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Thread: NIH Grants

  1. #1

    NIH Grants

    Dr Young,

    In the letter to Bush thread you mentioned that grants usually last 3-5 years. Can you explain why this takes so long? To someone outside of this process [like me ], it looks fairly simple once you get the money.

    My idea of how things go:
    <UL TYPE=SQUARE>
    <LI>Get all of the supplies needed (3 months?)
    <LI>injure the animals (2 weeks?)
    <LI>take care of animals until they are in a chronic state (6 months?)
    <LI>treat animals (2 weeks?)
    <LI>see what happens[/list]

    Can you correct my procedure list?

    -Steven

  2. #2

    Steven

    You are really asking two sets of questions. Let me address the first one regarding NIH procedurs. First, it takes NIH about 9 months to review and award the grant. It takes most investigators about 3 months to write the grant (I write pretty fast and it takes mte that long to write a competitive grant). Second, most NIH grants are for a period of 3-5 years. You have specific aims that you propose for each year.

    As for the second set of questions regarding why research takes so long. I don't want to sound as if I am making excuses but research is not a one shot deal. Yes, one experiment takes about a year. But the experiments don't always work out and both preparation and analyzing the data take longer than 3 months on each end. Let me outline the bottlenecks.

    1. People. The most serious obstacle to research is the availability of trained people to do the research. If you have to hire somebody to do the work, it takes months to find a person or persons. Generally, it takes a student about a year, a postdoctoral fellow about 6 months, and an experienced technician about 3 months to learn how to do the procedures. For a laboratory that is starting up on histology, tissue culture, and animal care, it sometimes take a year or more to get everything going. For stem cell work, you essentially need four teams of people to do the work. One team has to do the tissue culture, a second team does the surgery, a third team does the animal care, and the a fourth team does the histology. Of course, you try to overlap the teams but it takes about 4-5 people to run a spinal cord injury laboratory that is able to do cell transplantation in a standardized animal spinal cord injury model.

    2. Culturing stem cells. You don't simply plop the stem cells into an animal. You have to first grow the stem cells to sufficient quantity for implantation. This is not easy. You have to set up a laboratory and be able to grow, isolate, and identify the stem cells. It took us over a year to learn how to culture rat stem cells consistently, even with a lot of help with colleagues and using the published procedures. While there are perhaps 30-40 laboratories that are routinely isolated stem cells in the quality and volume for transplantation, very few or none of the laboratories have the people and facilities to do spinal cord injury. By the way, that is the main reason why we devoted so much effort in the past year to train 50 laboratories around the world to do spinal cord injury research with our Impactor model.

    3. Animal surgery and care. Even for a laboratory like ours with a lot of experience, it takes quite a bit of time to carry out the surgery and animal care. For example, if you are transplanting the animals, you really cannot injure more than 4 animals a day. Say that the surgical team works 4 days a week on the surgery and spends one of the days evaluating the walking behavior of the rats. This means that it will take 4 weeks to injured 50 rats. Frequently, there may be other experiments going on and no laboratory that I know of in the United States has the capability of caring for more than 60 spinal-injured rats at a time. I am not sure that people understand what it means to take care of a spinal-injured rat. We have to squeeze the bladder twice a day, and treat the rats for infections, decubiti, pain, etc. Let's say that it takes 5 minutes to empty the bladder of one rat. That means that you can only do 12 rats an hour. It takes a person 5 hours of continuous work to squeeze the bladders of 60 rats. By the time that is finished, it is time to start the second squeeze of the day. If the animal has any other problems, it will take additional time. By the way, this has to be done 7 days a week. This is one of the reasons why there are so few laboratories doing chronic spinal cord injury experiments. There may be delays in scheduling the animals so that the animal care team is not overwhelmed. You usually have to do an extra 20% animals because some may die of urinary tract infections or other problems. Also, if you wait until they are chronic (4 weeks) and then transplant, this means a second procedure. There is a third procedure, the dye injection to label the spinal cords.

