Surprise: Th2 cells, inflammation high in both allergic, non-allergic eczema

When I talked to Jon Hanifin last year he mentioned an intriguing fact: eczema comes in two general types. About 80% of atopic eczema patients have allergies and high levels of IgE antibodies. But twenty per cent of patients have eczema without allergies.

The technical term for allergic eczema is “extrinsic” atopic dermatitis; the non-allergic kind is “intrinsic” AD.

Production of IgE—and most antibodies—is activated by type 2 helper T cells. So scientists have generally assumed that extrinsic AD patients had overactive type 2 helper T cells. But new research shows that type 2 helper T cells are overactive in both intrinsic and extrinsic AD patients.

The scientists, led by Emma Guttman-Yassky at Rockefeller University in New York City, analyzed skin and blood samples from 42 extrinsic and 9 intrinsic AD patients, looking at molecular and cellular differences in the immune system and the skin.

They found that type 2 helper T cell activation is actually higher in intrinsic AD patients than extrinsic AD patients. In fact, markers of inflammation in general are higher in intrinsic AD.

Figure 6 from the paper. Scientists now resort to "word clouds" to convey the complexity of molecular biology!

The results are surprising. Patients with intrinsic AD generally do not go on to develop asthma or allergic rhinitis; yet if you just looked at their helper T cells you’d think they were guaranteed to experience even more severe allergies than those suffered by extrinsic AD patients.

So what's keeping down the IgE levels in intrinsic AD? In the paper, the authors speculate freely, but so far there is no answer.

It also appears that a special class of helper T cells known as type 17 (so-called because they produce the signaling molecule IL-17A) are also more active in intrinsic than extrinsic AD. It’s not clear yet how scientists might  use this knowledge to design therapies more specific than current T cell-suppressing options such as ciclosporin, which can have severe side effects.

The research suggests that future T-cell related therapies will likely be similar for intrinsic and extrinsic AD, despite the different nature of the disease in the two patient groups.

Hat tip to KMO.

Where to look for a surprise eczema cure to emerge

As I wrote in the previous post, the outlook is bleak for new eczema therapies that might qualify as a “cure.” On the fronts of barrier protection and repair and anti-inflammatories, nothing revolutionary is in the works apart from, perhaps, dupilumab, Regeneron’s antibody to IL-4. I can’t see anything emerging from research and entering and successfully exiting clinical trials for at least 25 years.

What might I have left out of this discussion? Where could a surprise come from?

Itch. Itch was the area that occurred to me. Imagine being able to break the itch-scratch cycle in eczema. You know what it’s like: your skin flares up and the itch becomes unbearable. You scratch to get relief. Sometimes you scratch in your sleep. Then your skin is torn up, which for a start can be embarrassing, but also often leads to infection. If there were no itch to begin with, eczema might never become anything more than a minor rash. Its impact on quality of life would be greatly minimized.

I believe we might see a convergence of two major trends that would result in a new anti-itch drug that patients could take in pill or cream form.

The first trend: In the past few years I have seen a number of papers describing newly identified neurons that transmit the sensation of itch, distinct from pain. The experiments were done on animals such as mice and cats; I don’t think these neurons have been found in people yet. But you can bet there are many scientists beavering away to be the first in the field.

Turning on or blocking neural receptors is what drugs do best. Think anesthetics. These itch neurons, if found in humans, are likely going to have receptors similar to those in other animals, and the search will be on to find drugs that block the receptors.

(You could also imagine a therapy using RNA interference to prevent neurons in the skin from making itch receptors in the first place.)

The second trend: scientists are developing powerful new techniques to speed the drug discovery process. While it does take around 15 years to take a new drug all the way through clinical trials to FDA approval, the path is shorter for “repurposed” drugs (such as Viagra, originally planned as a heart medication). The barrier is lower because the drug has already been proven nontoxic. Repurposed drugs have been approved as treatments for one condition but have side effects that, depending on your perspective, qualify as primary effects. There could well be an FDA-approved anti-itch drug out there already. It’s just being used to treat toenail fungus.

A company I am familiar with (I know the founders), SeaChange Pharmaceuticals, developed a rigorous way to search through databases of drugs and identify potential side effects or secondary uses, based on the chemistry of the protein targets for the drugs. (Wired magazine named SeaChange’s technology one of the top 10 breakthroughs of 2009.)

The idea would be that scientists would identify itch neurons in humans, and pin down the itch receptor; then somebody at Pfizer or Novartis or whatever would use a SeaChange-like technique to find FDA-approved drugs that block the receptor. Presto: no more itch. Conceivably this might happen within a decade.

