Life is in the center of existence, and food is in the center of life. All living things are in pursuit of their sustenance to continue their lives. Failing this pursuit means the end of it all. Yet, it is not only the lack or scarcity of food, but also its abuse that is a major cause for disorders. Consuming food without any criteria of lawfulness, or with no heed to virtues like contentedness or gratitude, but with greed and wastefulness, leads to many health problems – mental and physical – at both individual and societal levels. Among these problems are many notorious eating disorders such as obesity, anorexia, and bulimia nervosa. Illnesses that relate to overeating, such as obesity, are now beginning to be considered as food addictions, even as a type of substance abuse, in some medical literature [1].

One serious consequence of eating and food addictions is a clinical condition that is called “metabolic syndrome” (MetS). Characterized by multiple cardiovascular disease risk factors such as obesity and high blood pressure, this syndrome has been recognized as a crucial public health problem worldwide. Characteristics such as geography, race, age and gender are influential in the frequency of the disease, which spreads daily as a pandemic that affects approximately 20-30% of the global adult population [2]. Among US adults aged 18 years or older, the prevalence of metabolic syndrome rose by more than 35% from 1988–1994 to 2007–2012, increasing from 25.3% to 34.2% [3].

First described by Dr. Gerald Reaven, MD, in 1988, metabolic syndrome is also referred to as “insulin resistance syndrome,” “deadly quartet,” and “civilization syndrome” [4]. In 2001, the Adult Treatment Panel (NCEP-ATP III) defined metabolic syndrome in adults as the combination of central obesity (waist circumference >102 cm in men, >88 cm in women), hypertriglyceridemia (>150 mg/dl), low HDL (<40 mg/dl in men, <50 mg/dl in women), hypertension (blood pressure> 130-85 mm-Hg), and hyperglycemia (fasting blood sugar >110 mg/dl). In 2005, the International Diabetes Federation (IDF) published a global guideline describing different thresholds for different ethnic groups. According to this guideline, the diagnosis of metabolic syndrome should be based upon central obesity and high triglyceride, low HDL, high blood pressure, and high fasting glucose. The IDF also reported that the presence of at least two factors sufficed for diagnosing anyone as a patient of metabolic syndrome.

as one of the likely pathological findings in metabolic syndrome, central obesity is observed in one in three adults. Hypertension, another crucial factor, is generally acknowledged to be originating from insulin resistance in metabolic syndrome, but the actual features of its development mechanism still remains controversial. Global awareness about hypertension, its treatment, and how to control it is low, and there are significant differences in between people worldwide. A National Health Examination Survey (NHANES) spanning 2011-2014 revealed that 34% of US adults aged 20 years and older are hypertensive and NHANES 2013-2014 data showed that 15.9% of these hypertensive adults are unaware they are hypertensive [5].

Dyslipidemia, which increases as a result of central obesity and insulin resistance in patients with metabolic syndrome, is characterized by low HDL cholesterol and high triglycerides, the most crucial factors that increase the risk of cardiovascular disease. In one study done in 2008, the average total cholesterol levels for American men and women were found to be 197 mg/dl [6].

The presence of overt diabetes or impaired glucose tolerance (fasting blood sugar above 110 mg/dl) indicates the first step of the diagnostic criteria of the metabolic syndrome, and insulin resistance is not sought for further. People diagnosed with metabolic syndrome are 2.34 times more likely to contract diabetes [7]. A 2011 study conducted in America reported that roughly half of all adults have impaired glucose metabolism as a result of type 1 diabetes, type 2 diabetes, and prediabetes. Diabetes has been a prevalent global ailment similar to asthma, autoimmune diseases, and cancer [6].

Insulin resistance, which can be observed in metabolic syndrome, increases the risk of cardiovascular disease by 2.35 times, deaths by cardiovascular disease by 2.40 times, risk of myocardial infarction by 1.99 times, and stroke by 2.27 times, as independent of other risk factors. However, the presence of metabolic syndrome, not obesity, increases the risk of cardiovascular disease [7]. Another significant result is that women with metabolic syndrome have a higher risk of cardiovascular disease than men. Women are more likely to have central obesity than men, have a different cholesterol profile, and higher triglyceride levels that cause more coronary artery disease, while polycystic ovary syndrome, hormone support therapies, and pregnancy diabetes pose additional risk for women [8]. Fatty liver disease, cirrhosis, chronic kidney disease, polycystic ovary syndrome, gout, dementia, and decreased cognitive functions are more common in individuals with metabolic syndrome than the normal population [7].

