The war on disease: Revisiting old haunts

Despite medical science's unbroken stream of discoveries, a number of high profile diseases still fox researchers. Today, scientists seek fresh clues along well-trodden paths.

As scientists delve deeper into the mechanisms that lie beneath difficult-to-treat conditions such as diabetes and Alzheimer's disease, they pick away at the edges of science, reaching for loose threads and poking their fingers into dimly lit nooks.

But because answers from fresh angles are not always forthcoming, it is well worth doubling back every once in a while, opening old doors and revisiting familiar faces.

Recently, for instance, a new organ was "discovered" hiding in plain sight. The interstitium — a system of fluid-filled bags — is now considered one of the body's largest organs.

Previously, the interstitium was thought to be fairly inconsequential; little more than anatomical glue paper supporting proper organs doing proper work. But when cutting edge imaging techniques zeroed in, its size and importance became clear.

Now, scientists are asking what it can teach us about edema, fibrosis, and cancer's troublesome ability to spread.

In research, everyone knows that no stone should be left unturned. The interstitium, however, reminds us that they should be turned multiple times and at regular intervals.

In this article, we cover some familiar aspects of cellular biology that are being revisited and providing unfamiliar ways to understand disease.

Microtubules: More than scaffolding

Running through the cytoplasm of each and every cell is a complex network of proteins called the cytoskeleton, a term first coined by Nikolai Konstantinovich Koltsov in 1903. One of the primary constituents of the cytoskeleton is long, tubular proteins called microtubules.

Microtubules help keep the cell rigid, but they also play pivotal roles in cell division and the transport of compounds around the cytoplasm.

Microtubule dysfunction has been linked with neurodegenerative conditions, including the big two: Parkinson's and Alzheimer's diseases.

Neurofibrillary tangles, which are abnormally twisted threads of a protein called tau, are one of the hallmarks of Alzheimer's. Usually, in conjunction with phosphate molecules, tau helps sure up microtubules. In Alzheimer's neurons, however, tau proteins carry up to four times as much phosphate as normal.

Hyperphosphorylation reduces the stability and the rate at which microtubules are manufactured, and it can also cause microtubules to be disassembled.

Exactly how this alteration in microtubule production leads to neurodegeneration is not fully understood, but researchers are interested in seeing whether intervening in these processes might one day help treat or prevent Alzheimer's disease.

Issues with microtubules are not reserved solely for neurological conditions. Since the 1990s, scientists have been discussing whether they might be at the root of cellular changes that lead to heart attack.

The most recent study to look at this question concluded that chemical changes to the microtubule network of heart cells made them stiffer and less able to contract as they should.

The authors believe that designing drugs that target microtubules might eventually be a viable way of "improving cardiac function."

Beyond the powerhouse

If you learned only one thing in biology class, it was likely that "mitochondria are the powerhouses of the cell." First glimpsed in the 1800s, today's scientists are asking whether mitochondria might be in cahoots with a range of diseases.

Mitochondria: more than just a powerhouse.

The role of mitochondria in Parkinson's disease has received the most attention.

In fact, over the years, a variety of mitochondrial failures have been implicated in the development of Parkinson's.

For instance, issues can arise in the complex chemical pathways that generate energy in mitochondria, and mutations can occur in mitochondrial DNA.

Also, mitochondria can be damaged by a buildup of reactive oxygen species that are produced as a byproduct of energy production.

But how do these failings produce the distinct symptoms of Parkinson's? Mitochondria are, after all, in virtually every cell of the human body.

The answer appears to lie in the type of cells affected in Parkinson's: dopaminergic neurons. These cells are uniquely susceptible to mitochondrial dysfunction. In part, this seems to be because they are particularly sensitive to oxidative attack.

Dopaminergic neurons are also heavily dependent on calcium, an element that mitochondria keep tabs on. Without mitochondrial calcium control, dopaminergic nerve cells suffer disproportionately.

A mitochondrial role in cancer has also been discussed. Malignant cells divide and replicate in an out-of-control manner; this is energetically expensive, making mitochondria prime suspects.

Beyond mitochondria's ability to generate power for cancer cells, they also help cells adapt to new or stressful environments. And, because cancer cells have an uncanny ability to move from one part of the body to another, set up shop, and keep multiplying without pausing for breath, mitochondria are suspected villains here, too.

Besides Parkinson's and cancer, there is evidence that mitochondria might also have a hand in the development of nonalcoholic fatty liver disease and some lung conditions. We still have much to learn about how these industrious organelles influence disease.

The microbiome's next level

Bacteriophages are viruses that attack bacteria. And, with the increased interest in gut bacteria, it is no surprise that bacteriophages have started to raise eyebrows. If bacteria can influence health, something that kills them surely can, too.

