recent years on the genetics of cancers of identical twins. In the journal Proceedings of the National Academy of Sciences, the researchers explain how they used genetic "fingerprinting" techniques to establish that the child's cancer cells came from the mother.

They found the cancer cells of mother and baby carried the identical mutated cancer gene (called BCR-ABL1), but the infant had not inherited this gene. This meant that the child could not have developed the cancer in isolation – the cells must have come from the mother.

To investigate how leukaemia cells could have crossed the placental barrier and survived in the baby, the scientists looked for evidence of some form of immunological acceptance or tolerance of the foreign cells by the foetus. They examined the genes of the cancer cells in the infant and found a deletion mutation – some DNA missing in the region that controls expression of the major histocompatibility locus (HLA).

This was significant because HLA molecules primarily distinguish one individual, and his or her cells, from another, so the absence of these on the cancer cells meant the infant's immune system would not have recognised that they were foreign.

Professor Mel Greaves, who led the study, said: "It appears that in this and, we presume, other cases of mother-to-offspring cancer, the maternal cancer cells did cross the placenta into the developing foetus and succeeded in implanting because they were invisible to the immune system. We are pleased to have resolved this longstanding puzzle.

"But we stress … the chances of any pregnant woman with cancer passing it on to her child are remote."

Dr David Grant, scientific director at Leukaemia Research, said: "The important message from this … is that leukaemia cells can be destroyed by the immune system. Harnessing the power of the immune system to cure and protect patients from leukaemia is one of our priority areas of research."

http://www.guardian.co.uk/science/2009/oct/12/cancer-passed-from-mother-foetus

The human genome in 3D

Scientists have worked out the 3D structure of the human genome.

Their findings, published in Science magazine, reveal how long strands of DNA code are folded and tightly packed into the nucleus of a human cell.

Unfolded, the cell's genome - those strands of DNA code - would be approximately 2m in length.

The team showed how this is organised into a tight ball to fit inside a nucleus, which is about one hundredth of a millimetre in diameter.

The US-based research team developed improved DNA sequencing and computational methods to build a model of the genome.

This is the first glimpse we're getting of a whole genome in 3D Job Dekker University of Massachusetts

Job Dekker, from the University of Massachusetts Medical School, led the research.

He explained to BBC News that, with its new approach, his team had discovered important patterns in the shape of the genome.

"For a given part of the genome, we can determine its neighbours," he said.

"And if you can do that for every gene - if you know which other genes surround it - you can work your way back computationally to calculate the structure.

"This is the first glimpse we're getting of a whole genome in 3D."

Professor Julian Parkhill visits the Wellcome Collection to unravel the science behind the genome

DNA is bundled into chromosomes. The combination of DNA and protein that makes up these chromosomes is called chromatin.

Dr Dekker explained how a 3D view showed how chromatin's complicated folding pattern was important in the regulation of genes.

"We now see that things that are far apart along the linear sequence of the genome are actually next to each other in the folded structure," he said.

"They're close together in the structure, and they're talking to each other."

This constant communication is the basis of the regulation that keeps a cell healthy and functional.

This means that a detailed view of the genome's structure could provide a new window into diseases such as cancer, which is caused by errors in the genetic code.

"Maybe we will be able to predict these [disease-causing] changes better now," said Dr Dekker.

The team also discovered that the human genome is organised into two separate compartments, keeping active genes accessible while keeping inactive DNA in a sort of storage compartment.

The chromosomes snake in and out of the two compartments - separating their active and inactive sections.

http://news.bbc.co.uk/1/hi/sci/tech/8296861.stm

IBM to announce new DNA sequencing technique

IBM will announce on Tuesday how it intends to hold DNA molecules in tiny holes in silicon in an effort to decode their genetic secrets letter by letter.

Their microelectronic approach solves one of two long-standing problems in "nanopore" DNA sequencing: how to stop it flying through too quickly.

The aim is to speed up DNA sequencing in a push toward personalised medicine.

IBM's chief executive Sam Palmisano will announce the plans to the Medical Innovation Summit in the US on Tuesday.

While sequencing the genomes of humans and animals has become relatively routine in a laboratory setting, the ability to quickly and cheaply sequence genomes of individuals remains out of reach.

That widely available genetic information will help bring about the era of "personalised medicine" - in which preventative or therapeutic approaches can be tailored to individuals based on their specific genetic makeup.

All-electronic

"There have been a number of attempts to sequence DNA much faster than it was sequenced when the first human genome was announced," said Gustavo Stolovitzky, a computational biologist from IBM.

Individual genetic information will lead to more directed therapies

"All of them use some complicated sample preparation - chopping the DNA, amplifying, reverse transcribing - and some sophisticated and labour-intensive optics," Dr Stolovitzky told BBC News.

"All this makes sequencing faster, but still slower and more expensive than it needs to be before it could be used for personalised medicine."