Treatment of Metabolic Syndrome

Since metabolic syndrome is caused by environmental and genetic factors, and is appearing in people with increasing frequency, the best treatment approaches involve a well-regulated lifestyle, with the main objective being to prevent diabetes and cardiovascular diseases that cause fatal or disabling conditions. Weight loss that results from an appropriate nutrition and exercise program has a corrective effect on almost all disorders observed in metabolic syndrome.

In the treatment of metabolic syndrome, prevention of central obesity seems to be a priority solution. This can be achieved by a lifestyle planning that provides and maintains a 7-10% reduction in total body weight by limiting caloric intake and increasing physical activity. Even methods that increase weekly physical activity by 150-300 minutes and provide only a 5-7% reduction in body weight are considered sufficient to correct the metabolic syndrome. This has especially been reported to have a positive effect on lipid disorders, glucose intolerance, and hypertension, with a 58% reduction in the risk of diabetes with additional lifestyle changes [9].

Since a well-regulated diet is one of the focal points of life style change for people with metabolic syndrome, dietary models that are limited to saturated fats and cholesterol, rich in complex carbohydrates, based upon an abundant consumption of fruits and vegetables, and a restricted use of salt (for those with hypertension) are strongly recommended.

Even though the traditional Mediterranean diet is lauded as one of the vibrant treatment options in the prevention of coronary heart disease and metabolic syndrome, it is not sufficient to correct the metabolic syndrome unless the diet is in tandem with significant weight loss [10]. According to numerous studies, increasing the consumption of nutrients such as fish, vegetables, fruits, dried legumes, and unrefined grains that are rich in olive oil, omega-3 fatty acids, and antioxidants reduce the risk of coronary diseases and death. It goes without saying, that smoking and alcohol use may increase cardiovascular, metabolic and hepatic complications in patients with metabolic syndrome.

Patients with metabolic syndrome should have their blood lipids checked annually, and should be determined to keep low-density lipoprotein (LDL) cholesterol lower than 100 mg/dL, high density lipoprotein (HDL) cholesterol higher than 40 mg/dL, and triglyceride levels lower than 150 mg/dL. Diabetic patients should set their blood pressure target as lower than 130/80 mm-Hg. Changes in lifestyle such as regular exercise and a controlled diet are extremely vital. The use of low-dose aspirin to prevent complications in patients with coronary artery disease is also among treatment recommendations.

The basic sustenance that is provided to us in the form of fruits, animals, grains, and other bounties is such a precious, rich and full-fledged treasure, for which we should be grateful for. However, gluttony and wastefulness pave the way for thanklessness, disease, and even conflicts with the wisdom in the universe.

Almost all living beings are engaged in the pursuit of sustenance and revolve around this goal. We humans have been equipped with the ability to taste and appreciate all kinds of food, and can draw an appreciation for the Divine through these gifts. Just as everything revolves around sustenance, thankfulness has been placed in the center of sustenance. That is, gratitude should be at the center of all sustenance. Through gratitude, we live healthier physical, spiritual, and mental lives.

Notes

1. Meule A, Rezori V, Blechert J. Food addiction and bulimia nervosa. Eur Eat Disord Rev. 2014;22:331–337.
2. Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol 2008; 28: 629-36.
3. Moore JX, Chaudhary N, Akinyemiju T. Metabolic Syndrome Prevalence by Race/Ethnicity and Sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. Prev Chronic Dis 2017;14:160287
4. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-53.
5. Alexander, Matthew R.; Eric H. Yang. “What is the prevalence of hypertension (high blood pressure) awareness of in the US?” https://emedicine.medscape.com/article/241381-overview#a2
6. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011.
7. Balcı M.K, Metabolik Sendrom, Türkiye Klinikleri J Med Sci 2008;28:102-106.
8. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010; 56: 1113-32
9. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403
10. Carbonneau É1, Royer MM2, Richard C3, Couture P4, Desroches S5, Lemieux S6, Lamarche B7. Effects of the Mediterranean Diet before and after Weight Loss on Eating Behavioral Traits in Men with Metabolic Syndrome. Nutrients. 2017 Mar 19;9(3).

