What is the most likely biochemical mechanism for the disease causing the patient's symptom or physical examination finding?
This is the fundamental question that basic scientists strive to answer—the underlying cause of a certain disease or symptom. Once this underlying mechanism is discovered, then progress can be made regarding methods of diagnosis and treatment. Otherwise, our attempts are only empiric—in other words, only by trial and error and observation of association. Students are encouraged to think about the mechanisms and underlying cause rather than just memorizing by rote.
For example, in sickle cell disease, students should connect the various facts together, setting the foundation for understanding disease throughout their life. In sickle cell disease, valine (a hydrophobic amino acid) is substituted for glutamate (a charged, hydrophilic amino acid) in the sixth position in the β-globin chain of hemoglobin. This decreases the solubility of hemoglobin when it is in the deoxygenated state, resulting in its precipitation into elongated fibers in the red blood cell.
This causes the red blood cell to have less distensibility and, thus, to sickle, leading to rupture of the red blood cell (hemolysis) and blockage in small capillaries. The sludging in small capillaries leads to poor oxygen delivery, ischemia, and pain.
Which biochemical marker will be affected by therapy?
After a diagnosis has been made and therapy initiated, then the patient response should be monitored to assure improvement. Ideally, the patient response should be obtained in a scientific manner: unbiased, precise, and consistent. Although more than one physician or nurse may be measuring the response, it should be as carefully performed with little intervariation (one person to the next) or intravariation (one person measuring) as possible. One of the therapeutic measures includes serum or imaging markers; for example, in diabetic ketoacidosis, the serum glucose and pH levels would be measured to confirm improvement with therapy. Another example would be to follow the volume of a pulmonary mass imaged by computed tomography following chemotherapy. The student must know enough about the disease process to know which marker to measure and the expected response over time.
Looking at graphic data, what is the most likely biochemical explanation for the results?
Medicine is art and science. The art aspect consists of the way that the physician deals with the human aspect of the patient, expressing empathy, compassion, establishing a therapeutic relationship, and dealing with uncertainty; the science is the attempts to understand disease processes, making rational treatment plans, and being objective in observations. The physician as scientist must be precise about how to elicit data and then carefully make sense of the information, using up-to-date evidence. Exercises to develop the skills of data analysis require interpretation of data in various representations, such as in tables or on graphs.
Based on the DNA sequence, what amino acid or protein would be produced, and how would the protein be manifested in a clinical setting?
The clinician–basic scientist collaboration requires each party to “speak the same language” and translate forward and backward from science to clinical, and vice versa. Biochemical thinking is very stepwise, for example, the relationship among DNA, RNA, proteins, and clinical findings. Because the genomic information (DNA) codes for proteins that affect physiologic or pathologic changes, it is of fundamental importance that the student becomes very comfortable thinking about these relationships:
Forward: DNA → Proteins → Clinical Manifestations
Backward: Clinical Findings → Effects of Protein → DNA
What hormone–receptor interaction is likely?
A hormone is a substance, usually a peptide or steroid, produced by one tissue and conveyed by the bloodstream to another part of the body to affect physiologic activity, such as growth or metabolism. A receptor is a cellular structure that mediates between a chemical agent (hormone) and the physiologic response. The way that the hormone causes its effect is vital to understand, because many diseases occur as a result of abnormal hormone production, abnormal hormone receptor interaction, or abnormal cellular response to the hormone–receptor complex. For example, diabetes mellitus is manifest clinically by high blood glucose levels. However, in type 1 diabetes (usually juvenile onset), the etiology is insufficient insulin secreted by the pancreas. (Insulin acts to put serum glucose into cells or store it as glycogen.) By contrast, the mechanism in type 2 diabetes (usually adult onset) is a defect of the insulin receptor messenger; in fact, the insulin levels in these individuals are usually higher than normal. Understanding the difference between the two mechanisms allows the scientist to approach individualized therapy, and it allows the clinician to understand the differences in these patients, such as the reason that people with type 1 diabetes are much more prone to diabetic ketoacidosis (because of insulin deficiency).
How does the presence or absence of enzyme activity affect the biochemical (molecular) conditions, and how does that in turn affect patient symptoms?
Enzymes are proteins that act as catalysts, speeding the rate at which biochemical reactions proceed but not altering the direction or nature of the reactions. The presence or absence of these important substances affects the biochemical conditions, which then influence the other physiologic processes in the body. Enzyme deficiencies are often inherited as autosomal recessive conditions and may be passed from parent to child. Clearly, when students begin to understand the role of the enzyme and the chemical reaction that it governs, they begin to understand the intricacies of the human biologic processes.