Now, evidently these new drug discovery techniques could be applied in the areas of anti-inflammatories, or barrier repair. I think, though, that itch is a prime candidate for a surprise eczema “cure” because it’s likely that the itch sensation comes down to a single receptor. Blocking that receptor by a conventional drug will be a relatively simple task, compared to controlling inflammation without leaving the patient vulnerable to infection, or taking on the dubious task of compensating for a defective skin barrier in infants.

That’s my opinion.

Why there will be no cure for eczema for at least 25 years

In a previous post, I made the Eeyore-like prediction that we are unlikely to see a cure for eczema during my lifetime, which means the next 40 years.

Upon reflection, I have become more optimistic: now I only think we might have 25 years to wait.

Several factors combine to make this so: our incomplete understanding of eczema; the ratchet-like course of the disease; its allergic component; and the expense and inertia of drug development.

As currently understood, eczema is initially a defective skin barrier that lets in allergens. In the first few years of life, children develop antibodies that protect them from disease over their lifetime. The defective barrier overstimulates this part of the immune system, and children build the capacity for allergic reactions to common things in the environment that most people don’t react to—pollen and foods for example.

The allergies get locked in. What may originally have been a leaky skin barrier now gets connected to allergies and inflammation.

In recent years scientists have discovered a number of genetic defects in various components of the skin barrier—the super-protein filaggrin, in particular. I can understand that the average patient must have the impression that with this genetic data is coming in, all that scientists have to do is develop targeted drugs to solve the defects. Or gene therapy to replace the bad genes. Surely these are on the horizon?

Here’s why they aren’t. Let’s start with gene therapy. Only one gene therapeutic has been approved anywhere in the world. The European Commission gave permission for Glybera to be used to treat a rare metabolic disease. Gene therapy is most famous in the US for the 1999 death of a teenager who signed up for a risky clinical trial. It is unlikely that over the next few decades we’ll see gene therapies emerge for anything but rare, fatal, incurable diseases. Eczema doesn’t qualify—and even if you could fix the skin barrier by gene therapy, you’d have to act within the first few months of life. What parent would let doctors give their newborn a potentially lethal treatment based only on the likelihood that the kid might grow up to have eczema?

Another possibility is RNA interference, a technique that blocks the conversion of genetic information into protein. RNAi was discovered sometime in the past two decades and recently the FDA approved the very first RNAi therapeutic, for a rare metabolic disease. To treat eczema, RNAi might be used to cut down on the amount of inflammatory molecules produced in the body or in the skin. A number of academic laboratories--I am aware of a couple in Japan--are looking at RNAi for eczema. However, there are no therapies anywhere near a clinical trial, and new "drugs" in this field would face even steeper regulatory hurdles than conventional drugs. Conversely, the reason to get excited about RNAi is that in theory it could allow us to choose which inflammatory molecules to turn off (rather than shutting down most of the immune system, as steroids do).

Now, let's consider traditional drug discovery. Research does show that filaggrin defects are found in up to 50% of patients with severe eczema. (Naturally, there are apparently unaffected people who have filaggrin defects, as well as eczema patients who do not.)

So you’re going to develop some drug to target filaggrin? Irwin McLean, the filaggrin expert, says that targeting filaggrin could have a big payoff. But he admits that little is known about how the filaggrin gene is turned on or off. Eventually we will know, and perhaps that knowledge will suggest what drug might work.

The question is how a drug might fix or compensate for the defect. [See the comments for a couple possibilities.] And if we eventually find a drug that can correct for a single or double filaggrin mutation, there is still the question of how much benefit that will provide if a patient has already developed allergies.

Drugs are just not custom-designed—that is currently a pipe dream. Drug discovery is time-consuming and costly. It takes $1 billion and 15 years of trials to get a drug approved by the FDA. Scientists start with the protein of interest. Then they screen gigantic libraries of drugs to see if any of them affect the protein in useful ways. They tweak those initial “lead” compounds to make them better.

Then they file an application for a new drug. Then they proceed to animal trials: mice, rats, dogs, pigs, chimps. Then human trials—phase 1, 2, 3, 4. At any stage, and if you’re lucky it’s the early going, it can become apparent that your drug is ineffective or toxic.

And here’s another factor: many proteins are just not “druggable” for various reasons. Because of the shape of the molecule or the way it interacts with something else, tiny drug molecules can’t get to the active site; or they get in but can’t get out. Etc.

It is extremely difficult to develop new drugs.

Also, in the past few years the pharmaceutical industry has been in a slow-motion crash. Big companies are laying off scientists because a lot of the original big moneymaking drugs are coming off-patent and not generating enough income for R&D anymore.

