Tag Archive | "DNA"

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Synthetic Biology Continued: Risks or Benefits?

Posted on 02 December 2012 by Jerry

The synthetic biology controversy continues.  The latest salvo was in the December 2012 Scientific American article entitled “World Changing Ideas: 10 innovations that are radical enough to alter our lives”.  The lead idea is “New Life-Forms, No DNA Required” written by Ferris Jabr.  This optimistic article again raises issues first identified on this blog seven months ago in a posting entitled, “Troubling Progress for Synthetic Biology”.  The Scientific American article largely ignores synthetic biology dangers and offers only modest possible future benefits. 

Citing Philipp Holliger of the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, the article states that when compared to DNA and RNA “Related polymers – at least six more – can do the same function.” That the earth’s flora and fauna rely only on DNA and RNA, Holliger says, is an “accident from the origin of life.” In another article he elaborates this thought by saying “There is nothing ‘Goldilocks’ about DNA and RNA – there is no overwhelming functional imperative for genetic systems or biology to be based on these two nucleic acids.”

The problem with these thoughts is that they ignore DNA and RNA have functioned successfully through fully 3+ billion years and have served as the flexible infrastructure allowing the development of the wide variety of life forms on the planet.  In addition, they survived all of the changes and dangers in Earth’s environment somehow helping the evolutionary process produce all the various and sundry species.  The reality is that “related polymers” and XNAs have not done this and have not naturally occurred anywhere to our knowledge.  It is as if with a sweep of the hand we negate the importance of DNA and RNA and their role in the history of life. At the same time we fail to acknowledge the uniqueness of the life phenomenon and how it integrates with the incredibly complex universe of which it is a part.

The Scientific American article credits Holliger with creating XNA or xeno nucleic acid, his replacement for DNA and RNA by “substituting entirely different molecules, such as cyclohexane and threose.  Just as important, they created enzymes that work with the XNAs to form a complete genetic system.  The enzymes enable XNAs to do something no other artificial nucleic acids can do: they evolve…Holliger reprogrammed natural polymerase enzymes to translate DNA into XNA and back again, establishing a novel system for storing and transmitting genetic information, which is the foundation of evolution.”

In another article written by Holliger entitled “XNA is synthetic DNA that’s stronger than the real thing” he uses an analogy to explain translation of DNA into XNA and back again.  He states “You can think of a DNA strand like a classmate’s lecture notes.  DNA polymerase is the pen that lets you copy these notes directly to a new sheet of paper.  But let’s say your friend’s notes are written in the ‘language’ of XNA.  Ideally, your XNA-based genetic system would have a pen that could copy these notes directly to a new sheet of paper.  What Pinheiro’s team did was create two distinct classes of writing utensil – one pen that copies your friend’s XNA-notes into DNA-notes, and a second pen that converts those DNA notes back into XNA-notes.  Is it the most efficient method of replication? No. But it gets the job done.”

These descriptions contain a contradiction.  In order to produce copies of the XNA, the research team uses the flexibility of DNA in the middle of the copying process.  Its reliance on the flexibility of traditional DNA means they have not formed a complete genetic system.  Instead they were forced to rely on DNA.  They go on to claim their enzymes evolve.  Absent DNA they do not replicate themselves or store their information.  Hence they do not evolve. Again we see an under-appreciated DNA dismissed as completely incidental to the evolution of their XNAs as opposed to the absolutely necessary role it performs.

Anticipating criticism from antagonists of synthetic biology, the article further states, “Holliger emphasizes that XNA-based life-forms are a long way off, but he already recognizes a distinct advantage.  If such a creature escaped into the wild, it would die without a steady supply of XNA-specific enzymes.  And XNA could not weave itself into the genomes of natural organisms, because their native enzymes would not recognize it.  XNA-based bacteria designed to devour oil spills or turn wastewater into electricity, for example, could not interfere with native organisms.” The Scientific American article further asserts, “Alternatively, scientists could enclose XNA within protocells – the origin of a new life-form that could evolve in ways no one can predict.”

