Team:Penn/Too Soon To Treat

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<header><h1><b><center>The Potential of Epigenetic Therapy and the Need for Elucidation of Risks</center></b></h1></header>
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<h1><p align="center">Epigenetic Therapy:Too Soon to Treat?</h1></header>
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<i>This article has been accepted for publication by "the nation's premiere peer-reviewed undergraduate bioethics journal", <a href="http://bioethicsjournal.com/index.html"> the Penn Bioethics Journal</a>. We're very appreciative of their support and excited to spread the word about iGEM and epigenetic engineering amongst their broad readership. </i><br/>
<i>This article has been accepted for publication by "the nation's premiere peer-reviewed undergraduate bioethics journal", <a href="http://bioethicsjournal.com/index.html"> the Penn Bioethics Journal</a>. We're very appreciative of their support and excited to spread the word about iGEM and epigenetic engineering amongst their broad readership. </i><br/>
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<p align="center"><strong>Abstract</strong> <br />
 
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Epigenetic phenomena are known to be at  the root of many common diseases. To date, the FDA has approved four epigenetic  therapies that show promising results, prolonging lives of terminal cancer  patients. However, there is a relative lack of knowledge about epigenetic  effects in the long-term and across generations, so epigenetic therapies may  have unforeseeable risks if they are used on younger people with non-lethal  epigenetic diseases. In this report, we propose a heightening of standards for  epigenetic therapy: therapies should be targeted to specific genes in specific  cells, patients&rsquo; epigenomes should be sequenced before and after treatment, and  germline effects should be unacceptable. Moreover, more research should be  performed to answer questions about transgenerational epigenetic effects, the  effects of altered epigenomes in the long term, and to develop superior assays  for screening epigenomes.</p>
 
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<p align="center"><strong>Epigenetics Background</strong><br />
 
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<strong>Introduction. </strong>The code of life is more than a  sequence of A&rsquo;s, C&rsquo;s, T&rsquo;s, and G&rsquo;s. Muscle cells in the human heart contain the  same DNA as skin cells in the foot, yet these two cell types behave in  radically different ways. Both contain the DNA for every one of over 20,000  human genes but express, only the ones needed for their own form and function.  These differences in gene expression are a result of epigenetic controls.  Epigenetics refers to any chemical modification on DNA that does not alter the  genetic sequence. In addition to governing cellular differentiation, epigenetic  mechanisms facilitate the proper functioning of a cell. Neurodevelopmental  disorders, immunodeficiency, cancer, and other illnesses can result when these  mechanisms go awry. </p>
 
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<p><strong>Methylation. </strong>DNA methylation is one of the most prominent and powerful  mechanisms of epigenetic control. In humans, enzymes called methyltransferases  add methyl groups to CpG sites, short DNA sequences which are abundant  throughout the genome. Methyl groups block transcription factors (gene  activators) from binding to DNA and performing their normal function. In short  DNA methylation has been shown to be able to silence gene expression (Feinberg  2004). Although epigenetic factors do not affect the actual sequence of DNA,  they do affect phenotype, the observable characteristics resulting from  patterns of gene expression. Specific patterns of methylation are necessary for  a cell to modulate the level of expression of each of its genes, controlling  which genes are turned on and off. </p>
 
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<p align="center"><strong>Epigenetic  Disease</strong><br />
 
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  <strong>Cancer. </strong>DNA methylation has been  referred to as the &ldquo;hallmark of cancer&rdquo; (Szyf 2004). Abnormal methylation  patterns throughout the genome that cause blockage of tumor suppressor genes,  and overexpression of oncogenes, have been linked to many types of cancer. For  instance, breast cancer cases generally exhibit inactivation of a gene called  BRCA1. In sporadic (i.e. non-familial) cases, this suppression is usually  caused by hypermethylation, rather than mutation, of the gene (<a href="http://carcin.oxfordjournals.org/content/21/9/1761.long">Rice 2000</a>). On the other hand, hypomethylation, the absence of methylation,  causes overexpression of the flap endonuclease 1 gene in some breast cancer  patients. (Singh 2008). In fact, hypomethylation is  associated with most types of cancer (Feinberg 2004). </p>
 
