Gottschalk Lecture 2015: Sensing and Transporting Sodium #ExpBio

(by whizbang) Mar 31 2015

Drum roll, please.

Without further delay, I present my summary of the excellent talk presented by Tom Kleyman:

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Orphan Returning Home #ExpBio

(by whizbang) Mar 30 2015

The kidneys provide half of our acid-base balance in the body, with the rest being performed by our lungs. Our pulmonary system regulates the intake and output of carbon dioxide, while the kidneys excrete acid and retain or generate bicarbonate, the primary buffer in the fluids outside of our cells.

It’s amazing how much of this process has been figured out over time. It takes a very complex system to regulate the balance of a critical component so tightly, yet we still find new systems to take into account.

Elucidating the Physiological Role of Gprc5c, a Novel Orphan GPCR in the Kidney. P Rajkumar and JL Pluznick

G protein coupled receptors (GPCRs) are a class of membrane bound molecules that sense signals outside a cell and then trigger other effects. This group found an orphan GPCR, one whose ligand (fancy science talk for the signal it senses). It was interesting, in part, because it is found abundantly within the kidney, at a comparable level to angiotensin receptors. Other investigators had developed an antibody to it, as well as a mouse with this gene knocked-out, making it an excellent target for further study.

The antibody showed lots of this protein, mostly in the apical or inside-membrane of proximal tubule cells. The proximal tubule of the kidney is a workhorse. These tubes have to reabsorb most of what gets filtered from the blood, since the kidney cleans blood by removing most stuff and then returning the good stuff. It’s similar to some organization shows on TV; instead of trying to take out unnecessary clutter, they start by clearing the room (filtration) and then putting only the useful, wanted things back in (proximal tubule reabsorption).

For their next step, they wanted to screen ligands, starting with known functions of the proximal tubule. Gprc5c becomes active when exposed to alkaline pH. No other GPCR studied does the same thing!

Metabolic studies on the knock-out mice that lack Gprc5c reveal mild acid build-up in the blood and loss of alkali in the urine. These observations are consistent with a role for this “orphan” in sensing alkali in the urine and promoting its reabsorbtion.

It’s fascinating to see systems we thought we had figured out get a new player. Of course, eventually this means altering my medical student lectures. I guess that’s the price of science!

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New Model, New Hope #ExpBio

(by whizbang) Mar 30 2015

I have written many times about my arch nemesis, hemolytic uremic syndrome (HUS). This disorder is what we medical docs call a thrombotic microangiopathy. Something damages the lining of small (micro) blood vessels (angio), causing platelets to clump (thrombotic) and form webs across the tiny capillaries. For some reason, organs hit by this damage include the kidney, brain, pancreas, and then pretty much anything else at random.

You can download a handout on HUS for parents here, or watch this video for the material we teach residents about HUS.

We see two forms of HUS in childhood. Atypical forms result from mutations in the complement system, a series of immune system proteins that respond rapidly to threats. This system is pretty complex, as shown in the diagram below from a great article; click the picture for the full reference. This system is always "on" and is regulated by proteins that dampen it. In atypical HUS, these regulatory proteins are deficient, allowing complement to rampage at will. The critical component is the Membrane Attack Complex (MAC) which destroys cells, be they foreign or host.

ComplActPath_v4

Click for source and review article.

 

 

Currently we can treat atypical HUS with eculizumab, an antibody to complement component C5, a protein just before the MAC. Antibody at c5 prevents formation of the MAC and provides miraculous results for patients with atypical HUS.

The most common form of HUS follows an episode of bloody diarrhea due to a bacteria that produces shiga toxin, most commonly E. coli. We will call this eHUS today. This toxin provides the damage to the blood vessels that triggers the thrombotic microangiopathy. Once the toxin clears, the patient usually recovers but with a high risk of kidney failure many years down the road.

In really bad cases of eHUS we have used eculizumab to help patients (desperate times and desperate measures, you know). It seems to turn off the thrombotic microangiopathy rapidly, suggesting that complement may be involved in these patients as well.

Human Mannose-Binding Lectin (MBL2) Inhibitor Prevents Renal Injury in a Novel Animal Model of Enteropathic Hemolytic Uremic Syndrome M Ozaki et al

This group, led by Gregory Stahl, took mice that lacked the mouse form of mannose-binding lectin (MBL2) and gave them the gene for the human form of this molecule. In the complement diagram above, MBL2 is a component of the Lectin activation pathway for the complement system. They then treated these mice with shiga toxin with or without an antibody to MBL2.

