Human Genome Sequenced for Price of Car

This is awfully important because it applies across the biological spectrum. Getting a genome has now become a lab procedure, not needing to organize a raft of resources.

We may have many thousands of life forms available, but we have actually only a handful that we are very interested in. This means that their genomes will be available to be worked on by their respective research communities. Cost and convenience is no longer a serious barrier.

The main event will continue to be the human genome and this is bringing us close to using it as a diagnostic tool. We have been given hints, but real delivery will be integrating millions of individual cases to shake out really obscure relationships with also obscure diseases.

I would like every doctor to act as a reliable source of data on patients so this can be statistically mined. A lot of real solutions are lying under our noses and need winkling out.




Human genome sequenced for the price of a car: study


http://www.terradaily.com/reports/Human_genome_sequenced_for_the_price_of_a_car_study_999.html


by Staff Writers
Paris (AFP) Aug 11, 2009

Sequencing the first human genome cost billions and required an army of scientists, but now a trio of researchers in the United States have matched that feat for the price mid-range BMW, according to a study published Monday.

"This can be done in one lab, with one machine, and at a modest cost" of about 50,000 dollars (36,000 euros), said Stanford University professor Stephen Quake, who designed the study and lent his DNA for the task.

At the close of the 20th century, piecing together a complete map of a genome -- the blueprint of human life itself spread across three-billion pairs of molecules -- was the all-consuming Manhattan Project of biotechnology.

The achievement, unveiled in draft form in 2001 and finished in 2003, was hailed as one of humanity's major scientific achievements.

Since then, sequencing "has become an order of magnitude cheaper and faster" every couple of years, said Lynda China, a medical researcher at the Dana-Farber Cancer Institute in Boston.

In 2007, the firm 454 Life Sciences did it in under three months and for less than a million dollars.

In September that year, scientific maverick Craig Venter published his own complete DNA code, the first of a single individual rather than an amalgam from multiple sources. Cost: not disclosed.

Last year, the price dropped to a quarter of a million, but still needed the input of dozens of experts.

The new breakthrough, reported in the journal Nature Biotechnology, has become the latest benchmark.

Even if only a dozen or so individual genomes have been sequenced to date, the process is on the verge of becoming commonplace and could, within a few years, cost even ten times less.

One biotech start-up, Pacific Biosciences in Menlo Park, vows that by 2013 it will be able to unpack a complete DNA in a quarter of an hour for under a thousand dollars.

A legion of potential applications are driving the research, ranging from "personalised medicine" tailored to your genetic profile, to exploring the earliest dawn of human evolution in the DNA of our ancestors' fossils.

Quake discovered, for example, that he carries a rare genetic mutation associated with a heart disorder.
He also learned that he is likely to respond well to cholesterol-lowering statin drugs that could help prevent heart disease.

Complete sequencing is not to be confused with the gebe kits offered by companies such as 23andMe or deCODEme, which offer only snapshots of DNA, not the whole shebang.

"It's really democratising the fruits of the genome revolution and saying that anybody can play in this game," Quake said in a statement.

Using a single fridge-sized machine and a process called single molecule sequencing, Quake and his colleagues diced up the more than three billion molecular pairings of the human DNA into millions of strands.

The four molecular building blocks of DNA are adenine (A), cytosine (C), guanine (G), and thymine (T).
The machine read each strand with the help of florescent markers, and then its powerful computers reassembled them back into a cohesive genome.

"It's like assembling an enormous jigsaw puzzle by referring frequently to the picture on the box," Quake said, alluding to the reference genome held by the US National Center for Biotechnology Information.

Overall, Quake's genome is 95 percent complete, on a par with earlier efforts.

Double Helix Electric Slide

This is an area of research in which we may start getting really exciting ideas into play. My own interest is derived from the apparent implied logic system that produces life itself. This is mathematically interesting and calls for a major effort in defining the parameters. If undertaken successfully, I cannot imagine any biologists ever thanking one for the implied headache.

Present efforts are focused on extracting a familiar Boolean system and some progress has been made. I am inclined to go in a different direction that may be simply a dead end but that needs to be confirmed. Even as a Boolean system, mathematics only gives us zero and one and that needs to be changed to a more generalized fuzzy logic style system all of which make ideas of rigor difficult.

In any case, this is becoming interesting and there is enough known to encourage an attempt at constructing a practical biological logic system.

Jun 17, 2009

Double helix is an 'electric slide' for proteins

Swarming proteins slide into place on DNA double helix

http://physicsworld.com/cws/article/news/39512/1

DNA may contain the blueprint for life but it takes proteins to read the plan and build an organism. The mechanism of this vital biological process has remained a mystery but now researchers in France are proposing a physical model wherein individual proteins can “slide” freely along DNA strands in search of target sequences.

