Three years in: what has the $42M Atopic Dermatitis Research Network produced?

In July it will be three years since the NIH awarded National Jewish Health in Denver, CO $31 million to create and administer the Atopic Dermatitis Research Network, a consortium of five academic sites across the US. A contractor, Rho Federal Systems of Chapel Hill, NC, won an $11 million contract to operate a center to coordinate statistics and clinical trials for the project.

That makes $42 million—spread over five years—which puts the project on the large end of NIH funding for individual biomedical efforts. The typical NIH research grant ranges from $100 thousand to $2 million, and anything bigger is fodder for university news releases. Which raises the question: what have US taxpayers gotten in return?

I ask this as a patient who is grateful that these scientists are working to understand a disease that affects me, my family, and millions in the US and worldwide.

The answer is not obvious, since the publications page on the ADRN website hasn’t been updated since July 2011.

According to the website:

The Atopic Dermatitis Research Network (ADRN) is a consortium of academic medical centers that will conduct clinical research studies in an attempt to learn more about skin infections associated with atopic dermatitis (AD). The studies will focus on antibiotic-resistant Staphylococcus aureus infections and widespread viral infections of the skin, both of which are more prevalent among AD patients. The ADRN will build on the work of the Atopic Dermatitis and Vaccinia Network (ADVN) which conducted clinical studies focused on making smallpox vaccinations safer for people with AD. 

This research will lead to a greater understanding of the immune system in AD patients and may lead to novel therapeutic strategies to manage or prevent infectious complications associated with this disease. 

The ADRN will conduct a number of clinical studies over the next five years and will be enrolling large numbers of people with AD.

A search on clinicaltrials.gov returns two entries for the ADRN: one (open) to create a database of patients for the study of genetic markers connected to susceptibility to infections, and one (completed) to look into how AD patients respond to a new flu vaccine.

The ADRN’s NIH contract number is HHSN272201000020C. A search in the NIH’s PubMed database returns 12 papers that acknowledge funding by that contract number. Three of those are review papers (which did not involve new research).

So that makes  two clinical trials and nine research papers, three years into a five-year $42 million project.

Should US taxpayers expect more; be satisfied; or be impressed?

The answer is probably that we will have to wait to find out.

In each year, a typical top university research lab operates on about $2-3M a year and publishes somewhere around ten papers. That’s roughly $200k a paper.

Three of the five years in the ADRN contract are up; three-fifths of $42M is around $24M. We might therefore naively estimate that we should have seen upwards of 100 papers produced so far.

Most likely the reasons there are only 12 at the moment are that you don't start publishing papers right at the outset of a project. The research must be done first and then written up; and the process of getting accepted to a journal takes months. And the ADRN appears largely to rely on clinical trials--which take time to set up.

So why do we only see two trials listed on clinicaltrials.gov?

I've never had anything to do with a clinical trial, but when I was a researcher, I conducted animal experiments, and there were formidable administrative hurdles to get over before I could start work. I imagine that trials with human subjects are heavily regulated by the government, and for good reason. So the apparently small output of the ADRN to date is, I'm guessing, because it takes a long time to plan trials, get approval, and conduct them, before you can begin analyzing data and reporting it.

Still, let's keep in mind that the ADRN is an extension of the ADVN. It’s not like the ADRN began from scratch—the scientists had the momentum of existing expertise and administration and research aims.

Looking at the titles of the published papers, I can't immediately judge which are the most important. So I emailed Donald Leung, the principal investigator for the ADRN (he's a professor and head of the Division of Pediatric Allergy and Immunology at National Jewish Health), and asked him whether he could summarize the consortium’s findings so far and highlight key points. I hope to hear back from him soon and perhaps to interview him on the phone.

I’d like to know what ADRN scientists have found that surprises them. What have they learned that is truly new?

