Rare-disease studies seek online giving

Those wanting to raise awareness about a rare disease will be able to take advantage of an initiative being launched later this year: a website that connects research projects with members of the public who can donate just a few dollars to help to develop cures.

The plan, called the Global Genes Fund, will "democratize the research proposal game", says Irwin Feller, an emeritus professor of the economics of science and technology at Pennsylvania State University in University Park.

The idea has been developed by the Children's Rare Disease Network, a non-profit organization based in Dana Point, California. The network plans to set up a test site by the end of 2011, with a formal launch in 2012. Potential funders will be able to choose from projects with funding goals of US$10,000-150,000. The fund will post proposals that are deemed by its committee to be likely to succeed within three to five years — that is, within the often-short lifetimes of people currently affected by the diseases.

Rare, or 'orphan', diseases are defined as those that afflict five or fewer people out of every 10,000 in the European Union or fewer than 200,000 Americans. The diseases are devastating but overlooked. Pharmaceutical companies are naturally interested in blockbuster drugs that will be taken by many people, whereas governments are often perceived as focusing their limited resources on more common conditions.

There is some funding: for example, in 2009 the National Institutes of Health announced US$24 million for the Therapies for Rare and Neglected Diseases programme to developing medicines for orphan diseases. But there is simply not enough money to support research on all rare diseases. There are some 7,000 orphan diseases affecting an estimated 350 million people worldwide. Of those, 75% are children, says Nicole Boice, founder and chief executive of the Children's Rare Disease Network. Parents often shoulder the burden of advocacy, running cake sales and other fund-raising events to support research.

Many hands

With the Global Genes Fund, Boice hopes to raise money and awareness to a level that is impossible for individual parents and scientists. She was inspired by the success of microloan websiteKiva.org. On Kiva, users browse a list of individuals worldwide who need a small loan to pay for business expenses, home improvements or other projects. Through loans of as little as $25, Kiva has raised $22 million since it was founded in 2005.

The Global Genes Fund will solicit money for defined short-term projects, Boice says. For example, it might support whole-genome sequencing for a child with an undiagnosed disorder. Or it might pay for children with a rare condition to travel to a trial centre.

The fund will also seek corporate sponsorship. Those larger gifts will help to cover projects that don't receive sufficient micro-donations, Boice says.

"It's not just the funds, it's the awareness" that the fund will raise, says Audrey Gordon, president and executive director of the Progeria Research Foundation, based in Peabody, Massachusetts. The foundation is a non-profit organization that promotes the study of progeria, which causes rapid ageing. The global nature of the new fund means that more families affected by rare diseases will find others dealing with the same problems, advocates say.

"There's a serious lack of funding for these various rare diseases," says Chris Hempel, a Reno, Nevada-based advocate and mother of twin girls who have Niemann–Pick type C disease also referred to as 'childhood Alzheimer's'. "We're all in the same boat and no one's getting drugs."

Regarding the fund, "I think it's an extremely interesting project", says Steve Groft, director of the NIH's office of rare disease research. "It will meet the needs of some of the rare-disease-community members." Even a tiny $50,000 pilot trial could give researchers enough data to apply for more funding, he adds.

http://www.nature.com/news/2011/110627/full/news.2011.387.html

How to make a human neuron

Researchers have worked out how to reprogram cells from human skin into functioning nerve cells.

By transforming cells from human skin into working nerve cells, researchers may have come up with a model for nervous-system diseases and perhaps even regenerative therapies based on cell transplants.

The achievement, reported online today in Nature¹, is the latest in a fast-moving field called transdifferentiation, in which cells are forced to adopt new identities. In the past year, researchers have converted connective tissue cells found in skin into heart cells², blood cells³ and liver cells⁴.

Transdifferentiation is an alternative to the cellular reprogramming that involves converting a mature cell into a pluripotent stem cell — one capable of becoming many types of cell — then coaxing the pluripotent cell into becoming a particular type of cell, such as neurons. Marius Wernig, a stem-cell researcher at Stanford University in California, and the leader of the study, says that skipping the pluripotency step could avoid some of the problems of making tissues from these induced pluripotent stem cells (iPSCs). The pluripotency technique can also take months to complete.

