… just to say that layoffs suck. No its not me that got laid off, however, days like today make me quite happy just to have a job. I’m gonna try not to forget that anytime soon.

I got the summary statement for my latest NIH grant (this one was for a special mechanism). The application was unscored, again, but you know, I’m cool with no scores now. The summary statement, on the other hand, I am not fine with. Not a single comment on the grant. I poured myself into learning an area that I knew nothing about for this grant. They could have at least given me one sentence. Otherwise, how am I supposed to know the thing was even reviewed.

In other news, my R01 gets resubmitted this week. I need a vacation. Luckily I have one coming up… Mr and Mrs Juniorprof are going to Quito and Galapagos. We’ve got a month before we leave so any advice from those that have been is most welcome.

Join the fight against sexual crimes against women by participating in the “Silence is the Enemy” campaign. Read Nicholas Kristof’s NYTimes piece that inspired Sheril Kirstenbaum’s post on Discover Blogs starting the campaign. Join the Facebook group. And go read about science on Scienceblogs where many of the bloggers are donating their page-view proceeds to Doctors without Borders in an effort to stop the violence and to bring needed medical attention to its victims. Finally, write your congress-person and let them know that you expect to see political action to reduce crimes against women worldwide.

So I got tagged for the “Covered” meme…. Here goes:
Greatest Ever:
Sinead O’Conner, Nothing Compares 2 U, written by Prince, originally performed by The Family.

Worst Ever: Seether, Careless Whisper, destroyed from the original Wham (which is a true classic).

I’m too lazy to tag, but if you’re reading and are so inclined, go for it!

Pain, as terrible as it can be when it outlasts its stay, is actually a vital protective function of our nervous system. The body detects pain through a subgroup of primary sensory neurons, called nociceptors, that innervate the entire body and which normally respond only to high-threshold stimuli such as extreme heat or strong mechanical stimulation. This nociceptive response to potentially tissue damaging stimuli is critical for reflexes and coordinated responses to the stimulus which generally result in a protective reaction (such as withdrawing your hand from a hot stove). Hence, the activation of peripheral nociceptors by pain-inducing stimulation serves a crucial teaching function insofar as it is the signal that protects us from further damage. This fact is best exemplified by studies of rare cases where individuals have a genetic mutation that makes them insensitive to pain. For instance, a family was recently discovered in Pakistan wherein mutations in a voltage-gated sodium channel (called Nav1.7) involved in generating pain signals in nociceptors led to a total lack of pain sensation. Members of this family were working as street entertainers, performing incredible feats such as placing daggers through their arms. Horrifically, one of these young men died after jumping off a roof during one such performance. As tragic as this story is, it serves as an excellent example of how we depend on pain signals to keep us safe from potentially life-threatening injuries.

This story also leads into another crucial factor for how we perceive pain. The expectation of pain is a strongly motivating feature of our endogenous pain system. The mere thought of the pain of landing after jumping from a roof is enough to motivate almost any person to come down safely by a ladder; however, in the absence of prior pain experiences, it is not clear that such a motivation is even possible. Hence, while the stimulation of nociceptors serves a major protective function, other systems that reside within higher brain centers are paramount for how we perceive pain. Clinical studies in human volunteers have shown that context, mood, memories, hypnosis, expectation and even the prior administration of a placebo can have profound influences on how we process incoming pain signals. Importantly, these processes appear to play a major role when pain transitions from acute to chronic.

Pain that might be experienced as a result of daily living (e.g. stubbing one’s toe) is actually quite different from clinically significant pain. Whereas the pain transmission system is normally only activated by high threshold stimuli, in clinical pain conditions the pain transmission system can be stimulated by low threshold stimulation. This may manifest as normally innocuous stimuli becoming painful, referred to clinically as allodynia. Moreover, there is frequently a mismatch between the duration of the stimulus and the duration of the pain. For example, stubbing a toe may cause pain for 5 minutes in a normal person whereas it may precipitate a day-long episode of extreme pain in someone with fibromyalgia. Such an increased response to a noxious stimulus is termed hyperalgesia. Clearly such changes are maladaptive and current research into the neurobiology of chronic pain is starting to unravel these mechanisms.