Add to this the fact that there’s hardly anything in the pipeline for atopic dermatitis. I know Anacor has two candidates in Phase II trials—new topical anti-inflammatories. Great,  but hardly revolutionary. Regeneron has something interesting going: dupilumab, a monoclonal anti-IL4 antibody. It’s in Phase I.

Venture capital won’t even invest in startup companies unless their technology has passed Phase II.

You can understand my pessimism.

Next: why I might be wrong

The Eczema Map Project: the big picture

Something I've wanted to do for a long time is create a world map of all the major centers or points of interest for eczema patients, doctors and scientists.

Why? Because I feel that we're all largely isolated, even in the internet age. Especially with a disease that makes you want to stay away from other people. We can get on our computers and search for blogs or advice or therapies, but there's very little sense of belonging to a greater community. We don't know what's going on in the big picture.

And so I would like to introduce to you the Eczema Map Project, a work in progress. It is a map of the world marking the locations of key researchers, therapy centers, and patient associations.

I've decided to make the map a permanent tab on this blog, so I can update it continually when I learn about new people or developments.

The items on this map are those that I consider significant--game-changers, not just good dermatologists. But please feel free to write a comment about your dermatologist if you think he or she is above average!

You can see that at present the map is a bit USA and UK-centric. This could be for a few reasons. I largely operate in English, and I live in California, so I tend to hear about developments in the USA more than anywhere else. But it is true that the USA is a very large and well-developed country with some of the best medical care in the world (for those who can afford it--an issue I have strong opinions on, but which I am not going to get into right now). So it may turn out that more of the most important sites are indeed here.

But please tell me what is missing from this map. Is there a major therapy center or a patient association I don't know about? Leading scientists not there? Tell me, and I'll add them. Or, if you think an item doesn't merit being listed, let me know. Nothing is set in stone.

And have fun exploring the world map from an eczema perspective.



View The Eczema Map Project in a full screen map

New type of white blood cell identified; may play role in eczema

Scientists have identified a new type of white blood cell found in the upper layers of the skin that can either trigger or shut down inflammation.

The research was carried out in mice, which are commonly used as models for the human immune system. There is no proof that the same cells exist in humans, but these results will certainly impel researchers to look for them. It is possible that the newly identified cells play a role in eczema.

The cell type, “group 2 innate lymphoid cells” (ILC2), protects mice against parasitic worms called helminths. In mice, the cells appear to be the main source of the signaling molecule IL-13, known to be important in type 2 immunity—the arm of the immune system that is over-active in allergic disease and eczema.

The scientists took video that showed ILC2 cells moving around in the skin and occasionally stopping to make physical contact with mast cells. Mast cells play an important role in the early stages of inflammation. They are suppressed by IL-13.

However, the researchers also introduced ILC2 cells into mice that had no B or T cells (the white blood cells responsible for much of the immune response). In these mice, stimulating ILC2 cells caused inflammation with symptoms that looked like eczema.

So it appears that ILC2 cells can increase or decrease inflammation, depending on the signaling molecules they secrete. Potentially, drugs might be discovered to control ILC2 cells in the skin and, through them, manage eczema.

The research was performed by a joint Australian/New Zealand/American team led by Wolfgang Weninger, a professor of dermatology at the University of Sydney. It was published in the journal Nature Immunology.

Rochester group to focus on skin barrier

Alice Pentland, chair of the Department of Dermatology at the University of Rochester Medical Center, whom I interviewed recently for a post on the NEA website, also directs the newly-formed Skin Barrier Research Consortium, a subunit of her department. The group, as its name suggests, brings together scientists studying the skin barrier--in particular, its permeability, which is thought to be a key factor in allergic eczema, and which could in normal skin be temporarily increased to administer needle-free vaccines.

I learned about the consortium from a Rochester press release. According to Pentland there is no special funding. They aren't applying for any large NIH grants. So the group's formation is symbolic. But it might give the department a mission, and could make it a more formidable applicant for future grants.

Pentland detailed the roles of the researchers in the consortium for me. Of particular interest to eczema patients:

• Lisa Beck, who is conducting a pilot-stage clinical trial of Actos, a drug originally developed for diabetics but also found to increase the integrity of the skin. Beck is also building a registry of patients (apparently more than 200 now) who have "classic" (and I'd assume that means "allergic") atopic dermatitis, partly characterized by high levels of IgE antibodies in the blood. A major problem for dermatologists, Pentland said, is that several conditions look like AD on the surface but aren't. A vetted registry of patients will help researchers study causes of AD.
• Anna De Benedetto, a doctor who is studying how the electrical resistance of skin is correlated with its permeability
• Ben Miller, a chemist who is synthesizing small drug molecules aimed at targets identified by others in the group
• Lisa DeLouise, a material scientist looking at how a changed skin barrier, caused by AD or sunburn, may make nanoparticles toxic when they normally wouldn't be
• and Elaine Gilmore, who studies the molecular mechanisms of itch.

