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');