Instead, Dr Stolovitzky and colleagues are pursuing a method involving silicon peppered with holes just three billionths of a metre across - 20,000 times thinner than a human hair and just wide enough for one strand of DNA to pass through.

Researchers have been looking into using such nanopores for a number of years - mimicking the proteins in cell membranes that perform the same trick - because using a semiconductor offers significant advantages over biochemical and optical techniques.

"DNA nanopore sequencing continues to be one of the great candidates to do fast and cheap DNA sequencing without sample preparation or sophisticated optics, using only electronics to fetch the signal out," Dr Stolovitzky said.

Moreover, the approach could be done in a "massively parallel" way - that is, with hundreds or thousands of DNA strands passing through an array of holes on a single chip.

Trap stack

The idea is conceptually simple but devilishly difficult to carry out. Because DNA naturally carries a net electric charge, simply applying a voltage across the two sides of the chip drives the DNA strands through the holes.

However, the DNA tends to pass through too quickly to decode the identities of the individual nucleotides - letters of the genetic code - as they pass.

More than that, until they can study DNA strands moving at a more carefully controlled pace, researchers cannot develop the techniques to query the precise nucleotide they have trapped in place.

The Blue Gene supercomputer simulated the nanopores' every atom

The IBM team have now hit on the idea of a chip composed of a stack of layers, each of which can hold a precisely-controlled voltage in a thin layer inside the nanopore.

These smaller voltages trap the negatively charged chemical groups called phosphates that separate individual nucleotides.

By cycling this internal voltage, the DNA strand can be made to advance one nucleotide at a time.

The team has used IBM's Blue Gene supercomputer to simulate the process in order to ensure it would work, and the team has built prototypes of the trapping nanopore. Tuesday's announcement marks the beginning of the testing and refinement stages of the process.

What remains is to investigate the means to identify the individual nucleotides trapped inside the nanopores, which is likely to rest on measuring some electrical or electronic property of each as it passes.

Stas Polonsky, another IBM researcher working on the project, remains convinced that with the benefit of a trapping mechanism, this last problem is tractable.

"As a company we have a lot of expertise with electrical measurements," he said.

"We have nanopores plus the whole arsenal of microelectronics - we can integrate all these ultrasensitive circuits right on a chip, which will boost the sensitivity for measurements tremendously."

http://news.bbc.co.uk/1/hi/sci/tech/8291185.stm

Remove index.php from the URL in Kohana

If you read the Kohana documentation they will tell you to edit your .htaccess file in order to remove index.php from your URLs, so that

http://localhost/kohana/index.php/controller/view

becomes

http://localhost/kohana/controller/view

But it is my experience that when creating URLs using the framework's helpers, like so:

<?php echo html::anchor('controller/view', 'Title'); ?>

Even with the htaccess modification, it will show the url as

http://localhost/kohana/index.php/controller/view

What you need to do is to edit the file:

/kohana/application/config/config.php

and modify this line to:

$config['index_page'] = '';

Now your URLs will not have index.php in them and the htaccess file can do its job.

Nobel Prize for chemistry of life

The 2009 chemistry Nobel Prize has been awarded to Venkatraman Ramakrishnan, Thomas Steitz and Ada Yonath.

The prize is awarded for the study of the structure and function of the ribosome - the cell's protein factory.

The ribosome translates genetic code into proteins - which are the building blocks of all living organisms.

It is also the main target of new antibiotics, which combat bacterial strains that have developed resistance to traditional antibiotic drugs.

These new drugs work by blocking the function of ribosomes in bacterial cells, preventing them from making the proteins they need to survive.

It's above and beyond my dreams and I am very thankful Ada Yonath

Their design has been made possible by research into the structure of the ribosome, because it has revealed key differences between bacterial and human ribosomes. Structures that are unique to bacteria can be targeted by drugs.

The announcement was made during a press conference at the Royal Swedish Academy of Sciences, during which the three winners were described as "warriors in the struggle of the rising tide of incurable bacterial infections".

Professor Ramakrishnan is based at the Medical Research Council's Molecular Biology Laboratories in Cambridge, UK.

Thomas Steitz is based at Yale University in the US, and Ada Yonath is from the Weizmann Institute in Rehovot, Israel.

The prize is to be shared equally between the three scientists, who all contributed to revealing the ribosome's huge and complex molecular structure in detail.

Professor David Garner, president of the Royal Society of Chemistry, described the three as "great scientists" and said their work was of "enormous significance".

'Molecular machine'

These scientists and their colleagues have helped build a 3D structure of the ribosome.

In doing so, they solved an important part of the the problem posed by Francis Crick and James Watson when they discovered the twisted double helix DNA structure - how does this code become a living thing?

Ultimately, when you look at any biological question it becomes a chemical problem Venkatraman Ramakrishnan

DNA is made available to the ribosome by "transcription" of genes into chunks of messenger RNA.

In the ribosome, these are read and translated into the various amino acid sequences that make up an organism's proteins.

By looking closely at its structure, scientists are able to study how this translation process works.