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<p><strong>Neurological. </strong>Methylation abnormalities have been linked  to a wide range of diseases. Fragile X syndrome, one of the leading genetic  causes of intellectual disability, is characterized by an excess amount of methylated  CpG sites in the <em>FMR1 </em>gene on the X-chromosome.  High levels of methylation in the <em>FMR1</em> gene disrupt the production of protein necessary for normal brain development.  Patients suffering from this disorder are at risk for autism, ADHD, decreased  IQ, infertility (in females), and distorted facial features. (Jacquemont  2011)<br />
 
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<p>                <strong>Psychological. </strong>Epigenetic mechanisms control  cellular function throughout the body, but also impact psychological states. In  an animal study, rat pups that received better maternal care soon after birth -  in the form of licking, grooming, and arched-back nursing - had lower levels of  methylation at the glucocorticoid receptor gene. These rats displayed less  intense responses to stressful situations than their counterparts who received  poor maternal care. The researchers were able to eliminate these differences  via epigenetic interference. This study demonstrates the great  extent to which epigenetic modifications affect an individual&rsquo;s psychological  state. (<a href="http://www.nature.com/neuro/journal/v7/n8/full/nn1276.html">Weaver  2004</a>) </p>
 
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<p align="center"><strong>Epigenetic  Therapy</strong><br />
 
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  <strong>Fundamental Advantages. </strong>The  aforementioned epigenetic roots of disease are attractive targets for therapy.  Aberrant DNA methylation patterns are inherently reversible, as opposed to  permanent genetic mutations. In the case of cancer, epigenetic therapy coaxes  tumor cells to return to a healthy state, rewiring their methylation patterns  so the cells express genes that halt their cancerous uncontrolled growth.  Traditional chemotherapy strategies, on the other hand, aim to kill cancer  cells and are fundamentally more toxic to patients.</p>
 
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<p><strong>Recent Successes. </strong>There have been some exciting clinical  successes with the first generation of epigenetic therapies. To date, four  epigenetics treatments have been approved by the FDA for use in cancer patients:  Zolinza, Istodax, Vidaza, and Dacogen (Claus 2005). The latter two are relevant  to DNA methylation, and work by inhibiting DNA methylation in myelodysplastics  syndromes (MDS). The drugs effectively reverse cancerous hypermethylation and return  standard function to cell-cycle genes, restoring normal growth rates. They do  not work for everyone, but fewer than 10% of patients do experience a complete  response, which means a total reversal from diseased to healthy bone marrow and  blood (Silverman 2002). </p>
 
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<p>                 <strong>Problems. </strong>The results of first generation epigenetic therapies are promising, but  these drugs should not be seen as the ideal model for future developing  therapies, especially if doctors want to treat younger patients with non-lethal  epigenetic diseases. First generation drugs fail to satisfactorily address many  issues. For one, they all inhibit epigenetic processes; that is, they only work  in one direction. As we discussed, many cancers are actually caused by  epigenetic inhibition, ie. low methylation levels, and would need to be treated  with drugs that restore normal methylation levels (Feinberg 2004).  Moreover, the current drugs work by blindly affecting all genes in the genome  of all the cells they encounter. One of the scientists behind the Dacogen  studies noted there is a &ldquo;potential for harm,&rdquo; but so far the adverse events,  including red blood cell suppression, diarrhea, anorexia, and others, have been  deemed acceptable by the FDA (<a href="http://www.pbs.org/wgbh/nova/body/epigenetic-therapy.html">http://www.pbs.org/wgbh/nova/body/epigenetic-therapy.html</a>). It is possible this potential for harm will be realized if  epigenetic therapies are used on patients with a much longer expected life span  than the current patient population. </p>
 
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<p align="center"><strong>Ethical  Questions</strong></p>
 