Bacteria, present in all ecosystems on earth, are famously numerous. Bacteriophages, however, outnumber them; one author refers to them as "virtually omnipresent."

The bacteriophage: adding complexity to complexity.

The microbiome's influence on health and disease is a convoluted web of interactions that we are only just starting to unravel.

And when the virome — our resident viruses — is added to the mix, it becomes exponentially labyrinthine.

Knowing how important bacteria are in sickness and in health, it requires only a small leap of the imagination to consider how bacteriophages — which are specific to different strains of bacteria — may one day be medically useful.

In fact, bacteriophages were used to treat infections in the 1920s and '30s. They fell out of favor primarily because antibiotics, which were easier and cheaper to store and produce, appeared on the scene.

But with the peril of antibiotic resistance rearing its head, a move back toward bacteriophage therapy might be on the cards.

Bacteriophages also have the benefit of being specific to one bacterium, as opposed to antibiotics' broad sweep across many species.

Although the resurgence of interest in bacteriophages is new, some already see a potential role in the fight against "cardiovascular and autoimmune disease, graft rejection, and cancer."

Set adrift on lipid rafts

Each cell is coated in a lipid membrane that allows certain chemicals in and out while blocking the paths of others. Far from being a simple bag full of bits, lipid membranes are complex, protein-studded entities.

Within the membrane complex, lipid rafts are discrete islands where channels and other cellular equipment congregate. The exact purpose of these structures is hotly debated, but scientists are busily getting to grips with what they might mean for a number of conditions, including depression.

The lipid membrane: much more than a simple bag.

Recent investigations concluded that understanding these regions could help us get to grips with how antidepressants work.

G proteins — which are signal-transmitting cellular switches — become deactivated when they drift into lipid rafts. When their activity drops, neuronal firing and communication is reduced, which, theoretically, could cause some symptoms of depression.

On the other side of the coin, antidepressants have been shown to shift G proteins back out of lipid rafts, thereby reducing depressive symptoms.

Other studies have investigated the potential role of lipid rafts in drug resistance and metastasis in pancreatic and ovarian cancer, as well as the cognitive slow-down on the way toward Alzheimer's disease.

Although the double-layered structure of the lipid membrane was first uncovered in the middle of the last century, lipid rafts are a relatively new addition to the cellular family. Many questions about their structure and function are, as yet, unanswered.

Good things come in small packages

In short, extracellular vesicles are tiny packages that ferry chemicals between cells. They help communicate and play a part in processes as varied as coagulation, cellular aging, and the immune response.

Because they carry messages to and fro as part of such a wide array of pathways, it is no wonder that they have the potential to go awry and become embroiled in disease.

Also, because they can carry complex molecules including proteins and DNA, there is every chance that they might shuttle disease-specific materials — such as the proteins involved in neurodegenerative diseases.

Tumors also produce extracellular vesicles, and, although their role is not yet fully understood, it is probable that they help cancer set up shop in distant locations.

If we can learn to read these intercellular smoke signals, we could gain insight into a myriad of disease processes. In theory, all we need to do is tap into them and break the code — which, of course, will be a monumental challenge.

Below the fold

If you took biology, you may have a dim recollection of the pleasing-to-pronounce endoplasmic reticulum (ER). You might also remember that it is an interconnected network of flattened sacs within the cytoplasm, nestled close to the nucleus.

The ER — first glimpsed under a microscope in the late 1800s — folds proteins and prepares them for life in the harsh environment outside the cell.

It is vital that proteins are folded correctly; if they are not, the ER will not transport them on to their final destination. In times of stress, when the ER is working overtime, misfolded or unfolded proteins can build up. This triggers a so-called unfolded protein response (UPR).

A UPR attempts to bring normal cellular functioning back online by clearing up the backlog of unfolded protein. To do this, it prevents further protein production, breaks down badly folded protein, and activates molecular machinery that can help crack on with some folding.

If the ER does not manage to get back on track and the UPR fails to bring the cell's protein situation back in line, the cell is marked for death by apoptosis, a type of cell suicide.

ER stress and the consequent UPR have been implicated in a range of diseases, one of which is diabetes.

Insulin is manufactured by pancreatic beta cells, and because production of this hormone varies across the course of a day, pressure on the ER rises and falls — meaning that these cells rely on efficient UPR signaling.

Studies have shown that high blood sugar puts increased pressure on protein synthesis. If UPR cannot manage to get things back on track, beta cells become dysfunctional and die. As beta cell numbers dwindle, insulin can no longer be created when needed, and diabetes will develop.

These are fascinating times to be involved in biomedical science, and as this brief glimpse proves, we still have much to learn, and covering old ground can be just as useful as carving out new horizons.