Wernig's team sparked the imaginations of cellular reprogrammers last year, when it transformed cells taken from the tip of a mouse's tail into working nerve cells⁵. That feat of cellular alchemy took just three foreign genes – delivered into tail cells with a virus – and less than two weeks. "We thought that as it worked so great for the mouse, it should be no problem to work it out in humans," Wernig says. "That turned out to be wrong."

Not quite right

Those three genes also made human cells that looked like nerve cells but that did not fire the electric pulses characteristic of neurons. However, the addition of a fourth virus-delivered gene, found through trial and error, pushed fibroblast cells — connective tissue cells found throughout the body and involved in wound healing — collected from aborted fetuses and the foreskin of newborns to become bona fide neurons. After a couple of weeks in culture, many of the neurons responded to electric jolts by pumping ions across their membranes. A few weeks later still, these neurons started to form connections, or synapses, with the mouse neurons they were grown alongside.

There are still kinks to work out, Wernig admits. Only 2–4% of the fibroblasts became neurons — lower than the roughly 8% efficiency his team achieved with the mouse tail cells. And most of the resulting neurons communicated using a chemical called glutamate, limiting their use for understanding or treating diseases such as Parkinson's, which is characterized by problems in neurons that communicate with this chemical.

Wernig says that his team expects their efficiency to improve and is trying to make neurons that communicate using other chemicals.

Quick success

Neurons forged through transdifferentation offer advantages over brain cells made from iPSCs, says Evan Snyder, a stem-cell biologist at the Sanford Burnham Medical Research Institute in San Diego, California. As well as being quicker to make, they are less likely to form tumours when they are implanted into tissue, he says.

On the downside, however, cellular signs of disease may only appear when a cell develops naturally, from a pluripotent stem cell into a differentiated neuron, Snyder says. Forcing a cell into becoming a neuron could cause scientists to miss aspects of a disease. Furthermore, the fibroblasts that are the starting material for transdifferentiation do not divide as readily as iPSCs, limiting their use in applications that require lots of cells, such as drug screening, Wernig says.

"I would say that both approaches should be actively pursued because you never know for which cases and specific applications one or the other may be more suitable," Wernig concludes. 

• References

1. Pang, Z. P. et al. Nature advance online publication doi:10.1038/nature10202 (2011).
2. Ieda, M. et al. Cell 142, 375-386 (2010). | Article | PubMed | ISI | ChemPort |
3. Szabo, E. et al. Nature 468, 521-526 (2010). | Article | PubMed | ISI | ChemPort |
4. Huang, P. et al. Nature advance online publication doi:10.1038/nature10116 (2011).
5. Vierbuchen, T. et al. Nature 463, 1035-1041 (2010). | Article | PubMed | ISI | ChemPort |

http://www.nature.com/news/2011/110526/full/news.2011.328.html

Epigenetics: What It Means and Why You Should Care

Fundamental shifts in the way we understand our world and ourselves are rare, and when they do happen it is often with uproar. When discovery of the DNA double helix by James Watson and Francis Crick in 1953 showed us that all of nature was bound together by a common molecular mechanism, it was assumed that the information held by the DNA sequence would be the primary determinant in the biology of any organism. After the last forty years of biological research and the completion of the human genome sequence a decade ago, the overwhelming realization is that the information contained in the DNA sequence alone is only a fraction of the total information needed to animate the cell, coordinate multicellular behavior, and orchestrate life’s unfathomably complex sequence of biological events. While the discovery that layers of information beyond DNA sequence are equally important to life is in many ways as fundamental a revelation as the discovery of DNA, it has not received such widespread recognition. This is surprising, considering that there are medical implications from choice of diet to cancer treatment. Epigenetics, as this fascinating range of mechanisms is called, deserves your attention and imagination because for the foreseeable future this new paradigm will be behind advances in our understanding of multicellularity, genome-environment interaction, and human disease.