The work is based on a technique called x-ray crystallography - where molecules are removed from cells, purified and made into crystals that can be examined using x-rays.

Professor Ramakrishnan told BBC News that until the ribosome's atomic structure was determined, "we knew this was a large molecular machine that translated genetic code to make proteins, but we didn't know how it worked".

"We still don't know exactly how it works, but we have made a tremendous amount of progress as a direct result of knowing what it looks like.

"It's the difference between knowing that when you put gasoline in a car and press on a pedal, it goes. But if you know that the gasoline gets ignited and pushes down pistons and drives the wheels, that's a new level of understanding."

Work together

Addressing the Nobel press conference by telephone, Professor Yonath said that modern techniques were allowing scientists to look at the structures on the atomic scale - individual bond after individual bond.

New drugs targeting the ribosome will help fight resistant bacteria

This is the 101st chemistry Nobel to be awarded since 1901, and Professor Yonath is only the fourth woman to win. She joins an illustrious list of female chemists that includes Marie Curie, who also won the physics award.

During the press conference, Professor Yonath said: "It's above and beyond my dreams and I am very thankful."

President of the American Chemical Society Thomas Lane told the BBC that the award was "a wonderful example of leaders in their disciplines - people from around the world - working towards a common goal and being able to achieve it.

"It shows that as scientists we don't just sit in our dark labs, we come together and share our research."

Professor Ramakrishnan paid tribute to the many generations of talented researchers who he said had contributed to this entire field.

Some scientists have commented negatively that the research recognised by this year's chemistry Nobel has a biological focus.

But Professor Garner pointed out that "when you get down to looking at biology at the molecular level - understanding the fundamental processes of life - it's all chemistry".

Professor Ramakrishnan said: "Ultimately, when you look at any biological question it becomes a chemical problem, because bio is done by molecules and molecules use chemical laws."

He concluded: "It's often the way with science that people study fundamental problems, like the ribosome, and they lead to important medical applications in completely unpredictable ways.

"It's important to realise that support for basic science is the seed that allows the medical applications and technology to grow."

http://news.bbc.co.uk/1/hi/sci/tech/8294421.stm

Avoid Boring People - Avoid James Watson

"Avoid Boring People: And other lessons from a life in science, by James D. Watson"

I read this book, James Watson's autobiography, a few days ago. It was not very good, and it didn't particularly raise my respect for James Watson as a person or a scientist. The format of the book is the best thing about it - each chapter represents a stage in his life and at the end of each chapter a list of lessons and advice with a short explanation is given. Some of the advice is pretty good - if you plan to look through this book then just read the lessons that are relevant to you - no point in reading the whole thing...

James Watson's autobiography makes it blatantly clear that he did not struggle very hard to get where he is. He and his parents were middle class and he did not have any emotional or money trouble. He didn't have any family problems. He was intelligent and did well in school and met all the required grades to get into the colleges and universities and he never had any problems funding any of this. He never failed at anything he did and was never forced to take any unsavoury career routes or make any large compromises. Also he barely mentions anything about politics or the state of the nation and its affects on him.

He was always in education or in employment and he always had something to do and everyone around him supported him. The universities he worked for paid him well and funded all his research without debate (and this was before he discovered the structure of DNA). His choice of research was in the best field of its time (and now) - genetics. He gives advice concerning this along the lines of: Pick a research subject on the cutting edge of science. He says that picking a subject that has been studied extensively already or has little to contribute to humanity is not beneficial to an active scientist's career. I agree with him and can think of quite a few fields in science where funding should be cut off. But the point he was making is that if you plan to be a highly successful researcher, discover lots of new things and perhaps get recognition and/or a nobel prize, look at a subject where you explore uncharted territory that is beneficial to man (and could make you money).

As for his personal life, what can I say except that he never divulges anything about personal relationships with women or even his close friends (if he even had really close friends). He never mentions a single disagreement or serious debate he had with any person either personal or professional. He met with some of the most eminent scientists like Renato Dulbecco, Linus Pauling, Rosalind Franklin and a few others I've forgotten the names of, but he never mentions their personalities, quirks or how he interacted with them. Going back to his dealing with women... what women? He did not form any deep relationships with individuals and I think he remained a virgin till marriage or something - heck, he doesn't mention anything concerning emotions or attractions. He never had "women trouble" and he married one of his assistants because "when she wasn't there he missed her presence". He doesn't mention the courtship period or his anxieties or emotional strife (if any). Lazy & Boring.

As for discovering the structure of DNA he does something honorable - he mentions the highly significant amd neccessary contribution of Rosalind Franklin with her stunning X-Ray Crystallography photos and suggestions. He also mentions the point that other scientists rejected Linus Pauling's hurried publication of a paper in nature in 1953 which made them drop the idea of a triple helix and that other scientists' work in the field pointed them towards base pairing with the bases on the inside with the backbone forming a winding ladder on the outside. It was Franklin's photo that showed an X-like striations in the middle that made them sure that they were on the right path with base pairing on the inside. One irritation in this chapter of the book is that I learn next to nothing about Francis Crick. Yes he mentions him as his partner in this and his work being key to the discovery, but he doesn't mention anything about him as a person.

