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Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Genome Biology, Medical and Population Genetics, Patient Experience: Personal Memories of Invasive Medical Intervantion, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Proteomics, Uncategorized, tagged Chief technology officer, Firefly, Messenger RNA, MicroRNA, MIT, national cancer institute, Small Business Innovation Research on March 28, 2013| 3 Comments »

Curator: Aviva Lev-Ari, PhD, RN

On 3/13/2013 Forbes Science Writer, Metthew Herper, presented a curated article about the protein Cas9. With a compelling title like 

This Protein Could Change Biotech Forever, we drew over 40 comments. 

A tiny molecular machine used by bacteria to kill attacking viruses could change the way that scientists edit the DNA of plants, animals and fungi, revolutionizing genetic engineering. The protein, called Cas9, is quite simply a way to more accurately cut a piece of DNA.

“This could significantly accelerate the rate of discovery in all areas of biology, including gene therapy in medicine, the generation of improved agricultural goods, and the engineering of energy-producing microbes,” says Luciano Marraffini of Rockefeller University.

The ability to make modular changes in the DNA of bacteria and primitive algae has resulted in drug and biofuel companies such as Amyris and LS9. But figuring out how to make changes in the genomes of more complicated organisms has been tough.

http://www.forbes.com/sites/matthewherper/2013/03/19/the-protein-that-could-change-biotech-forever/?goback=.gde_48920_member_227143277

In this article we bring all the pieces to one place, telling the evolution of a series of discoveries, which together may have the Protein, Cas9,  changing the Biotech Industry forever with its contributions to Diagnosing Diseases and Gene Therapy by Precision Genome Editing and Cost-effective microRNA Profiling. 

MicroRNA detection on the cheap

MIT alumni’s startup provides rapid, cost-effective microRNA profiling, which is beneficial for diagnosing diseases.

Rob Matheson, MIT News Office

March 28, 2013

Current methods of detecting microRNA (miRNA) — gene-regulating molecules implicated in the onset of various diseases — can be time-consuming and costly: The custom equipment used in such tests costs more than $100,000, and the limited throughput of these systems further hinders progress.

Two MIT alumni are helping to rectify these issues through their fast-growing, Cambridge-headquartered startup, Firefly BioWorks Inc., which provides technology that allows for rapid miRNA detection in a large number of samples using standard lab equipment. This technology has helped the company thrive — and also has the potential to increase the body of research on miRNA, which could help lead to better disease diagnosis and screening.The company’s core technology, called Optical Liquid Stamping (OLS) — which was invented at MIT by Firefly co-founder and Chief Technical Officer Daniel C. Pregibon PhD ’08 — works by imprinting (or stamping) microparticle structures onto photosensitive fluids. The resulting three-dimensional hydrogel particles, encoded with unique “barcodes,” can be used for the detection of miRNAs across large numbers of samples. These particles are custom-designed for readout in virtually any flow cytometer, a cost-effective device that’s accessible to most scientists.“Our manufacturing process allows us to make very sophisticated particles that can be read on the most basic instruments,” says co-founder and CEO Davide Marini PhD ’03.The company’s first commercial product, FirePlex miRSelect, an miRNA-detection kit that uses an assay based on OLS-manufactured particles and custom software, began selling about a year ago. Since then, the company has drawn a steady influx of customers (primarily academic and clinical scientists) while seeing rapid revenue growth.

To date, most of the company’s revenue has come from backers who see value in Firefly’s novel technology. In addition to a cumulative $2.5 million awarded through Small Business Innovation Research grants — primarily from the National Cancer Institute — the company has attracted $3 million from roughly 20 independent investors. Its most recent funding came from a $500,000 grant from the Massachusetts Life Sciences Center.

Pregibon developed the technology in the lab of MIT chemical engineering professorPatrick Doyle, a Firefly co-founder who serves on the company’s scientific advisory board. Firefly’s intellectual property is partially licensed through the Technology Licensing Office at MIT, along with several other Firefly patents. Firefly’s technology, from OLS to miRNA detection, has been described in papers published in several leading journals, including Science, Nature Materials, Nature Protocols and Analytical Chemistry.

Shifting complexity from equipment to particle

The success of the technology, Marini says, derives from an early business decision to focus attention on the development of the hydrogel particle instead of the equipment needed. Essentially, this allowed the co-founders to focus on developing a high-quality miRNA assay and hit the market quickly with particles that are universally readable on basic lab instrumentation.

“Imagine sticking a microscopic barcode on a microscopic product,” Marini says. “How do you scan it? At the beginning we thought we would have to build our own scanner. This would have been an expensive proposition. Instead, by using a few clever tricks, we redesigned the barcode to make it readable by existing instruments. You can write these ‘barcodes,’ and all you need is one scanner to read different codes. To quote an investor: ‘It shifts the complexity from the equipment to the particle.’”

Firefly’s particles appear to a standard flow cytometer as a series of closely spaced cells; these data are recorded and the company’s FireCode software then regroups them into particle information, including miRNA target identification and quantity.

But why, specifically, did the company choose a flow cytometer as its primary “scanner”? Pregibon answers: “To start, there are nearly 100,000 cytometers worldwide. In addition, we are now seeing a trend where flow cytometers are getting smaller and closer to the bench — closer to the actual researcher. We’re finding that people are tight for money because of the economy and are trying to conserve capital as much as possible. In order to use our products, they can either buy a very inexpensive bench-top flow cytometer or use one that already exists in their core facility.”