The team envision the process involving ‘DNA-binding proteins’ swarming around the iconic double helix on account of electric attraction — proteins have a net positive charge and DNA has a net negative charge. Miraculously, these proteins can then bind to exactly the right section of the long, coiling DNA so they can carry out vital functions such as copying genetic information and translating genes into templates for protein production.

Vincent Dahirel of the Pierre and Marie Curie University in Paris and his colleagues have reduced this complex biological set-up into more general physical shapes. Using Monte Carlo computer simulations, DNA was modelled as a long cylinder, and the protein as one of four solids: a sphere; a cylinder; or a cube or cylinder with a groove carved in one side.

Grooved cylinders

Dahirel and colleagues find that as the first three protein-shapes approach the DNA the electric attraction continues unabated. However, in the case of grooved cylinders, the proteins start to be repelled once they get to within 0.1 to 0.75 nm of the DNA.

Dahirel and his team attribute this force to the solution that bathes these biological molecules. As the protein approaches the DNA, positively charged ions in the solution become trapped in the gap, driving more water into the region as a result of osmosis. If the inward electric attraction is balanced by the outward water pressure, the protein can slide along the helix until it reaches its target. The hydrogen-bond attraction between DNA and protein then overpowers the osmotic barrier and the two bind together.

The research is published in Physical Review Letters.

Genesis of Life

This was not an easy problem to solve and as it turns out, the research took years of trying every possible combination. Now we have a clear road forward to understanding how life may have fallen together to be formed in the first place.

Somehow in a primitive environment not unlike a test tube, a lot of necessary organic chemistry got done. A lot of it was low energy chemistry and the world filled up with a solution of stray organics.

I wonder if anyone has ever separated the fluid contents of ordinary cells and subjected that fluid to a variety of environments to see if further self assembly was plausible and what did occur. Of course, what is important may be also low yield.

This is an important breakthrough and clearly directs further research and is very welcome.

Last year we had a report of a twenty year frozen experiment that produced precursor chemicals. This is all food for thought and it finally looks as if the tools are falling into place.

Life began in a flash; Science takes four billion years to catch up
By Brendan Borrell


http://www.scientificamerican.com/blog/60-second-science/post.cfm?id=life-began-in-a-flash-science-takes-2009-05-14&sc=DD_20090515


This week's issue of Nature features a welcome discovery for those of us enthralled, mystified and frustrated by the study of the origins of life. John Sutherland, a chemist at the University of Manchester, and his colleagues claim to have figured out how ribose, phosphate and the nitrogenous (nitrogen-bearing) molecules known as nucleobases first came together to form nucleotides—the building blocks of the RNA world from which life is thought to have emerged."My assumption is that we are here on this planet as a fundamental consequence of organic chemistry," Sutherland told The New York Times. His secret was running the experiment in stages, only adding phosphate in the final step. So far, the team has succeeded in building two of the four nucleotides; the molecule pictured [left] is cytosine, the nucleobase that, until now, scientists were unable to combine with sugars and phosphates to form the RNA nucleotide ribocytidine phosphate.*

Is the latest discovery a real breakthrough or just another high-profile paper to tease the navel-gazers of the science world? Jack Szostak of the Massachusetts General Hospital wrote in a commentary that the new discovery "will stand for years as one of the great advances in prebiotic chemistry."

The findings also serve as a reminder that the pace of scientific discovery does not always move as quickly as scientists would like. In 1871 Darwin first postulated that life began in a "warm little pond, with all sorts of ammonia and phosphoric salts."

Almost a century later, Stanley Miller conducted the great-grandaddy of origin-of-life studies at the University of Chicago with his colleague Harold Urey, experiments which left scientists with more questions than they answered.

In 1994 Leslie Orgel wrote in the pages of Scientific American that growing evidence was supporting the theory that life emerged from RNA, but he despaired, "how that RNA came into being remains unknown." Last year, scientists got perhaps a little bit too giddy when some minor results were published in Science based on forgotten vials from the original Miller–Urey studies.

Chemist Robert Shapiro of New York University, who wrote about his alternative theory on the origin of life for Scientific American in 2007, told Chemistry World that Sutherland's results "have nothing to do with the origin of life on Earth whatsoever."

*Correction (5/15/09): This sentence was changed after posting. It originally incorrectly identified cytosine as a nucleotide.

Letter

Nature 459, 239-242 (14 May 2009) doi:10.1038/nature08013; Received 11 December 2008; Accepted 24 March 2009

Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions
Matthew W. Powner1, Béatrice Gerland1 & John D. Sutherland1
School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Correspondence to: John D. Sutherland1 Correspondence and requests for materials should be addressed to J.D.S. (Email: john.sutherland@manchester.ac.uk).