The genious behind the discovery of the DNA double helix structure was their using templates, initially paper cutouts, to fit together and see if the distances between the atoms in the molecules were acceptable. The fact that they used cutouts and arranged them in different ways is how they got to the answer. Sometimes visualisation is the key to discovery - imagine a large table of numerical values - as a table it might not look like there is a pattern in the data but once you plot it on a chart/graph and perhaps carry out a function on it, then you can discover a pattern and even model it. You would find it very hard to discover a trend just dealing with a list of numbers.

Nothing else is particularly interesting after that. He doesn't make any massive blunders, nor has he any serious problems. Yeh, he won a nobel prize which he was happy to get but a nobel comes quite a few years after the discovery and the scientist has moved on to a different challenge by then. He was happy to receive it but not extatic.

In summary, it's not a good book if you're looking to find out about his personality or personal life - he keeps his cards very close to his chest. He doesn't insult or mock anyone or bring up arguments or debates - either he is very cold emotionally or he wants to play it very safe. He doesn't describe himself, other people in character, quirks or appearance to make it interesting. The most controversial thing he ever did happened later on in his life a long time after the publication of this book when he said some things people saw as very racist (see here). If you do plan to look this book up there is no point in reading it fully - look at the photos and read the points at the end of each chapter instead. James Watson decided to call his autobiography "Avoid Boring People" and I agree - avoid James Watson.

I'm currently reading "Next" by Michael Crichton, a fiction book concerning genetics and its misuse. So far so good - I might write a post about this later. I might look at a Linus Pauling book next.

Key cancer spread gene found

Scientists have pinpointed a gene linked to more than half of all breast cancers.

The gene, NRG1 (neuregulin-1), is also thought to play a role in many bowel, prostate, ovarian and bladder tumours.

The University of Cambridge team said the breakthrough should provide "vital information" about how cancer spreads.

Experts agreed the finding, published in the journal Oncogene, could represent a very significant advance in the fight against cancer.

I believe NRG1 could be the most important tumour suppresser gene discovery in the last 20 years Dr Paul Edwards University of Cambridge

The Cambridge team showed that the gene - which helps to suppress the growth of cancer - is located on chromosome 8.

Cancerous cells are known often to miss part of that chromosome, and when the researchers analysed breast cancer samples they found that at least part of the key gene had often been lost.

Everybody is born with an intact NRG1 but it seems that in some cases it can become damaged - leaving the way open for cancer to thrive.

Lead researcher Dr Paul Edwards said: "I believe NRG1 could be the most important tumour suppresser gene discovery in the last 20 years as it gives us vital information about a new mechanism that causes breast cancer.

"We have got strong evidence that the gene is implicated in breast cancer but we have no reason to think it's not the same for other cancers, including prostate and colon cancer.

"Finding out what genes have been turned off in these cancers is enormous help in understanding what has gone wrong with their biology."

Arlene Wilkie, of the Breast Cancer Campaign, which part-funded the study, said: "Knowing the identity of this gene will lead to far more detailed studies of how it works and how it is involved in breast cancer development.

"This research is a major step forward in understanding the genetics of cancer and could open up a host of new strategies to improve diagnosis and treatment."

Lesley Walker, of the charity Cancer Research UK, which also funded the study, said more research was now needed to understand how the gene was silenced, and how exactly it influences the development of cancer.

She said: "It might then be possible to develop ways to bypass the gene or target treatments to the defect."

http://news.bbc.co.uk/1/hi/health/8290507.stm

Nobel prize for chromosome find

This year's Nobel prize for medicine goes to three US-based researchers who discovered how the body protects the chromosomes housing vital genetic code.

Elizabeth Blackburn, Carol Greider and Jack Szostak jointly share the award.

Their work revealed how the chromosomes can be copied and has helped further our understanding on human ageing, cancer and stem cells.

The answer lies at the ends of the chromosomes - the telomeres - and in an enzyme that forms them - telomerase.

The 46 chromosomes contain our genome written in the code of life - DNA.

When a cell is about to divide, the DNA molecules, housed on two strands, are copied.

But scientists had been baffled by an anomaly.

For one of the two DNA strands, a problem exists in that the very end of the strand cannot be copied.

Protecting the code of life

Therefore, the chromosomes should be shortened every time a cell divides - but in fact that is not usually the case.

If the telomeres did repeatedly shorten, cells would rapidly age.

The discoveries ... have added a new dimension to our understanding of the cell, shed light on disease mechanisms, and stimulated the development of potential new therapies The Nobel Assembly

Conversely, if the telomere length is maintained, the cell would have eternal life, which could also be problematic. This happens in the case of cancer cells.

This year's prize winners solved the conundrum when they discovered how the telomere functions and found the enzyme that copies it.