Almost all of us are familiar with the fact that our bodily organs are composed of tissues, which are made of cells. The perfect machinery of the cells is controlled by our genes; i.e. DNA and RNA. Therefore, a minor defect or mutation in the genetic code may affect either partial or entire systems within the body. Some of these genetic diseases are inherited from our parents or relatives. Others may be introduced into our body through environmental mutagens, such as ionizing radiation, ultraviolet rays, or different chemicals within our food and drink; these can result in cancer or cardiovascular diseases. We can protect ourselves from the latter by using appropriate outfits, taking care with our diet, etc. However, inherited genetic disorders are usually unavoidable and sometimes have fatal consequences. Modern medicine is striving to find a way to treat these diseases. Although there are some medical procedures that may lessen the pain of patients or extend their life expectancy, there is no available comprehensive curative therapy for genetic disorders.

Gene therapy has become one of the rising stars in the field of molecular medicine during the last decade, with more than 1500 proposed or ongoing clinical trials worldwide. Gene therapy promises to provide curative therapies for a large number of inherited or acquired diseases, such as monogenic disorders, cancer, or cardiovascular disease. Gene therapy is universally defined as the replacement of an abnormal/dysfunctional gene in the cells of an individual with its correct and functional version. Mechanics use a number of tools to fix our cars for us when they give us trouble; in the same way, gene therapy can be used by doctors to alleviate or completely eradicate some diseases from our bodies.

Gene therapy is classified into two categories based on the target cells that are to be treated. The transduction of the differentiated cells of an individual, i.e. the somatic cells, is known as somatic gene therapy; the transduction of reproductive cells, i.e. gametes (sperm or ova), is known as germ-line gene therapy. Currently, there are many regulations in place that limit the likelihood of the modification of the germline in any gene therapy approach. This is because fear exists that the ability to alter the germline will result in the widespread application of gene therapy to achieve eugenic genetic enhancements, such as improvement of intelligence or physical characteristics. On the other hand, transgenic animals, which are used to detect the function of the genes within an organism, can be generated by modifying the germ-line. Furthermore, gene therapy is also classified into two groups: adult and fetal (in utero) gene therapy, according to the individual to be treated. There are several advantages and disadvantages to these methods, such as immune response, the pooling of mitotic cells, the amount of vector that is required, etc.; however, these are matters for a different article.

Gene therapy is achieved by using special exogenous genetic material transfer agents which are called vectors; these can be compared to the special tools used by auto mechanics. Over the years, a number of gene transfer vehicles, i.e. vectors, have been developed and these can be divided into two principal categories: non-viral (synthetic) and viral (virus-based) gene delivery systems.

Non-viral gene transfer can be achieved by using both physical and chemical methods. The physical methods include: i) Electroporation, in which areas of the cell membrane break down as result of an applied electric pulse, thus allowing DNA to enter the cell, ii) Ballistic gene transfer (the Gene Gun), which bombards particles coated with DNA into the cells, and iii) Microinjection, in which DNA is transferred through microcapillaries into the cells [1]. In terms of chemical gene transfer, lipofection is the most promising method; in this method negatively-charged DNA molecules bind to cationic lipid particles through electrostatic interaction and the DNA–lipid complex enters the cell through endocytosis/pinocytosis. Although these non-viral delivery systems exhibit low toxicity and can be easily produced in high concentrations on a commercial scale, in general, gene transfer using these agents is inefficient and often transient. Therefore, as a result of the viral vectors’ ability to efficiently deliver and integrate genes into the host genome, they are being engineered extensively to achieve a sustained and high-level expression of the gene of interest (transgene).

Viral vectors

Have you ever thought that one of the major pathological agents that cause catastrophic and even fatal diseases could be used to treat the same or a similar disease?

