ScienceDaily (Sep. 13, 2012) Scientists at Karolinska Institutet in Sweden describe in a new study how so-called DNA origami can enhance the effect of certain cytostatics used in the treatment of cancer. With the aid of modern nanotechnology, scientists can target drugs direct to the tumour while leaving surrounding healthy tissue untouched.

The drug doxorubicin has long been used as a cytostatic (toxin) for cancer treatment but can cause serious adverse reactions such as myocardial disease and severe nausea. Because of this, scientists have been trying to find a means of delivering the drug to the morbid tumour cells without affecting healthy cells. A possible solution that many are pinning their hopes on is to use different types of nanoparticles as 'projectiles' primed with the active substance.

In the present study, which is published in the scientific journal ACS Nano, scientists at Karolinska Institutet show how DNA origami can be used as such a projectile (or carrier) of doxorubicin. DNA origami is a new technique for building nanostrucutres from DNA, the hereditary material found in the cell nucleus. Using this technique, researchers can produce highly complex nanostrucutres with surfaces to which complex patterns of proteins and many other molecules can easily be attached.

What the researchers did on this occasion was to package the doxorubicin in a DNA origami configuration designed in such a way that relaxed the degree of twist of the DNA double helix. This allowed the drug to be released more slowly and operate more effectively on the cancer cells at lower concentrations than is otherwise possible.

"When the DNA has a lower degree of twist, there's more room for the doxorubicin to become attached, which leads to its slower release," says group leader Dr Bjrn Hgberg. "Another advantage to using DNA origami is that we will quickly be able to develop the targeted protein system. This will enable us to deliver drugs in a way that is even more sparing of healthy cells."

The study has been financed with grants from several bodies, including the Swedish research Council, Vinnova (the Swedish governmental agency for innovation systems), the Royal Swedish Academy of Sciences, the Falk Foundation, the Jeansson foundations, Carl Bennet AB and the Axel and Eva Wallstrm Foundation.

Publication: 'A DNA Origami Delivery System for Cancer Therapy with Tunable Release Properties', Yong-Xing Zhao, Alan Shaw, Xianghui Zeng, Erik Benson, Andreas M. Nystrm & Bjrn Hgberg, ACS Nano, online first 5 September 2012.

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Under-twisted DNA origami delivers cancer drugs to tumors

Sequenom has appointed Myla Lai-Goldman to its board of directors and to the board's science committee. Lai-Goldman is a managing partner at Personalized Science and CEO of GeneCentric Diagnostics. Previously, she served as executive vice president, chief medical officer, and chief scientific officer at Laboratory Corporation of America.

Aushon BioSystems has appointed Martin Verhoef to be company CEO and to serve on its board of directors. Verhoef takes over the position from company Founder Peter Honkanen, who will assume the post of COO and will continue as a board director.

Verhoef has spent 25 years in the life science research tools and molecular diagnostics business. He formerly was CEO at MiraDx and PrimeraDx, he led Ciphergen's Biosystems Division, and he held senior management jobs at Agilent in Germany and in the US.

The New York Genome Center has appointed Dirk Evers and Kevin Shianna to its leadership team. Evers, who will serve as senior vice president of bioinformatics, joins NYGC from Illumina, where he led the company's computational biology efforts in the UK. Previously, he served as managing director of the International Graduate School in Bioinformatics and Genome Research at the Center for Biotechnology at Bielefeld University. Shianna will serve as senior vice president of sequencing operations at the NYGC. He joins from Duke University, where he was an assistant professor in the School of Medicine, director of operations for the Center for Human Genome Variation, and founding director for the Genomic Analysis Facility.

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LBNL Seeks Licensees for Highly Specific and Sensitive DNA Extraction Method

Among the many mysteries of human biology is why complex diseases such as diabetes, high blood pressure and psychiatric disorders are so difficult to predict and, often, to treat. An equally perplexing puzzle is why one individual gets a disease such as cancer or depression, while an identical twin remains perfectly healthy.

Now scientists have discovered a vital clue to unraveling these riddles.