In turn, opting out of equipment development and manufacturing costs has helped the company stay financially sound, says Marini, who worked in London’s financial sector before coming to MIT. As an additional perk, the manufacturers of flow cytometers have begun “courting” Firefly, Marini says, because “our products help expand the capability of their systems, which are now exclusively used to analyze cells.”

The company’s FirePlex kit allows researchers to assay (or analyze) roughly 70 miRNA targets simultaneously across 96 samples of a wide variety — including serum, plasma and crude cell digests — in approximately three hours.

This is actually a “middle-ground” assaying technique, Pregibon says, and saves researchers time and money: Until now, scientists were forced to use separate techniques to look at a few miRNA targets over thousands of samples, or vice versa.

Marini adds that if a scientist suspects a number of miRNAs, perhaps 50 or so, could be involved in a pancreatic-cancer pathway, the only way to know for sure is to test those 50 targets over hundreds of samples. “There’s nowhere to do this today in a cost-effective, timely manner. Our tech now allows that,” he says.

‘Over the bridge of validation’

Because miRNAs are so important in the regulation of genes, and ultimately proteins, they have implications in a broad range of diseases, from cancer to Alzheimer’s disease. Several studies have suggested these relationships, but the field currently lacks the validation required to definitively demonstrate clinical utility.

With that in mind, Pregibon hopes that Firefly’s technology will help push miRNA-based diagnoses “over the bridge of validation,” giving scientists the means to validate miRNA signatures they discover in diagnosing diseases such as cancer. “That’s where we want to fit in,” he says. “With the help of a technology like ours, you’ll start to see more tests hitting the market and ultimately, more people benefitting from early cancer detection.”

Firefly’s aim is to strengthen preventive medicine in the United States. “In the long term, we see these products helping in the shift from reactive to preventative medicine,” Marini says. “We believe we will see a proliferation of tools for detection of diseases. We want to move away from the system we have now, which is curing before it’s too late.”

Pregibon says Firefly’s technology can be used across several molecule classes that are important in development and disease research: proteins, messenger RNA and DNA, among many others. “Essentially, the possibilities are endless,” Pregibon says.

SOURCE:

 http://web.mit.edu/newsoffice/2013/microrna-detection-on-the-cheap.html

Editing the genome with high precision

New method allows scientists to insert multiple genes in specific locations, delete defective genes.

Anne Trafton, MIT News Office

 

Researchers at MIT, the Broad Institute and Rockefeller University have developed a new technique for precisely altering the genomes of living cells by adding or deleting genes. The researchers say the technology could offer an easy-to-use, less-expensive way to engineer organisms that produce biofuels; to design animal models to study human disease; and  to develop new therapies, among other potential applications.To create their new genome-editing technique, the researchers modified a set of bacterial proteins that normally defend against viral invaders. Using this system, scientists can alter several genome sites simultaneously and can achieve much greater control over where new genes are inserted, says Feng Zhang, an assistant professor of brain and cognitive sciences at MIT and leader of the research team.“Anything that requires engineering of an organism to put in new genes or to modify what’s in the genome will be able to benefit from this,” says Zhang, who is a core member of the Broad Institute and MIT’s McGovern Institute for Brain Research.Zhang and his colleagues describe the new technique in the Jan. 3 online edition ofScience. Lead authors of the paper are graduate students Le Cong and Ann Ran.Early effortsThe first genetically altered mice were created in the 1980s by adding small pieces of DNA to mouse embryonic cells. This method is now widely used to create transgenic mice for the study of human disease, but, because it inserts DNA randomly in the genome, researchers can’t target the newly delivered genes to replace existing ones.

In recent years, scientists have sought more precise ways to edit the genome. One such method, known as homologous recombination, involves delivering a piece of DNA that includes the gene of interest flanked by sequences that match the genome region where the gene is to be inserted. However, this technique’s success rate is very low because the natural recombination process is rare in normal cells.

More recently, biologists discovered that they could improve the efficiency of this process by adding enzymes called nucleases, which can cut DNA. Zinc fingers are commonly used to deliver the nuclease to a specific location, but zinc finger arrays can’t target every possible sequence of DNA, limiting their usefulness. Furthermore, assembling the proteins is a labor-intensive and expensive process.

Complexes known as transcription activator-like effector nucleases (TALENs) can also cut the genome in specific locations, but these complexes can also be expensive and difficult to assemble.

Precise targeting

The new system is much more user-friendly, Zhang says. Making use of naturally occurring bacterial protein-RNA systems that recognize and snip viral DNA, the researchers can create DNA-editing complexes that include a nuclease called Cas9 bound to short RNA sequences. These sequences are designed to target specific locations in the genome; when they encounter a match, Cas9 cuts the DNA.

This approach can be used either to disrupt the function of a gene or to replace it with a new one. To replace the gene, the researchers must also add a DNA template for the new gene, which would be copied into the genome after the DNA is cut.

Each of the RNA segments can target a different sequence. “That’s the beauty of this — you can easily program a nuclease to target one or more positions in the genome,” Zhang says.

The method is also very precise — if there is a single base-pair difference between the RNA targeting sequence and the genome sequence, Cas9 is not activated. This is not the case for zinc fingers or TALEN. The new system also appears to be more efficient than TALEN, and much less expensive.

The new system “is a significant advancement in the field of genome editing and, in its first iteration, already appears comparable in efficiency to what zinc finger nucleases and TALENs have to offer,” says Aron Geurts, an associate professor of physiology at the Medical College of Wisconsin. “Deciphering the ever-increasing data emerging on genetic variation as it relates to human health and disease will require this type of scalable and precise genome editing in model systems.”