Chronic pain is characterized by plasticity within the nervous system leading to “sensitization” in how the pain system responds to noxious or innocuous stimulation. First, peripheral nociceptors themselves can become strongly sensitized to circulating or local hormones or inflammatory mediators. This process may make nociceptors responsive to much lower concentrations of these pain-promoting agents than they would under normal circumstances. In addition to the sensitization of peripheral nociceptors, neurons within the spinal cord that send pain signals onto higher brain centers, where pain perception occurs, can also become sensitized. Remarkably, these spinal cord neurons show a particular type of plasticity, called long-term potentiation, that is molecularly similar to processes that are thought to be involved in the formation of memories within the brain. Sensitization of the pain system is not limited to peripheral nociceptors or spinal cord neurons. Neurons in the “nociceptive amygdala (the amygdala is a brain area strongly linked to emotion and fear) and neurons in the anterior cingulated cortex (ACC, a brain area involved in the affective component of pain) are also sensitized in chronic pain conditions such that they show enhanced responses to painful stimuli and they acquire novel low threshold inputs (a neural correlate of allodynia). Thus far, our discussion of pain amplification in the setting of chronic pain has been limited to evoked stimuli; however, it is also clear that stimulation of peripheral structures (e.g. the skin) is not a requisite for the precipitation of pain in people that suffer from chronic pain. In fact, spontaneous pain, especially the dull ache that characterizes so many chronic pain conditions, is often the primary complaint of chronic pain patients and is the most difficult feature to treat. Persistent questions in pain neurobiology are: why does this type of pain arise, what are its origins and how can it be treated or reversed?

A major focus of work to understand why spontaneous pain arises has been on the peripheral sensory system. We now know that a peripheral nerve injury, metabolic neuropathy (e.g. diabetic neuropathy) or chronic inflammation can lead to persistent “ectopic” activity in injured sensory nerves that can persist even after an injury resolves. The current view on this activity, in the absence of any obvious stimulus, is that a redistribution or change in expression in voltage gated sodium channels causes injured nerves to become ectopically active leading to a persistent, low level peripheral input that drives spontaneous pain perception. Work from the laboratory of Marshal Devor has shown that changes in voltage gated sodium channel expression can lead to sub-threshold membrane oscillations and this mechanism may be a major cause of ectopic activity in sensory nerves after injury. Such sub-threshold membrane oscillations lead to fluctuations in membrane potential, which would otherwise be stable, changing the excitability of these nerves and leading to action potential generation in the absence of any other stimulus. While these recent electrophysiological and biophysical findings are a critical key to solving the mystery of why pain becomes chronic it is also true that this low level, pathological peripheral input is coupled with neural adaptations throughout the CNS that contribute strongly to changes in pain perception in chronic pain patients.

The first processing center for incoming pain information from the periphery is the dorsal horn of the spinal cord. Here peripheral nociceptors synapse onto CNS neurons that send projections onto the major areas of the brain that are involved in nearly all aspects of the pain experience. In the late 1990s Patrick Mantyh and colleagues discovered that a subset of these dorsal horn neurons that reside in the outermost layer of the spinal cord are critical for chronic pain. This group used a toxin coupled to a neurotransmitter to selectively ablate these neurons and found that when these neurons are absent most forms of chronic pain fail to develop. These experiments were powerful indicators that sensitization of the central nervous system is crucial for the development of chronic pain but the actually mechanisms of this plasticity remained to be fully elucidated. In the past five years at least one of these mechanisms have been discovered. Jurgen Sandkuhler’s group has demonstrated that long-term potentiation (LTP) can be established by low frequency stimulation in the same subset of neurons ablated by Mantyh and colleagues. As mentioned above, this LTP shares many of the same molecular mechanisms associated with LTP in learning and memory; however, whereas LTP in brain areas such as the hippocampus requires high frequency input, this spinal form of LTP can be evoked by low frequency input. Hence, LTP in spinal neurons known to be involved in spinal pain processing and the generation of chronic pain can be sensitized by an input frequency that matches the low level, pathological ectopic activity that arises in peripheral nerves after injury. Therefore, it is likely that ectopic activity in peripheral nerves couples to LTP in spinal neurons to create a powerful amplification mechanism to send pain signals onto the brain in the setting of chronic pain.

Unfortunately peripheral plasticity and spinal LTP are not the end of the story for amplification systems that drive chronic pain. It is also clear that descending pain modulatory systems exist and that these systems also play a key role in amplifying incoming pain information after chronic inflammation or nerve injury. This system, first described by Howard Fields and Allan Basbaum arises in the periaqueductal grey area (PAG) and connects to the rostral ventromedial medulla (RVM) which then sends outputs caudally down to the spinal dorsal horn creating a pain modulation circuit arising in the brain stem. This circuit is perhaps best known for its role in endogenous analgesia mechanisms wherein endogenous opioids released from PAG neurons engage a descending output from the RVM that promotes a powerful inhibition of spinal dorsal horn neuron activity leading to analgesia. On the other hand, work from Frank Porreca’s group has shown that the RVM can also mediate a prominent pain promoting effect called descending facilitation. After peripheral nerve injury or chronic inflammation blockade of RVM output or ablation of RVM neurons leads to an alleviation of chronic pain in animal models. These experiments have led to the view that the RVM is a critical switch for the emergence of chronic pain wherein the RVM transitions from a brainstem area that promotes endogenous analgesia to one that facilitates spinal amplification. While the mechanisms that lead to this switch have not been fully elucidated they are likely to be important future targets for chronic pain control. In support of this view are recent human functional MRI studies from the group of Irene Tracey which demonstrate that inhibition of RVM circuitry in a human pain model is a valuable predictor of analgesic efficacy. This finding supports the importance of the RVM for the amplification of pain perception and points to a potential screening mechanism for the efficacy of novel analgesic drugs.