The human genome is packed with at least 4 million gene switches that reside in bits of DNA that once were dismissed as junk but that turn out to play critical roles in controlling how cells, organs and other tissues behave.

The discovery, considered a major medical and scientific breakthrough, has enormous implications for human health because many complex diseases appear to be caused by tiny changes in hundreds of gene switches.

The findings are the fruit of an immense federal project, involving 440 scientists from 32 labs around the world.

As they delved into the junk parts of the DNA that are not actual genes containing instructions for proteins they discovered it's not junk at all. At least 80 percent of it is active and needed.

The result is an annotated road map of much of this DNA, noting what it's doing and how.

It includes the system of switches that, acting like dimmer switches for lights, control which genes are used in a cell and when they are used, and determine, for instance, whether a cell becomes a liver cell or a neuron.

The findings have immediate applications for understanding how alterations in the nongene parts of DNA contribute to human diseases, which may in turn lead to new drugs.

They also can help explain how the environment can affect disease risk.

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DNA ‘junk' contains a treasure of information about disease

ENCODE (Image: Ed Yong)

The recent dustup over the ENCODE project and its confusing finding that 80% of DNA is functional surprises me greatly. What surprises me especially is that people are surprised by junk DNA. Unfortunately this time the scientists are also culpable since, while the publicity surrounding ENCODE has been a media disaster, the 80% claim originated in the scientific papers themselves. There is no doubt that the project itself which represents a triumph of teamwork, dogged pursuit, technological mastery and first-rate science has produced enormously useful data, and there is no doubt it will continue to do so. What is in doubt is how long it will take for the public damage to be repaired.

Theres a lot written about the various misleading statements about the project made by both scientists and journalists and I cannot add much to it. All I can do is to point to some excellent articles:Larry Moran has waged a longstanding effort to spread the true wisdom about junk DNA for years on his blog. Ed Yong exhaustively summarizes a long list of opinions, links and analysis. T. Ryan Gregory has some great posts dispelling the myth of the myth of junk DNA. And John Timmer has the best popular account of the matter. The biggest mistake on the part of the scientists was to define functional so loosely that it could mean pretty much all of DNA. The second big mistake was not in clarifying what functional means to the public.

But what I found astonishing was why its so hard for people to accept that much of DNA must indeed be junk. Even to someone like me who is not an expert, the existence of junk DNA appeared perfectly normal. I think that junk DNA shouldnt shock us at all if we accept the standard evolutionary picture.

The standard evolutionary picture tells us that evolution is messy, incomplete and inefficient. DNA consists of many kinds of sequences. Some sequences have a bonafide biological function in that they are transcribed and then translated into proteins that have a clear physiological role. Then there are sequences which are only transcribed into RNA which doesnt do anything. There are also sequences which are only bound by DNA-binding proteins (which was one of the definitions of functional the ENCODE scientists subscribed to). Finally, there are sequences which dont do anything at all. Many of these sequences consist of pseudogenes and transposons and are defective and dysfunctional genes from viruses and other genetic flotsam, inserted into our genome through our long, imperfect and promiscuous genetic history. If we can appreciate that evolution is a flawed, piecemeal, inefficient and patchwork process, we should not be surprised to find this diversity of sequences with varying degrees of function or with no function in our genome.

The reason why most of these useless pieces have not been weeded out is simply because there was no need to. We should remember that evolution does not work toward a best possible outcome, it can only do the best with what it already has. Its too much of a risk and too much work to get rid of all these defective and non-functional sequences if they arent a burden; the work of simply duplicating these sequences is much lesser than that of getting rid of them. Thus the sequences hung around in our long evolutionary history and got passed on. The fact that they may not serve any function at all would be perfectively consistent with a haphazard natural mechanism depending on chance and the tacking on of non-functionality to useful functions simply as extra baggage.

There are two other facts in my view which should make it very easy for us to accept the existence of junk DNA. Consider that the salamander genome is ten times the size of the human genome. Now this implies two possibilities; either salamanders have ten times functional DNA than we do, or that the main difference between us and salamanders is that they have much more junk DNA. Wouldnt the complexity of salamander anatomy of physiology be vastly different if they really had so much more functional DNA? On the contrary, wouldnt the relative simplicity of salamanders compared to humans be much more consistent with just varying degrees of junk DNA? Which explanation sounds more plausible?