The research team has deposited the necessary genetic components with a nonprofit called Addgene, making the components widely available to other researchers who want to use the system. The researchers have also created a website with tips and tools for using this new technique.

Engineering new therapies

Among other possible applications, this system could be used to design new therapies for diseases such as Huntington’s disease, which appears to be caused by a single abnormal gene. Clinical trials that use zinc finger nucleases to disable genes are now under way, and the new technology could offer a more efficient alternative.

The system might also be useful for treating HIV by removing patients’ lymphocytes and mutating the CCR5 receptor, through which the virus enters cells. After being put back in the patient, such cells would resist infection.

This approach could also make it easier to study human disease by inducing specific mutations in human stem cells. “Using this genome editing system, you can very systematically put in individual mutations and differentiate the stem cells into neurons or cardiomyocytes and see how the mutations alter the biology of the cells,” Zhang says.

In the Science study, the researchers tested the system in cells grown in the lab, but they plan to apply the new technology to study brain function and diseases.

The research was funded by the National Institute of Mental Health; the W.M. Keck Foundation; the McKnight Foundation; the Bill & Melinda Gates Foundation; the Damon Runyon Cancer Research Foundation; the Searle Scholars Program; and philanthropic support from MIT alumni Mike Boylan and Bob Metcalfe, as well as the newscaster Jane Pauley.

SOURCE:

http://web.mit.edu/newsoffice/2013/editing-the-genome-with-high-precision-0103.html

Proc Natl Acad Sci U S A. 2012 September 25; 109(39): E2579–E2586.

Published online 2012 September 4. doi:  10.1073/pnas.1208507109

PMCID: PMC3465414

PNAS Plus

Cas9–crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria

Giedrius Gasiunas,^a Rodolphe Barrangou,^b Philippe Horvath,^c and Virginijus Siksnys^a,1

Author information ► Copyright and License information ►

ABSTRACT

Clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems provide adaptive immunity against viruses and plasmids in bacteria and archaea. The silencing of invading nucleic acids is executed by ribonucleoprotein complexes preloaded with small, interfering CRISPR RNAs (crRNAs) that act as guides for targeting and degradation of foreign nucleic acid. Here, we demonstrate that the Cas9–crRNA complex of the Streptococcus thermophilus CRISPR3/Cas system introduces in vitro a double-strand break at a specific site in DNA containing a sequence complementary to crRNA. DNA cleavage is executed by Cas9, which uses two distinct active sites, RuvC and HNH, to generate site-specific nicks on opposite DNA strands. Results demonstrate that the Cas9–crRNA complex functions as an RNA-guided endonuclease with RNA-directed target sequence recognition and protein-mediated DNA cleavage. These findings pave the way for engineering of universal programmable RNA-guided DNA endonucleases.

Keywords: nuclease, site-directed mutagenesis, RNA interference, DNA interference

Comparison with Other RNAi Complexes

The mechanism proposed here for the cleavage of dsDNA by the Cas9–crRNA complex differs significantly from that for the type I-E (former “Ecoli”) system (7). In the E. coli type I-E system crRNA and Cas proteins assemble into a large ribonucleoprotein complex, Cascade, that facilitates target recognition by enhancing sequence-specific hybridization between the crRNA and complementary target sequences (7). Target recognition is dependent on the PAM and governed by the seed crRNA sequence located at the 5′ end of the spacer region (24). However, although the Cascade–crRNA complex alone is able to bind dsDNA containing a PAM and a protospacer, it requires an accessory Cas3 protein for DNA cleavage. Cas3 is an ssDNA nuclease and helicase that is able to cleave ssDNA, producing multiple cuts (10). It has been demonstrated recently that Cas3 degrades E. coli plasmid DNA in vitro in the presence of the Cascade–crRNA complex (25). Thus, current data clearly show that the mechanistic details of the interference step for the type I-E system differ from those of type II systems, both in the catalytic machinery involved and the nature of the molecular mechanisms.

In type IIIB CRISPR/Cas systems, present in many archaea and some bacteria, Cmr proteins and cRNA assemble into an effector complex that targets RNA (6, 12). In Pyrococcus furiosus the RNA-silencing complex, comprising six proteins (Cmr1–Cmr6) and crRNA, binds to the target RNA and cleaves it at fixed distance from the 3′ end. The cleavage activity depends on Mg²⁺ ions; however, individual Cmr proteins responsible for target RNA cleavage have yet to be identified. The effector complex of Sulfolobus solfataricus, comprising seven proteins (Cmr1–Cmr7) and crRNA, cuts invading RNA in an endonucleolytic reaction at UA dinucleotides (13). Importantly, these two archaeal Cmr–crRNA complexes perform RNA cleavage in a PAM-independent manner.

Overall, we have shown that the Cas9–crRNA complex in type II CRISPR/Cas systems is a functional homolog of Cascade in type I systems and represents a minimal DNAi complex. The simple modular organization of the Cas9–crRNA complex, in which specificity for DNA targets is encoded by crRNAs and the cleavage enzymatic machinery is brought by a single, multidomain Cas protein, provides a versatile platform for engineering universal RNA-guided DNA endonucleases. Indeed, by altering the RNA sequence within the Cas9–crRNA complex, programmable endonucleases can be designed both for in vitro and in vivo applications. To provide proof of principle of such a strategy, we engineered de novo into a CRISPR locus a spacer targeted to a specific sequence on a plasmid and demonstrated that such a plasmid is cleaved by the Cas9–crRNA complex at a sequence specified by the designed crRNA. Experimental demonstration that RuvC and HNH active-site mutants of Cas9 are functional as strand-specific nicking enzymes opens the possibility of generating programmed DNA single-strand breaks de novo. Taken together, these findings pave the way for the development of unique molecular tools for RNA-directed DNA surgery.