"It's a good broad-spectrum effort," Pentland says of the consortium. I'll be following their work. I'm most excited about the Actos trial, but I look forward to learning about collaborations between members of the group.

Staph aureus throws a party in untreated eczema patches

We are not alone. Wherever we go, we carry our personal microbiological party along with us--in our gut, in our intestine, and naturally on our skin. We're crawling, even the healthiest of us, with ten bacteria, viruses, protozoa, etc. for every cell in our body.

New research has revealed an interesting difference between the skin microbiomes of patients who do and don't use pharmaceuticals to control their eczema. A recent study in the journal Genome Research finds that Staphylococcus aureus has pooped the party--it dominates the population of bacteria in untreated skin. On the skin of patients who use steroids, calcineurin inhibitors such as Protopic, or antibiotics, S. aureus shares its living quarters much more equitably with its bacterial cousins.

The authors of the paper, led by Heidi Kong and Julia Segre at NIH, used a technique called "16S ribosomal RNA bacterial gene sequencing" to catalog the bacterial population in two body locations at which eczema commonly occurs--the insides of the elbows and the backs of the knees--in 12 kids with eczema and 11 healthy controls.

(They used this type of sequencing because the method usually used to assay bacteria, which is to swab and try to grow a culture, may favor the growth of certain species over others. 16S sequencing provides a snapshot of all bacteria species present at any one time.)

S. aureus dominates flareup regions in patients who don't treat eczema. (Fig 3A.  from Kong et al.)

In the controls and the eczema patients before flareups, the bacterial populations were quite similar, with the eczema patients hosting populations in which S. aureus owned twice as much market share as it did in the controls.But during flares, the main finding was that in the patients who didn't treat their eczema (to be specific: they hadn't taken an oral antibiotic for the previous 4 weeks, or applied a topical treatment in the previous week), 90% of the bacterial population was Staphylococcus, compared to 20% for the patients who had treated their skin.

The scientists observed other shifts in the bacterial population on untreated skin, too. Several other species increased their relative numbers--especially Staphylococcus epidermidis, often thought to be a "commensal"--which I take to mean relatively harmless--species on healthy skin. It appears that S. aureus and S.epidermidis have some kind of symbiotic relationship--the two are helping each other out, or one is parasitic on the other in some way.

Very interesting research, although there's not much for an eczema patient to take away. Naively, one might think that this shows it is better to treat one's eczema than not. But there was nothing about the eczema in untreated skin being worse; the number of patients in the study is small; and there's a lot of variation (of course) among the data for the patients who treated their skin. What did they treat it with? We don't know. Could it be that applying a steroid helps keep down the S. aureus population? That would be weird indeed, because S. aureus folliculitis is a known side effect of strong steroid use. I'll go out on a limb and say that antibiotics are probably better than steroids for keeping S. aureus down in the short term.

One small frustrating point is that the 16S sequencing technique doesn't seem to provide absolute numbers. I'll exaggerate to make the point: Maybe there are 100 bacteria total in your elbow to start, 20 of which are S. aureus, and during a flare there are now 100,000 bacteria, but 90,000 of them are S. aureus. Or maybe there are 90 billion S. aureus out of 100 billion during a flare. This paper doesn't give you any idea of the scale.

Itch, and scratch relief, depends where it is on the body

A new study [media summary] by itch guru Gil Yosipovitch and colleagues at Wake Forest University has shown that the intensity of itch, and the pleasure of relieving it by scratching, depends on the precise location on the body that a standard itch stimulus is applied.

In standard studies of itch (and, one would presume, creams and ointments designed to relieve it) the usual site of focus has been the underside of the forearm. But Yosipovitch and colleagues, who compared itch on the forearm, the back (slightly to one side of the spine, near the middle) and the ankle, find that itch is sensed more intensely on both ankle and back, and the pleasure of scratching lasts longer on the ankle--even after the itch has dropped off--than on the forearm.

They used "cowhage spicules," which I think are akin to nettle spines, to cause the itch, and a standard laboratory scratching brush to relieve it in 18 volunteers. The paper, which is open-access, doesn't mention whether any of the volunteers had eczema. This matters, I think, because you'd expect eczema patients to perceive and respond to itch differently than "normal" people.

