Week 4 - L1 - Principles and Mechanisms of Personalized Medicine

Personalized medicine represents the culmination of the process of characterizing specific genes of interest and the proteins they encode. This information is leveraged to develop targeted treatment approaches tailored to the specific dysfunction identified at either the DNA or protein level.
This lecture, which is the final in the series delivered by Doctor Daniel Andrews for the course $VMS\,2062$ , is the $7^{th}$ lecture and focuses on the clinical and practical applications of these genomic insights.
The learning outcomes for this session include:
- Understanding the definition and objectives of precision (personalized) medicine.
- Identifying the methodologies used to achieve precision in medical treatment.
- Examining the role of biomarkers in personalizing medical care and how they can be leveraged.
- Reviewing specific examples of personalized medicines, focusing on their mechanisms of action.
- Developing scenarios for targeting DNA or protein levels in specific disease contexts, particularly Tuberous Sclerosis.
A practical application of these concepts will be required for the protein-based disease website assignment, where students must design a version of a personalized medicine treatment specific to a chosen genetic disease and its associated gene or protein.

Personalized medicine is a medical model that facilitates the customization of healthcare decisions and treatments based on the unique individuality of each patient.
To make these individualized decisions, healthcare providers require high-resolution information beyond standard clinical observations. This includes:
- Genetic Information: The primary focus of this lecture, involving the analysis of an individual's genome to identify specific variations.
- Lifestyle Information: Data regarding the patient's habits, diet, and daily routines.
- Clinical Signs and Symptoms: The specific physical manifestations of the disease in that individual.
- Environmental Exposure: The external factors and surroundings the patient has been subjected to.
All these components contribute to a comprehensive picture of the individual, allowing for a better-informed approach to assisting them with their specific disease presentation.

The core aim of personalized medicine is the selection of the most appropriate therapies for an individual to maximize the probability of a positive outcome while simultaneously reducing the risk of side effects.
It is a shift away from the "one size fits all" paradigm. A treatment that is highly effective for one person may be ineffective or even harmful to another. Identifying these differences through genetic variation allows for a tailored approach.
Pharmaceutical companies are increasingly utilizing genomic and other biological data to develop more targeted treatments under the personalized medicine umbrella.
The transition in pharmaceutical development involves:
- Moving away from observational studies where drugs are developed and then factors mitigating efficacy or causing side effects are identified post-hoc.
- Moving toward identifying genetic profiles first and then crafting therapies that are unique to those specific profiles.

A genetic profile in the context of personalized medicine can take several forms:
- A single genetic mutation.
- A set of similar mutations that result in a comparable dysfunction within a specific disease context.
- Patterns in a transcriptomics profile (RNA levels).
- Patterns in a proteomics profile (protein levels).
Once a genetic profile is established and the pattern of dysfunction is understood, there are two broad levels at which therapeutic intervention can occur:
- DNA Level Intervention: Attempting to correct the mistake or mutation at its source within the genetic code.
- Protein Level Intervention: Attempting to correct or mitigate the dysfunction after the protein has already been synthesized.

The Traditional Approach:
- Involves identifying a group of individuals with a common disease (e.g., a group of colon cancer patients).
- Administering a standard therapy or combination of therapies (e.g., standard chemotherapy).
- Observing the results, which typically fall into three categories: substantial benefit, minimal benefit, or adverse/toxic effects.
- Historically, this often results in cases where more than half of the patient group may not receive the desired beneficial effect.
The Personalized Medicine Approach:
- Begins with the same group of individuals diagnosed with a specific disease.
- Instead of immediate treatment, as much data as possible is collected through various tests, including genetic analysis, blood work, urine tests, and tissue tests.
- This data is used to differentiate individuals within the group, building a detailed picture of their specific biological similarities and differences.
- Clinicians then correlate this information with how effective known treatments are likely to be for those specific subgroups or individuals.
- Therapy is adapted based on this data, which may involve changing the specific drug used or adjusting the dosage.
- The ultimate objective is to ensure a higher percentage of the original group receives a positive effect from the intervention compared to the traditional model.

The lecture utilizes Tuberous Sclerosis as a primary case study for developing new personalized medicines.
Tuberous Sclerosis is caused by mutations in the $TSC1$ gene.
By understanding the specific mutations in $TSC1$ and how they translate to protein dysfunction, researchers can devise strategies to intervene specifically at the DNA or protein levels to treat the symptoms or causes of the disease.