Viruses are equipped with specialized molecular mechanisms that allow them to efficiently transport the genomes into the cells they infect and use the cell’s machinery for their own reproduction. Molecular biologists first harnessed this machinery of transduction in the 1970s. Paul Berg used a modified SV40 virus containing DNA from the bacteriophage lambda to infect monkey kidney cells that were being maintained in culture. Viral delivery systems are based on replicating viruses that have the ability to deliver genetic information into the host cell, a process known as transduction [2]. Due to the fact that there are several advantages to viral vectors, these are the vehicles being employed in approximately 75% of all ongoing clinical trials worldwide. Numerous viruses are being used as the basis for the vectors, including, but not limited to, adenovirus (24%, n=377), retrovirus (20.9%, n=329), adeno-associated virus (4.3%, n=67), herpes simplex virus (3.2%, n=51), vaccinia virus (7.9%, n=124), poxvirus (5.8%, n=91), and baculovirus (more detailed information is available at www.wiley.co.uk/genmed/clinical). The first step to construct a viral vector for transferring the gene of interest involves the identification of the viral sequences that are necessary for replication and pathogenesis. Then some of the genes are removed to make room for the transgene and to render the viral vector replication-incompetent. Consequently, the vector is unable to replicate within the host, and therefore is safe for delivering genes to human cells or tissues (Figure 1).

There are advantages and disadvantages to all of the currently available vectors; the suitability of the vector, therefore, actually depends on the disease or condition that is being treated. For instance, if the goal of the gene therapy is to increase bone marrow engraftment with the transient expression of a growth factor, the use of chemical transfection or naked DNA transfer methods would suffice. However, if the objective is to provide long-term treatment for an inherited disease, then the use of an integrating viral vector is more desirable. Thus, a vector that might be ideal for treating one defect may not be ideal for another. Driven by the desire to develop the “perfect” vector, scientists are continually striving for novel forms of gene delivery that might become the “magic bullet.” Somia and Verma [3] have proposed that the ideal gene therapy vector should include all of the following properties: 1) easy production at a high titer on a commercial scale with a reasonable shelf-life for transport and distribution 2) sustained or regulated expression of the transgene product that is adjustable to the nature of the disease, 3) absence of immune response against the vector and the transgene product, 4) ability to target specific tissues and/or cell types while avoiding professional antigen-presenting cells, 5) absence of size limitations for the genetic material to be delivered by the vector, 6) site-specific integration of the transgene into the chromosome of the target cell to avoid insertional mutagenesis, or faithful division and segregation if it is to reside in the nucleus as an episome independent of local chromatin environments, and 7) an ability to infect dividing and post-mitotic cells. Unfortunately, none of the currently available gene delivery vectors carry all of these features; however, many vectors have enough of the attributes to make them promising for clinical use.

Candidate diseases

During the last 4 decades, gene therapy for many diseases has progressed from preclinical to clinical studies; these range from monogenic recessive disorders such as hemophilia and cystic fibrosis to more complex diseases such as cancer, cardiovascular disorders, human immunodeficiency virus (HIV), neurological and ocular pathologies. The prevalence of diseases that fall under the scope of gene therapy is enormous and most of them have catastrophic or fatal outcomes. Therefore, gene therapy approach for almost any of the diseases mentioned above has an obvious appeal and rationale. To date, more than 1,540 gene therapy clinical trials have been initiated, and these are continuing or have been completed in 28 countries, using more than 100 genes, including antigens, cytokines, tumor suppressors, growth factors, and deficiency genes [4].

Candidate monogenic disorders that are considered to be good candidates for treatment by gene therapy include the hemoglobinopathies, X-linked genetic disorders, amino acid metabolism disorders, and lysosomal and other storage diseases. Currently, there are more than 4000 monogenic diseases registered in the OMIM database. The ultimate aim in treating monogenic diseases with gene therapy is the correction of the disorder by the stable transfer of the functioning gene into dividing cells (stem/progenitor cells), which will ensure the permanence of the correction [5]. The first recognized successful clinical gene therapy trial involved the treatment of 11 children who suffered from SCID-X1 (Severe Combined Immunodeficiency), an X-linked inherited monogenic disorder caused due to a mutation in the common cytokine receptor gamma chain (&#947;c). In these patients, immunity was not fully developed due to the blocking of T-cell and natural killer cell development as a result of mutation. Unfortunately, the trial in SCID-X1 also exemplified one of the potentially serious side effects of gene therapy. Three of the children developed uncontrolled clonal T-cell proliferation, that is, leukemia, almost 3 years after treatment. This case was associated with the integration of the retroviral vector close to the promoter of the LMO-2 proto-oncogene. As a result, LMO-2 protein expression was up-regulated in an abnormal way and resulted in leukemia [7]. Another candidate monogenic disorder for gene therapy is cystic fibrosis (CF), in which abnormally thick mucus is produced in the lungs of the patients, causing difficulty in breathing and increasing the frequency of serious lung infections. CF is known as the most common inherited genetic disease in Europe and USA, especially within the Ashkenazi Jewish population. The average life expectancy of patients with CF is less than 40 years; hence the treatment of this disease has become one of the prime targets of gene therapy research.