    4. Histological studies of the rats, to determine what the stem cells did (whether it is remyelinating the axons or regenerating the axons) is not trivial. To trace the spinal tracts, you have to inject the animals 2 weeks before and allow the dye to travel down the axons in the spinal cord. Even with two people working full-time, it takes over a week to do serial sectioning, staining, and analyzing the spinal cords of a single rat. There may be as many as 200 slides per rat to look at. It takes 4 hours to just look at 100 slides. If you do 25 rats, that is a minimum of 6 months of histological work. By the way, it is not enough today to show that the rats walked... No journal will accept a paper that reports just walking. They want to know why and whether there is regeneration or remyelination.

    Wise.

  3. #3
    Senior Member mk99's Avatar
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    Big Task

    That sure sounds like a lot of work, time & effort.

    Assuming that everything goes well what happens next?

    Do you have to repeat the same experiment over and over to prove that it is safe for humans? Do different labs have to achieve the same results using the same procedures? Or does the whole thing then get done with a different animal?

    And the final question: when does it finally get to humans?

  4. #4

    just curious

    what are the differences between a rat spinal cord injury and human spinal cord injury? Will they typically lose the same amount of function as humans at the same level? What level are they typically injured at for research studies?

  5. #5

    Yearly aims

    Dr. Young,

    You say that you have specific aims for each year of the 3-5 year grants. Can you give a brief overview of what a proposal would look like?
    <UL TYPE=SQUARE>
    <LI>Year 1 - Treat animals with L1
    <LI>Year 2 - Treat animals with M1
    <LI>Year 3 - Treat animals with combination of L1 and M1[/list]

    I doubt it -- but is that anywhere close?

    Are the people attained and trained before or after the grants are disseminated? I understand that this is a growing field and new people are coming in, but how many in the field would be "experts" or "veterans"?

    Thanks again. :-)

    -Steven

  6. #6

    Steven

    Four years ago, we had a plan that is very similar to the one that you outlined... treat with L1, treat with M1, and combine the two Just getting the L1 experiment going took longer than we thought. We had to make the L1 ourselves, growing vats of genet ically modified cells that expressed minute amounts of mouse L1, purifying liters of the cells and culture media into 1.5 mg of L1 that was just enough to treat 20 rats for two weeks. Those initial experiments showed promising results. We immediately switched over to human L1, thinking that it was essential that we start working on the molecule that would be used in people. It took a year to make the the human L1 and we then tried it out in rats. The human L1 did not work on rats but we were not sure why. After repeating the experiments, we decided that it was because human L1 does not bind well to rat L1. So, we are now making rat L1 and retesting the molecule again. We also tried M1 and found that M1 by itself did not do much for long term recover y of function in rats, when given to chronic spinal injurd rats. As soon as we have a form of L1 again that works in the rat, we will be testing L1 and M1 together.

    In the meantime, we are currently assessing several other treatments for chronic SCI:
    • Olfactory ensheathing glial transplants.
    • Neonatal stem cells (from the subventricular zone)
    • Therapeutic vaccine (the same stuff that Sam David is using)
    • Activated macrophage in acute and chronic rats
    • Radial glial cell transplants
    • Biomaterials that can serve as axonal guides

    We also have projects assessing:
    • New biomaterials that prevent adhesion and scarring of the dura to the spinal cord
    • Acetaminophen and GM1 to prevent autophagia (which we believe is neuropathic pain) in rats
    • Injecting stem cells into muscles to prevent atrophy
    • Regeneration associated genes
    • Pain associated genes
    • Differences between male and female rat responses to injury and therapies

    Much of our time of the past year was devoted to setting up a system so that we can do 3000 experiments per year, developing more efficient techniques to visualize tissue damage-regeneration-remyelination, developing cell lines of olfactory ensheathing glial cells and stem cells, and testing a new genetically modified rat that expresses green fluorescent protein (GFP) so that we can study the transplanted cells without having to stain them. Over the past 12 months, we also developed the first rat gene chip that is designed evaluating spinal cord injury and therapies.