All of the cells in your body have the same genetic code, and hence the same set of instructions, but carry out drastically different functions. This begs several questions. How does a cell know which instructions to carry out? How can the genetic instructions of a cell or an organism respond to their environment? How can some cells become cancerous while others remain healthy? The answers to these questions lie in the differences in epigenetic information between cells. The Greek prefix epi-means “above” or “in addition to”, and epigenetics refers to the layers of information superimposed on top of the genetic information contained in DNA sequence. If your genetic code gives you your individual identity, epigenetics gives each of your cells their own identity. Thus, any organism is a manifestation not only of its genetic content, but also of the sum total of its epigenetic states.

The term epigenetics dates back to 1942, before the discovery of DNA [1], but it has taken sixty years of biology to describe how it works on the molecular level. To understand why epigenetics is distinct from “regular” genetics, posing a new set of challenges and fundamentally altering the way we perceive biological information, we must get into the gritty details of DNA and its multitude of partners.

DNA, by itself, does not do anything. It is chemically inert, and the information it contains is only relevant when accessed by proteins and RNA machinery. The central idea of epigentics is perhaps that the genomic information is not just a jumble of sequence to be read in a linear manner: the information is finely organized through a series of overlayed mechanisms that control how that information is utilized.

The first level of epigenetic regulation and higher order genome structure is the way in which strands of DNA are packaged by proteins called histones. Imagine a string (the DNA) being wound around a hockey puck (the histone). These string-wrapped hockey pucks (protein-DNA complexes) are bundled into a solenoid-like pattern, which are then wrapped into even larger strands called chromatin, which make up whole chromosomes. Chromatin is the basic structure of the genome in a cellular context, but it is not all in a uniform state. Some regions are tightly packed together, which means genes in those regions are turned off, while others are less tightly packed and the genes inside can be turned on.  Strands of DNA can be chemically modified by addition of a single carbon atom (methylation), which causes chromatin to pack together more tightly, leading to repression of that area of the genome [2]. Think of it as making the string stickier. The clumps of hockey pucks would be hard to unwrap.

The second level is the behavior of the histones themselves. For the string of DNA to be read by the transcriptional machinery, the hockey pucks must slide away or be removed to allow proteins to bind to the DNA. The behavior of histones, and therefore the transcriptional status of a gene, is modulated by chemical modifications that cause the hockey pucks of the histones to move further away from one another and expose the DNA string, or clump together and conceal it. Patterns of these modifications are closely related to levels of gene expression, and it appears that cells have an epigenetic “histone code” of sorts, adding another layer of information with strong consequences for cellular activity and development [3].

The third level of epigenetic regulation occurs on a larger scale. The vast majority of your genome is full of long repeats, remnants of erstwhile genes, and a hefty portion of viruses that encountered us at some ancient point in evolutionary history and decided to stay. Most of this is hardly transcribed, if at all, but it must be managed in a way that does not interfere with the active regions of the genome. This leads to a non-random ordering of the genome within the nucleus, and of regions within the same chromosome [4]. Active regions clump together, and inactive regions are repressed in a common space [5]. The spatial organization of the genome is a problem of third-order complexity, and today it is unclear what functional consequences these arrangements have. However, recent work shows that genome organization is to some degree cell-type specific, and changes during development [6].

These regulatory mechanisms, along with others such as the surprisingly varied role of RNA, comprise a rich network of information that influences cellular and organismal behavior in profound ways. Epigenetic mechanisms explain why two individuals with extremely similar genome sequence can have different physical characteristics. Identical twins have identical genomes, and are epigenetically identical at birth, but as they age, different environmental factors cause their methylation and histone modification profiles diverge, and they end up with differing patterns of gene expression and disease [7]. These changes arise within a single lifetime, but some epigenetic traits can be inherited across generations. For example, the diet of pregnant mothers can change DNA methylation patterns in the fetus, which may lead to various diseases later in life for their children [8].