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<p><strong>Long Term Risk. </strong>We do not yet fully understand all the  effects of DNA methylation (Rothstein 2009). Perhaps the un-targeted nature of  these drugs really does not affect patients, but how can we be sure we are not setting  patients up for adverse events later in life? The approved trials were primarily  done with elderly, very sick cancer patients; but we know epigenetic  modifications can affect us on a longer, even transgenerational, time-scale  (Rothstein 2009). Of course, clinical trials are not normally designed to  detect side-effects ten, twenty, or thirty years after treatment. If these treatments provide disease alleviation in the short  term but end up causing unforeseeable epigenetic abnormalities in the long  term, are they acceptable for younger patients with non-terminal disease? Most  would argue this depends on the gravity of the adverse effects - a risk/benefit  analysis similar to that performed for any drug approval. Can we design  clinical trials that take these risks into account? Should they last 10 years? Should  the follow-ups last even longer? If the drug does show an immediate benefit in  the trial subjects, is it fair to keep it off the shelf for that long? Certainly,  a trial of this duration with these looming questions would be a non-starter  with the pharmaceutical investment community. At a minimum, researchers should monitor  &ldquo;off-target&rdquo; epigenetic effects by performing methylation-sensitive sequencing on  parts of their patient&rsquo;s genomes in multiple cell types. This is difficult and  expensive with existing technologies, which is another problem worth addressing  (Laird  2010). </p>
 
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<p>                <strong>Trans-generational Risk. </strong>These are not the  only potential issues with first generation epigenetic therapies. They act  blindly, not only on a genomic level, but also in terms of affected cell type. We  cannot exclude the possibility that they will affect the epigenomes of germline  cells. In fact, recent studies demonstrate that Dacogen could harm the fetus if  given to a pregnant woman or a father planning on having children (Ding  2012). Currently, the  drug is marketed alongside strong warnings against having children while being  treated (<a href="http://www.dacogen.com">www.dacogen.com</a>). There is evidence that epigenetic modifications can be  inherited by children and even grandchildren, so doctors need to keep the  health of these unborn people in mind if they prescribe epigenetic drugs  to reproductive-age patients (Grossniklaus 2013). The  effect of epigenetic therapies on germline cells should be measured not only while  the drug is being administered, but also in follow-ups after the treatment is  finished. It is critical that more basic research is performed to determine the  extent of transgenerational epigenetic effects, especially now that the  question has become clinically relevant. If it turns out that these epigenetic  treatments will preclude patients from safely having children, we must consider  the consequences for the younger people with diseases like Down syndrome, autism,  fragile X syndrome, and ICF, which could potentially be epigenetically treated  (Kondo 2000 and Kerkel 2010). As aberrant DNA  methylation is increasingly correlated with more common diseases like heart  disease and obesity, it should be noted that the epigenetic patient pool is not  trivial in size, so these questions will only become more pressing in time as  they become relevant to a larger portion of the younger population (Campion  2010). If we acknowledge that some patients will have  children regardless of any warnings, we must consider if it is acceptable to  have synthetically altered epigenomes in the population pool.</p>
 
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<p align="center"><strong>Second  Generation Epigenetic Therapies</strong></p>
 
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<p>                <strong>Higher Standards. </strong>If we continue developing  first generation epigenetic therapies that affect whole genomes and any cell  type, we should more openly acknowledge that we are inviting an exceptional  amount of potential for future harm in unforeseeable (and difficult to detect)  ways when they are used on non-terminal patients. So far, epigenetic therapy  has been held to the same safety standards of other cancer therapies. However,  as these drugs affect gene expression, the basis of our existence, it is more  appropriate to hold them to the standards of gene therapies. That entails an  expectation to target only the genes, pathways, and cells relevant to the  disease (www.fda.gov).  Germline transmission of epigenetic modifications  should be unacceptable. Any MDS patient is eligible for Dacogen, but  individuals have different epigenomes – this may explain the low response rates.  Patients&rsquo; epigenomes should be screened, so doctors can be sure the proposed  therapy is relevant to the individual, just as they would sequence a patient&rsquo;s  genome to be sure of a genetic disease. Genome wide epigenetic sequencing has  recently become feasible, although it is still difficult, and somewhat error  prone (Laird 2010). There is a need for further development of this technology  to enable the promise of personalized epigenetic treatment.</p>
 