SOURCE:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465414/

Cheap and easy technique to snip DNA could revolutionize gene therapy

By Robert Sanders, Media Relations | January 7, 2013

BERKELEY —A simple, precise and inexpensive method for cutting DNA to insert genes into human cells could transform genetic medicine, making routine what now are expensive, complicated and rare procedures for replacing defective genes in order to fix genetic disease or even cure AIDS.

The bacterial enzyme Cas9 is the engine of RNA-programmed genome engineering in human cells. Graphic by Jennifer Doudna/UC Berkeley.

IMAGE SOURCE:

http://newscenter.berkeley.edu/2013/01/07/cheap-and-easy-technique-to-snip-dna-could-revolutionize-gene-therapy/

Discovered last year by Jennifer Doudna and Martin Jinek of the Howard Hughes Medical Institute and University of California, Berkeley, and Emmanuelle Charpentier of the Laboratory for Molecular Infection Medicine-Sweden, the technique was labeled a “tour de force” in a 2012 review in the journal Nature Biotechnology.

That review was based solely on the team’s June 28, 2012, Science paper, in which the researchers described a new method of precisely targeting and cutting DNA in bacteria.

Two new papers published last week in the journal Science Express demonstrate that the technique also works in human cells. A paper by Doudna and her team reporting similarly successful results in human cells has been accepted for publication by the new open-access journal eLife.

“The ability to modify specific elements of an organism’s genes has been essential to advance our understanding of biology, including human health,” said Doudna, a professor of molecular and cell biology and of chemistry and a Howard Hughes Medical Institute Investigator at UC Berkeley. “However, the techniques for making these modifications in animals and humans have been a huge bottleneck in both research and the development of human therapeutics.

“This is going to remove a major bottleneck in the field, because it means that essentially anybody can use this kind of genome editing or reprogramming to introduce genetic changes into mammalian or, quite likely, other eukaryotic systems.”

“I think this is going to be a real hit,” said George Church, professor of genetics at Harvard Medical School and principal author of one of the Science Express papers. “There are going to be a lot of people practicing this method because it is easier and about 100 times more compact than other techniques.”

“Based on the feedback we’ve received, it’s possible that this technique will completely revolutionize genome engineering in animals and plants,” said Doudna, who also holds an appointment at Lawrence Berkeley National Laboratory. “It’s easy to program and could potentially be as powerful as the Polymerase Chain Reaction (PCR).”

The latter technique made it easy to generate millions of copies of small pieces of DNA and permanently altered biological research and medical genetics.

Cruise missiles

Two developments – zinc-finger nucleases and TALEN (Transcription Activator-Like Effector Nucleases) proteins – have gotten a lot of attention recently, including being together named one of the top 10 scientific breakthroughs of 2012 by Science magazine. The magazine labeled them “cruise missiles” because both techniques allow researchers to home in on a particular part of a genome and snip the double-stranded DNA there and there only.

Researchers can use these methods to make two precise cuts to remove a piece of DNA and, if an alternative piece of DNA is supplied, the cell will plug it into the cut instead. In this way, doctors can excise a defective or mutated gene and replace it with a normal copy. Sangamo Biosciences, a clinical stage biospharmaceutical company, has already shown that replacing one specific gene in a person infected with HIV can make him or her resistant to AIDS.

Both the zinc finger and TALEN techniques require synthesizing a large new gene encoding a specific protein for each new site in the DNA that is to be changed. By contrast, the new technique uses a single protein that requires only a short RNA molecule to program it for site-specific DNA recognition, Doudna said.

In the new Science Express paper, Church compared the new technique, which involves an enzyme called Cas9, with the TALEN method for inserting a gene into a mammalian cell and found it five times more efficient.

“It (the Cas9-RNA complex) is easier to make than TALEN proteins, and it’s smaller,” making it easier to slip into cells and even to program hundreds of snips simultaneously, he said. The complex also has lower toxicity in mammalian cells than other techniques, he added.

“It’s too early to declare total victory” over TALENs and zinc-fingers, Church said, “but it looks promising.”

Based on the immune systems of bacteria

Doudna discovered the Cas9 enzyme while working on the immune system of bacteria that have evolved enzymes that cut DNA to defend themselves against viruses. These bacteria cut up viral DNA and stick pieces of it into their own DNA, from which they make RNA that binds and inactivates the viruses.

UC Berkeley professor of earth and planetary science Jill Banfield brought this unusual viral immune system to Doudna’s attention a few years ago, and Doudna became intrigued. Her research focuses on how cells use RNA (ribonucleic acids), which are essentially the working copies that cells make of the DNA in their genes.

Doudna and her team worked out the details of how the enzyme-RNA complex cuts DNA: the Cas9 protein assembles with two short lengths of RNA, and together the complex binds a very specific area of DNA determined by the RNA sequence. The scientists then simplified the system to work with only one piece of RNA and showed in the earlier Science paper that they could target and snip specific areas of bacterial DNA.

