Decoding genetic diseases through synthetic biology
In 2016, Singapore declared war on diabetes. Despite this call to action, and the resulting public awareness of the importance of a healthy lifestyle, the disease continues to be a major health issue and economic burden on the nation.
Diabetes is a chronic metabolic syndrome that results from the body’s inability to produce, or respond to, a hormone called insulin, which regulates the human body’s blood sugar levels. An estimated 90 per cent of diabetes patients suffer from the preventable Type 2 diabetes (T2D), meaning that although their bodies produce the hormone, it is ineffective at maintaining healthy blood sugar levels. When left untreated, T2D can lead to several complications including heart disease, kidney failure, high blood pressure and stroke. In some severe cases, diabetic neuropathy — nerve damage due to diabetes — will require limb amputations.
As one of 22 countries in the International Diabetes Federation (IDF), Singapore is at the front line in the global effort to treat and manage this health issue.
According to the IDF, there were over 600,000 cases of T2D in Singapore in 2017 and this number is expected to surpass 1 million by 2050. This creates a substantial economic burden on both patients and society. By 2050, it is expected that medical costs and lost productivity will amount to an excess of $1.8 billion.
According to a recent World Health Organization (WHO) report, certain racial backgrounds are predisposed to developing T2D, including American Indians, Asian-Americans, and Chinese. South and East Asians are also particularly affected by T2D.
Within Singapore, a racial link to disease susceptibility is also evident, with T2D being more prevalent among Indian (17.2 per cent) and Malay (16.6 per cent) populations, compared to those of Chinese decent (9.7 per cent). There is also strong evidence of diabetes running in families, whilst environmental factors, obesity and lifestyle also contribute to the disease. Indeed, genetics has long been implicated in the racial predisposition to the disease; however, it remains unclear exactly which variations in DNA impact how the body responds to insulin to metabolise sugars in the blood.
Now, researchers from NUS are taking the war on diabetes to a new level – they are seeking innovative ways to better understand the genetic causes of the disease. To do this they are turning to an emerging field of biomedical science known as 'synthetic biology'.
This interdisciplinary field, where biology meets engineering, has made significant progress in recent years developing what are known as 'human artificial chromosomes'. These chromosomes, assembled in yeast or bacterial cells, combine various elements from human DNA into a single 'library'. Once assembled, they are transferred into lab-grown mammalian cells, which allow researchers to assess how various elements and mutations interact and alter a cell’s behaviour or response.
At NUS, efforts are now ongoing in the lab of Associate Professor Matthew Chang, Director of NUS Synthetic Biology for Clinical and Technological Innovation, to create a yeast artificial chromosome. This technology could one day be transferred to create human artificial chromosomes that could unlock the secrets of various genetic based diseases.
“We believe that such technologies will be instrumental in improving our understanding of the genetic links to diseases such as Type 2 diabetes,” said Assoc Prof Chang.
Currently there are over 100 variations involving individual building blocks of DNA (nucleotides) that are associated with T2D. As Assoc Prof Chang explained, artificial chromosomes that contain all of the known single nucleotide variations in genes linked to glucose metabolism and insulin resistance, and that are present in local populations may soon be developed. These artificial chromosomes can then be introduced into cells grown in the lab, thereby providing researchers with a platform that reveals the functional relationship between specific genetic variations and diseases such as T2D.
Assoc Prof Chang and his colleagues believe that innovative methods grounded in synthetic biology are necessary to tackle complex diseases such as T2D.
It is hoped that through these continued efforts, tailored interventions and improved diagnostics can be delivered to T2D patients. This, along with necessary lifestyle changes and public engagement efforts, we could finally see victory declared in the war on diabetes.