Shiga toxin damaged the cells lining blood vessels, releasing MBL2. This then turned on the complement system,and these mice got thrombotic microangiopathy with kidney damage. Those that received the antibody to MBL2 with the shiga toxin had far less damage from the toxin. Giving the antibody up to a day later also provided some protection from HUS.

This study is so exciting! First, it provides a mouse model of eHUS that we can use to examine the complement pathways in more detail and to develop new drug targets. Second, their anti-MBL2 antibody may be used as a treatment someday. #Winning!

Atypical HUS without treatment almost always results in kidney failure, and the disease more often than not destroys transplanted kidneys as well. Patients with eHUS recover and come off of dialysis in 90% of cases; however, they generally have 2-4 weeks of hospitalization with multiple surgeries. A treatment that could rapidly reverse kidney failure would provide substantial reductions in costs and make patients much happier. They also face an increased lifetime risk of kidney failure, depending on the level of damage at the time of the illness. New treatments beyond supportive care with dialysis may reduce this issue as well.

As a pediatric kidney doc, this study makes me very, very happy!

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Solving Kidney Mysteries #ExpBio

(by whizbang) Mar 29 2015

UPJ

Gross Urinary Anatomy

 

As a pediatric nephrologist (children's kidney doctor), hydronephrosis or water on the kidney is one of the most common problems I see. The kidney can be thought of as two general parts: (1) A bunch of blood vessels that filter “dirty” blood and return it to the body after cleansing and (2) Tubes made of cells that carry filtered material from the blood vessels, taking good stuff back into the body and taking out more bad stuff to make urine.

As these tubules travel through the kidney, they eventually come together to form bigger and bigger tubes until they form the pelvis (see diagram), the main part of the urine collecting system within the kidney. When these central collecting systems look enlarged on ultrasound or other study, we call it hydronephrosis.

The pelvis of the kidney becomes a fine muscular tube, the ureter, once it leaves the kidney. This transitional area, the ureteropelvic junction (UPJ, lower image) is a fairly common place for obstruction to develop before children are born. In most cases, the actual obstruction resolves early on, leaving an enlarged but fully functional collecting system. Think of a balloon that you have blown up and then the air let out. It is never as tight as it was before (and so seems a little floppy), but nothing is blocking it up.

In some cases, the UPJ obstruction persists after birth but gets better over months to years. In other cases, the obstruction tightens and may require surgical repair or result in the loss of kidney function.

We know all of this from following lots and lots of kids with UPJ obstruction for years. What we do not know is why this portion of the collecting system is so prone to obstruction.

A Novel Transgenic Mouse Model for Congenital Obstructive Nephropathy; AJ Lee et al

One reason we know so little about the how and why of UPJ obstruction is that there have been no non-surgical models where it develops spontaneously. That no longer seems to be a problem as this group, led by Ben Fogelgren at the University of Hawaii (I'm available to collaborate and I will come to you) now has a mouse that develops severe UPJ obstruction. Unfortunately, these mice have complete anuria, resulting in death at birth.

How did they do this? The model involves a conditional knock-out of Sec10 in the ureteric buds of embryonic mice. These cells are destined to become the ureter and pelvis within the kidney. Sec10 is a protein in exocysts, structures in the cells that help other proteins get to their correct location.

Cells run on proteins. Some have to be in the apical (top) membrane, some have to be in the basal (bottom) membrane, while others have to attach to stuff within the cell. The cells in the developing ureter have a number of proteins that must be on the apical membrane that lines the tube. One of these proteins, Uroplakin 3, fails to end up there in these mice. The cells look abnormal, and other cells (muscle or scar cells) grow more until the ureter tube closes.

This model obviously has some differences from what we see in people. Most children have mild UPJ obstruction only on one side, so it seems likely that environmental factors may disrupt these processes transiently in clinical situations. However, this model should increase our understanding of what controls this process and why it happens in this particular location.

This model provides an important opportunity to study a major cause of pediatric kidney problems. I look forward to seeing a lot more data from this lab!

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Males & Females Are Different #ExpBio

(by whizbang) Mar 29 2015

I live-tweeted this excellent lecture and then collected my thoughts here via Storify:

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But It's Already Been Done! #ExpBio

(by whizbang) Mar 29 2015

Despite the proliferation of journals and publications, our basic science efforts often do not pay off in new treatments. Part of this is time; it generally takes 15-20 years for a new science observation to be translated to the bedside.

The uglier part of the story is lack of reproducibility of preclinical studies.

In 2011 a pharmaceutical company published what proportion of preclinical studies could be replicated for drug development:

ReproFail

The bottom line: well under half! Inconsistent effects do not make good treatment prospects.

