Project Description

Defining the Problem

Inspired by the urgency to rethink modern healthcare challenges, our team set out this year to tackle a condition often misunderstood and underestimated: obesity. Today, over 1 billion people worldwide live with this condition, including 650 million adults, 340 million adolescents, and over 39 million children, according to the World Health Organization. This number is expected to rise dramatically, with projections estimating that the global population affected by obesity will reach 2 billion by 2035.

Assessing the Impact

It is commonly associated with a diverse set of symptoms that can range from physical to metabolic and even psychological ones.

The physical symptoms include a significant increase in the patient’s body weight and the accumulation of excess adipose tissue. The sufferers are likely to experience shortness of breath and chronic fatigue due to alarmingly low energy levels. Moreover, obesity can cause joint and back pain attributable to the increased mechanical stress, while severe hyperhidrosis and even skin problems are considered quite common among patients.

From a metabolic and hormonal perspective, individuals with obesity often face significant endocrine imbalances. In men, this may include reduced testosterone levels, while in women, menstrual irregularities and infertility are common. In some cases, women may also develop Polycystic Ovary Syndrome (PCOS), a condition strongly associated with obesity-related insulin resistance and hormonal imbalance.

As a chronic disease, obesity can be commonly associated with a wide range of health complications such as various cardiometabolic disorders. For instance, it has been found that individuals suffering from obesity are susceptible to Type 2 Diabetes -Diabesity-, Hypertension, Dyslipidemia and increased risk of cardiovascular disease. A number of respiratory issues are also commonly attributed to obesity with Asthma and Obstructive Sleep Apnea growing in prevalence. Moreover, it is quite crucial that we mention the gastrointestinal and liver complications that patients may have to deal with. Such complications usually include Non-Alcoholic Fatty Liver Disease and Gastroesophageal Reflux Disease. Last but definitely not least, it has been found that obesity is linked to a subsequently higher risk of several types of cancer.

Obesity is also known to severely affect the patients’ mental health as it takes a serious toll on their self-esteem. Individuals are likely to suffer from mental disorders such as depression and anxiety, that can trigger emotional or binge eating episodes, while also having to battle the heavy social stigma that often comes with obesity.

Limitations of Current Strategies

Pharmacological Treatments: Effectiveness and Drawbacks

The currently available drugs for obesity fall into two categories: FDA-approved weight-loss medications and emerging therapeutic agents. The first category includes GLP-1 receptor agonists, monoamine modulators, and lipase inhibitors that mainly suppress appetite or reduce calorie absorption.

While these drugs offer measurable weight loss, they do not address the underlying causes of obesity and often require continuous administration, potentially leading to adverse side effects. Among the most commonly reported are gastrointestinal symptoms, including nausea, vomiting, and abdominal pain. Although less frequent, more serious complications such as pancreatitis, gastroparesis, and kidney disease, have also been documented.

The two primary limitations of current pharmacological treatments are, first, the significant weight regain observed following discontinuation, and second, the disproportionate loss of lean body mass relative to adipose tissue. Moreover, most of these drugs were originally approved for diabetes rather than weight loss, and their off-label use poses health risks for non-diabetic individuals, while also causing shortages for diabetic patients.

Experimental Therapies and Surgical Interventions

Emerging therapeutic agents, such as drugs targeting energy expenditure, adipose tissue browning, or gut microbiota, aim to tackle obesity more holistically, but remain largely experimental and unapproved.

Although bariatric surgery can lead to substantial weight loss, it is far from an ideal or widely applicable solution. It is invasive, carries non-negligible perioperative and long-term risks, and entails high costs. Additionally, a proportion of patients experience clinically significant weight regain as more time passes after surgery.

Our Approach: A Targeted and Lasting Solution

In contrast, our therapeutic approach introduces a novel and potentially long-lasting solution for obesity, with minimal side effects. Our strategy directly tackles the root neuroendocrine dysfunction underlying the disease, rather than merely suppressing appetite or altering nutrient absorption.

From Vision to Action: The Morphe Project

Obesity is frequently framed as a matter of personal willpower or appearance, an oversimplification that fuels stigma and obstructs effective care.Rather than managing symptoms, we chose to focus on the biological roots of this complex condition, leveraging the potential of synthetic biology to explore more effective and lasting solutions.

Our project began with a simple yet powerful question:

What if the body could be guided to heal itself?

"Morphe" is more than a scientific initiative, it is a call to reshape how we perceive obesity, health, and human transformation.

The name Morphe, drawn from the Ancient Greek "μορφή" (form, shape), reflects not only the physical structure of the body, but also the fluid nature of identity and our capacity for change. Inspired by Morpheus, the god of dreams who gave shape to the intangible, our project seeks to give form to possibility: a future in which obesity is addressed not through force or stigma, but through biological understanding, technological precision, and human compassion.

Morphe is a reminder that science can heal not only the body, but also the way we understand ourselves—and each other.

Engineering a Targeted Genetic Solution

The primary aim of Morphe is to develop a precision gene therapy that reverses pathological leptin resistance in diet-induced obesity (DIO) by selectively silencing histone deacetylase 6 (HDAC6) mRNA through an AND-gate–controlled shRNA.

Precision at the Core: Targeting HDAC6 in the Hypothalamus

This therapy specifically targets the arcuate nucleus of the hypothalamus, focusing on Agouti-related peptide (AgRP)–expressing neurons, which are key regulators of hunger and energy balance and exhibit dysregulated leptin signaling in obese individuals.

HDAC6 is overactive in DIO, interacting with and deactivating the leptin receptor (LepRb), thereby driving central leptin resistance despite hyperleptinemia. Silencing HDAC6 restores LepRb activity, enhances leptin signaling, suppresses hyperphagia, and induces weight loss without affecting lean mass, making it a validated node for anti-obesity intervention.

Precision by Design: A Dual-Sensing Genetic Circuit for Targeted Silencing

To achieve high specificity, our design employs a dual-promoter, split-intein transcription factor system, ensuring that the miRE-embedded shRNA is expressed only when both tissue and metabolic conditions are met.

The lentiviral construct features two independent promoters: one tissue-specific, active only in AgRP neurons, and one leptin-resistance–responsive that detects the pathological metabolic state. Each promoter drives expression of one fragment of a split-intein–fused transcription factor (TF). Upon co-expression, protein trans-splicing reconstitutes the active TF, which binds to response elements upstream of a minimal promoter controlling the miRE-based shRNA, thus triggering shRNA expression only under AND-gate conditions.

By implementing this strategy, we build a highly specific, tunable, and modular genetic circuit, minimizing off-target effects and ensuring tight regulation.

Therapeutic Delivery Approach

To bypass the blood–brain barrier non-invasively, Morphe employs intranasal spray delivery. Our genetic circuit will be delivered via a third-generation lentiviral vector, surface-modified with peptide ligands that selectively recognize AgRP neuron surface biomarkers, enabling targeted delivery to the hypothalamus.