Translational Research Needs

The critical first step in a research project occurs when the investigator chooses a model. Can the experiment be performed in cultured cells? Is a clinical trial in people necessary? Or will something in between be needed?

Something in between often means an animal model. I spent my training studying kidneys from people. The next questions I asked could not be studied that way; they required a setting with more control of variables, one in which the basic workings of the tissues could be dissected and explored. Would cell or tissue culture do? Perhaps for some of it, but I wanted to examine puberty. This complex physiological period involves sexual maturation and the acceleration then cessation of linear growth. Our understanding of all its processes is elementary at best, so they cannot (yet) be modeled in vitro or in silico. I had to find a model.

At that time, a search of PubMed revealed a whole bunch of animal models of diabetes and its complications. The array of species and variables sent my head spinning. Now, genetically altered mice flood the field, each with its own particulars! On Tuesday mouse models of diabetic kidney disease will occupy 2 hours of symposium time at Experimental Biology. New models are published every month.

Sunday I learned about LAMHDI , the initiative to Link Animal Models to Human DIsease, while strolling the exhibit hall. This emerging resource results from efforts of the National Center for Research Resources of the NIH. The goal is a simple yet comprehensive catalog of animal models, including the gene(s) affected (when available) and phenotype information. Similarities and differences from human disorders will be included as well.

Services available include the following:

LAMHDI Database Search - The LAMHDI Database Search is a search of data from partner websites. Currently JAX Mice and ZFIN have made their databases available to LAMHDI. A search returns pertinent information about animal models. Other websites with information about animal models are welcome to join as LAMHDI partners. We also invite you to share your feedback.

Animal Model Web Search - The Animal Model Web Search is a Google-like search of select websites that contain information about animal models. Currently LAMHDI indexes more than 75 sites with over 1.2 million pages that you may search with a single search strategy. Search results take you back to the originating site. Please suggest other sites that LAMHDI might include.

Featured Resources - Eventually LAMHDI will link all appropriate animal model databases in a single search. In the meantime, several additional resources have been identified as most useful to animal model researchers to supplement LAMHDI today. If you have other resources to suggest, please let us know.

LAMHDI may accelerate translational research by allowing the best model, not merely the one most familiar to the investigator, to be used. Right now the searches are dominated by rodent and zebrafish models. Eventually, the developers plan to include all species, and the nation’s leading primate centers are participating.

In addition to its potential to speed up bench to bedside, the database might also reduce the number of animals used in a given line of research. By selecting the best possible model for the experimental question, a series of less relevant experiments may be eliminated. Faster, better, and lower costs (in both dollars and animal lives)- sounds like a winner to me.

LAMHDI is described as a prototype. The developers want scientists to use it and give feedback. How is it working? What other resources should be included? How can we make this thing rock? So click on over there and try it out.

I will update the EB tweet-match throughout the day; my twitterfeed can be found in the right-hand column above.

Questioning a Paradigm

Mostly I post my personal musings on science, healthcare, and other nonsense that catches my eye. Today I am going to post about a medical study that was just published in the July 2 issue of New England Journal of Medicine.

The first author is Michael Mauer, a pediatric nephrologist at the University of Minnesota and my research mentor during my fellowship (consider this my disclaimer of potential bias). The study examines changes in kidney function and structure over 5 years in patients with type 1 diabetes, the type most common in young children. This study examined primary prevention of diabetic kidney disease; patients without albuminuria (thought to be the earliest manifestation of the problem) or hypertension (high blood pressure), and with normal kidney function (glomerular filtration rate) were assigned to receive enalapril (which inhibits angiotensin converting enzyme), losartan (which blocks the angiotensin II receptor), or placebo. They not only examined all of these functional studies before and after 5 years of treatment, but also performed kidney biopsies with morphometric studies for the lesions seen in diabetic nephropathy (primarily expansion of the mesangium of the glomerulus).

Drugs that block the renin-angiotensin system, like enalapril and losartan, have been shown to benefit patients with advanced kidney disease from diabetes (shown in photo) and other causes. They also seem to benefit patients with early type 2 diabetes (the type seen more commonly in adults and associated with obesity). It has been hoped that they would prevent kidney disease entirely, although smaller, shorter studies have failed to demonstrate this phenomenon. Thus, the hope that this study would answer the question: should all patients with type 1 diabetes be put on these drugs at the time of diagnosis of diabetes?

The answer seems to be no for now. Neither drug showed a clear benefit over placebo in any parameter measured. The study is not perfect; a number of questions arise with careful reading of the article and the supplementary material. Like most studies, the results will breed discussion, more questions, and more experiments.

Probably the most important point I can make here is that

paradigms are meant to be shifted.

We cannot prove anything merely by arguing its logic or making observations from other situations. Logic and other situations suggest that these drugs would work!

 We must do the appropriate experiment if we really want to answer the question.

Diabetes is the most common cause of kidney failure in the United States, although most patients have type 2 diabetes. Drugs like enalapril and losartan still play an important role in the management of this disorder, especially in patients with type 2 disease and more advanced kidney problems. For now, though, we will not be starting these drugs along with insulin in newly diagnosed type 1 patients. And we must keep looking for treatments and cures.

Click below to link to the abstract: