in the past two decades , molecular biology research has revealed the intimate mechanisms of epidemiologically significant diseases , such as cancer , infections and immunological disorders . as the next step beyond seeking the mechanisms involved ,
scientists are now increasingly making it possible to regulate human biological reactions . in recent years
, there have been breakthroughs in genetic engineering related to the inventory and methods necessary to physically construct and assemble biomolecular parts , such as synthetic rna - based regulatory systems .
synthetic biology relies on the engineering of biological systems that perform human - defined functions and on the synthesis of complex , biologically based systems that show functions that do not exist in nature . despite the possible advantages for clinical applications ,
more work remains to be done to elucidate the principles of biological design , and to overcome the scientific and technical challenges in designing and building more effective systems that are harmless to humans and therefore useful for clinical applications .
a recent study by chen et al .   has produced a significant advance in solving such issues and therefore potentially bridging the gap between the bench and the bedside for synthetic rna - based regulatory systems .
the authors   developed a modular device composed of a sensor ( an aptamer ) and a gene - regulatory component ( a hammerhead ribozyme ) and tested its ability to affect the expression of cytokines important for the function of t - lymphocytes in mouse and human systems .
first , it represents the logical continuation of years of experimental work performed by the same group , coming from a team that understands the way a synthetic rna - based regulatory system works and its immediate practical applications .
in fact , in a previous study , also published in proceedings of the national academy of sciences of the united states of america , the authors were the first to develop and set up universal rna - based regulatory platforms , called ribozyme switches , by using engineering design principles . in the present report
, the authors expanded the advantages of such biomodular platforms to a broader range of applications .
they were able to do so by the reliable de novo construction of modular , portable and scalable control systems that can achieve flexible regulatory properties , such as up- and down - regulation of target expression levels and tuning of regulatory responses to fit application - specific performance requirements .
second , the authors   applied the synthetic rna regulatory device to a significant medical issue , the use of adoptive cell transfer ( act ) .
the act strategy uses t - cell - based cytotoxic responses to attack malignant cells ( or any other types of abnormal cells ) that escape the body 's natural surveillance by using t cells that have a natural or genetically engineered reactivity to a patient 's cancer cells . for this purpose ,
t cells have first to be naturally or genetically engineered to react against a tumor - specific antigen , then expanded and made more effective in vitro , and finally adoptively transferred into a cancer patient . however , the clinical efficacy of act , so far , has been limited .
there are many reasons for this , and insufficient persistence and reactivation of infused t cells are among the main ones .
conventional strategies for enhancing the persistence of transferred t cells include ablation of all white blood cells ( myeloablative methods ) , such as total body irradiation and administration of toxic levels of interleukin ( il)-2 .
however , myeloablation is associated with considerable morbidity , caused by decreased immune response and increased risk of infection .
report on a synthetic rna regulatory system , which marks a new era in adoptive t - cell therapy because of the increase in the amount and survival of infused t cells found with this system .
their system for the control of mammalian t - cell proliferation is based on a platform of assembled rna devices formed by a modular sensor ( aptamer ) and a gene - regulatory ( hammerhead ribozyme ) component .
this device converts a small - molecule input to an increased gene expression output , in this particular case cytokine production . in more detail , the authors   fused a theophylline ribozyme switch to the 3 ' untranslated region of a tri - functional transgene ( cd19-tk - t2a - il15 ) encoding il-15 ( potent survival / proliferative cytokine of t cells ) , mutant hsv-1 thymidine kinase ( acting as a reporter and as a suicide protein in the presence of ganciclovir ) and cd19 ( a marker for fluorescence - activated cell sorting and immunomagnetic selection ) . using this system ,
they could strictly measure ( by monitoring the expression of cd19 ) and control ( by modulating the levels of the input molecule ) the biological response ( cell proliferation / viability ) .
