Team:Evry Paris-Saclay/HP/Annexe/Giovana

IGEM Evry Paris-Saclay


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Background on Biomanufacturing

The use of living organisms to produce goods and services is not new. Men have, since the dawn of humanity, used microorganisms to produce fundamental or accessory goods such as bread, yogurt or alcoholic beverages. Before Pasteur and the acknowledgment of the existence micro-organisms, the use of micro-organisms is purely empirical, then these living organisms started being use in an industrial perspective. It’s only after the second world war that Biotechnology and Biomanufacturing as we know it started to develop. Biomanufacturing uses biological systems to obtain at an industrial level, biomolecules. Those compounds are then used in the medical, food and beverages or industrial fields enabling us to produce growth factors, amino acids, antibodies, vaccines, enzymes and so on. Thus, the efficiency and accuracy of bioproduction is a social issue that must be supported and perfected constantly. This process rests primarily on the effectiveness of enzymes allowing such production. For those reasons, for each one of them a rigorous and arduous characterization has to be made. To this day, this work uses tools like mass spectrometry or high-performance liquid chromatography making it incredibly expensive.

Project application

In light of these facts, the Team of IGEM Evry Paris Saclay has decided to develop a new solution that could be a game changer: a Biosensor-based Screening method. This sensor is a simple genetic construct divided in two parts: a sensing module that is a specific transcription factor (TF) for the molecule of interest recognition and a reporter module activated by this TF that would correlate the amount of sensed molecules to the efficiency of the producing enzyme thanks to a fluorescent signal detected by FACS or Plate Reader. This method would be easily adaptable to screen all kind of enzyme, as long as there is an specific TF for the molecule to screen, and allow a certain time saving as soon as the modules are effective. In the case of a single process, a compared analysis of enzymes efficiency would also be a way to maximize production. As a whole, this process would enable industries to produce more quickly and if possible in larger quantities. It goes without saying that this optimization will be beneficial both for the industries that would lower their production costs for the consumers that would see the price drop on some medicine and food.

The controversy surrounding sugar

In order to create an accurate Bioscreening method, we needed to create a proof of concept. Hence, we decided to focus our study on sugar as its consumption is a major social health issue. Worldwide, the increasing burden of Obesity and Diabetes is worrisome, just like the increase chronic disease levels. Since the end of the twentieth century, and the beginning of “sugar’s trial”, we quickly discovered that sugar is not only the primary cause of tooth decay but is also involved in acute obesity, diabetes, cardiovascular diseases or even dementia. As a matter of fact, the real problem is not sugar in itself though, it is our level of consumption, for example, studies show that the average American consumes 22 teaspoons of sugar per day. And, so we are clear, we are not talking, but 22 teaspoons of added refined sugars which represents 3 times the sugar adult needs in a balanced diet.

In light of this facts, the food and beverage industry started to replace sucrose with artificial sweeteners. Primarily, aspartame and sucralose which are the most used alternatives were marketed as an alternative that could help weight loss, dental decay, diabetes or reactive hypoglycemia.

Ironically enough, the effect that we were trying to avoid with sucrose came running back as people who consumed diet soda were more likely to gain weight than those who consumed naturallysweetened soda. (University of Texas Health Science Center at San Antonio) What was the reason for that? Just like sugar, consuming an artificial sweetener causes the release of insulin. But unlike sugar though, artificial sweeteners cannot be stored leading to an hypoglycemia state which increases the food uptake and ultimately body gain. Moreover, Aspartame for example decomposes during its catabolism in methanol which is a highly neurotoxic substance causing among others metabolic acidosis and ocular toxicity.

However, there was an alternative many of us have never heard of: Psicose. Also called D-allulose, this very low caloric natural sweetener. 70% as sweet as sugar is proved to have health benefits such as hypoglycemic controls, improving insulin resistance and antioxidant enhancement. Too good to be true? Well, while this monosaccharide has been known for quite a while now, it’s only present in really small quantities in natural products which makes it extremely rare and expensive. Luckily enough, Psicose appears to be an epimer of Fructose and enzymes (five) that can transform fructose (easily extractable) into D-allulose has already been identify in A. tumefaciens, C. cellulolyticum, F. plautii, P. cichorii. To this day, the process is not efficient enough for a large-scale distribution which makes Psicose unviable to the food and beverages industry to use as a sweetener alternative.