Epigenetic approaches to therapy are showing promise as well, particularly in cancer, where both genetic and epigenetic profiles are drastically altered. The FDA has approved the drug decitabine, which inhibits enzymes that methylate DNA. Aberrant methylation patterns are a hallmark of several blood cancers, including acute myeloid leukemia, where decitabine has shown the most success [9]. Inhibitors of histone-modifying enzymes have also been approved for treating cancer of immune cells. Unfortunately, the complexity and redundancy of methylation and histone modifications makes it difficult to use single inhibitors of epigenetic machinery. For unknown reasons they are most effective in blood cancers, but have little effect on solid tumors. It seems that epigenetic therapies will have the most benefit when they are used in combination with one another and as supplemental therapy for more decisive interventions like bone marrow transplants or radiation therapy [10].

But there’s still the question: why should you care about epigenetics? Most importantly, epigenetics has opened new approaches to treating disease, and is promising to unleash the power of personalized medicine that sequence information alone was unable to provide. It also unravels the connections between our environment and our genomes, and provides a mechanism for how our experiences can feed back into our genetic identity. Lastly, it has redefined our understanding of how biological information is stored, processed, and transmitted. Together, these advances constitute a profound shift in how we conceptualize life, and are the foundation for the next century of biology and medicine. That is certainly worthy of an uproar.

References:

1. Waddington, CH. The epigenotype. Endeavour. 1942;1:18–20.
2. Bird, A. DNA mehtylation patterns and epigenetic memory. Genes & Dev. 2002;16:6-21.
3. Jenuwein T, Allis CD. Translating the histone code. Science. 2001 Aug;293(5532):1074-80.
4. Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009;326(5950):289-93.
5. Misteli T. Beyond the sequence: cellular organization of genome function. Cell. 2007;128:787-800.
6. Rajapaske I, Groudine M. On emerging nuclear order. JCB. 2011;192(5):711-721.
7. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005;102(30):10604-10609.
8. Heijmans B, Tobi EW, Stein AD, Putter H, Blauw GJ, SUsser ES, et al. Persistent epigenetic differences associated with prenatal exposure to famine in humans. . Proc Natl Acad Sci USA. 2008:105(44);17046-17049.
9. Claes B, Buysschaert I, Lambrechts D. Pharmaco-epigenomics: discovering therapeutic approaches and biomarkers for cancer therapy. Heredity. 2010;105(1):152-60.
10. Thurn KT, Thomas S, Moore A, Munster PN. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer.  Future Oncol. 2011;7(2):263-83.

http://triplehelixblog.com/2011/05/epigenetics-what-it-means-and-why-you-should-care/

Dying Without Sleep: Insomnia and its Implications

Ideally, humans sleep for at least eight hours every day, meaning that we spend about a third of our lives “unconscious.” Scientists have yet to agree on why this unconsciousness is vital, but we know that without sleep, all mammals and birds would die [1]. Because sleep has only become the subject of research in the recent past, rare neurological disorders like fatal familial insomnia (FFI), which causes patients to die within a year or two of its onset, (usually in the patient’s early fifties) ranks very low on the list of things to cure. Though in this case the cause of death is mostly attributable to neural degeneration, death is clearly hastened by a marked “disruption of critical functions” due to lack of sleep [2]. And before death, all FFI patients display symptoms that are clear manifestations of damage to a mass of grey brain matter called the thalamus.  In fact, according to National Geographic, “before FFI was investigated, most researchers didn’t even know the thalamus had anything to do with sleep” [1]. By studying the effects of FFI, it is likely that scientists will accrue key insight into the exact role of the thalamus in sleep—and maybe even insights into the function of sleep as well.