And what is going to be truly useful to patients in the end? Publishing papers should not be the be-all and end-all of scientific research. What about patents? I’d like to know whether anyone in the ADRN has thought about controlling intellectual property and commercialization. While it’s true that clinical studies may highlight the ideal dosing amount or schedule for existing therapies, and this does not involve creating a new commercial enterprise, most medical technology must pass through the marketplace before it can benefit the consumer/patient.

Someone has to do the dirty work of developing scientific discovery into therapy, and it’s not academic scientists.

More to come.

"Itch molecule" discovery a big step forward

All over the media last week was the news that two scientists at the National Institutes of Health in Bethesda, MD had discovered “the molecule responsible for itch.”

This molecule, “Nppb,” relays signals from certain neurons that detect itch in the skin to other neurons that carry the signals up the spinal cord to the brain. The scientists, Santosh Mishra and Mark Hoon, engineered mice in which the gene for Nppb had been turned off. The mice could not, apparently, feel itch.

The media hype is evident. Nppb is not THE molecule responsible for itch. Several molecules are known to be involved in detecting itch in the first place, and we know many others must be involved in the signaling pathway.

What is remarkable, though, is that the scientists were able to define a model for how itch gets from the skin to the spinal cord.

Mishra and Hoon's model of how neurons carry the itch signal. (Fig 4G from their Science paper.)

We now know that there are at least two pinch points: the synapse across which Nppb carries the signal, and a second downstream synapse across which another molecule, GRP, sends the information to the next stage of neurons.

Blocking the receptors for Nppb or GRP would seem to be a prime candidate for an anti-itch therapy. 

But, of course, there are complications. Nppb was originally known because it is important in the heart, where it controls blood pressure. GRP controls digestion. The genetically engineered Nppb-free mice died early. (The scientists said so in their media interviews.) 

So you can’t just take a pill that blocks Nppb receptors everywhere. That would be a disaster.

But this kind of restriction on where a drug can act is well-known in pharmacology. That’s why, e.g., I can use the anti-pain Voltaren gel (diclofenac) safely by rubbing it into my joints, but diclofenac is known to be pretty toxic if you swallow it.

You can’t design an Nppb receptor-blocking topical cream, because the important synapses are in the spinal cord. A cream would only be effective on the surface.

But it might be possible to take a pill that blocks Nppb only in the spinal cord. I’m not sure how, but that’s what major pharma companies are paying their scientists the big bucks to find out. Maybe the receptors in the spinal cord are subtly different than those elsewhere in the body.

This is very exciting stuff. The massive question is whether the work applies to humans. I would expect it did. Mice and human immune systems are quite different, but our nervous systems are not. We most likely have an analog of Nppb that carries our itch signals.

Just to put this in context—the new work tells us substantially more about itch signaling than previous work in the field. I’d been aware of studies that had identified a class of itch neurons, or certain molecules important in detecting itch in the skin, but this research builds on those foundations in a big way.

Thinking about a comeback

Hey all.

I have been thinking about returning to this blog--I miss keeping up with the latest research, and sharing ideas with people.

But as you might have read below, I am struggling with some neck and back trouble probably caused by computer use or poor ergonomics. My job involves sitting in front of a computer, and it doesn't feel good toward the end of the day, and I sure don't feel like aggravating it with more computer time after I get home and help feed the kids and put them to bed and do my prescribed physiotherapy. Plus I don't have much spare time anyway.

So bear with me--maybe I can write shorter posts during the odd lunch time; maybe I can do some video posts.

At least I feel like I owe you the second half of my interview with Gil Yosipovitch.

One new thing for now: did anyone notice this link, part of the NIH's campaign for public accountability? It's a list of all the NIH's research expenditures--I think their annual budget is $20 billion, but I haven't taken the time to add up the totals. The list shows money spent per disease, and there are a lot of diseases in the list. But there's one that seems to be missing: eczema. Is it really not there? Not under atopic dermatitis or some other name? Apparently not. Maybe it comes under psoriasis? Does anybody know?

Surely they can't not be funding eczema research. (I KNOW they are at least funding Donald Leung's multisite project.)