Elizabeth Blackburn, of the University of California, San Francisco, and Jack Szostak, of Harvard Medical School, discovered that a unique DNA sequence in the telomeres protects the chromosomes from degradation.

Joined by Johns Hopkins University's Carol Greider, then a graduate student, Blackburn started to investigate how the teleomeres themselves were made and the pair went on to discover telomerase - the enzyme that enables DNA polymerases to copy the entire length of the chromosome without missing the very end portion.

Their research has led others to hunt for new ways to cure cancer.

It is hoped that cancer might be treated by eradicating telomerase. Several studies are under way in this area, including clinical trials evaluating vaccines directed against cells with elevated telomerase activity.

Some inherited diseases are now known to be caused by telomerase defects, including certain forms of anaemia in which there is insufficient cell divisions in the stem cells of the bone marrow.

The Nobel Assembly at Sweden's Karolinska Institute, which awarded the prize, said: "The discoveries... have added a new dimension to our understanding of the cell, shed light on disease mechanisms, and stimulated the development of potential new therapies."

Carol Greider, now 48, said she was phoned in the early hours with the news that she had won.

She said: "It's really very thrilling, it's something you can't expect."

Elizabeth Blackburn, now 60, shared her excitement, saying: "Prizes are always a nice thing. It doesn't change the research per se, of course, but it's lovely to have the recognition and share it with Carol Greider and Jack Szostak."

Professor Roger Reddel of the Children's Medical Research Institute in Sydney, Australia, said: "The telomerase story is an outstanding illustration of the value of basic research."

Sir Leszek Borysiewicz, chief executive of the Medical Research Council, said: "The Medical Research Council extends its congratulations to Blackburn, Greider and Szostak on winning the 2009 Nobel Prize.

"Their research on chromosomes helped lay the foundations of future work on cancer, stem cells and even human ageing, research areas that continue to be of huge importance to the scientists MRC funds and to the many people who will ultimately benefit from the discoveries they make."

http://news.bbc.co.uk/1/hi/health/8290094.stm

Another Zend Framework Error - missing index.phtml

Something that isn't made especially clear is the way views and controllers work together. It hints at the issue in the ZF official tutorial here, but provides no clear message.

OK, the scenario - I've just created a new controller:

<?php

class UserController extends Zend_Controller_Action {

public function indexAction(){
echo "You are in the index of User";
}
?>

Running this in the browser by going to http://localhost/public/user will cause this error:

An error occurred

Application error

Exception information:

Message: script 'user/index.phtml' not found in path (C:\wamp\www\application\views\scripts\)

And it also outputs a stack trace and other stuff.

Evidently, there is a missing file issue here. Believe it or not, you need to create a phtml file corresponding to your controller and action! You have to go to the /applications/views/scripts/ directory and create a new folder called 'user' (or whatever you have called your controller), and you need to create a file in it called index.phtml and an additional phtml file for every action you create in all your controllers.

So lame.

Zend Framework View not found

I was messing about with a new installation of the Zend Framework on my system after reading through the basic tutorials on the web (the official ZF website tutorial is horrible) and I came across something that didn't work when using Views.

Here is the typical usage as shown in a tutorial on the IBM site (tut 2 [sign in required]):

<?php
//You should have require_once 'Zend/Loader.php'; in your bootstrap (index.php)

Zend::loadClass('Zend_Controller_Action');
Zend::loadClass('Zend_View');

class IndexController extends Zend_Controller_Action
{
public function indexAction()
{
$view = new Zend_View();
setScriptPath('views'); //the offending line
echo $view->render('indexIndexView.php');
}
}
?>

This is a typical controller class that makes a View object in order to render the HTML in the indexIndxView.php file to your browser. What should happen is that the contents of indexIndexView.php are displayed on your webpage. What actually happens is you get this error:

An error occurred

Application error

Exception information:

Message: script 'indexIndexView.php' not found in path (views\)

And then it outputs the stack trace and other stuff.

Evidently, this is a path problem - it doesn't know where to look for the files. Believe it or not, Zend didn't make their scripts auto-discover the location of the views folder! The thing is, the people who write the software and these tutorials should really mention these errors and how to get past them because it's things like this that put people off learning frameworks in the first place because the simplest things don't even work. Trying to Google this error is next to useless as it's really difficult to find the solution.

The fix is actually really easy:

$view->setScriptPath(APPLICATION_PATH . '/views/');

The APPLICATION_PATH is a constant set in the bootstrap file that can be used to make sure your files gets found. Why do people negelect to mention such important things?

Anyway, seeing the inadequecy of needing to create a view object and set its script path in every controller method, I decided to just create an instance of the view object in the bootstrap (index.php):

Zend_Loader::loadClass('Zend_View');
$view = new Zend_View();
$view->setScriptPath(APPLICATION_PATH . '/views/');

Then in every controller method I need to render a view in I just write this code (without the silly file naming OC):

global $view;
echo $view->render('indexIndexView.php');

Kohana PHP framework - some tips

Recently, I've been working with the Kohana PHP Framework and there are a few hurdles I've come across and gotten past - here are a few tips.