“The beauty of this compared to any of the other systems that have come along over the past few decades for doing genome engineering is that it uses a single enzyme,” Doudna said. “The enzyme doesn’t have to change for every site that you want to target – you simply have to reprogram it with a different RNA transcript, which is easy to design and implement.”

The three new papers show this bacterial system works beautifully in human cells as well as in bacteria.

“Out of this somewhat obscure bacterial immune system comes a technology that has the potential to really transform the way that we work on and manipulate mammalian cells and other types of animal and plant cells,” Doudna said. “This is a poster child for the role of basic science in making fundamental discoveries that affect human health.”

Doudna’s coauthors include Jinek and Alexandra East, Aaron Cheng and Enbo Ma of UC Berkeley’s Department of Molecular and Cell Biology.

Doudna’s work was sponsored by the Howard Hughes Medical Institute.

RELATED INFORMATION

• RNA-programmed genome editing in human cells (accepted for publication in eLife)
• RNA-Guided Human Genome Engineering via Cas9 (Church article, Jan. 3 Science Express)
• Multiplex Genome Engineering Using CRISPR/Cas Systems (Wang article, Jan. 3 Science Express)
• Programmable RNA Complex Could Speed Genome Editing in the Lab (HHMI story, June 28, 2012)
• Jennifer Doudna’s Web page

SOURCE:
http://newscenter.berkeley.edu/2013/01/07/cheap-and-easy-technique-to-snip-dna-could-revolutionize-gene-therapy/

Matthew Herper, Forbes Staff on 3/24/2013

 A Cancer Patient’s Quest Hits DNA Pay Dirt

 

Kathy Giusti

Kathy Giusti has faced her cancer with the verve of an entrepreneur. Now her fight with multiple myeloma has moved to a new front: DNA.

Giusti was a 37-year-old marketing executive at Searle (now part of Pfizer) when she was diagnosed in 1996 with myeloma, a deadly blood and bone marrow cancer. She had a 1-year-old daughter. Sixty percent of myeloma patients die within five years, but Giusti beat the odds, living for a decade and a half through multiple rounds of drug therapy and a bone marrow transplant from her twin sister.

She has also changed the way her disease is treated. Giusti founded an advocacy group, the Multiple Myeloma Research Foundation, that works with companies like Novartis, Celgene, and Merck to develop new treatments. It played a key role in the development of Velcade and Revlimid, two of the biggest advances in treating the disease, which is diagnosed in 20,000 patients a year.

Now a new research effort, funded with $14 million of MMRF money, has revealed new hints at what causes the disease and potential avenues for treating it. “This is going to be the next wave of how health care gets changed over time,” Giusti says. The results are published in the current issue of Nature.

Working with patient samples collected by the MMRF and using DNA sequencers made by Illumina of San Diego, researchers at the Broad Institute of MIT and Harvard sequenced the genes of 38 myeloma tumors and the DNA of the patients in whom they were growing. Tumors are twisted versions of the people in which they are growing; their DNA is mutated and disfigured, turning them deadly. By comparing DNA from healthy cells with malignant ones, researchers can find genetic differences that might be what led the tumors to go bad in the first place.

This experiment would have been unthinkable just a few years ago, when sequencing a human being was so expensive that all the people whose DNA had been read out could fit in a small room. In 2005, the idea of producing 38 DNA sequences was laughable. Now it’s par for the course, and researchers expect thousands of genomes will be sequenced by the end of the year – and experiments like this are expected to become commonplace.

What’s so exciting is that sometimes the DNA changes scientists find are completely unexpected. “There were genes we found to be recurrently mutated and yet no one had any clue that they had anything to do with multiple myeloma or any other cancer,” says Todd Golub, the Broad researcher who led the study. He splits his time with the Dana-Farber Cancer Institute.

One gene, called FAM46C, was mutated in 13% of the cancers, but has never been studied in humans. “It appears no one had been working on it,” says Golub, but from studies in yeast and bacteria it appears that it has to do with how the recipes in genes are used to make proteins, the building blocks of just about everything in the body.

Another surprise gene, called BRAF, is generating excitement because it is the target of a skin cancer drug developed by Plexxikon, a small biotech firm that is partnered with Roch and is being purchased by Daiichi Sankyo. For the 4% of myeloma patients who have this mutation, this drug might be an option. The challenge will be testing it: it will be difficult to find enough of these patients to conduct a clinical trial. The MMRF says early discussions on such a study are moving forward. Giusti imagines that in the future, the MMRF may fund studies not of myeloma, but of a mix of different cancers caused by similar genetic mutations.

Several of the genes seem involved in the proteins that help guide epigenetics, a kind of molecular code written on DNA that may represent another kind of genetic code. The MMRF is already supporting some small drug companies that hope to create cancer drugs that target this second code.

Golub, the Broad scientist, says that right now it doesn’t make sense for most multiple myeloma patients to get their full DNA sequences outside of clinical trials, although he can imagine that for patients who have failed every available treatment it might make sense as a way to come up with another drug to try.

Giusti says, however, that the kinds of genetic tests that are done are changing the way that patients understand their disease. “Patients like me are starting to know, ‘I have this DNA translocation, maybe a proteasome inhibitor [a type of drug] is better for me.’ We become forerunners in the role patient can plan and the importance it has in drug development.”

Moving past old ways of thinking about inventing new medicines to a new path that is based on genetics and a flood of biological data is going to be difficult. But Giusti has never been afraid of hard — and she is sure there will be ways to drive the science forward.