in addition to all the in vitro evidence , the authors   demonstrated that this system worked in vivo and effectively modulated the t - cell growth rate in mice in response to theophylline administration .
the growth rate was increased to 32% in the presence of theophylline over a 14 day study in mice .
they further investigated its possible clinical application by transducing primary human central memory t cells with this system . in vitro results showed that the population of live central memory t cells increased by 24% and that apoptotic cell population was decreased by 54% in the theophylline - responsive system .
finally , the presented gene regulatory system   showed significant advantages over available gene regulatory techniques ( synthetic inducible promoters ) ; in particular , it provides a wide range of flexibility for clinical settings .
firstly , the ribozyme switches can be easily programmed to respond to different drug molecules .
secondly , the system can be stringently controlled and finely tuned by adding additional drug - responsive ribozyme switches ( up to four ) , therefore achieving lower basal gene expression levels .
thirdly , this system shows tight drug - mediated regulation of growth over an extended time period . taking all these features into consideration , it is feasible that this new synthetic rna - based regulatory system could have straightforward clinical utility .
it is likely that combining this new modular device framework with upcoming advances in synthetic biology will strongly support the tailoring of rna - based regulatory systems to diverse applications in various clinical and laboratory environments . yet applying these rna - based regulatory systems in clinical practice
in addition , there are many other factors that limit the use of adoptive t - cell therapy for cancer . for example
, the failure of adoptive immunotherapy against cancers lies in the absence of tumor - specific sources of t cells .
if such obstacles are not overcome , efficacy of these systems will be significantly limited in clinical practice .
also , recent data support the combined roles of protein - coding genes and non - coding rnas , such as micrornas , in the pathogenesis of frequent diseases ( such as cancer , immune and cardiac disorders ) .
one question for the future is whether such devices can be adapted for the regulation of the functions of non - coding rnas and micrornas .
the published research is good news , but it would be better to hold our cheers until the clinical trials are successfully completed , which we hope will be in the near future .
gac received his md and phd at carol davila university of medicine in bucharest , romania . after working on cytogenetics as an undergraduate student with dragos stefanescu in bucharest , he completed training in cancer genomics in massimo negrini 's laboratory at the university of ferrara , italy . in 2000
he became a postdoctoral fellow at the kimmel cancer center in philadelphia , in carlo croce 's laboratory .
since july 2007 he has been an associate professor in experimental therapeutics at the md anderson cancer center and studies the roles of micrornas and other non - coding rnas in cancer initiation and progression , as well as the mechanisms of cancer predisposition , and explores new rna therapeutic options for cancer patients .
skl graduated from yonsei university medical school , seoul , south korea with an md and phd and is an assistant professor in the department of gastroenterology , severance hospital , seoul .
the focus of his scientific research is understanding the roles of non - coding rnas in gastrointestinal cancers . in march 2009
, he began working in gac 's laboratory studying the roles of non - coding rnas , including micrornas in the initiation and development of gastrointestinal cancers , as well as the identification of new non - coding rna biomarkers .
gac is supported as a fellow at the university of texas md anderson research trust , as a fellow of the university of texas system regents research scholar and by the cll global research foundation .
work in gac 's laboratory is supported in part by nih , by dod , by developmental research awards in breast cancer , ovarian cancer and leukemia spores , and by a 2009 seena magowitz pancreatic cancer action network aacr pilot grant .
 synthetic rna - based regulatory systems are used to program higher - level biological functions that could be exploited , among many applications , for in vivo diagnostic and therapeutic applications . chen and colleagues have recently reported a significant technological advance by producing an rna modular device based on a hammerhead ribozyme and successfully tested its ability to control the proliferation of mammalian t lymphocytes . 
 like all exciting research , this work raises a lot of significant questions . 
 how quickly will such knowledge be translated into clinical practice ? how efficient will this system be in human clinical trials involving adaptive t - cell therapy ? 
 we discuss the possible advantages of using such new technologies for specific therapeutic applications . 
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