Making your own Controller

The default gateway controller with a fresh install of Kohana is 'welcome'. This means that URIs are written a bit like this:

http://localhost/kohana/welcome/index

But it's not ideal to have 'welcome' in the URI all the time. So, if you want to choose a custom name like 'site', you need to make your own controller...

1. Copy the welcome controller (welcome.php) in /kohana/applications/controllers/ and paste into the same folder.
2. Rename the file to site.php
3. Open the site.php file and change the class declaration to 'class Site_Controller extends Template_Controller'
   
4. Now, go to /kohana/system/config/ and copy the file called routes.php to /kohana/application/config/ .
5. Open up the file and edit like so: $config['_default'] = 'site';
   

That should do it. Your site will now build its URIs and route through the 'site' controller by default. You should make urls like so:

<?php html::anchor('site/index', 'Home Page'); ?>

Making your own default template

Simply go to /kohana/system/views/kohana/ and copy the template.php file to /kohana/application/views/kohana/. Edit the file as you wish. But, make sure your controller has this line pointing to it: public $template = 'kohana/template';

Making your CSS and Javascript work (get found)

So you make your XHTML template file and are ready to test everything - you stick your CSS in a .css file and your Javascript into a .js file and your images into an 'images' folder and put them in the root (/kohana/). You go to the page through the URI, e.g. http://localhost/kohana/site/index

Huh? What's this? Your CSS, Javascript and image files were not found!

Turns out you need to change the location of your files and add some PHP to your template.

1. make a folder in root (/kohana/) called 'media'.
   
2. make 3 folders called images, css and js inside your media folder and move your images, css and javascript files into their respective folders
3. Edit your css and js files to point to the right path for the images, e.g: background-image: url(/kohana/media/simages/bg.png); (make sure the first / is there otherwise it won't work
4. Now edit your template file to include this bit of code in the head section (I called my css file and js file css.css and js.js (imaginative huh?)):
   

<?php echo html::stylesheet(array('media/css/css'), array('screen')) .
html::script(array('media/js/js'), FALSE); ?>

Now this will put the typical XHTML tags into your page to include outside css and js files:

<link rel="stylesheet" type="text/css" href="/kohana/media/css/css.css" media="screen" />

<script type="text/javascript" src="/kohana/media/js/js.js">
In 1935, one of the founders of modern genetics, JBS Haldane, studied a group of men with the blood disease haemophilia. He speculated that there would be about 150 new mutations in each of us. 
Others have since looked at DNA in chimpanzees to try to produce general estimates for humans. 
However, next generation sequencing technology has enabled the scientists to produce a far more direct and reliable estimate. 
They looked at thousands of genes in the Y chromosomes of two Chinese men. They knew the men were distantly related, having shared a common ancestor who was born in 1805. 
By looking at the number of differences between the two men, and the size of the human genome, they were able to come up with an estimate of between 100 and 200 new mutations per person. 
Impressively, it seems that Haldane was right all along. 
Unimaginable
One of the scientists, Dr Yali Xue from the Wellcome Trust Sanger Institute in Cambridgeshire, said: "The amount of data we generated would have been unimaginable just a few years ago. 
"And finding this tiny number of mutations was more difficult than finding an ant's egg in an emperor's rice store." 
New mutations can occasionally lead to severe diseases like cancer. It is hoped that the findings may lead to new ways to reduce mutations and provide insights into human evolution. 
Joseph Nadeau, from the Case Western Reserve University in the US, who was not involved in this study said: "New mutations are the source of inherited variation, some of which can lead to disease and dysfunction, and some of which determine the nature and pace of evolutionary change. 
"These are exciting times," he added. 
"We are finally obtaining good reliable estimates of genetic features that are urgently needed to understand who we are genetically."
http://news.bbc.co.uk/1/hi/sci/tech/8227442.stm

DNA clue to honey bee deaths

Scientists say that mass bee deaths may be caused by viruses that disrupt gene expression.

The team analysed which genes were turned on and which were turned off in healthy bees and those from hives with colony collapse disorder (CCD).

Since 2006, CCD has caused the catastrophic loss of US bee hives and is implicated in bee deaths elsewhere.

Writing in PNAS journal, the team say they used "whole genome microarrays" to compare cells from bees' guts.

Lead scientist May Berenbaum from the University of Illinois told BBC News that the research was made possible by publication of the bee genome in 2006.

We talk about a smoking gun. We have the bullet hole! Professor May Berenbaum

"It's an incredibly useful repository of information which allowed the construction of the microarray - a slide which has all 10,000 bee genes on it," she said.

"We used it to compare colony collapse disorder bees with healthy ones and looked at the differences. There are of course 10,000 genes. So there were a whole lot of differences but we could rule out many of them."