When thinking about a creature of his creation escaping “into the wild” Holliger uses the word ‘wild’ as a substitute for the word ‘world’.  People do not live in the wild.  They do live in the world within which these organisms would escape. When contemplating an escape he observes his creature would die without a steady supply of XNA-specific enzymes.  There are several problems with this statement.  If he was able to modify enzymes to work with DNA in copying his XNAs, is it not possible for the same enzymes to mutate to the new form or become truly self-replicating?  Is it also not possible for existing DNA to produce a mutation that allows it to recognize, accept and incorporate these XNAs into the DNA of our normal life forms?  In other words, are our researchers not ignoring the most powerful life processes, mutation and evolution?

Against the obvious risks of what Holliger and others are doing is an array of unimpressive and limited applications they offer to justify the risks they are taking. They suggest XNAs could be injected into the human body to detect early, subtle signs of viruses or other infections.  They indicate that XNA-based bacteria could be designed to devour oil spills or turn wastewater into electricity.  So what happens if these bacteria get underground in oil fields or get loose in the world’s water supplies?  Does anyone really know what will happen with the release of Holliger’s creatures?  No one knows, but are these the types of “earth shaking” developments that would justify the risks?

We know that life forms are incredibly tenacious always seeking survival and replication.  Holliger claims his creature will evolve.  The author of the article mentions “The origin of a new life-form that could evolve in ways that no one can predict.”  This last sentence describes simply the threat Holliger’s creatures represent.

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Chimeric Systems: Living and Non-Living Components

Posted on 06 August 2012 by Jerry

As is often the case, the line between one scientific area and another blurs over time.  A prime example is synthetic biology and its new category called a Chimeric System.  A Chimeric System represents the fusion of synthetic non-living material with living tissue.  Three examples spanning 2010 to 2012 show the intersection of regenerated tissue, stem cells, and synthetic biology in the formation of this new category of chimera.

In 2010 scientists from Yale University used a lung’s collagen support structure with lung cells removed, to provide the base for their experiment.  They then took eight or nine types of existing lung cells, cultured them for eight days, and grew new lung tissue on the collagen infrastructure which was subsequently transplanted to living rats where it functioned normally for about two hours.  This is an example of the use of regenerated tissue to artificially create organ tissue.

Taking the lung experiment one step further, scientists and doctors at Karolinska University hospital in Sweden in 2011 implanted a synthetic trachea in a cancer patient.  The synthetic organ was completely lab-grown using a Y-shaped plastic-like “nanocomposite” polymer material for the underlying support structure.  Upon the structure the physicians grew the patient’s own stem cells over a two day period.  This procedure avoided the risk of rejection by the patient’s immune system because of the use of his own stem cell tissue.  This experiment created one of the first of these Chimeric Systems in that it is composed of a synthetic infrastructure upon which living tissue was grown.

The final example represents the use of silicone and heart muscle tissue from a rat to create an artificial jellyfish.  In a series of experiments to understand the inner workings of muscular pumps like a heart muscle, Kit Parker, a biophysicist at Harvard University, led an effort with two groups at Caltech and Harvard to understand how jellyfish swim.  Janna Nawroth a graduate student at Caltech mapped every cell in the bodies of young moon jellyfish.

A July 22, 2012 article in Nature magazine describes the artificial jellyfish as follows, “Nawroth created a structure with the same properties (as a jellyfish) by growing a single layer of rat heart muscle on a patterned sheet of polydimethylsiloxane.  When an electric field is applied across the structure, the muscle contracts rapidly, compressing the medusoid and mimicking a jellyfish’s power stroke….When placed between two electrodes in water, the medusoid swam like the real thing.”  See the identified link below for a connection to an article with an embedded film that shows the artificial jellyfish swimming.

Beyond the three accomplishments mentioned in our May 2012 post of “Troubling Progress for Synthetic Biology” or the creation of a bacterial living shell, an inventory of synthetic genetic parts, and complex molecules of synthetic nucleotides, enzymes, and proteins, these experiments represent significant advances in a new field within Synthetic Biology.  Unlike what many have called the over-reaching ambition of earlier efforts and the perennial risk of negative use, this new field holds great promise for beneficial future developments.  As in any unregulated, scientifically advanced, new area we need to carefully monitor progress and developments to insure we have good outcomes.

