Imagine a river bringing water to a village or town. What if there was a sudden rainstorm or drought? How would that impact the river’s flow, and the people and habitats that depend on this system?
Just as an ecosystem relies on a river for life, so does the body rely on proper water transport through its cells in order to function. Whether there is too much or too little water being transported or if it is not getting to the right places, it is incredible how much our health can be affected by issues with water transport.
Dennis Brown, PhD, Director of the Massachusetts General Hospital Program in Membrane Biology, has spent much of his research career looking at the body as a system of water transportation. His research began with studying water balance in the kidneys due to their critical role in regulating body water content. Over the years, his areas of investigation have spread to other systems in the body as well to address water imbalance’s many impacts and resulting health complications.
Throughout his basic and translational research pursuits, Brown’s continual goal has been to generate treatments for life-threatening water balance disorders.
Regulating water balance in the kidney
Brown’s fascination with water transport started with the kidney during his postdoctoral studies. “I just fell in love with the kidney because of its many functions and different cell types,” says Brown. “It was a great model for looking at cell biology in general, and it was applicable to other organs and tissues as well.”
The kidneys are responsible for determining how much water is expelled from the body through urine, and how much is retained for use within the body. Water channels help to move water from the bloodstream to the bladder, and an anti-diuretic hormone called vasopressin prompts the water channels to move from the center of the cell to the outside to allow water through.
When this process gets interrupted, the body expels either too much water or not enough, and the consequences can be severe. Moreover, there are currently no existing therapies to restore the water handling function of the kidney to normal levels.
Patients who don’t produce enough urine often develop edema and serious hypertension as a result of the body reabsorbing too much water and increasing blood volume. Brown’s lab is investigating strategies to help patients get rid of this excess fluid load. Thus far, they have found about 30 or 40 chemical compounds that could potentially address the issue.
Other patients develop nephrogenic diabetes insipidus (NDI), which is caused by either a defect in the water channel itself or, more commonly, a defect in the receptor for vasopressin. As a result, the body does not receive the signal to stop expelling fluid.
“These people produce copious amounts of urine every day,” explains Brown. “You can somewhat alleviate the symptoms by restricting water consumption, but it’s a horrible life.” Individuals with NDI experience a constant need to go to the bathroom which can result in social and sleep-related issues. NDI also increases risk for dehydration, brain damage, bladder rupture and kidney failure.
In the hopes of finding a solution for patients with NDI, Brown’s lab uses a combination of directed drug testing (based on current knowledge of the mechanisms of water reabsorption) and a non-biased drug discovery approach (an open-ended approach based on large-scale chemical screening) to identify promising treatments to help these patients produce less urine.
Lithium and NDI
The impacts of water imbalance also extend to the mental health world.
Lithium is one of the most powerful drugs for treating an array of mental illnesses, including bipolar disorder and post-traumatic stress disorder. While the drug is highly effective, it also reduces or desensitizes the kidney’s ability to respond to vasopressin, resulting in negative side effects for patients. “30-40 percent of people who start on lithium develop some form of NDI,” says Brown. “More worryingly, in the long term, 1-5 percent of these patients will develop some kind of end stage renal disease which may even require transplantation.”
Brown recognizes that there’s a need to figure out why lithium causes this response in the body, and why it only impacts a certain subset of patients taking lithium. In addition to utilizing a combined informed and unbiased approach to identify potential new therapies, he is partnering with Andrew Nierenberg, MD, and Roy Perlis, MD, of the department of psychiatry at Mass General to answer these questions. Brown believes the solution will be a combination of modifying lithium treatments through adjustments to dose, delivery rate and length of time, as well as potentially balancing lithium with other drugs.
Water channels in the gut
Brown is also collaborating with gastrointestinal experts to address water transport’s impact on gut health. He is working with Wayne Lencer, MD, Chief of the Division of Gastroenterology, Hepatology and Nutrition at Boston Children’s Hospital, and a former postdoc in Brown’s lab.
One of the water channels found in the kidney is also found in the gut. Current research suggests that levels of this specific water channel are lower in patients with IBD. Brown and Lencer plan to investigate this water channel to understand its effect on inflammatory bowel disease (IBD) and intestinal permeability.
Translating basic science
While the majority of Brown’s research to date has emphasized basic research conducted in the lab, he has started to shift his focus. “What we’re doing right now is basic research, but we’re moving into the translational arena as well because, quite frankly, that’s where the funding is these days.”
Although his most recent grants have incorporated translational science aims, Brown still sees the value in basic research and will continue seeking funding for his basic science pursuits. “We’re always interested in seeing our discoveries move into the clinic. But on the other hand, there’s still some kind of intellectual interest and importance in discovery for its own sake.”