Gut feeling

The team concentrated on analysing gene expression from cells in the bees' guts because this is the primary site of pesticide detoxification and immune defence.

Previous theories for CCD have included pesticide poisoning as well as infection and mite infestation.

But the team's genetic analysis of the bees' guts failed to reveal elevated expression of pesticide response genes.

In addition, genes involved in immune response showed no clear expression pattern despite the increased prevalence of viruses and other pathogens in CCD colonies.

What did show up in the guts of the CCD bees was an abundance of fragments from the ribosome, a structure which is the cell's protein making factory.

According to the researchers, this finding suggests that protein production is likely to be compromised in bees from CCD hives.

Previous research shows that the viruses that bees carry all attack the ribosome.

Little problem

The microbes in question are known as "picorna-like" viruses. The word derives from pico, which means little, and RNA (ribonucleic acid).

"These picorna-like viruses all attack at the same spot," said Professor Berenbaum.

"What they do is to work their way into the ribosome and instead of making honey bee protein they make virus proteins.

"So maybe what's happening is basically the ribosome wears out. So we looked to see if the CCD bees have more of these viruses than healthy bees. And they do.

The viruses in question include "deformed wing virus" and "Israeli acute paralysis virus".

The scientists believe that if a number of similar picorna-like viruses attack simultaneously, they may be able to overwhelm the ribosome.

"We talk about a smoking gun. We have the bullet hole!" said May Berenbaum.

"We now need to look for how multiple viruses might interact on the ribosome."

The honey bee is the US's key agricultural pollinator. As such it is worth $14bn to the country's economy.

CCD was first identified in 2006. In the winter of 2007-8 more than a third of US bees were lost.

Similar losses have been reported in Europe, giving rise to fears that CCD is a global problem.

http://news.bbc.co.uk/1/hi/sci/tech/8219202.stm

40 years of Unix

The computer world is notorious for its obsession with what is new - largely thanks to the relentless engine of Moore's Law that endlessly presents programmers with more powerful machines.

Given such permanent change, anything that survives for more than one generation of processors deserves a nod.

Think then what the Unix operating system deserves because in August 2009, it celebrates its 40th anniversary. And it has been in use every year of those four decades and today is getting more attention than ever before.

Work on Unix began at Bell Labs after AT&T, (which owned the lab), MIT and GE pulled the plug on an ambitious project to create an operating system called Multics.

The idea was to make better use of the resources of mainframe computers and have them serve many people at the same time.

"With Multics they tried to have a much more versatile and flexible operating system, and it failed miserably," said Dr Peter Salus, author of the definitive history of Unix's early years.

Time well spent

The cancellation meant that two of the researchers assigned to the project, Ken Thompson and Dennis Ritchie, had a lot of time on their hands. Frustrated by the size and complexity of Multics but not its aims of making computers more flexible and interactive, they decided to try and finish the work - albeit on a much smaller scale.

The commitment was helped by the fact that in August 1969, Ken Thompson's wife took their new baby to see relatives on the West Coast. She was due to be gone for a month and Thompson decided to use his time constructively - by writing the core of what became Unix.

He allocated one week each to the four core components of operating system, shell, editor and assembler. It was during that time and after as the growing team got the operating system running on a DEC computer known as a PDP-7 that Unix came into being.

By the early 1970s, five people were working on Unix. Thompson and Ritchie had been joined by Brian Kernighan, Doug McIlroy and Joe Ossanna.

The name was reportedly coined by Brian Kernighan - a lover of puns who wanted Unics to stand in contrast to its forebear Multics.

The team got Unix running well on the PDP7 and soon it had a long list of commands it could carry out. The syntax of many of those commands, such as chdir and cat, are still in use 40 years on. Along with it came the C programming language.

But, said Dr Salus, it wasn't just the programming that was important about Unix - the philosophy behind it was vital too.

"Unix was created to solve a few problems," said Dr Salus, "the most important of which was to have something that was much more compact than the operating systems that were current at that time which ran on the dinosaurs of the computer age."

Net benefits

Back in the early 1970s, computers were still huge and typically overseen by men in white coats who jealously guarded access to the machines. The idea of users directly interacting with the machine was downright revolutionary.

"It got us away from the total control that businesses like IBM and DEC had over us," said Dr Salus.

Word about Unix spread and people liked what they heard.

"Once it had jumped out of the lab and out of AT&T it caught fire among the academic community," Dr Salus told the BBC. What helped this grassroots movement was AT&T's willingness to give the software away for free.

That it ran on cheap hardware and was easy to move to different machines helped too.

"The fact that its code was adaptable to other types of machinery, in large and small versions meant that it could become an operating system that did more than just run on your proprietary machine," said Dr Salus.

In May 1975 it got another boost by becoming the chosen operating system for the internet. The decision to back it is laid out in the then-nascent Internet Engineering Task Force's document RFC 681, which notes that Unix "presents several interesting capabilities" for those looking to use it on the net.