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See a link in this article to a film of the artificial jellyfish – http://www.nature.com/news/artificial-jellyfish-built-from-rat-cells-1.11046


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Troubling Progress for Synthetic Biology

Posted on 17 May 2012 by Jerry

In the last couple of years substantial progress has been made towards creating synthetic life.  At the beginning of the century synthetic biologists identified a series of accomplishments they would need before synthetic life that would never occur naturally, would be possible. This year marks a point in time by which substantial progress has been made in all of the key areas they identified. 

They knew as a first step, they might have to work with a natural living “shell” they could insert their synthetic creations into, counting on the life shell to continue living and sustaining its synthetic parts. This was viewed as a more practical target than trying to create brand new life in a laboratory. They knew they needed an inventory of synthetic parts that could be manufactured to order and mixed and matched to create a targeted life form.  Probably hardest of all, they knew they had to create complex molecules, synthetic nucleotides, enzymes and proteins that were capable of retaining genetic information, replicating and allowing change and mutation over time.  Only this would mimic the evolution of a natural living system.

In May of 2010, Craig Venter and his research team at the J. Craig Venter Institute announced the accomplishment of the first step or the creation of a laboratory produced synthetic bacterial cell.  The researchers took two related mycoplasma species, M. mycoides subspecies Capri (GM12) as donor and M. capricolum subspecies capricolum (CK) as recipient to make their synthetic bacterial cell.  These two bacterial species are forms of a microorganism parasite in ruminants, like cattle and goats, causing lung disease.

The team created in the laboratory a synthetic but faithful copy of the GM12 bacterial chromosome referred to as the donor and inserted it into a stripped down CK cell, which had selected genes removed and was identified as the recipient.  This was the natural living shell referred to earlier.  The CK cell accepted the transplanted chemically synthesized chromosome.  The resulting bacterial cell was controlled by the synthetic GM12 chromosome and the accepting CK cell functioned as a GM12 cell.  The team proclaimed they were first to synthesize, assemble, clone, and transplant a synthetically produced chromosome, creating a new cell controlled by the synthetic genome.  Others would argue a similar achievement was accomplished some years earlier by Eckard Wimmer and a research team that chemically synthesized a complete viral genome that was used to regenerate a live polio virus.

Significant progress was made in creating an inventory of synthetic parts when a 2011 research team headed by Steven Benner, founder of the Westheimer Institute for Science and Technology, announced it had created two new molecules which could be slotted into DNA alongside a chromosome’s natural bases, adenine (A), guanine (G), cytosine (C), and thymine (T).  An August 2011 article in the RSC Chemistry World stated “The new bases, dubbed ‘P’ and ‘Z,’ look similar to natural ones but have orthogonal hydrogen bonding patterns.”  While this was not the first time unnatural nucleotides have been inserted into DNA, they typically are eliminated during replication by un-accepting copying enzymes.  Benner’s team claims they have overcome this rejection.  Benner says his group “have already obtained GACTZP DNA replication in artificial cells, and are working to introduce [it] into E. coli.”

Finally, in the search for a complex molecule that will mimic life by retaining genetic information, replicating and allowing change and mutation over time, a research team headed by Phillip Holliger at the UK Medical Research Council’s Laboratory of Molecular Biology reports they have created selected alternatives to or competitors with DNA.  The team has developed six alternative polymers that they call xeno-nucleic acids (XNA).  These XNAs differ from the familiar DNA in that the team has substituted different sugars for the deoxyribose (the D in DNA).  Dr. Holliger explained, “We’ve been able to show that both heredity – information storage and propagation – and evolution, which are really two hallmarks of life, can be reproduced and implemented in alternative polymers other than DNA and RNA.”

A DNA strand is composed of three basic materials, sugars, phosphates and bases.  An article appearing in discovermagazine.com explains these XNAs as follows, “DNA looks like a twisting ladder.  Its sides are chains of a sugar called deoxyribose (the D in DNA), connected by phosphate groups.  Each sugar is attached to one of four ‘bases’ – these form the rungs of the ladder, and are signified by the letters A, C, G and T.”  Each of the six XNA’s has a slightly different molecule making up its sugar replacement.  Like DNA “all the XNAs use the same bases and the same phosphate groups.  Any of them could pair up with a complementary strand of DNA or RNA.”

