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Thread: To identify world's best practice for animal testing of new spinal cord injury 2003

  1. #1
    Senior Member Leo's Avatar
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    To identify world's best practice for animal testing of new spinal cord injury 2003

    Stumbled across this report by Ferguson. Every time I read it I get more frustrated with researchers. Wise had talked about this standard problem but it didn't hit home until i read this. Also noticed some well estabished relationships between researchers that bothers me. The I'll scratch your back thing. If you have a foundation or a state group handing out money you should read this for sure.
    http://www.churchilltrust.com.au/Fel...Ian%202003.pdf

    "All you have to decide is what to do with the time that is given you."
    Gandolf the Gray

  2. #2
    Leo, could you explain? What did you feel after reading this pdf?

  3. #3
    Leo,
    Scientific research in all it's glory is...
    a big business enterprise.
    And a business we so desperately count on.

    There is never all good or all bad.
    And egos abound in every facet of life.

    Look at Gallo and the French in the first days of AIDS studies.
    Heck Sabin and Salk became enemies that didn't speak to each other again in their lives.
    And the list is long.

    There was only one Jesus..then money, fame,
    and power took over.

  4. #4
    "There was only one Jesus"
    Thank god for that!

  5. #5
    Senior Member Leo's Avatar
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    Hi Wise, Not sure if you saw this. Have any of these issues raised as problems in this study been addressed yet or in the process of being?

    In no way being critical to you, but the research community seems as screwed up as us SCI. But yet we're getting there.

    Findings
    1. Failure to replicate important SCI treatment approaches is reflected in lack of enthusiasm by some SCI experts for rapidly progressing into clinical trials.
    2. Institution level replication testing of published SCI study now underway.
    3. Replication studies will rely on methods described in the publication, not on the study authors.
    4. The results of the replication studies will be published.
    5. The selection process is important with about 10 studies to be replicated over 5 years.
    6. Basic SCI research appears more important than translation in leading SCI centers in USA.
    7. Individual researcher preference is driving SCI animal study design.
    8. SCI methods publications may contain insufficient detail to perform the method properly.
    9. SCI Technique training programs are critical to facilitating translation.
    10. SCI Foundations have a duty to champion translation efforts.

    At least two things jumped out,

    4 differant type of injury causing models being used for no valid reason and the consiquences.

    Conflict of interest, just by looking at MP and California Irvine.
    --------------------------------------
    10. SCI Foundations function as defacto industry partners to SCI researchers and Institutes. Neither party appears to appreciate the implicit contract entered into creating an obligation for SCI researchers and Institutes to develop and progressing into clinical trials promising SCI treatment approaches.
    SCI Foundations raise funds on the pretext that these funds will used to facilitate the development of practical treatments for human SCI. This is either implicitly or explicitly stated when SCI Foundations make grants available to SCI researchers or SCI institutions. When SCI researchers and/or institutions accept these SCI Foundation funds, they also take on board an obligation to use these funds for the underlying purpose of developing and progressing treatments for SCI. Most (all) SCI researchers (and SCI Foundation representatives) interviewed seemed unaware of this implicit contractual obligation. In interviews, some SCI researchers described grants from SCI Foundations as providing complementary or supplemental support for their (NIH) sponsored research programs or support for student projects. In harmony with basic research interests, a general assumption seemed to be that more research is needed to understand the processes involved in SCI before effort could be directed towards translational studies.
    --------------------------------------
    I like the phrase used in this study frequently "Transitional Research"

    The committee from our Quest group meets again soon and this study is helpful. The more I learn though the more confused I get about what direction to go.

    BigB, at first I was angry. But if your not part of the solotion your part of the problem.

    Lindox, one of my new hero's 53 years of SCI and in the Cure Forum. YES

    "All you have to decide is what to do with the time that is given you."
    Gandolf the Gray

  6. #6
    Leo,

    Thanks for posting this. I read this report with considerable interest. I met Ian Ferguson last spring in Adelaide and knew that he was travelling to various centers in the United States. He unfortunately could not come to visit our center but nonetheless described our device in some detail. Over the past five years, we have provided the Impactor to and trained over 200 laboratories around the world to use the device. By the way, we give four workshops a year, training 10-12 investigators per workshop. The Impactor costs $6500 compared to about $20,000 for the Horizon and OSU devices.

    It is not surprising that there is some disagreement concerning models and outcome measures but I think that Ian Ferguson should have emphasized how closely the various centers work with each other. For example, I go every summer to the Reeve-Irvine Center to teach students in their course. We send our people to OSU to train in the BBB scores and work very closely with the investigators there. We work with the Miami Project, and many other centers. The standards of the field are very high.

    I am not sure that we should be blaming spinal cord injury models as the reason why treatments are not going to clinical trial. The situation today is much better than it was 10 years ago when every meeting was dominated by arguments concerning spinal cord injury models. Many laboratories are working on replication of promising therapies, including the W. M. Keck Center. Spinal cord injury is very hard work and relatively few laboratories have the experience and resources to carry out the work properly. Most of the results that have not been replicated involve hemisections or transections, not the contusion model. In fact, the record of the contusion model is very good in terms of reproducibility.

    The main reason that therapies are not going to clinical trial is the lack of funding for clinical trials. With the exception of a few small companies, such as Acorda Therapeutics, Proneuron, and Diacrin, there has been little industry investment in spinal cord injury trials. Other than an initial spate of funding for methylprednisolone in the 1980's and 1990's, NIH has not funded any clinical trials other than rehabilitative therapies. The past four years has been particulary bad for spinal cord injury research.

    Wise.

  7. #7
    Senior Member Leo's Avatar
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    Wise then you see no big problem with folks useing differant models?

