Team:Hong Kong HKUST/hp/article/genet

Overview

The Hong Kong University of Science and Technology (HKUST) iGEM 2013 team has built a fatty acid inducible system that enables inducible glyoxylate shunt to serve as an artificial futile cycle in human liver cells. Our vision is to introduce genes necessary for the cycle into the human body, with the aim of ultimately increasing energy expenditure in response to high circulating fatty acid levels. The idea is this would help obesity patients increase expenditure of calories and alleviate health complications such as cardiovascular disease, diabetes, and cancer. Because introducing genes into the human body is currently not a common therapeutic method, we thought it would be necessary to research on the details of how our project could be actually applied. Even though the application of our project may not occur in the near future, we thought it necessary to evaluate our project’s application as a potential biotechnology product. We have investigated a possible method that is under serious research in the scientific community: gene therapy. In this article, we will introduce the approach in more detail, examine the biosafety and bioethical issues, and lastly examine whether our project could be applied using this method.

Gene Therapy

Introduction

Gene therapy is a method that involves introducing changes in the genome to treat or prevent disease. In general this can be done by replacing a gene, inactivating a gene, or introducing a new gene into the body. Currently, scientists are trying to make gene therapy safer and more effective. In the future, effective gene therapy might replace the use of drugs or surgery (Handbook, 2013).

History

In 1966, Edward Tatum first published a paper suggesting the use of viruses in somatic-cell genetics and gene therapy. The first clinical trial was conducted by Rogers et al. to cure urea cycle disorder by introducing the gene for arginase using Shope papilloma virus. The result of the trial was negative. They later found out that was so because the Shope papilloma virus genome actually does not encode an arginase. Despite a string of negative results during clinical trials, gene therapy received great attention from many scientists until the death of Jesse Gelsinger. In 1999, Jesse Gelsinger, an omithine transcarbamylase (OTC) deficiency patient, took part in a gene therapy clinical trial at the University of Pennsylvania in Philadelphia. High doses of adenovirus were administered and Gelsinger’s immune system responded instantly. He died because of multi organ failure. This case was very important in the study of gene therapy because Gelsinger became the first patient who showed that viral vector for gene therapy can cause death to the patients (Wirth, Parker & Ylä-Herttuala, 2013).

Currently more than 1800 approved gene therapy clinical trials have or are being conducted around the world. Cancer is the most common disease being investigated for gene therapy, being the topic of over 60% of clinical gene therapy trials worldwide. In 2003, China made history by becoming the first country to approve the commercial production of a gene therapy method.

Methods

In general, there are two categories of gene therapy: germ line cell gene therapy and somatic cell gene therapy. The difference is whether the genetic materials inserted will be passed on to the next generation. In somatic cell gene therapy, genetic material is not passed down while the genetic material is passed down in germ line gene therapy (Wirth, Parker & Ylä-Herttuala, 2013). Both of these methods require a carrier called a vector that can transport the new gene into the desired cell (Handbook, 2013). Adenoviral vectors, retroviral vectors and naked plasmids have been used most for gene transfer vectors in clinical trials (Wirth, Parker & Ylä-Herttuala, 2013). When virus vectors are used they are modified so that they won’t infect the subjects. Different types of virus vectors can produce different outcomes. For example, if retroviruses are used as vectors, the genetic material gets integrated into the subject’s genome. If adenoviruses are used, DNA is introduced into the nucleus of the cell, but the DNA is not integrated into the genome (Handbook, 2013).

Non-viral vectors can also be used for gene therapy. Free plasmids can be delivered into the cells using physical methods such as: electroporation, gene gun, ultrasound and hydrodynamic pressure. Non-viral methods were at a disadvantage because of their low efficiency, but with the development of more efficient vector technology, non-viral vectors are becoming more popular; they can reduce problems that occur while using viral vectors such as endogenous virus recombination, oncogenic effects and unexpected immune responses (Huang & Niidome, 2002).

Biosafety & Bioethics

As promising as gene therapy appears, there are many biosafety issues that it raises. The indisputable concerns are whether transferring genes is safe and whether the transferred genes could lead to harmful effects. Technical issues also exist. For example, the use of retroviruses raised criticism from the start. Because of transgene integration that can cause mutations, the use of retroviruses is considered most dangerous for patients. The main argument against gene therapy is that in the worst scenario, unexpected changes in the genetic makeup of the gene therapy patient may be passed down to offspring. To refute this argument, some scientists say that other therapies such as mutagenic drugs and radiation therapy can also cause genetic alteration that can be passed down to offspring. They argue that these therapies are being used without extensive biosafety concerns (Wirth, Parker & Ylä-Herttuala, 2013).

Bioethical issues are also a great concern surrounding gene therapy. The first concern is that there is no clear boundary on what is a “good” or “bad” use of gene therapy. It is also very hard to determine what traits are normal and which traits should be considered as disorders. Gene therapy might also be used not only to cure a disease, but also to enhance basic human traits such as height and intelligence causing social disparity between the poor and the rich (Handbook, 2013).

Our Project & Gene Therapy

With the background information mentioned above, we have investigated the application of gene therapy for our project. It seems like gene therapy is a feasible method to deliver desired genes into target human cells. Currently, gene therapy, however, is only tested and used for incurable diseases such as cancer and rare genetic diseases (Handbook, 2013). The complication that we want to alleviate, obesity, at this current stage of scientific research is not considered an incurable disease. In fact, many people do not even consider obesity as a disease. The severity of obesity, nonetheless, is slowly being recognized by the scientific community and, in June 2013, the American Medical Association decided to classify obesity as a disease (Dailey, 2013).

Application of gene therapy for our project is indeed an invasive method to treat obesity. Presently, many people will be reluctant to use this method unless obesity and its complications are life threatening (Yu, 2013). On the contrary, other methods currently used to cure diseases such as medicine and surgery are also invasive. The difference is that these invasive techniques have gained enough trust from public through clinical trials and tests. If gene therapy becomes safer and publicly accepted and if the severity of obesity constantly increases, the use of our project through gene therapy does not seem very improbable in the future.

Conclusion

Gene therapy is a promising method to cure diseases. Although the public currently has doubts about it, scientists are eagerly trying to make it safer and more efficient. In the future, when gene therapy becomes more accepted by the public, we speculate that this method would begin to be applicable for obesity, as more and more people recognize the severity and pathology of obesity.

References

Dailey, K. (2013, June 25). Obesity is a disease in the us. should it be?. BBC. Retrieved from http://www.bbc.co.uk/news/23011804

"Handbook." Genetics Home Reference. U.S. National Library of Medicine, 23 Sept. 2013.

Huang, L., & Niidome, T. (2002). Gene therapy progress and prospects: nonviral vectors. Gene Therapy,9(24), 1647-1652. Retrieved from http://www.nature.com/gt/journal/v9/n24/abs/3301923a.html

Pearson, S., Jia, H., Kandachi, K. (2004). China approves first gene therapy. Nature Biotechnology, 22, 3-4.

Wirth, T., Parker, N., & Ylä-Herttuala, W. (2013). History of gene therapy. Elsevier-Gene, 525(2), 162-169. Retrieved from http://ac.els-cdn.com/S0378111913004344/1-s2.0-S0378111913004344-main.pdf?_tid=42ad73a2-108c-11e3-a4a5-00000aab0f6c&acdnat=1377768215_ab7a2ccc7dc6f1f218759a92fccfc8ba

Yu, C. H. (2013, July 16). Interview by J.H. Lee ]. HKUST iGEM 2013 team informative interview with Professor Yu.