In addition to its use in the treatment of monogenic diseases, gene therapy is also becoming a therapeutic alternative for the treatment of various forms of cancer. Indeed, almost 65% of ongoing clinical trials are related to cancer (more detailed information is available at www.wiley.co.uk/genmed/clinical), an area in which much more promise can be seen; this is also a reflection of the urgent need for new therapies to tackle the escalating incidence of this disease. Several different principles are used to treat cancer, including gene therapy that is targeted at tumor suppressor genes, such as p53, or central signaling molecules, as well as “suicide gene” therapy, in which the transgene is capable of converting pro-drugs (selectively less active drugs) into drugs that are toxic for tumor cells. Furthermore, various gene therapy protocols have been developed to strengthen the host’s anti-tumor immune responses by immunotherapy. Most of these studies have been early clinical trials designed primarily as studies of the safety, applicability, and toxicity of gene therapy. Several of these phase I and II studies have, however, shown partial remission of tumors and, in rare cases, complete remission. However, complete cure of the tumor has not yet been achieved. In some trials, including TP53 gene therapy trials, regression in tumor size has been observed in up to 50% of patients. China has become the first country to license gene therapy as a regular treatment for neck and head cancer; here Gendicine, a replication-defective Ad5 vector expressing p53 from a Rous sarcoma virus (RSV) promoter, is used for therapy [6].

In addition to its applications for cancer and monogenic diseases, gene therapy has become one of the favorite methods in cardiovascular research field. This is in step with the rise in clinical trials for cardiovascular gene therapy from 8.3% to 9.1% during the last few years, becoming the second most popular application for gene therapy. In accordance with the variety and occurrence of cardiovascular diseases, different gene therapy strategies have been developed to tackle each disease on its own terms. The expectation is that gene therapy will provide a new avenue for therapeutic applications in the growth of blood vessels, as well as the protection, regeneration, and repair of heart tissue, the prevention of the reoccurrence of constricted or narrowed arteries following cardiovascular intervention, the prevention of the rejection of a bypass, and risk-factor management [4]. Long-term therapeutic gene expression is required in some diseases, such as hypertension research, where reversal and prevention are the key targets. On the other hand, for some other types of cardiovascular diseases, such as ischemia, atherosclerosis, and restenosis, shorter-term gene control will be sufficient to prevent further progress of the symptoms. Therefore, different gene-therapy vectors have to be considered for the treatment of each specific cardiovascular disorder.

Consequently, gene therapy offers new avenues of treatment for diseases including monogenic disorders, cancer, cardiovascular diseases, infectious pathologies and many more. As we follow the tradition, “God did not send down any illness for which He did not also send a cure (Bukhari)”, gene therapy using either viral, non-viral, or any other novel methods may pave the way for the cure of many diseases that are highly prevalent in the world and which for decades have been perceived as untreatable.

Dr. Ferhat Ozturk is a postdoctoral research associate at University of Nebraska Medical Center.

References

1. Wells DJ. “Gene therapy progress and prospects: electroporation and other physical methods.” Gene Ther. 2004 Sep;11(18):1363-9.
2. Kootstra, N.A. and I.M. Verma, “Gene therapy with viral vectors.” Annu Rev Pharmacol Toxicol, 2003. 43: p. 413-39.
3. Somia, N. and I.M. Verma, “Gene therapy: trials and tribulations.” Nat Rev Genet, 2000. 1(2): p. 91-9.
4. Edelstein, M.L., M.R. Abedi, and J. Wixon, “Gene therapy clinical trials worldwide to 2007–an update. J Gene Med, 2007. 9(10): p. 833-42.
5. http://www.biomedisch.nl/en/gene_therapy_targeted_diseases.php
6. Peng, Z., “Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers.” Hum Gene Ther, 2005. 16(9): p. 1016-27.
7. Cavazzana-Calvo M, Fischer A, Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest. 2007 June. 117(6):1456-65