The article further describes a key breakthrough by Vitor B. Pinheiro, a research team member, “Pinheiro created his XNAs by tweaking a natural enzyme called DNA polymerase, which copies DNA.  It ‘reads’ a piece of DNA, grabs nearby bases, and assembles a matching strand….Here is the clever bit. DNA polymerase is normally very fussy about the bases it grabs. It only selects ones with a deoxyribose sugar so that it assembles DNA, rather than any other nucleic acid.  But Pinheiro evolved the enzyme so it prefers to use the building blocks of his XNAs instead.” The replication is accomplished using these special polymerases (enzymes) that not only synthesize XNA from a DNA template but also copy XNA back into DNA. The copying to and from DNA is achieved with a high degree of accuracy which is a requirement that is essential to evolution.

Pinheiro cited yet another advantage researchers see with the new XNAs.  The natural nucleic acids, DNA and RNA, can be made to evolve so they bind tightly to specific molecular targets.  The problem is they are unstable because they are rapidly broken down by enzymes called nucleases which snip and degrade things in the body.  The new XNAs because of their different chemical composition, should not be easily recognized by these enzymes.  Their chemistry already makes them more stable and consequently more resistant to the enzymes.  As an example, Pinheiro incubated one of them, HNA (with a five carbon sugar called anhydrohexitol), in an extremely acidic solution for an hour and the XNA molecule was unaffected.  “DNA just would have been shredded,” said Pinheiro.

Gerald F. Joyce, a professor at The Scripps Research Institute, commented on the limitations of this research in an article in the April 20, 2012 issue of Science.  He observed that the replication that was achieved was still dependent on the participation of DNA.  He stated, “Finally, construction of genetic systems based on alternative chemical platforms may ultimately lead to the synthesis of novel forms of life.  For that goal to be realized, the XNA must be able to catalyze its own replication, without the aid of any biological molecules, and thus be capable of undergoing Darwinian evolution in a self-sustained manner.”

What is of greatest concern about all of these developments is the repeated and continued involvement of life.  None of the supposed accomplishments would have been possible without the flexibility of life processes and chromosomes.  It could be argued this flexibility is one of the strengths of life’s genetics for it facilitates life’s ongoing evolution.  Not only was the inherent malleability of natural chromosomes necessary for these changes to work but it is the absence of a “firewall” or barrier, in fact an actual attractiveness, between the resulting synthetic life properties and the rest of the gene pool that is the most troubling.  Should any of these experiments expose life outside the laboratory environment to these altered elements there are very large risks the changes would be incorporated into the mainstream genetics of life.  At the end of the aforementioned article in the April issue of Science, Dr. Joyce issues a telling admonition, “Synthetic biologists are beginning to frolic on the worlds of alternative genetics but must not tread into areas that have the potential to harm our biology.”

Background: In Beyond Animal, Ego and Time, Chapter 13: Protect Life Imperative – Synthetic Biology discusses the evolution of Synthetic Biology from genetic engineering. This dedicated chapter on Synthetic Biology identifies it as one of four looming global threats to the continuation of life on our planet.

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RNA at the Beginning

Posted on 11 December 2011 by Jerry

In beginning-of-life experiments scientists have looked for that first life that could form and retain a genetic code and replicate the code in another organism.  The farther back in the life process this discovery could be made, the closer humanity would be to understanding how life began.  Over the years many have speculated that before the first life as we know it there was a macromolecule ribonucleic acid (RNA) which developed these properties.  The theory holds that it evolved before deoxyribonucleic acid (DNA) which today is the main component of our chromosomes.

As reported in the April 8, 2011 Science magazine, researchers Aniela Wochner, James Attwater, Alan Coulson, and Philipp Holliger of the Medical Research Council Laboratory of Molecular Biology in the UK have created a very general and flexible RNA polymerase ribozyme that can synthesize a wider spectrum of RNA sequences. This is essentially an RNA macromolecule that has its own genetic information and can cause a chemical reaction that expresses its genetic code in another active RNA molecule.

This development adds significant support for the RNA-First hypothesis.  While not yet creating life in a laboratory, this does demonstrate an RNA macromolecule which has its own genetic code and can replicate it in another, different, RNA macromolecule.

Background: In Beyond Animal, Ego and Time, in Chapter 2: Life, Death, and the Biogenic Sphere there is a summarization of the various beginning of life experiments that led to the present view of the beginning of life.  On page 22 there is discussion of the theory that RNA is where the first self replicating entity evolved.

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