SOURCE:

http://www.forbes.com/sites/matthewherper/2011/03/24/a-cancer-patients-quest-hits-dna-pay-dirt/

REFERENCES

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465414/

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16. Sapranauskas R, et al. The Streptococcus thermophilus CRISPR/Cas system provides immunity inEscherichia coli. Nucleic Acids Res. 2011;39:9275–9282. [PMC free article] [PubMed]

17. Deveau H, et al. Phage response to CRISPR-encoded resistance in Streptococcus thermophilus. J Bacteriol. 2008;190:1390–1400. [PMC free article] [PubMed]

18. Horvath P, et al. Diversity, activity, and evolution of CRISPR loci in Streptococcus thermophilus. J Bacteriol. 2008;190:1401–1412. [PMC free article] [PubMed]

19. Mojica FJM, Díez-Villaseñor C, García-Martínez J, Almendros C. Short motif sequences determine the targets of the prokaryotic CRISPR defence system. Microbiology. 2009;155:733–740. [PubMed]

20. Garneau JE, et al. The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. Nature. 2010;468:67–71. [PubMed]

21. Deltcheva E, et al. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III.Nature. 2011;471:602–607. [PMC free article] [PubMed]

22. Armalyte E, et al. Mva1269I: A monomeric type IIS restriction endonuclease from Micrococcus varians with two EcoRI- and FokI-like catalytic domains. J Biol Chem. 2005;280:41584–41594.[PubMed]

23. Chan SH, Stoddard BL, Xu SY. Natural and engineered nicking endonucleases—from cleavage mechanism to engineering of strand-specificity. Nucleic Acids Res. 2011;39:1–18. [PMC free article][PubMed]

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25. Westra ER, et al. CRISPR immunity relies on the consecutive binding and degradation of negatively supercoiled invader DNA by Cascade and Cas3. Mol Cell. 2012;46:595–605. [PMC free article] [PubMed]

26. Tamulaitis G, Zaremba M, Szczepanowski RH, Bochtler M, Siksnys V. Nucleotide flipping by restriction enzymes analyzed by 2-aminopurine steady-state fluorescence. Nucleic Acids Res.2007;35:4792–4799. [PMC free article] [PubMed]

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What about Circular RNAs?

Posted in Cell Biology, Signaling & Cell Circuits, Genome Biology, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Technology Transfer: Biotech and Pharmaceutical, tagged Berlin, Biology, DNA, gene expression, Max Delbrück Center for Molecular Medicine, MicroRNA, RNA on March 4, 2013| 3 Comments »

What about Circular RNAs?

Reporter: Larry H Bernstein, MD, FCAP

Circular RNAs throw genetics for a loop

RNA ‘sponges’ mop up sequences that curb gene expression.
Heidi Ledford       27 Feb 2013

At least some of the loops, described in two papers published this week by Nature1, 2,

• act as molecular sponges’,
  • binding to and
  • blocking tiny gene modulators called microRNAs.

The researchers suspect that the circular RNAs have many other functions. The molecules comprise “a hidden, parallel universe” of unexplored RNAs, says Nikolaus Rajewsky, the lead author of one of the studies and a systems biologist at the Max Delbrück Center for Molecular Medicine in Berlin. The discovery is yet another a reminder that

• RNA is much more than a mundane messenger ­between DNA and the proteins it encodes.

http://www.nature.com/polopoly_fs/7.9190.1361961929!/image/494415a.jpg_gen/derivatives/landscape_300/494415a.jpg

http://www.nature.com/news/circular-rnas-throw-genetics-for-a-loop-1.12513?WT.ec_id=NATURE-20130228

1. Memczak , S. et al. Nature 2013         http://dx.doi.org/10.1038/nature11928/

2. Hansen, T. B. et al. Nature 2013        http://dx.doi.org/10.1038/nature11993/

3. Salzman, J., Gawad, C., Wang, P. L., Lacayo, N. & Brown, P. O. 2012        http://www.PLoSONE.org/7/30733

Consensus secondary structure of yjdF RNAs. This figure is adapted from a previous publication. (Photo credit: Wikipedia)

RNA (Photo credit: AJC1)

By Richard Wheeler (Zephyris) 2007. Lambda repressor protein bound to a lambda operator DNA sequence. From . (Photo credit: Wikipedia)

Consensus secondary structure of mini-ykkC RNAs. Layout is similar to that used in a previously published drawing. (Photo credit: Wikipedia)

Related articles

• Weird Molecular Hoops Made From Human Genome (livescience.com)
• microRNA biomarker (pharmaceuticalintelligence.com)
• How Genes Function (pharmaceuticalintelligence.com)
• Weird molecular hoops dispel ‘junk DNA’ myth (science.nbcnews.com)
• ‘Activating’ RNA Takes DNA On A Loop Through Time And Space (medicalnewstoday.com)

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When Clinical Application of miRNAs?

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmacogenomics, Scientist: Career considerations, Technology Transfer: Biotech and Pharmaceutical, tagged Biology, gene expression, Georgia Institute of Technology, Larry H. Bernstein, Messenger RNA, MicroRNA, ovarian cancer, RNA on March 4, 2013| 1 Comment »

When Clinical Application of miRNAs?

Author: Larry H Bernstein, MD, FCAP

Clinical Application of miRNAs Remains a Ways Off
When its time comes, prognostic tests will be first.
Patricia Fitzpatrick Dimond, Ph.D             GEN Insight & Intelligence

It’s still early to tell how well microRNAs (miRNAs) will prove clinically useful.  Preclinical research findings indicate their central role in controlling cellular pathways.