The authors, in their discussion section, speculate on why itch intensity and scratch relief differ across the body. They discuss various types of nerve fibers that might be responsible, but come to no conclusion. Really the paper just poses a question: why are these differences there? And we could expect, in following work, that they might narrow the answer down to the presence or absence of nerve types. It's clear that the mechanism of itch and relief is far from understood.

[It occurred to me later that maybe this research points to the need for different anti-itch treatments for different parts of the body. Whether they work or not, I can imagine companies claiming that various ointments and creams are optimized for your hands or whatever.]

Common antibacterial also suppresses mast cells--maybe why it works for eczema

Triclosan is a well-known antibacterial found in soaps. I know I've seen it listed on every pump-container of liquid soap that claims to "kill 99% of bacteria," whatever that means. (99% of species? 99% of one species?) What I didn't know until recently about triclosan, which is found in a wide range of consumer products, is that it relieves symptoms of eczema. But scientists are not sure exactly how it works.

New research by scientists led by Julie Gosse at the University of Maine shows that at least one reason that triclosan helps reduce eczema symptoms is that it prevents mast cells in the skin from releasing histamine and other allergy-mediating molecules. Triclosan prevented the scientists' model cells from getting activated in general. In short, it's an immunosuppressant.

Mast cells have molecules on their surfaces that bind to IgE antibodies--the type responsible for allergic hypersensitivity. When mast cells encounter antigen, perhaps from food or pet dander, they release histamine and other molecules, which cause inflammation.

The scientists, working with a laboratory cell line that they claim is identical to mast cells, found that doses of triclosan significantly reduced the amount of one molecule, beta-hexosaminidase, released by the cells when they met antigen.

Activated mast cells change shape, ruffling around the edges. Triclosan also prevented this from happening.

The scientists claim their results show that reducing "degranulation"--the release of granules stored by mast cells--is the way that triclosan helps alleviate skin inflammation in eczema.

Through the paper, the authors refer to histamine--but reducing histamine probably isn't the main avenue by which triclosan acts. If you have eczema, you know that antihistamines don't help. I don't know why some doctors prescribe them. Relatively recent research (I wrote about it here) has identified a neural itch pathway independent of histamine.

So what good is this research?

It helps clarify the picture of what triclosan is doing. It's a contribution that could, in the end, help produce another topical anti-itch ointment that incorporates triclosan or some derivative, possibly together with a steroid. You'd think it'd be a no-brainer, because of its antibacterial properties. But, like any drug, triclosan comes with its own side effects.

[Edited Jan.13]

Scientists: We want you to stop the itch

On Twitter I heard about this survey that the University of Nottingham is doing. You can do it too!...it's not exactly a big investment of effort. They ask you what you would like to learn from eczema research. I'd assume that they are hoping to get some interesting questions, like "how do food allergies develop in children aged 1-3" or "what are the genetic defects in structural proteins in the skin that are most strongly linked to adult eczema."

As a relatively well-educated guy with an interest in eczema, I was interested to step outside my skin, so to speak, and watch as I entered in my questions in the survey--I didn't think too hard, so they were my knee-jerk reactions, what I want to know at a primal level:

1. how can I stop scratching?
2. how can I stop scratching at night?
3. how can I stop my scratched skin from getting infected?

Not exactly PhD material, eh?

But I think this illustrates what patients want from researchers. We are not interested in the science. We want results. And there's basically one thing we want: we want the itch to stop. If the itch stops, the scratching stops, and then there's much less risk of infection. So our challenge to researchers is "figure out what's causing the itch in eczema. Then figure out how to stop it."

I do have to say that eczema is a fascinating condition, though, when you start to read the scientific literature. I just wish my interest in it was purely intellectual.

Julie Block at the NEA asked me to write a brief research summary for the next e-newsletter, about a new discovery in itch pathways. When the newsletter comes out I'll comment on it.

Math nerds identify possible cause of persistent inflammation in eczema

Researchers in London have developed a mathematical model of a molecular feedback loop thought to cause persistent inflammation in eczema patients.

Normal skin is maintained in a steady state in which old skin cells slough off and are continually replaced by new ones pushing from beneath. Flattened skin cells called keratinocytes are initially held together with bonds that are digested by enzymes called "kallikreins," according to a recent paper in the journal PLoS One. Kallikreins also cleave a receptor called PAR2 that, in normal skin, controls the skin steady state but, in eczematous skin, turns on a type of autoimmune response.