    "By the way, we give four workshops a year, training 10-12 investigators per workshop. The Impactor costs $6500 compared to about $20,000 for the Horizon and OSU devices."

    OSU had 60 applicants but could only afford to take 20.

    Mr. Ferguson seemed to, by saying something like the data gathered useing differant models couldn't fairly be compared.

    Your training folks and the other groups train folks with their model the problem if one just keeps building.

    If a true problem shouldn't groups investing in research be asking the question. Are the folks you are colaberating with useing the same model?

    Yes I know the biggest problem is lack of investment.

    From article,

    "The SCI training courses provides vehicles to both disseminate standardised methods and to introduce new animal procedures (that can facilitate translation). A considerable investment of time and resources is required to learn new techniques. Given the absolute dependency on SCI animal models, the learning of new surgical and monitoring techniques constitutes a barrier to entry for researchers wishing to enter the SCI field. Indeed, while the SCI training courses provide a vehicle for efficiently disseminating standardised sets of technical skills, demand for training far exceeds supply. For example, OSU received approximately 60 applications for only about 20 available places. Given that demand exceeds supply, a compelling argument can be constructed for pro-actively shaping the development of SCI field towards translation by offering training in surgical and monitoring techniques appropriate for translational studies. For example, while the proportion of the SCI population with chronic SCI is far larger than that of acute SCI, the majority of the published studies in the SCI field make use of acute SCI animal models studies. Some balance may be introduced where SCI researchers are provided with opportunities to learn chronic SCI models designed for translation studies and how to implant and administer test therapeutic substances via intrathecal catheter (given that this is a clinically useful route for drug administration into the spinal cord). The following are observations relate to observed SCI animal procedures and comment related to usefulness for translation.
    1. At all the institutions, extensive dorsal laminectomy was performed to enable firm clamping of the vertebral column prior to contusion injury. This spinal column musculature suffers considerable trauma as a result of this surgery and it is unlikely that such procedures would be readily approved by a clinical ethics committee. Also, not all institutes took care to minimise the amount of vertebral bone removed to gain access to the spinal cord. Spinal orthopaedic surgeons should be consulted to identify clinically acceptable methods for gaining surgical access to the spinal cord. This may require development of alternative methods for stabilising the spinal column prior to SCI.
    2.
    Different institutions preferred different contusion devices. The most popular injury devices were the MASCIS unit (NYU weight drop device), OSU device and Infinite Horizons device. All primary centres had at least 2 of these 3 devices. In contrast, these devices can represent a significant capital investment by a small SCI group. There does not seem to be a comparison of these different instruments that would help such SCI researchers in justifying purchase of one device over another. Ideally, such a comparison would include histological analysis (eg corticospinal tract tracing, thickness of spared white matter tracts, etc) in addition to BBB score. While a number of the SCI researchers indicated that contusion injury devices produce identical injuries if they yield identical BBB scores, there does not appear to be rigorous data to support this claim.
    3.
    While the BBB method has become the de-facto standard method for monitoring recovery of hindlimb function after SCI, evidence of changes to BBB score measurements in the rodent can not easily be used by clinical ethics committees to predict expected changes in human SCI. Knowledge of clinical outcome measures that may be used in clinical trials may enable SCI researchers to develop monitoring procedures for use in rat SCI.

    "All you have to decide is what to do with the time that is given you."
    Gandolf the Gray

  8. #8
    Leo,

    Over 50% of the groups that do contusion models use the MASCIS model. By far, the most extensive validation has been carried out with this model. All experiments have their own controls. It is sometimes useful to have different models (because human spinal cord injury is different as well) to see how robust a treatment effect is. If a treatment works on all different models, this is good reason to believe that the treatment is effective.

    Getting scientists to agree on something is a little like herding cats. They all have their own opinions and preferences. It is important that there is diversity and at the same time have some standardization. This is what we have achieved in the field. Please note that Ian Ferguson may have been biased by the centers that he visited because these are the big centers that can afford the Horizons model and the OSU models. All the major spinal cord injury centers (Irvine, OSU, Miami, OSU) and others (Galveston, Yale, Zurich, St. Louis, Gainesville, San Francisco, etc.) that use a contusion model have and use the MASCIS (NYU) model that we developed. This is the way it should be. Scientists do their studies and they have access to the model if they want to use it. A model is just a tool.

    Wise.

  9. #9
    The reason there is not yet a cure for spinal cord injury is lack of funding and urgency by the people with power, mainly politicians. Politicians, I believe, think in one or more of several ways:
    1) they are totally unaware of sci,
    2) believe it would never happen to them because they are older and wiser than young men who usually have these accidents
    3) sci people appear superficially to live OK lives and don't complain that much about lack of a cure, instead complain about lack of ramps etc etc

    Just my thoughts

    Chris

  10. #10
    Leo, one other point. There is really not so much difference between the models. OSU have long done studies with both models and have compared the results. I think that what they call "severe" injury in the OSU model is similar to the moderate injury in our Impactor (I guess that I am more optimistic). I have long taught my students that the model is not just the device. The device is a small part of the model. Anesthesia (can make as much as a 20% difference in lesion volume), differences in surgical technique (is very important), age of the animal (affects injury severity because age determines the size of the spinal cord), animal care (bladder infections can drop a point or two off the BBB scores), and even how much activity the animal has after injury (for example, our model keeps the rats in separate cages whereas the OSU and Irvine group likes to keep multiple animals together in the same cages which seems to increase the amount of activity of the rats). Even if you have the most accurate device in the world, the extent of damage and outcomes depend on keeping all the other factors constant.

    Wise.

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