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<p>                <strong>Our Work. </strong>These more stringent safety  standards demand the development of second-generation epigenetic therapeutics  that are properly targeted at the genomic and cellular level, so we can begin  treating non-lethal epigenetic disease in younger patients. Our research team,  Penn iGEM, took initial steps by designing a novel enzyme that selectively  restores methylation at specific DNA sites. We can now achieve this  site-specific methylation with greater specificity, easier customization, and 70  times lower costs than the previously reported technologies (<a href="https://2013.igem.org/Team:Penn">https://2013.igem.org/Team:Penn</a>). We can achieve these cost savings by using a TALE system,  easily customizable with a $425 kit from Addgene, as opposed to a zinc-finger  system, which can cost $30,000 to have constructed by Sigma (addgene.com and protomag.com).  Moreover, we have developed an alternative DNA methylation assay, called MaGellin,  which is significantly simpler, faster, and cheaper than methylation-sensitive  sequencing for applications like ours. MaGellin will accelerate the laborious  development process that stands between today and a future with safer and smarter  second generation epigenetic therapies.</p>
 
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<p>                <strong>Conclusion. </strong>Epigenetic phenomena have a  significant impact on the way we live and grow, and can be responsible for the  way we die. The need for epigenetic therapies is clear, the initial successes  are promising for cancer patients, but the model for future developments is not  yet set in stone. If doctors want to treat younger patients with non-lethal  epigenetic diseases, the consideration of risks must include the long term, and  the decisions in the clinic must be based on data from researchers asking  fundamental questions. Epigenetics is still an emerging field (Rothstein 2011).  To crudely quantify this, we performed a simple search on Web of Knowledge and  retrieved only 559 &ldquo;epigenetic therapy&rdquo; publications in 2012 as opposed to  36,328 for &ldquo;chemotherapy&rdquo; (wokinfo.com). The proposed second generation  epigenetic therapies could overcome the hurdles of restoring methylation as  opposed to only inhibiting methylation, and targeting specific genes as opposed  to the entire genome. However, the issues of their delivery and cellular  targeting still loom. It will require significant effort from basic researchers  to determine the relevant mechanisms, and translational researchers to optimize  the clinical strategies, but the path forward is promising.</p>
 