The authors of the PLoS One paper observe that, in eczema, inflammation that can start with a mild or short-lived stimulus (such as scratchy clothing) persists far longer than it does in healthy skin. They make the hypothesis that this is the result of a feedback loop between PAR2 and kallikreins. Even when the initial stimulus is gone, this feedback loop--like a screaming speaker connected to a microphone in front of it--keeps eczematous skin inflamed.

The authors ran their model on a computer (actually, they probably ran many models thousands of times on different computers, and tweaked tens or hundreds of parameters until they got the answers they wanted) and showed that it behaved consistently with data from real patients. So it's consistent with reality that there may be a positive feedback between PAR2 and kallikreins, or a negative feedback between PAR2 and a molecule called LEKTI that inhibits kallikreins.

They don't say this right out, but a potential benefit of this work--way, way, way down the line--is that if further modelling and experiments show that this feedback loop is real, then we may be able to break the loop with a custom-designed or -discovered drug, and stop inflammation quickly in eczema.

NEA eczema research grants too small. Philanthropist needs to step up

Julie Block at the National Eczema Association recently announced that the NEA offers research grants of $10-25k/year. I am all for supporting eczema research, both basic investigations into the causes of eczema and applied projects to help treat it. That’s why, as a patient and parent, although I applaud the NEA’s program--who else is doing this for us?--but I think it’s way too small. Someone needs to give it a boost.

Now, I know that the NEA’s primary purpose is patient support, and I know that sometimes these tiny grants can be used as leverage on bigger grant applications. Martin Steinhoff, I think, told me that NIH “study groups” that decide who gets federal money give great weight to grants from patient advocacy groups like NEA. They're a seal of approval.

Nevertheless, let me give a bit of perspective. Modern biology is expensive. The salary alone of a single graduate student is $50k/yr (counting overhead). The last time I looked at NIH research grants, the median grant was $250k. And, from what I’ve seen, the budget for a single lab at the University of California is at least $1M/year. Bigger labs, $2.5M/yr, a hundred times as much as an NEA grant.

Plus, here’s another issue: I don’t think leading scientists are going to bother applying for $10-25k grants. They’re not worth the time of a Kevan Shokat or a Carolyn Bertozzi: an innovator who could make radical discoveries that would transform a research field.

So we need to think bigger. How can the NEA get more money for its grant programs? We can’t rely on the NIH alone to fund eczema research. They don’t even include eczema as a condition worth listing in their public accounts.

The NEA is not going to get money from the government. And at their current annual subscription fee, they’re not going to get it from you or me. They might get it from one or more wealthy philanthropists who either themselves suffer from eczema or who have close family members who do.

And these philanthropists are going to want to know that they are not throwing their money away, giving it to scientists to buy expensive toys. They are going to want to know there is good management in place, with a plan that includes milestones. Would we be ready to convince such a philanthropist that we merit their money?

Or, possibly, someone would be interested in offering a prize, like an X Prize (an Ecz Prize?) of a million dollars or more for the first research group to, say, provide an effective pH-balanced filaggrin-based scalp moisturizer. Big prizes, so the scuttlebutt goes, offer a factor of ten leverage. You pay a prize of $1 million, but you get $10 million worth of research done by competing groups. Plus, a prize draws attention to a challenge.

The question is: what goal would a prize be offered for? Eczema is such a complex problem, and we’re far from a complete understanding of it. So what realistic, inspirational goals could a prize committee set? I’d be happy to learn of parallels where this approach has worked for other conditions.

End Eczema's mission: please donate to the NEA for research

This past Thursday I spoke on the phone with Julie Block, president and CEO of the National Eczema Association, and Diane Dunn, the NEA's communications and program manager.

I thought that Julie and Diane's outlook was very similar to mine. Eczema is a disease that affects millions of people (in the U.S., 20% of children and 2% of adults, which probably means that 50 million people live with it in the home). It can drastically affect quality of life. It leaves a sufferer open to serious infections such as MRSA, and disqualifies them for military service.

And yet you hardly ever see eczema mentioned in the media. (Can you think of any blogs? Any celebrities?) You rarely, if ever, hear of any fundraising efforts for it. It is, despite being a disease of the skin--and we use the term "skin deep" for something that you have to look beyond to find the essence--virtually invisible.

This is probably because most of us cover it up. I know I do. Why would I want to expose an unsightly rash that reveals my lack of self-control? I wear long pants and shirts with collars and long sleeves. I go to the swimming pool only with great reluctance. People stare, sometimes. They hustle their babies away from your kids to avoid what looks like a contagious rash. We who live with it are ashamed; those who don't are ignorant.