The thalamus belongs to the limbic system, which lies deep in the cortex and extends to the top of the brain stem [4]. The cortex is the outer layer of the cerebrum, the front part of the mammalian brain. Generally, scientists agree that the limbic system is involved in olfaction, the interpretation of emotions, storage of certain types of memories, and regulation of certain hormones. [4] The thalamus itself acts as a sort of control tower, receiving sensory messages from the spinal cord and then relaying those signals along to their corresponding locations in the cerebrum [5].  Ann M. Akroush of the University of Michigan’s Department of Natural Sciences calls the thalamus “the area [of the brain] responsible for sleep,” noting that during sleep, it is generally thought that “the thalamus becomes less efficient…allowing for the vegetative state of sleep to come over an individual” [3].

Sleep includes long periods of non-rapid eye movement, punctuated by rapid eye movement (REM), the latter that amounts to about a quarter of the total sleeping time. During non-REM sleep, most neurons in the brain stem, cerebral cortex, and adjacent forebrain regions—all connected to the thalamus—stop firing [6].  Non-REM sleep, it seems, gives cells a chance to repair themselves from daily wear and tear. Jerome M. Siegel of the Brain Research Institute at University of California, Los Angeles, accounts for this conjecture by pointing to the fact that “bigger animals,” such as humans, “need less sleep” on the whole than smaller animals, such as cats, because smaller animals “have higher metabolic rates” [6]. The set of chemical reactions that constitute a metabolism generate free radicals, chemicals that are known to cause a lot of damage to or even kill cells; thus, these smaller animals are likely to experience greater rates of tissue injury, and a higher need for self-repair [6].

Victims of FFI are unable to “get past” the first stages of sleep and enter REM sleep, which is generated by the brain stem—right below the thalamus [1]. Although the exact purpose of REM sleep remains a mystery, we know it “profoundly affects brain systems that control the body’s internal organs” [6]. For example, during REM our heart rate and breathing become “irregular” as in our waking state [6]. Like a reptile’s, our body temperature drifts toward that of our environment [6]. The body temperature of sufferers of FFI instead “soars and crashes” marked by extensive sweating and chills [1].

Additionally, in 1973 a group of scientists discovered that during REM sleep, neurons completely cease their release of a group of neurotransmitters called monoamines—which include dopamine and serotonin [6].  Siegel believed that this halt could be “vital for the proper function of these neurons and of their receptors,” due to the fact that a “constant release” of monoamines tends to desensitize their receptors [6]. Thus, he says, the “interruption of monoamine release during REM sleep…may allow the receptor systems to “rest and regain full sensitivity” [6]. Without either type of sleep, and consequently neither a period of rest nor a chance for cell repair, the outlook for FFI patients seems dim. Furthermore, the question of whether FFI patients actually die from lack of sleep seems intimately tied to understanding the exact function of the thalamus, as evidenced by the locations of brain activity during sleep.  Could it be that the thalamus is most vital to us because of its connection to sleep?

FFI is part of a family of diseases called transmissible spongiform encephalopathy (TSE), or prion disease.  “Spongiform encephalopathies” are brain infections distinguished by the appearance of a bunch of little holes in the affected region, as in a sponge.  They are transmissible because they can spread.  TSEs are caused by fatal misfoldings of “prion” proteins, which in turn recruit the cells around them to misfold, and together these proteins become indigestible to enzymes [7]. In FFI patients, rogue malformed prion proteins attack the thalamus [1]. First, the victim will display signs of worsening insomnia. Then, he or she will start to panic, hallucinate and sweat. After the patient loses all ability to sleep, rapid weight loss will ensue. Next, the patient will experience dementia and irresponsiveness, and finally sudden death [3].  Like the rest of the TSEs, FFI is “autosomal dominant”: if one of your parents is a carrier of the gene for FFI, you are automatically doomed to be a victim of the disease.

A particular case report by psychologist Joyce Schenkein and neurologist Pasquale Montagna describes the efforts of one patient who was able to exceed the average survival time by nearly one year. He tried various strategies, including vitamin
therapy and meditation, using different stimulants and narcoleptics and even complete sensory deprivation in an attempt to induce sleep at night and increase alertness during the day [2]. Nonetheless, over the course of his trials, the patient succumbed to the classic four-stage progression of symptoms.  The fact remains that there is no cure for FFI.