Abstract
At some stage in the origin of life, an informational polymer must have arisen by purely chemical means. According to one version of the 'RNA world' hypothesis1, 2, 3 this polymer was RNA, but attempts to provide experimental support for this have failed4, 5. In particular, although there has been some success demonstrating that 'activated' ribonucleotides can polymerize to form RNA6, 7, it is far from obvious how such ribonucleotides could have formed from their constituent parts (ribose and nucleobases). Ribose is difficult to form selectively8, 9, and the addition of nucleobases to ribose is inefficient in the case of purines10 and does not occur at all in the case of the canonical pyrimidines11. Here we show that activated pyrimidine ribonucleotides can be formed in a short sequence that bypasses free ribose and the nucleobases, and instead proceeds through arabinose amino-oxazoline and anhydronucleoside intermediates. The starting materials for the synthesis—cyanamide, cyanoacetylene, glycolaldehyde, glyceraldehyde and inorganic phosphate—are plausible prebiotic feedstock molecules12, 13, 14, 15, and the conditions of the synthesis are consistent with potential early-Earth geochemical models. Although inorganic phosphate is only incorporated into the nucleotides at a late stage of the sequence, its presence from the start is essential as it controls three reactions in the earlier stages by acting as a general acid/base catalyst, a nucleophilic catalyst, a pH buffer and a chemical buffer. For prebiotic reaction sequences, our results highlight the importance of working with mixed chemical systems in which reactants for a particular reaction step can also control other steps.
School of Chemistry, The University of Manchester, Oxford Road, Manchester M13 9PL, UK
Correspondence to: John D. Sutherland1 Correspondence and requests for materials should be addressed to J.D.S. (Email: john.sutherland@manchester.ac.uk).

Chemist Shows How RNA Can Be the Starting Point for Life
By NICHOLAS WADE
Published: May 13, 2009


An English chemist has found the hidden gateway to the RNA world, the chemical milieu from which the first forms of life are thought to have emerged on earth some 3.8 billion years ago.
http://www.nytimes.com/imagepages/2009/05/14/science/14rna_graph.ready.html


Multimedia
Graphic
Reconstructing the Chemistry of Early Life
May 14, 2009)
http://www.nytimes.com/2009/05/14/science/14rna.html?_r=2
He has solved a problem that for 20 years has thwarted researchers trying to understand the origin of life — how the building blocks of RNA, called nucleotides, could have spontaneously assembled themselves in the conditions of the primitive earth. The discovery, if correct, should set researchers on the right track to solving many other mysteries about the origin of life. It will also mean that for the first time a plausible explanation exists for how an information-carrying biological molecule could have emerged through natural processes from chemicals on the primitive earth.
The author, John D. Sutherland, a chemist at the University of Manchester, likened his work to a crossword puzzle in which doing the first clues makes the others easier. “Whether we’ve done one across is an open question,” he said. “Our worry is that it may not be right.”
Other researchers say they believe he has made a major advance in prebiotic chemistry, the study of the natural chemical reactions that preceded the first living cells. “It is precisely because this work opens up so many new directions for research that it will stand for years as one of the great advances in prebiotic chemistry,” Jack Szostak of the Massachusetts General Hospital wrote in a commentary in Nature, where the work is being published on Thursday.
Scientists have long suspected that the first forms of life carried their biological information not in DNA but in RNA, its close chemical cousin. Though DNA is better known because of its storage of genetic information, RNA performs many of the trickiest operations in living cells. RNA seems to have delegated the chore of data storage to the chemically more stable DNA eons ago. If the first forms of life were based on RNA, then the issue is to explain how the first RNA molecules were formed.
For more than 20 years researchers have been working on this problem. The building blocks of RNA, known as nucleotides, each consist of a chemical base, a sugar molecule called ribose and a phosphate group. Chemists quickly found plausible natural ways for each of these constituents to form from natural chemicals. But there was no natural way for them all to join together.
The spontaneous appearance of such nucleotides on the primitive earth “would have been a near miracle,” two leading researchers, Gerald Joyce and Leslie Orgel, wrote in 1999. Others were so despairing that they believed some other molecule must have preceded RNA and started looking for a pre-RNA world.
The miracle seems now to have been explained. In the article in Nature, Dr. Sutherland and his colleagues Matthew W. Powner and Béatrice Gerland report that they have taken the same starting chemicals used by others but have caused them to react in a different order and in different combinations than in previous experiments. they discovered their recipe, which is far from intuitive, after 10 years of working through every possible combination of starting chemicals.
Instead of making the starting chemicals form a sugar and a base, they mixed them in a different order, in which the chemicals naturally formed a compound that is half-sugar and half-base. When another half-sugar and half-base are added, the RNA nucleotide called ribocytidine phosphate emerges.
A second nucleotide is created if ultraviolet light is shined on the mixture. Dr. Sutherland said he had not yet found natural ways to generate the other two types of nucleotides found in RNA molecules, but synthesis of the first two was thought to be harder to achieve.
If all four nucleotides formed naturally, they would zip together easily to form an RNA molecule with a backbone of alternating sugar and phosphate groups. The bases attached to the sugar constitute a four-letter alphabet in which biological information can be represented.
“My assumption is that we are here on this planet as a fundamental consequence of organic chemistry,” Dr. Sutherland said. “So it must be chemistry that wants to work.”
The reactions he has described look convincing to most other chemists. “The chemistry is very robust — all the yields are good and the chemistry is simple,” said Dr. Joyce, an expert on the chemical origin of life at the Scripps Research Institute in La Jolla, Calif
Dr. Sutherland’s proposal has not convinced everyone. Dr. Robert Shapiro, a chemist at New York University, said the recipe “definitely does not meet my criteria for a plausible pathway to the RNA world.” He said that cyano-acetylene, one of Dr. Sutherland’s assumed starting materials, is quickly destroyed by other chemicals and its appearance in pure form on the early earth “could be considered a fantasy.”
Dr. Sutherland replied that the chemical is consumed fastest in the reaction he proposes, and that since it has been detected on Titan there is no reason it should not have been present on the early earth.
If Dr. Sutherland’s proposal is correct it will set conditions that should help solve the many other problems in reconstructing the origin of life. Darwin, in a famous letter of 1871 to the botanist Joseph Hooker, surmised that life began “in some warm little pond, with all sorts of ammonia and phosphoric salts.” But the warm little pond has given way in recent years to the belief that life began in some exotic environment like the fissures of a volcano or in the deep sea vents that line the ocean floor.
Dr. Sutherland’s report supports Darwin. His proposed chemical reaction take place at moderate temperatures, though one goes best at 60 degrees Celsius. “It’s consistent with a warm pond evaporating as the sun comes out,” he said. His scenario would rule out deep sea vents as the place where life originated because it requires ultraviolet light.
A serious puzzle about the nature of life is that most of its molecules are right-handed or left-handed, whereas in nature mixtures of both forms exist. Dr. Joyce said he had hoped an explanation for the one-handedness of biological molecules would emerge from prebiotic chemistry, but Dr. Sutherland’s reactions do not supply any such explanation. One is certainly required because of what is known to chemists as “original syn,” referring to a chemical operation that can affect a molecule’s handedness.
Dr. Sutherland said he was working on this problem and on others, including how to enclose the primitive RNA molecules in some kind of membrane as the precursor to the first living cell.