The NEA was the first eczema patient advocacy organization I have heard of in my lifetime. I think they're amazing and they deserve our support. They are primarily dedicated to education and outreach; and this is good. We need to educate ourselves about the best therapies. We need to educate others so they understand. We need to exert pressure on our representatives in government so they direct federal research funding to eczema.

The NEA doesn't make a priority of research, and it can't be faulted. If you've got an annual budget of $500k and several salaries to pay, along with the travel expenses of a national association, you can't  make a significant investment in research. A single molecular biology laboratory, at any major university or institute--Johns Hopkins, U. of Washington, Stanford--runs on at least $1 million a year. A single graduate student costs $50,000 a year. Reagents, antibodies, experimental animals are terribly expensive. The responsibility for funding the research effort lies with the federal government, via the National Institutes of Health.

But there are ways in which grants on the order of $100,000 can make a difference. They can prime the pump; often, in academic research, to get money, you need to have money already, because many agencies will only deliver matching funds. And if you can show that someone believes in your project to the extent of handing over $100k, you can make a better case for why the NIH should give you $1 million. The NEA has seen this happen with grants to researchers Eric Simpson and Gil Yosipovitch.

Also, there is one crucial, oft-neglected zone called the "valley of death." Scientists may make a discovery, funded by the NIH, and this discovery may hold the potential to be a world-changing cure, but if it doesn't get translated into a product or service that can be delivered or manufactured by a commercial company, it stands virtually no chance of helping anyone in the real world. NIH funding drops off steeply after a discovery is made. And venture capitalists won't invest in a project or startup that hasn't shown a viable prototype or undergone clinical trials. The "valley of death" is the arid region between federal and venture funding where many promising ideas have met their end.

Proof-of-concept funding, in packages of $100k, can enable an academic scientist to fund a postdoctoral fellow for a year and buy equipment and supplies to run crucial experiments, build vital prototypes, and do the research to show that their technology has a market. Two examples of institutes that provide this type of funding are University College London Business and QB3, the California Institute for Quantitative Biosciences. In the U.S., proof-of-concept funding can enable a startup company to win a federal Small Business Innovation Research (SBIR) grant that helps it get off the ground.

So: if the NEA were able to make several annual awards of about $50-100k, it could give eczema research leverage that would amplify federal funding and/or increase the rate at which practical cures emerge.

I believe in the NEA and so I am dedicating this blog to the purpose of raising $1 million for the NEA to devote to research. I'm hoping that people who are thus inspired to donate to the NEA will mention my blog to the NEA, so I can have some idea whether I'm getting close to my goal.

And ultimately, the real goal is to end eczema.

Dr. Jazz and a truly massive eczema research grant

Today's a special day for me: yes, I'm officially one year older. At this stage of life, I'm satisfied with "Happy birthday, daddy" from the kid who can talk, a slobbery mauling from the one who can't, and a rendition of "Happy Birthday" from Hidden B, who doesn't sing out of tune so much as she sings each line in a different key.

My birthday present to myself? Either I am going to crack open that bottle of Aussie white wine and enjoy a few glasses, or I'm NOT going to open it, and spare myself the consequent itching. Ah, it's no contest: I'm going to open the bottle. You only live once.

I made my first inquiries today, to a doctor I work with professionally, about how to start a foundation. I'll call him Dr. Jazz, since he likes to play jazz on his stereo when he's in the office, so when you're in the conference room you feel like all you need is a highball and a cigarette. Dr. Jazz is deeply involved in translational research (that is, turning bench science into cures). His specialty is prostate cancer. He didn't have a ready answer for me-- he said that if someone suddenly handed me $100k I could, for starters, open a bank account in the name of the foundation. But to create a real foundation you need a lawyer. There has to be a lawyer out there willing to bill this pro bono. Dr. Jazz happens to know a wealthy donor who is on the boards of several patient advocacy foundations, and he's going to put me in touch with him, so I can get some advice and maybe an introduction.

Everyone knows that in the U.S., the National Institutes of Health are by far the most important source of funding for biomedical research. The NIH makes its funding numbers public, and you can look them up. Go to projectreporter.nih.gov and use the search engine. Type in "eczema" and see what comes up.

So I made an interesting discovery. About 45 grants were given in fiscal year 2010. Since some grants are portioned out over several years, and some major grants may have been given in 2008 or 2009 or whatever and still be active, this is just a snapshot, but it's very useful. Most of the grants are for amounts in the range $300k to $500k, with a handful at $2M. So $1M is clearly enough to fund two significant projects, but not a remarkable amount-- I am not out of line to plan on raising $1M.