This novel class of nucleotides, about 20–25 nucleotides in length, affects gene expression by interacting with messenger RNAs. But unlike Small Interfering RNA,  siRNAs, miRNAs are encoded in the human genome and function as natural regulators of global gene expression.

Each of the more than 1,500 encoded miRNAs appears to regulate the expression of tens to hundreds of different genes, on-off switches, regulating multiple cellular functions including

• growth and
• proliferation.

miRNAs regulate the translation of genes through

• sequence-specific binding to mRNA.

Depending on the degree of sequence complimentarity, they can inhibit

• the translation and/or degradation of their target mRNAs.

Because of their role in controlling “suites” of genes and, ultimately, pathway function, these molecules have attracted considerable scientific and investor interest in the control of diseases ranging from cardiovascular diseases to cancer.

miRNAs target numerous biomolecules that play a role in carcinogenesis,

• functioning as both tumor promoters or suppressors.

Aberrant expression of miRNAs

• correlates with the development and progression of tumors;

inhibition of their expression can

1. modulate the cancer phenotype,
2. suggesting their potential as anticancer drug targets.

Further supporting their potential use as drug targets, miRNA expression profiling in a variety of tissue, cell, and disease types has revealed

• a “miRNA signature” specific to those cell types or disease states.

Research

Carlo Croce, M.D., director of Human Cancer Genetics at the Ohio State University Comprehensive Cancer Center, and colleagues reported that

• they identified a 9-miRNA signature that differentiated invasive (IDC) from in situ carcinoma (DCIS).

In studying the global changes of the miRNA repertoire along the transitions defining breast cancer progression, the scientists found that

1. let-7d, miR-210, and miR-221 were downregulated in the in situ and
2. upregulated in the invasive transition, thus
3. featuring an expression reversal along the cancer progression path.
4. in addition,  miRNAs for overall survival and time to metastasis.

Dr. Croce posed that targeted prognostic tests using miRNA will be available within the next two years.

• the problem he suggests is validating the signature in a large enough cohort of patients.

They used deep sequencing, an extremely sensitive approach to the determination of miRNAs because you count the molecules. Studies have used microarrays and RT-PCR, and his group used general microarrays and validated RT-PCR.  Their method avoided the possibility of artifacts (by counting).  Sequencing permits counts of molecules to provide good data.

John F. McDonald, Ph.D., CSO Ovarian Cancer Institute, and colleagues at the Georgia Institute of Technology

1. separately transfected two miRNAs (miR-7 and miR-128) into the ovarian cancer cell line (HEY) and
2. then monitored global changes in gene expression levels.

• 20% of the changes in expression patterns of hundreds to thousands of genes
• could be attributed to direct miRNA–mRNA interactions, but
• the majority of the changes were indirect,

involving the downstream consequences of miRNA-mediated changes in regulatory gene expression.

The pathways most significantly affected by miR-7 transfection, are involved with

1. cell adhesion and
2. developmental networks previously associated with epithelial-mesenchymal transitions and
3. processes linked with metastasis.

http://www.genengnews.com/insight-and-intelligenceand153/clinical-application-of-mirnas-remains-a-ways-off/77899650/

ATVB in Focus

MicroRNAs 

From Basic Mechanisms to Clinical Application in Cardiovascular Medicine

Christian Weber, Ludwig-Maximilians-Univ and German Centre for Cardiovasc Res, Munich, Germany

Arterioscler Thromb Vasc Biol. 2013;33:168-169.  http://dx.doi.org/10.1161/ATVBAHA.112.300920

MicroRNAs (miRs) are small noncoding RNAs (≈23 nucleotides) that regulate gene expression at a posttranscriptional level by degradation or translational inhibition of target mRNAs. Initially discovered as regulators of development in plants, worms, and fruitflies,

miRs are emerging as

• pivotal modulators of cardiovascular biology and disease in mice and men.

Besides a cell-specific transcription factor profile,

• cell-specific miR-regulated gene expression is integral to cell fate and activation decisions.

Thus, the cell types involved in

• atherosclerosis,
• vascular disease, and
  • its myocardial sequelae may be
• differentially regulated by distinct miRs, thereby
  • controlling highly complex processes
    • smooth muscle cell phenotype and
    • inflammatory responses of endothelial cells or macrophages.

The generation of mature miR strands requires several steps of processing of the primary miR gene transcript, including

• cleavage of the terminal loop of miR-precursors by the RNase III enzyme,Dicer, to produce miR duplexes.

Although either strand of the miR duplex can be stably associated with an Argonaute (Ago) family protein,

• preferential loading of a specific strand (ie, the guide strand) onto the miR-induced silencing complex (RISC) is common.

The strand that is not loaded into the RISC (ie, the passenger strand or miR*) is typically degraded.3 Strand selection may be tissue-specific, and an accumulation observed for both strands implies that

• each strand can separately enter the silencing complex.4

Because of the often imperfect complementary binding of the miR seed sequence to the mRNA recognition element,

• an individual miR can affect the expression of hundreds of target mRNAs.

http://atvb.ahajournals.org/content/33/2/168.extract

Life’s Tiniest Architects Pinpointed by Yale Researchers

Feb 25, 2013        http://www.technologynetworks.com/Genomics/news.aspx?ID=149385

If a genome is the blueprint for life, then the chief architects are

• tiny slices of genetic material that orchestrate how we are assembled and function.