Saturday’s seesion, Reproducibility in Research: What are the problems? How can we fix them? What happens if we don’t?,   addressed these issues. Sponsored by the Policy Committee, the session brought together several speakers to address the issues.

Perhaps the most intriguing idea involved unconscious bias. This concept receives a lot of attention during discussions of diversity issues. Most of us have been conditioned to see a white male as the default for a professor or a leader. In science, the bigger problem is the way we do it. As humans, we are programmed to find evidence that supports our bias and, perhaps, minimize findings that contradict it. In forming a hypothesis, we develop a bias requiring support.

So what can we do about this unconscious process?

One though is to stop making hypotheses.

Now, before you start screaming about scientific sacrilege, just listen. The idea would be to have multiple potential thoughts about possible outcomes or to just define a scientific question without defining outcomes.

Obviously, eliminating our current well-defined hypothesis testing model will not solve all these issues, especially with such pressure for high-impact publications to get funding and keep jobs. A variety of other ideas came up, but the problem clearly does not have an easy fix.

This great session left us with more questions than answers. What a great way to start the meeting!

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To Sleep: 2015 Cannon Award #ExpBio

(by whizbang) Mar 29 2015

The American Physiological Society portion of Experimental Biology officially opened Saturday evening with the Cannon Lecture. This year's recipient of the award, Masashi Yanagisawa, addressed his work in understanding sleep.

Solving the mystery of sleep: from orphan receptors to forward genetics started with studies of the orexin knock-out mouse. They thought the mouse would have abnormal body weight; however, it ended up being a model of narcolepsy! He then went on to outline neural control pathways for sleep and genetic work in this area (disclaimer: brain stuff confuses me).

The talk outlined some fascinating finds;however, inspite of all of this study, we still do not know why we sleep. What purpose do these hours of unconscious helplessness serve? It must be important for all mammals to enter this vulnerable state every day.

More questions mean more science.

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Packing Time for #ExpBio

(by whizbang) Mar 26 2015

Last night OKC had its first rough weather for 2015. It all stayed south of my home, so our fully-equipped storm shelter (AKA personal tomb) remains unused. Today I pack for a different sort of weather in Boston. It looks like we will avoid having more snow fall on us, but even with temps above freezing, the ground won’t be clear before we leave.

LogoThis year I am taking a different approach to blogging at the meeting. I have picked a bunch of interesting abstracts, and I will attend presentations. I may or may not write about each of them. I will cover major lectures and the communications workshop.

So stay in touch here at the blog. Follow me on twitter (@PHLane) or connect with me on LinkedIn.  Remember to tag your tweets and posts with #ExpBio.

I promise you some hot science in a cold city.

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One Week to Boston #ExpBio

(by whizbang) Mar 20 2015

This time next week I will be in an aircraft nearing the end of my first segment to Boston for Experimental Biology 2015 (#ExpBio is the official hashtag). I am beginning to plan my packing list, and the weather in the northeast is completely depressing.

At least the snow should be clearing...

At least the snow should be clearing...

At least the attendees will be warm, and the science will be hot!

I will once again be an official APS blogger, so expect to see lots of posts, tweets, and updates about the conference.

If you're there and you see me, say hello!

 

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What I'm Reading: Herding Cats Edition

(by whizbang) Mar 18 2015

Even an experienced speaker like Guy Kawasaki says, “Moderating a panel is deceptively hard--harder, in fact, than keynoting."

What makes a good moderator panel? We all know bad ones, or at least bad performances. Now Denise Graveline, an internationally renown public speaking expert who blogs at The Eloquent Woman, fills the gap in panel moderation. Her ebook, The Eloquent Woman’s Guide to Moderating Panels, provides a brief 51 page collection of thoughts and checklists to make moderation successful.

PanelsPanel moderation is too often an afterthought; she encourages planners to engage moderators with speakers early in the planning process. That way ground rules can be set, and the moderator(s) can reinforce his or her plans to enforce the rules. One section of the guide gives the reader 9 reasons to turn down an offer to moderate. For example, women often get asked to moderate groups of male speakers to provide an appearance of diversity. Just say no if that seems to be the case.

The usual roles of moderators are addressed, like better panelist introductions and calling on questions from the floor. One delightful section presents smart ways to interrupt speakers, primarily so you can shut them up and stay on time, for the win.

In about ten days I will join my colleagues in Boston for Experimental Biology 2015. I’m sure I will remember many of these points during symposia at that meeting and others farther in the future. I highly recommend this quick read for anyone involved in meeting presentations.

 

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