Here's the humdinger. One of the grants is for $32M. It is by far the largest, two orders of magnitude greater than the median. Donald Leung (in the NIH database, he's listed as "David," but that's not his name) at the National Jewish Health Center in Denver, Colorado, is the principal investigator for an absolutely massive project called the Atopic Dermatitis Research Network. The ADRN brings together scientists from ten campuses for a five-year effort to understand and contain staph-related infections in people with eczema.

I'm going to find out more about the ADRN. From my perspective as a patient with eczema, and the father of one (and cousin, and brother, and grandson) staph infections are a truly nasty aspect of the condition. I've had two severe whole-body outbreaks in my life and I continually experience minor infections that I'm aware could always bust out into something that could put me in hospital. The possibility that the ADRN could produce valuable knowledge and real therapeutics is exciting.

Second thoughts? Nope

Since my first post I've certainly had second thoughts. What the hell was I doing, signing up for this? Raise a million bucks? I was watching an episode of Life on DVD with Hidden B, and suddenly I broke out in a cold sweat. It's like the time someone signed me up for the talent show in grad school and there's a week to go and I still haven't figured out what I'll be doing; all I know is that I'll be making an ass of myself in front of a lot of people.

Fortunately the internet allows me a degree of anonymity. I'll be making an ass of myself but I'll have a paper bag over my head. I'm still serious about this thing.

What really freaked me out at first was not the thought of writing, but the thought that at some point someone might write me seriously and offer funding, but demand that I tell them what I planned to do with it. Let me be perfectly clear: nobody's handing ME money. I'm going to set up a foundation with pro bono legal advice, and get a first-class scientific advisory board. My model for this is the Multiple Myeloma Research Foundation--something I have to look into in greater detail-- but those guys have it worked out right. They distribute money, but they make damn sure the scientists receiving it do what they're supposed to. They set goals and run the foundation like a business.

A random thought that occurred to me. When I said $1 million, I meant $1 million USD. (I'm a dual Canadian-American citizen and ought to make the distinction.) But that's just an amount. The currency doesn't matter.

What might matter, I think, is where drug trials get done, when it comes to that. Drug trials probably have to be done in the U.S. If the FDA doesn't approve a drug it won't have the necessary market potential to make it viable to produce.

Let's start with $1 million

What is the purpose of this blog?

Hey, I'm allowed to be ambitious.

I want to end eczema. Nobody should have to live with this nasty condition. It can make your life hellish; it can make you wish it was over. I know all about eczema. I was born with it about 40 years ago and it has been with me ever since. It's in my family. My father's father had it. A cousin has it. My sister does. And guess what, I've managed to pass it on to my daughter.

To start with, I want to raise a million dollars for eczema research. That's right, a million bucks. This is not a number I associate with any bank account of mine. But I work at a major research university and I know roughly what it takes to get a real project that produces results off the ground.

In fact, a million isn't anywhere near enough to start solving this problem. But we have to start somewhere.

In posts to come I will talk about what we might get started with a million dollars. Now let me say what inspired me to get off my ass and write.

Last year I signed up for the newsletter from the National Eczema Association. These folks are wonderful. I felt like "at last, here's a charity that means something to me." I'm always getting unsolicited phone calls from foundations for breast cancer research, AIDS, veterans, policemen, terminally ill children. And I know that these are all worthy causes. Hell, I have relatives who have died from cancer and someone dear to me is living with it. But I live every day with my personal curse and I never hear about anyone doing anything for me. Now it's not even about me--it's about my children and (I hope) grandchildren. And anyone else who lives with the pain and shame of chronic itch.

So yesterday I get the NEA's annual report in the mail. It lists all their accounting numbers and the times they were mentioned in the media. In short, eczema is not on the media map. And the NEA's budget is too small by a factor of 10, if I'm being generous. Total revenues for fiscal year 2009: $529,668. Total expenses: $525,582. Of the expenses, for support, education, and awareness: $372, 415. For research: $30,961.

That's right, thirty-one thousand dollars.

My business is science, and I know $31k is not enough to pay a single graduate student salary for a year. (I also know that the National Institutes of Health are the major research funding agency in the U.S., and I would like to find out at what level they're supporting eczema research.) But I am convinced, and I have evidence, that patient advocacy groups can make a difference. For one thing, the NIH tends to support basic research and loses interest once that research becomes useful for anything. Patients themselves only care about results.

I know that wealthy philanthropists regularly write checks for many millions of dollars. One or more of these people either has eczema or has a child or grandchild with it. And they might like to donate, but it hasn't occurred to them that they can, or they don't know where to give, or which scientists or doctors are really worth supporting.

I'm going to find the big donors and get their money to work. My hope is that this blog helps them find me. I'll work out the details as I go along. Are you with me?