The third reason for accepting the reality of junk DNA is to simply think about mutational load. Our genomes, as of other organisms, have undergone lots of mutations during evolution. What would be the consequences if 90% of our genome were really functional and had undergone mutations? How would we have survived and flourished with such a high mutation rate? On the other hand, its much simpler to understand our survival if we assume that most mutations that happen in our genome happen in junk DNA.

As a summary then, we should be surprised to find someone who says they are surprised by junk DNA. Even someone like me who is not an expert can think of at least three simple reasons to like junk DNA:

1. The understanding that evolution is an inherently messy and inefficient process that often produces junk. This junk may be retained if its not causing trouble.

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Three reasons why junk DNA makes evolutionary sense

Researchers show that DNA supercoils are dynamic structures that can hop long distances, a phenomenon that could affect gene regulation.

Scientists understanding of how long strings of DNA are packaged into tiny spaces just got a little more complicated. New research on single molecules of DNA show that supercoilssegments of extra-twisted loops of DNAcan moving by jumping along a DNA strand. The results, published today (September 13) in Science, give researchers new insights into DNA organization and point to a surprisingly speedy mechanism of gene regulation inside cells.

This is the first study that addresses the dynamics of DNA supercoils, said Ralf Seidel, who studies movement of molecular motor proteins along DNA at the University of Technology Dresden, but was not involved in the research. This supercoil hopping motion allows DNA strands to transmit supercoiling, bringing sites together in very fast manner.

DNA, being a double helix, is naturally twisted. In vivo, its packaged with proteins called histones that help condense the millions or billions of nucleotides into the small space of a cells nucleus. Constant interaction with proteins moving along the strand, like transcription factors that need to open the helix to read the DNA sequence, can affect both the double helixs twist, and the strands writhethe coiling of the strand around itself. These extra-twisted coils, called plectonemes or supercoils, form not unlike coils in phone cords. By bringing together distant segments of DNA, such as regulatory elements and the genes they control, supercoiling can affect expression.

In order to get a better sense of how supercoils behave, Cees Dekker at Delft University of Technology and his colleagues induced supercoils in single strands of DNA molecules, labeled with fluorescent dye. One end of the DNA was anchored to the side of a glass capillary tube and a magnetic bead was attached to the other end. This allowed the researchers to use miniscule magnets to twist the DNA and induce supercoils, and watch their movement using fluorescence microscopy.

Unexpectedly, the team found that supercoils move along DNA strands in one of two ways. Sometimes they slowly diffuse along the strand; other times, the supercoils hoppeddisappearing suddenly from one location while simultaneously appearing at a distant location further down the strand.

This is far more complicated than diffusion of supercoils down the DNAs length, said Prashant Purohit, who studies DNA behavior at the University of Pennsylvania, but was not involved in the study. The DNA is behaving non-locally, he noted. It shows that writhethe coiling of the DNA strandis a global, not local quantity [of the strand].

So far the intriguing phenomenon has only been observed on single strands of naked DNA, Seidel cautioned, so its unclear how supercoils might act in vivo, when the DNA is well-packaged and studded with proteins. It may be that such behavior is more important for DNA in prokaryotic cells, which have less packaged DNA than eukaryotic cells, noted Bryan Daniels, who models biological systems at the Wisconsin Institutes for Discovery at the University of Wisconsin-Madison.

The ionic environment of the cell is also likely to influence supercoiling behavior. DNA is more likely to condense in the presence of multivalent ions (3 or more positive charges), for example, than in an environment of singly-valent ions. And Dekker and his colleagues, who used singly-valent ions in their experiments, found that more supercoils formed at lower concentrations of ions.

Dekker and his team are now looking at how different DNA sequences and the presence of DNA-binding proteins can influence supercoil formation and motionthe first step toward understanding supercoil movement in vivo.

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DNA with a Twist