    This summer has consequently been the busiest one of my life. Our Center ramped up from 30 rats per month to 300 rats per month. To do so, we had to automate most of our manual procedures, carry out extensive quality control procedures to make sure that things were working right, and retrained our staff to handle the load and the new instrumentation. We also manufacture the spinal cord Impactor here. Before this year, we were making about 10 Impactors a year with a long list of 2-3 dozen laboratories waiting for the device; we ramped up the production to 100 impactors a year. Over the past 12 months, we trained 50 laboratories to use the model, sharing with them all the other techniques that we are developing, including the impactor model, the new methods of labelling regenerating axons, cell transplantation methods, and our new gene chip designed to assess gene expression in rat spinal cord injury. Our goal is to train another 200 laboratories over the coming three years and form a consortium of all the laboratories so that they can share data through Internet.

    Wise.

  7. #7
    Super Moderator Sue Pendleton's Avatar
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    About autophagia

    Wise, I know you need to keep the rats you're working on as comfortable and ehealthy as possible. But could you use the GM-1/tylenol on a larger animal to speed up any program/progress using it? I'm thinking of the Purdue Vet School's Paralysis Center that works with naturally hurt dogs. But instead of hurt, how about golden retreivers and labradors that suffer autophagia due to allergies?

    Think you might find a dual use treatment for humans and dogs. On my own Golden, Reggie, we have gone the doggie dermatologist route of allergy shots for 18 months--no luck, steroids, 2.5 mg 3 times a week. I hate that. It's doing a number on her hips. We have tried benadryl that works some for pollens but most retreivers are allergic to tons of things. Now the vet has her on the prednisone and Elavil. That had her sleeping 24 hours a day. So we just pulled the Elavil, keeping her on glucosimine/chondritine (vet approves wholeheartedly)and recently stopped the omega 3 & 6 acids because the first batch appeared to work well but this one may be rancid. So now I'm trying to find refrigerated omega 3's..

    Anyway, just kind of curious if giving GM-1 to allergic dogs and also those with SCI might show some effects when given long term to chronic animals.

  8. #8

    Sue

    I think that both the GM1 and acetaminophen can go to clinical trial rapidly if the respective companies become interested. Fidia was recently bought by Merck (I was told this) and I hope will be able to pursue more GM1 studies. They also have synthetic gangliosides that is supposed to be much more potent than GM1 itself.

    Regarding acetaminophen, the dose (64 mg/kg) that we use is not that different from the standard dose that people take. The only problem is that prolonged acetaminophen can cause liver damage and so we are trying to see if there is a way to getting around that. Most of the liver toxicity is related to the oxidative effects of one of acetaminophen's metabolic byproducts. The safety profile of acetaminophen is very well known. We are thinking of combining the acetaminophen with some antioxidants. There is also, interestingly, some new literature coming out suggesting that acetaminophen may have COX-2 inhibiting activity. In any case, it really stops autophagia in rats and this is saving more than several experiments in our lab and others.

    Wise.

  9. #9
    Super Moderator Sue Pendleton's Avatar
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    I know that Fidia has reopened their office in Washington, DC. They closed it right after the 5 year study results came out. I figure that alone was good news.

    And I'll ask my vet about the tylenol. Right now I can just give her 3 baby asprin on non-steroid days. The vet said the stuff coated in maalox doesn't help the stomach at all. Anyway, I hope the stuff comes in cherry flavor because Reggie will at least eat those. Otherwise it's finding the cream cheese to get it into her.

  10. #10
    Dr. Young, after reading some of the abstract that you have posted earlier tonight, I'm still curious to know how rats differ from humans in their injuries. Can you explain?

    what are the differences between a rat spinal cord injury and human spinal cord injury? Will they typically lose the same amount of function as humans at the same level? What level are they typically injured at for research studies?

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