Remember when you were in biology class, right around your freshman year of high school, and you were learning all about the difference parts of a cell? You probably remember that the mitochondria — an organelle that takes in nutrients, breaks them down, and creates energy – was called the “powerhouse of the cell.” It may seem silly now, but when it comes to presenting information in an easy to understand way, clinicians and researchers at Penn Medicine often turn to analogies – much like our 9th grade bio teachers did – to help explain the complexities of what they do, to boil down seemingly common but not always easily defined treatments and diseases, and to give some relatable context to their research.
While much of the population has heard the terms type 1 and type 2 diabetes, they may not really understand the differences. In fact, it’s common for one to hear about someone having type 1 diabetes and wonder why that same person is not overweight or obese – which often goes hand-in-hand with type 2 diabetes. To explain the difference in the most basic terms, Mitchell Lazar, MD, PhD, chair of Endocrinology, Diabetes and Metabolism, turns to a cell phone.
“With type 1 diabetes, the pancreas stops producing insulin, the hormone that allows us to process sugars. This would be like a cell phone with a dead battery. In order for the phone to work you’d need to replace or charge the battery, just like for the body to produce insulin you’d need to replace (transplant) the pancreas or it’s insulin-producing cells,” Lazar explains. “For Type 2 diabetes, insulin is made but the body lacks the ability to process it. This is like having a phone that is on and looks like it should be working just fine, but as you try to use an app or make a call, the phone won’t connect to the network or access the cell server – it’s more an internal issue.”
Basic science may be one of the areas that needs the most lay-friendly explanation, as the average person likely did not take advanced chemistry or biology. While knowing what a chromosome is may be fairly common, knowing all the parts of the chromosome certainly is not – queue telomeres.
“Telomeres are what we see at the end of each chromosome, and they protect the chromosomes from deteriorating or fusing to the one next to it. The best way to explain these are to think about shoe laces,” said Roger Greenberg, MD, PhD, director of Basic Science at Penn’s Basser Center for BRCA. “If each end of the shoe lace is the end of a chromosome, then the telomere would be the plastic coating at the tip which prevents fraying or deterioration.” In an October 2016 study published in Nature, Greenberg found that these shoelace-style caps might hold important implications for designing new cancer therapies.
Muffins and Scones
Anecdotally, Jim Eberwine, PhD, a professor of Systems Pharmacology and Translational Therapeutics, likens the difference in cell types to baking. “There is tremendous variety in different types of cells, from osteoclast to erythrocyte to microglia, all of which are made from the same building blocks. Similarly, there is a wide variety of baking recipes that utilize the same exact ingredients,” he said. “Each type of cell is composed of essentially the same DNA but differing amounts of DNA products — like proteins, mRNA, enzymes, etc. — just like certain recipes are made up of the same ingredients but at varying levels — eggs, flour, sugar, etc. In order to bake a scone you use the same ingredients but in a different mixture from what you would to make a muffin, just like the body makes a neuron with the same components as a white blood cell.”
Another basic scientist, John Trojanowski, MD, PhD, director of the Institute on Aging, has been relying on a transport-based analogy for over two decades, when discussing his work with his long-time collaborator Virginia Lee, PhD, the John H. Ware 3rd Endowed Professor in Alzheimer's Research, on tau amyloids — misshaped, insoluble proteins that clump in the brain and elsewhere and cause a host of debilitating diseases. Normally tau binds to microtubules, filamentous intracellular tubular structures that are responsible for various kinds of movements in all eukaryotic cells and are key elements in the life-sustaining transport in neurons, the most asymmetrical cells in the human body that require just-in-time delivery of products made in neuronal cell bodies to their synapses. Mutations in the tau gene cause neurons to lose their ability to send and carry signals over time because the mutant tau does not bind to and stabilize microtubules.
To make a little more sense of it all, Trojanowski says, “Think of tau as the cross-ties of train tracks. The tracks will handle the traffic as long as they are parallel and there are substrates for transport. If the cross-ties are missing, the tracks will wobble and the train will run off the tracks. Alterations in the tau gene affect the tau proteins so they no longer bind to microtubules, and this loss of function causes neurons to lose their ability to send and carry, ultimately leading to debilitating diseases. This loss of function also occurs in tau proteins without mutations due to pathological changes in the wild type tau proteins. Essentially this would be the equivalent to a railroad without any cross-ties (i.e. tau with or without mutations, but both pathologically altered) causing the train to crash (i.e. debilitating disease).”
The good news is there are many drugs that correct this loss of function, one of which Trojanowski and his colleagues had advanced to a phase 1 clinical trial. They continue to develop additional drugs with these properties for use as treatments for Alzheimer’s disease wherein tau function is lost due to the aggregation and misfolding of tau.
Back to this, “misfolding of tau.” Trojanowski used another analogy to help explain how pathological changes in tau affect its function and behavior in Alzheimer’s disease and related disorders, work that he has been involved with at Penn Medicine for more than 25 years: crumpled up paper.
"The main underlying problem behind neurodegenerative diseases such as Parkinson's and Alzheimer's is the misfolded proteins, which effects the information being carried from one cell to the next," Trojanowski said. "Imagine you have two pieces of paper with text on each. Normally, when the two pieces of paper are smooth and flat, you're able to read the information written on both. But when you crumple one of the papers up into a ball, you can no longer read the copy easily, if at all. When disease spreads, it is like the crumpled paper encountering the smooth paper and corrupting it or templating it to misfold, and we speculate that the continuation of this process is what causes the spread of disease."
Trojanowski noted that conveying information is a critical part of what proteins do. If they become misfolded, the information being carried is no longer accessible or useable as intended-which he explains further in here.
"If the crumpling or misfolding continues to happen year-over-year, and cell-after-cell, the pathologically altered proteins can then corrupt their normal counterparts in other cells, leading to a string of tainted cells that then cause these disorders."
Whether it’s explaining common illnesses to help people better understand terms they may hear all too often or detailing the inner-workings of proteins and cells construction, even the most advanced minds in science and medicine lean on everyday analogies to break down and describe their work. Like the mitochondria-powerhouse metaphor that you might remember many years later, these are intended to help us better understand of how our bodies work, how we respond to disease treatments, and how clinicians and researchers are advancing medicine to the betterment of patients across the world.