The study pinpoints the molecular regulators of epigenetics — the process by which unchanging genes along our DNA are switched on and off at precisely right time and place.

“Our genome is like a landscape with lakes, mountains, and rivers, but it is not yet a community or a city full of buildings,” said Haifan Lin, director of the Yale Stem Cell Center and senior author of the study. “What this system does is decide where and when to send out the masons, carpenters, and electricians to build a city or a community.”

In the past 20 years, scientists have discovered that some proteins, called epigenetic factors, traverse the static genome and turn the genes on or off. The staggering number of potential combinations of active and inactive genes explains why a relatively small number of genes can carry out such a wide range of functions.

What guides these epigenetic factors to their target? The answer:

• specialized RNAs called piRNAs.

In the latest study, the Yale team discovered that

• piRNAs guide epigenetic factors to numerous sites throughout the genome of the fruit fly Drosophila, where
  • these switches  work to turn genes on or off.

The dramatic change in gene expression patterns found illustrated

• piRNAs key role in coordinating biological activity.

“This is the first major mechanism discovered that controls where epigenetic factors —the gene switches — are to be placed in the genome,” Lin said.

Several types of cancers appeared to be

• triggered when the wrong kinds of piRNAs guide epigenetic factors to activate the wrong genes.

Blocking the action of these piRNAs should become a new opportunity to treat cancers, Lin said.

Xiao A. Huang and Hang Yin of Yale are co-lead authors of the paper.

The research was funded by a National Institutes of Health Pioneer Award to Haifan Lin and a grant from Connecticut Stem Cell Research Fund to
Lin and former Yale professor and co-author Michael Snyder, now of Stanford University.

English: A diagram showing at which stages in the DNA-mRNA-protein pathway expression can be controlled. (Photo credit: Wikipedia)

Virus-Encoded microRNAs (Photo credit: AJC1)

English: A Tet-ON doxycycline inducible transgene expression system. (Photo credit: Wikipedia)

Related articles

• microRNA biomarker (pharmaceuticalintelligence.com)
• MicroRNA Expression in Alpha and Beta Cells of Human Pancreatic Islets (plosone.org)
• In Ovarian Cancer MiR-506 Works By Blocking Epithelial-To-Mesenchymal Cell Transition (medicalnewstoday.com)
• Identification and Characterization of miRNA Transcriptome in Potato by High-Throughput Sequencing (plosone.org)
• Weird Molecular Hoops Made From Human Genome (livescience.com)
• http://venturebeat.com/2013/01/27/the-personalized-medicine-revolution-is-almost-here/
• ERCC1 Isoform Expression and DNA Repair in Non–Small-Cell Lung Cancer

 

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microRNA Biomarker

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Scientist: Career considerations, Technology Transfer: Biotech and Pharmaceutical, tagged biomarker, Breast, breast cancer, Cancer - General, Cell Biology, Cell culture, metastasis, MicroRNA, RNA, Stem cell on March 4, 2013| 2 Comments »

microRNA Biomarker

Reporter: Larry H Bernstein, MD, FCAP

MicroRNA Molecule May Serve as Biomarker

miRNA molecule called miR-7 decreased in highly metastatic cancer stem-like cells.

February 18, 2013

Researchers have identified two molecules that could potentially serve as biomarkers in

• predicting brain metastases in patients with breast cancer.

MicroRNAs are involved in

• tumor initiation and
• progression, and
• may play a role in metastasis, particularly in relation to
• cancer stem-like cells.

miR-7 is a metastasis

• suppressor in cancer stem-like cells, and when they
• increased expression of miR-7 in cancer stem-like cells from
  • metastatic human breast cancer cell lines,
  • it suppressed their metastatic properties.

miR-7 suppressed ………….expression of KLF4.
However, miR-7 significantly suppressed the ability of cancer stem-like cells to metastasize to the brain but not the bone.

http://CancerResearch.com/miRNA-decreased-in-highly-metastatic-cancer-stem-like-cells/Watabe/

A gram illustrating the disctinction between cancer stem cell targeted (above) and conventional (below) cancer therapies (Photo credit: Wikipedia)

Related articles

• The Era of MicroRNAs (ajkdblog.org)
• MicroRNA Molecule May Serve As Biomarker, Target For Brain Metastases In Breast Cancer Patients (medicalnewstoday.com)
• In Ovarian Cancer MiR-506 Works By Blocking Epithelial-To-Mesenchymal Cell Transition (medicalnewstoday.com)
• Insights on the Functional Impact of MicroRNAs Present in Autism-Associated Copy Number Variants (plosone.org)
• MicroRNA molecule may serve as biomarker, target for brain metastases in breast cancer patients (sciencedaily.com)
• Emerging Pharmaceutical Technologies – Stem Cells to Play a Significant Role in the Pharmaceutical Industry of the Future (prweb.com)
• MicroRNA molecule may serve as biomarker, target for brain metastases in breast cancer patients (eurekalert.org)
• Using MicroRNA To Identify Triple-Negative Breast Cancer Subtypes (medicalnewstoday.com)
• Transcriptome Profiling of microRNA by Next-Gen Deep Sequencing Reveals Known and Novel miRNA Species in the Lipid Fraction of Human Breast Milk (plosone.org)
• Differential Expression of Exosomal microRNAs in Prefrontal Cortices of Schizophrenia and Bipolar Disorder Patients (plosone.org)
• ERCC1 Isoform Expression and DNA Repair in Non–Small-Cell Lung Cancer

 

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