Evolution of Intelligent Design

This short item is extremely important because it identifies a mechanism by which a single cell organism can rewire its own DNA and thereby the information that it passes on to its offspring. I had come to this conclusion in my manuscript and had said exactly this must be possible. It is always nice to land confirmation this handily and this directed.

The idea that directed design managed the evolutionary process was never a bad one. What was a bad idea was to go looking outside the cell itself for the decision making process. This is slowly clarifying the process and ending the debate.

I came to the conclusion that some form of decision making process was involved in the evolutionary process a long time ago. The support for it was always in your face, and the survival of the fittest concept really fails to hold up well and is obviously far too wasteful. It made sense that such a process be internal to the organism and as our appreciation of biological complexity has improved, the biological markers and answers are now showing up.

The only negative was the misplaced enthusiasm of the intelligent design crowd who fail to realize that any solution short of divine intervention was counter productive to their cause.

Study finds new way for disease to evolve

http://www.terradaily.com/reports/Study_finds_new_way_for_disease_to_evolve_999.html

by Staff Writers
Hamilton, Ontario (UPI) Feb 17, 2009
A Canadian-led study has discovered a new mode of disease evolution, giving scientists another way to identify and assign risk to emerging diseases.
Scientists at McMaster University, the University of Melbourne and the University of Illinois found bacteria can develop into illness-causing pathogens by rewiring regulatory DNA, the genetic material that controls disease-causing genes in a body. Previously, disease evolution was thought to occur mainly through the addition or deletion of genes.
"Bacterial cells contain about 5,000 different genes, but only a fraction of them are used at any given time," said McMaster University Assistant Professor Brian Coombes, who led the research. "The difference between being able to cause disease, or not cause disease, lies in where, when and what genes in this collection are turned on. We've discovered how bacteria evolve to turn on just the right combination of genes in order to cause disease in a host."
With infectious diseases on the rise, the finding has implications on how new pathogens are identified in the environment, he said.
"This opens up significant new challenges for us as we move forward with this idea of assigning risk to new pathogens," Coombes said. "Because now, we know it's not just gene content -- it is gene content plus regulation of those genes."