It didn't stop there. Unix was adapted for use on any and every computer from mainframes to desktops. While it is true that it did languish in the 1980s and 90s as corporations scrapped over whose version was definitive, the rise of the web has given it new life.

The wars are over and the Unix specification is looked after by the Open Group - an industry body set up to police what is done in the operating system's name.

Now Unix, in a variety of guises, is everywhere. Most of the net runs on Unix-based servers and the Unix philosophy heavily influenced the open source software movements and the creation of the Linux desktop OS. Windows runs the communication stack created for Unix. Apple's OS X is broadly based on Unix and it is possible to dig into that software and find text remarkably similar to that first written by Dennis Ritchie in 1971.

"The really nice part is the flexibility and adaptability," said Dr Salus, explaining why it is so widespread and how its ethic fits with a world at home with the web.

"Unix is the best screwdriver ever built," said Dr Salus.

http://news.bbc.co.uk/1/hi/technology/8205976.stm

Oestrogen can be used to treat breast cancer

While estrogen-lowering drugs are currently used to treat breast cancer, a new study shows that estrogen itself can fight the tumor in those suffering a comeback.

Previous studies had reported that drugs such as tamoxifen and the aromatase inhibitors can treat breast malignancy through cutting off the estrogen required for feeding the estrogen-receptor-positive tumors.

According to the study published in the Journal of the American Medical Association, a very low dose of estrogen can treat relapses in 30 percent of women on estrogen-blocking drugs.

It is also reported to be more effective and much better tolerated than chemotherapy.

Failure, however, is noted in 30 percent of those who had previously responded to the treatment. The study, however, showed that going back on the aromatase inhibitors could stop the progression of the cancer in one third of these patients.

"We demonstrated clearly that the low dose was better tolerated than the high dose and was just as effective for controlling metastatic disease," said lead researcher Matthew Ellis.

He added that a high dose of the drug may cause headaches, bloating, breast tenderness, fluid retention, nausea and vomiting.

Scientists concluded that estrogen can be used to treat metastatic hormone-dependent breast cancer in postmenopausal women.

http://www.presstv.ir/detail.aspx?id=103942&sectionid=3510210

The relevant research papers from the journal can be accessed here:

Estradiol in Breast Cancer Treatment: http://jama.ama-assn.org/cgi/content/extract/302/7/797
Lower-Dose vs High-Dose Oral Estradiol Therapy of Hormone Receptor–Positive, Aromatase Inhibitor–Resistant Advanced Breast Cancer: http://jama.ama-assn.org/cgi/content/short/302/7/774?home

'Dostoevsky mice' cured of epilepsy

Epilepsy may be sparked by a metal imbalance in the brain caused by a singlegene mutation, a study in mice suggests. The finding could help develop new treatments in humans who suffer from the condition.

Steven Clapcote's team at the University of Leeds, UK, pinpointed a gene that seems to play an important part in the genesis of epileptic seizures, which result from abnormal bursts of electrical activity in the brain and can occur even when there is no underlying neurological condition.

The Atp1a3 gene is one of three that produce a chemical pump mechanism to keep sodium and potassium levels in brain nerve cells and the surrounding tissue at the levels needed for normal activity.

"It's been known for a long time that injecting the sodium/potassium pump inhibitor ouabain into the brain can induce seizures in rats," says Clapcote, and it's also known that mice lacking two of three forms of the pump – either the "alpha1" or "alpha2" forms – are free from seizures.

Cured offspring

Clapcote's team have now determined that mice with a mutated copy of theAtp1a3 gene and reduced activity of the "alpha3" pump were prone to epileptic seizures. The mouse strain has been dubbed Myshkin after a Dostoevsky character in The Idiot, who suffered from epilepsy. "Mysh" also comes from the Russian for mouse.

The team could treat some of the symptoms in the Myshkin mice with valproic acid, a standard epilepsy treatment. But the researchers found they could also prevent seizures from occurring completely – at least in the next generation.

They injected DNA fragments containing the normal Atp1a3 gene into mouse eggs to establish a second strain of mice that produced extra copies of the normal alpha3 pump, and crossed them with the Myshkin mice.

"Half of the offspring of this cross had the faulty alpha3 gene from the Myshkin parent," he says. "However, they did not have epilepsy because they also inherited the extra copies – we didn't work out how many – of the normal alpha3 gene from the other parent."

'Ideal tool'

The mouse and human version of the Atp1a3 gene are almost identical, and Clapcote thinks it is a "strong candidate" gene to explain some forms of human epilepsy.

Working with colleagues at the University of Swansea, UK, the researchers have begun to screen DNA from people with epilepsy to search for mutations in the gene. If there's a positive match, the Myshkin mice would be an ideal tool to help in the development and testing of new epilepsy therapies, Clapcote says.

Journal reference: Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.0904817106)

http://www.newscientist.com/article/dn17549-dostoevsky-mice-cured-of-epilepsy.html?DCMP=NLC-nletter&nsref=dn17549