Cell Signaling, Genetic Projects, and the RAS Pathway

Gene Selection and Case Study Project

• The project involves creating an Original Project (OP) or Case Study based on a specific gene.

• Gene Selection Criteria:

  • Students must choose a gene to research its function and health relevance.

  • The lecture encourages selecting genes associated with high-risk health conditions.

  • Preference is given to genes related to premature aging diseases, Alzheimer’s disease ($AD$), or Parkinson’s disease ($PD$).

  • While cancer genes are an option, the instructor is selective about teams choosing cancer because it is often an ‘easy go-to’ topic. If cancer is chosen, it should involve less common types or specific pathways.

• Project Components:

  • Background and Patient Profile: Students must write a background based on research but applied to a fictionalized patient. The patient can be named, and students are encouraged to use creativity in developing the patient's narrative.

  • Phenotype and Genotype: The case study must clearly discuss the connection between the patient's genotype (genetic makeup) and phenotype (observed characteristics/symptoms).

  • Treatment Plan: Based on the research, students must develop a hypothetical treatment plan for their patient.

• Sign-up Process:

  • A sign-up sheet will be posted.

  • Selection is on a first-come, first-served basis to avoid multiple groups presenting on the same topic (e.g., preventing four groups from all presenting on breast cancer).

Public Health Announcement (PSA) Requirements

• The second part of the project is to create a public service announcement (PSA) or a public health announcement.

• Goal: Communicate scientific information to a general audience without using excessive scientific jargon. The information should be clear and accessible to ‘the person off the street.’

• Media Formats: The announcement should be approximately $1$ to $2$ minutes long. Options include:

  • A short video or animation.

  • A podcast or audio PSA.

  • A digital poster (e.g., created using Canva).

  • A social media mock-up.

• Content Guidelines:

  • Use statistics and data to support the claims, but present them in an aesthetically pleasing and understandable way.

  • Avoid relying on AI to generate the content; students must use their own ideas and feed their specific research into any tools used.

  • The focus is on making the public aware of the chosen gene and its health implications.

Principles of Cell Signaling and Signal Transduction

• Signal Transduction: This process refers to how cells communicate and respond to external signals. There are typically three main parts to a cell signaling pathway.

• Receptor Types:

  • Membrane-bound Receptors: These are located on the cell surface. They interact with a signal molecule called a ligand.

  • Intracellular Receptors: These are located inside the cytosol. An example is the estrogen receptor ($ER$).

• Mechanism of Signaling:

  • A signal molecule ($‘ligand’$) travels from the outside of the cell and binds to a receptor.

  • The signal is then relayed through the cell, eventually reaching the nucleus to trigger a response.

  • The human body contains over $200$ different cell types, all of which are constantly performing these signaling processes.

Protein Chemistry and Phosphorylation

• Signaling pathways often involve protein chemistry and post-translational modifications, such as acetylation or the addition of sugars (glycosylation).

• Phosphorylation: This is a primary method for activating proteins within a signaling pathway.

  • Kinases: These enzymes add phosphate groups to proteins to activate them.

  • Phosphatases: These enzymes remove phosphate groups, thereby deactivating the protein.

• Energy Requirements: Phosphorylation requires Adenosine Triphosphate ($ATP$).

  • For every phosphate group added, one molecule of $ATP$ is used, yielding inorganic phosphate ($P_i$).

  • Example: If a protein requires $8$ phosphate groups for autophosphorylation, it requires $8 \times ATP$.

• Structural Domains: Signaling proteins have distinct parts located outside the cell, in the middle (transmembrane), and on the inside of the cell to facilitate the relay of messages.

Intracellular Receptors: The Estrogen Receptor

• The estrogen receptor is found in the cytosol and functions as a transcription factor once activated.

• Mechanism of Activation:

  • The hormone (ligand) binds to the receptor protein.

  • Binding causes the protein to undergo a conformational change (it changes shape).

  • This shape change ‘locks in’ the hormone and releases specific domains of the protein, allowing it to signal.

• Biological Impacts: Over time, these signals can level off. This process is relevant to:

  • Menopause in women.

  • Health of the mammary glands and uterus in women.

  • The prostate gland in men.

Clinical Genetics and Personalized Medicine

• Doctor Barnabas’s Perspective: As a developer of molecular tests and an advisor to physicians, Dr. Barnabas emphasizes that medicine is not ‘one size fits all.’

• Patient Variability: In clinical settings, patients are categorized as ‘responsive,’ ‘not responsive,’ or to be treated ‘with caution’ based on their genetic makeup.

• Molecular Biology in Diagnosis: Understanding pathways and genes allows clinicians to identify the ‘problem areas’ that cause disease. This knowledge helps in determining whether to inhibit or induce certain proteins or even use genetic engineering to fix aberrations.

• Side Effects and Error Prevention: Dr. Barnabas shared an anecdote about a patient at risk for blood clots where a cardiologist failed to account for the patient's specific genetic aberrations before prescribing medication. Reading the medical chart and understanding molecular biology are critical for safety.

MAP Kinase Cascade and the RAS Pathway

• The Receptor Tyrosine Kinase ($RTK$) cascade is one of the most studied signaling pathways and is implicated in various aging diseases.

• Key Proteins:

  • RAS: A small GTPase that initiates the pathway. It is considered a ‘molecular switch.’

  • RAF (including BRAF): Activated by RAS.

  • MEK: Activated by RAF.

  • ERK: Activated by MEK.

• Cellular Response: This pathway is essential for cell growth, proliferation, survival, and repair. Every cell in the body utilizes this pathway.

• RAS and Cancer:

  • Approximately $30\%$ of all human cancers are driven by mutations in the $RAS$ gene.

  • Mutations can ‘lock’ RAS in the active (phosphorylated) position, causing it to signal constantly for cell growth even without a ligand.

  • Druggability: For decades, $-RAS-$ was considered ‘undruggable’ because its protein shape made it difficult for drugs to bind. Recently, a drug was developed that successfully binds to $RAS$ in pancreatic cancer tissue.

Questions & Discussion

• Student Question: "I had a question on the estrogen receptor negative breast cancer. Yeah. What do you mean when it's not controlled by estrogen? Does it mean…"

• Instructor Response: Estrogen receptor negative ($ER-negative$) breast cancer means the cancer growth is not driven by the estrogen receptor pathway. There are many different pathways that can be perturbed to cause breast cancer. Clinicians must diagnose the specific subtype (e.g., triple-negative breast cancer) to ensure the treatment is tailored correctly. For example, if the $ER$ is not mutated but another aberration exists in a different signaling route, that alternative route is what must be targeted.

• Discussion on Isoforms: Isoforms refer to different versions of proteins produced from the same gene (one gene, many transcripts, many proteins). Proteins in the same family do not necessarily perform the same function or activity within these signaling pathways.

Administrative Details and Field Trip

• Saturday Field Trip:

  • Mandatory for residential students (unless a parent email or sign-out is provided to Brian).

  • Optional for commuting students.

  • Schedule: Meet at $9:00\,AM$; depart around $9:15\,AM$.

  • Itinerary:

    • Part 1: Visit the pier to see sea lions and shops.

    • Part 2: Visit the Exploratorium for science demonstrations.

  • Return: Back before dinner.

  • Action Item: All students must fill out the provided form regardless of attendance.

• Project Sign-ups: Students should choose partners and sign up for their genes as soon as possible to secure their topic.