By creating an Biosensor-based Screening as depicted earlier, we aim to identify, a mutated enzyme efficient enough to offer an enhance Psicose’s production and lower its cost. The Bio-production of Psicose is catalyzed by Psicose Epimerazes from Fructose. Indeed, Psicose is an epimer of Fructose, which means that both sugars are almost identical but different from the position of one simple carbon, offering all these properties to Psicose. To achieve this bio-production efficiently, we aim to provide a large bank of mutant epimerazes modifiying their transformation site to enhance Psicose bio-production. All we need to at this stage is to screen for the best producing enzyme.

Food for our health

As we said earlier, our consumption of sugar cannot stay this way, it’s a matter of public health. But the transition to a less sugary diet is not an easy thing to do. Because yes, it is everywhere. Cakes, yogurt, sugary beverages are, as expected, loaded with unhealthy amounts of sugar but it’s also in BBQ sauce, ketchup, salad dressings and soups. And just like drugs, the more you eat it the more you want it: food and even more so sugar, is a natural reward which activates reward pathways associated with the reward system. Sugar such as drugs, activates this cerebral system producing dopamine triggering this feeling of pleasure and addiction. High consumption of sugar leads to remaining modifications of this dopaminergic system causing troubles and neuropsychological disorders that can cause diabetes and obesity (positive neuropsychological reactions leading to obesity).

By switching partially Sucrose or its artificial alternatives for Psicose we would be able to maintain a diet with healthy amounts of sugar.

Thanks to its metabolic proprieties, Psicose turns out to be of incredible help for those struggling with diabetes especially concerning its property to maintain balance glycemia which allows control of postprandial hyperglycemia and preservation of normal glycemic levels. This is of critical importance when it comes to diabetic patients, as, by consuming foods using this natural sweetener instead of sucrose, it will prevent metabolic problems as well as enabling patients to have a less restricted everyday diet: fewer risks for a more normal life.

Moreover, studies show that the consumption would not only help ex post but also prevent the development as well as the progression of type II diabetes. Indeed, a reducing inflammation of pancreas β-cells thus protecting the normal secretion of insulin. Indeed, there is a clear correlation between sugar consumption (especially in the case of sugary beverages) and the appearance.

The low caloric ratio of Psicose would be of great value to help decrease the dramatically high level of obesity. Indeed, in 2014 13% of adult over 18 were struggling with obesity worldwide. Though to be a western issue only, obesity turns out to be of global impact as the number of children overweighed or living with obesity has double in Africa since 1990. In Asia, half the children under the age of 5 were considered overweighed or obese in 2014. The important thing to keep in mind is the avoidability of this phenomenon. Joined to a healthy lifestyle, a balance diet would prevent and decrease obesity worldwide. As a fact, on the WHO recommendation against Obesity is to reduce calorie intake from fat and sugar. By making sure Psicose is not only available but also economically viable as a whole would provide a healthy alternative to regular sugar.

Food for our soul

A palatable diet, without being hyperpalatable, has been proven to be beneficial. As stated earlier, the intake of “tasty” food results in the activation of our reward system and has the tendency to lower our cortisol level acting as a stress reducing factor. If this characteristic can lead to food addiction, the fact is that increase restraint in our food uptake might, on the other hand, play an important role in promoting overreaction. In other terms, restriction and deprivation from a particular food may deplete our cognitive abilities to deal with stress factors acting as a vulnerability in our reward system. These periods of high restriction are thus usually followed by binging causing an increased risk of obesity.

For those reasons, cutting all palatable, and sweet foods for that matter wouldn’t be advised on a regular basis. Using, even partially, Psicose as an alternative sweetener would prevent parts of the negative aspects of other sugars without creating a complete restraint in our sugar intake limiting the risks of frustration and food induced stress. By making the production process more efficient hence, economically viable, our project would help to meet the recommendation of a 20% decrease of sugar consumption.

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