We do not know if prions destroy every FFI victim’s thalamus in the same way—that is to say, if physiological function in the region directly corresponds to symptom manifestation.  Schenkein and Montagna concluded that death was hastened by “the disruption of critical functions,” including ones related to “hypometabolism,” in which biochemical processes of the body move at a slower pace, and others related to “dysautonomia”, in which, the sympathetic nervous system, the control center for the “fight-or-flight” response, goes into overdrive, resulting in metabolic exhaustion [2]. So, does the thalamus indeed become “less efficient” during sleep, as Akroush put it, or do its functions simply shift?  These directed questions could allow researchers to better understand the disease, its manifestations, and potential routes to cures.

Akroush cites gene therapy as a starting point for treatment possibilities. This would generally involve the re-introduction of a non-mutated version of the rogue gene into an affected individual’s genome with aims to correct his or her protein expressions.   But this treatment is only an option if it is performed far before any FFI symptoms visibly manifest [3]. Worse, scientists have yet to isolate the corrective gene or to identify a proper vector for transfer.  Indeed, if sleep weren’t such a private and mysterious bodily function, argues National Geographic, “governments would [themselves] declare war on” sleep disorders [1]. Still, our understanding does seem to be progressing, if slowly.  We know that patients diagnosed with fatal familial insomnia die after substantial damage to the thalamus that directly causes an inability to sleep.  From this, we can infer that the thalamus’s role is necessary to sustain human life and important for elucidating the mysteries behind mammalian sleep.

Yet the National Institutes of Health (NIH) contributes “only about $230 million a year to sleep research,” while spending well over $100 billion per year to treat obesity-related conditions, that might be solved simply with dietary modifications and moderate exercise.  While obesity has only become an issue in the last century, the first accepted case of FFI was recorded in the eighteenth century [1].  Similarly, about thirty percent of Americans are obese, while over fifty percent of Americans complain of symptoms of insomnia [8].  Incidentally, there is an increasing body of research linking certain obesity cases to lack of sleep— but we sleep about “an hour and a half less a night than we did just a century ago” and our struggles continue [1]. For now, the fight against insomnia has been “largely left to drug companies and commercial sleep centers,” who target general client bases, while FFI victims and future generations of their family will continue to die until a cure is found [1].

References:

1. Max DT. The Secrets of Sleep. National Geographic [serial on the Internet]. 2010 May; [cited 2011 January 24]; [about 5 screens]. Available from: http://ngm.nationalgeographic.com/2010/05/sleep/max-text
2. Schenkein J, Montagna, P. Self-management of Fatal Familial Insomnia Part 2: Case Report. MedGenMed [serial on the Internet]. 2006 September 12; [cited 2011 January 24]; 8(3): [about 12 screens].  Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781276/?tool=pmcentrez
3. Akroush, AM. Fatal Familial Insomnia [homepage on the Internet]. Case Studies in Virtual Genetics 1996-1997: John C. Thomas; [cited 2011 January 24]; Available from: http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997%20Case%20Studies/AAkroush.html
4. Regina Bailey. Limbic System [homepage on the Internet]. Biology About.com Guide. [updated 2011; cited 2011 January 24]. Available from: http://biology.about.com/od/anatomy/a/aa042205a.htm
5. Thompson Learning, Inc. What are the main anatomical structures of the brain and what are their functions? [homepage on the Internet]. Thompson Learning, Inc; [updated 2002; cited 2011 January 24]. Available from: http://163.16.28.248/bio/activelearner/40/ch40c2.html
6. Siegel, JM. Why We Sleep. Scientific American. 2003 November: 92-97.
7. Zeman, A. A Portrait of the Brain. New Haven: Yale University Press; 2008.
8. WB&A Market Research. 2002 Sleep in America Poll [homepage on the Internet]. Washington DC: National Sleep Foundation [updated 2002 April 2; cited 2011 May 3] Available from: http://www.sleepfoundation.org/sites/default/files/2002SleepInAmericaPoll.pdf                                         

http://triplehelixblog.com/2011/06/dying-without-sleep/

Methylation: The Cause of Brain Tumor?