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<p align="center"><strong>Works Cited</strong></p>
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<a href="https://static.igem.org/mediawiki/2013/a/ae/Penn_iGEM_2013_PBJ_Article.pdf">Download the full article as a PDF.</a>
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<p><a href="http://www.pbs.org/wgbh/nova/body/epigenetic-therapy.html">http://www.pbs.org/wgbh/nova/body/epigenetic-therapy.html</a> <br />
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  <a href="http://www.dacogen.com/Content/Documents/Dacogen_PI.pdf">http://www.dacogen.com/Content/Documents/Dacogen_PI.pdf</a> <br />
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  <a href="http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/default.htm">http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/CellularandGeneTherapy/default.htm</a> <br />
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  <a href="https://2013.igem.org/Team:Penn">https://2013.igem.org/Team:Penn</a> <br />
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  <a href="http://www.wokinfo.com">www.wokinfo.com</a><br />
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  <a href="http://protomag.com/assets/zinc-fingers-entry-fee">http://protomag.com/assets/zinc-fingers-entry-fee</a> <br />
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  <a href="http://www.addgene.org/TALeffector/goldengateV2/">http://www.addgene.org/TALeffector/goldengateV2/</a></p>
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<p>Campion, J., Milagro, F., &amp; Martinez, J. A.  (2010). Epigenetics  and obesity. Prog Mol Biol Transl Sci, 94, 291-347.</p>
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<p>Claus,  R., Almstedt, M., &amp; Lubbert, M. (2005). Epigenetic treatment of  hematopoietic malignancies: in vivo targets of demethylating agents. Semin  Oncol, 32(5), 511-520.</p>
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<p>Ding,  Y. B., Long, C. L., Liu, X. Q., Chen, X. M., Guo, L. R., Xia, Y. Y., et al.  (2012). 5-aza-2'-deoxycytidine leads to reduced embryo implantation and reduced  expression of DNA methyltransferases and essential endometrial genes. PLoS One,  7(9), e45364.</p>
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<p>Feinberg,  A. P., &amp; Tycko, B. (2004). The history of cancer epigenetics. Nat Rev  Cancer, 4(2), 143-153.</p>
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<p>Grossniklaus,  U., Kelly, B., Ferguson-Smith, A. C., Pembrey, M., &amp; Lindquist, S. (2013).  Transgenerational epigenetic inheritance: how important is it? Nat Rev Genet,  14(3), 228-235.</p>
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<p>Jacquemont,  S., Curie, A., des Portes, V., Torrioli, M. G., Berry-Kravis, E., Hagerman, R.  J., et al. (2011). Epigenetic modification of the FMR1 gene in fragile X  syndrome is associated with differential response to the mGluR5 antagonist  AFQ056. Sci Transl Med, 3(64), 64ra61.</p>
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<p>Kerkel,  K., Schupf, N., Hatta, K., Pang, D., Salas, M., Kratz, A., et al. (2010).  Altered DNA methylation in leukocytes with trisomy 21. PLoS Genet, 6(11),  e1001212.</p>
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<p>Kondo, T., Bobek, M. P., Kuick, R., Lamb, B., Zhu, X.,  Narayan, A., et al. (2000). Whole-genome methylation scan  in ICF syndrome: hypomethylation of non-satellite DNA repeats D4Z4 and NBL2.  Hum Mol Genet, 9(4), 597-604.</p>
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<p>Laird,  P. W. (2010). Principles and challenges of genomewide DNA methylation analysis.  Nat Rev Genet, 11(3), 191-203.</p>
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<p>Rice,  J. C., Ozcelik, H., Maxeiner, P., Andrulis, I., &amp; Futscher, B. W. (2000).  Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA  levels in clinical breast cancer specimens. Carcinogenesis, 21(9), 1761-1765.</p>
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<p>Rothstein,  M. A., Cai, Y., &amp; Marchant, G. E. (2009). The ghost in our genes: legal and  ethical implications of epigenetics. Health Matrix Clevel, 19(1), 1-62.</p>
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<p>Silverman,  L. R., Demakos, E. P., Peterson, B. L., Kornblith, A. B., Holland, J. C.,  Odchimar-Reissig, R., et al. (2002). Randomized controlled trial of azacitidine  in patients with the myelodysplastic syndrome: a study of the cancer and  leukemia group B. J Clin Oncol, 20(10), 2429-2440.</p>
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<p>Singh,  P., Yang, M., Dai, H., Yu, D., Huang, Q., Tan, W., et al. (2008).  Overexpression and hypomethylation of flap endonuclease 1 gene in breast and  other cancers. Mol Cancer Res, 6(11), 1710-1717.</p>
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<p>Szyf,  M., Pakneshan, P., &amp; Rabbani, S. A. (2004). DNA methylation and breast  cancer. Biochem Pharmacol, 68(6), 1187-1197.</p>
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<p>Weaver,  I. C., Cervoni, N., Champagne, F. A., D'Alessio, A. C., Sharma, S., Seckl, J.  R., et al. (2004). Epigenetic programming by maternal behavior. Nat Neurosci,  7(8), 847-854.</p>
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Latest revision as of 03:52, 29 October 2013

Penn iGEM

The Potential of Epigenetic Therapy and the Need for Elucidation of Risks

 

This article has been accepted for publication by "the nation's premiere peer-reviewed undergraduate bioethics journal", the Penn Bioethics Journal. We're very appreciative of their support and excited to spread the word about iGEM and epigenetic engineering amongst their broad readership.

 

 

Download the full article as a PDF.