When one thinks of the word “cancer” breast cancer, lung cancer, and skin cancer are among the various types that first come to mind. One type of cancer that is often neglected is Brain Tumor. According to the National Tumor Society, more than 500 people per day are diagnosed with primary or metastatic brain tumor and what’s worse is that the mortality rates for those diagnosed with brain and nervous system tumors haven’t improved over the past decade. The desperate need for new treatments and therapies for brain tumor is evident and it is the hope of many people whose loved one have suffered the wrath of this incurable disease that 2011 will bring new treatments and bring the path to the cure closer than ever before [1].

Neuroscience is an area of science that has faced its fair share of failures, yet that doesn’t mean scientists should give up on the field itself. Recently, researchers at the Alpert Medical School made an important discovery that may change the face of brain tumor treatments and diagnosis forever.

This new discovery is developed from the hypothesis that a relationship exists between mutations in tumors and methylation patterns found in their genomes (2). Chemically speaking, methylation is the addition of a methyl group to a substrate or the substitution of an atom or group by a methyl group. When DNA is methylated, gene silencing often occurs which could be the cause of the tumor. Gene silencing is a process of gene regulation which “switches off” a gene through a mechanism. Researchers and neuroscientists speculate that the methylated regions mark the genes involved in metabolic processes which explain the abnormal behavior of tumor cells [2]

Brooke Christiansen, a Brown post-doctoral research associate conducted a study using the Illumina GoldenGate methylation array. The research associate speculated that brain tumors specifically dealt with the IDH gene, an enzyme that is involved in glucose sensing which is an important aspect for metabolic processing. The study found that brain tumor patients with the IDH gene survive longer than those without the mutation. The reason behind this is unknown, however pharmaceutical companies are trying to develop  a drug that inhibits the process of methylation. If such a drug is developed, then perhaps the cell will return to its normal state instead of undergoing methylation. Christiansen’s research may be a medical breakthrough however his hypothesis’ have a long way to go until they can be considered true. An immediate result of his research is that IDH mutation can be measured clinically [2].

The National Cancer Society has recently conducted similar research on a type of brain tumor common in children called medulloblastoma. Similar to Christiansen’s research, researchers such as Dr. Victor Velculescu of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center discovered that some tumors harbored previously unknown mutations in the genesMLL2 and MLL3. These genes are involved in histone methylation, an epigenetic process that affects the structure of chromatin and the regulation of other genes. While the drug that inhibits methylation hasn’t been discovered yet, an experimental drug called GDC-0449, which inhibits the hedgehog signaling pathway, is being evaluated in children with recurrent medulloblastoma [3].

“Right now, there is hope and excitement that we may have new therapies to introduce for these patients,” said Dr. Amar Gajjar of St. Jude, who is leading ongoing NCI-sponsored trials with the drug on behalf of the Pediatric Brain Tumor Consortium [3].

Brain tumor may not be the first thing on the minds of people when they hear the word cancer, however it is one of the most vigorous and brutal forms of cancer. Almost every single patient with an inoperable tumor dies within a 5 year set time interval after diagnosis. However, with the new studies being conducted on histone methylation and developing a drug that inhibits this epigenetic process, the cure for brain tumor isn’t far away.  Furthermore, the studies that have already been conducted in the pediatric field dealing with medulloblastoma can prove to be helpful in developing a way to inhibit methylation. The cure to brain tumor is in sight, however there is still a long way to go in curing one of the most deadliest disease in the world.

References

1. http://presszoom.com/story_164408.html
2. Villacorta, Natalie. Tumor Research Could Lead to Treatment Breakthrough. http://www.browndailyherald.com/mobile/tumor-research-could-lead-to-treatment-breakthrough-1.2450647
3. Seeking Better Treaments for Brain Tumors in Children .

Written by The Triple Helix at Ohio State University