While the pain research community has made major strides in understanding pain amplification leading to chronic pain, a major question persists: what is the impact of this amplification on higher brain centers involved in the perception of pain and how does it manifest in other symptoms that are frequently found in chronic pain patients? Here it is useful to return to your imaginary patient. While his continuing pain is clearly problematic, other symptoms are arising such as inability to concentrate, depression and a general cognitive decline. Why are these symptoms common in chronic pain patients and how can we understand these processes mechanistically with a view toward better treatment? Until recently these co-morbid problems were largely unexplored from a basic science perspective but the advent of more sensitive human brain imaging techniques and the incorporation of behavioral tests in laboratory animals that assess the emotional or cognitive state of the animal have led to several major breakthroughs on this front.

Human fMRI studies from the groups of Vania Apkarian, Bud Craig, Cathy Bushnell, Irene Tracey, Karen Davis and others have pioneered the notion that a “pain axis” exists in the human brain that is activated by peripheral noxious input. Interestingly, pain not only stimulates sensory areas of the brain but is also a powerful activator of brain areas involved in emotion such as the anterior cingulated cortex (ACC), the insula and the amygdala. Moreover, these areas can become hyperactive in chronic pain conditions. For instance, fibromyalgia patients show an enhanced response to noxious stimulation in the ACC. In animal models, lesions of the ACC have no effect on nociceptive reflexes but strongly inhibit the aversive qualities of persistent pain and peripheral nerve injury and chronic inflammation lead to neural plasticity in the ACC. These findings suggest that the ACC may be a critical region for amplification of the aversive qualities of chronic pain. Interestingly, human imaging studies have shown that pain responses in the ACC are powerfully modulated by mood, placebo and hypnotic suggestion indicating that the ACC is likely to be an integrator of sensory input with emotional state likely leading to some of the affective disturbances associated with chronic pain. One such problem is known as pain catastrophizing, which is associated with the expectation or fear that pain will be intense and unmanageable. Pain catastrophizing is a particularly salient feature of many chronic pain disorders and several human imaging studies have shown that the ACC is also engaged during pain catastrophizing. As our understanding of the role of the ACC in chronic pain, expectation of pain and pain catastrophizing continues to emerge it is likely that therapeutic strategies that are capable of targeting these mechanisms will be discovered with the opportunity to treat these symptoms more efficaciously.

Cognitive decline and problems with concentration or attention have long been recognized as features of chronic pain but basic science has only recently begun to understand how this occurs. A major milestone in this line of research was the observation of cortical thinning in chronic back pain patients. Vania Apkarian’s group discovered that, compared to age matched controls, chronic back pain patients demonstrated a loss of cortical grey matter roughly equivalent to 10-20 years of ageing. This important finding has now been replicated in other groups of chronic pain patients, including fibromyalgia, and may represent a major mechanism through which cognitive decline can occur. Findings from animal models have suggested other mechanisms through which cognitive problems may be generated in the setting of chronic pain. Volker Neugebauer’s group has shown that chronic arthritic pain leads to neural adaptive changes in the amygdala that potentially exert a powerful inhibitory influence on the prefrontal cortex, an area involved in cognition and decision making. This circuit involves amplification of pain signaling in the “nociceptive amygdala” that then influences other amygdalar output regions that exert inhibitory control over the prefrontal cortex. A set of elegant behavioral experiments have demonstrated that this cortical inhibition leads to an impairment of decision making in a modified Iowa Gambling Task wherein rats with chronic pain are unable to detect changes in the game that would lead to better chances of their receiving a food pellet. Remarkably, these findings parallel similar experiments in the Iowa Gambling Task in chronic back pain patients where these patients also show impairments in decision-making. Hence, the combination of chronic pain-induced neurodegeneration and feed-forward inhibition of cortical circuits from areas of the brain that become hyperexcitable in chronic pain conditions (e.g. the nociceptive amygdala) may represent a neural basis for cognitive decline, depression and even pain catastrophizing when pain becomes chronic.

The view that emerges from the experimental and clinical findings discussed above is that chronic pain is a disease in and of itself that needs treatment as such to improve outcome and prevent or reverse structural changes. Disease modification may be possible, even with existing drugs that target mechanisms involved in the maintenance of chronic pain – e.g. tumor necrosis factor α, interleukin 6 or nerve growth factor sequestering treatments. Therapeutics targeting these mechanisms are either currently available or are in late stage clinical development and preclinical findings suggest that these treatments may be able to modify chronic pain by targeting molecules that are involved in its maintenance in the periphery. Another major focus is on biomarkers of chronic pain and early detection through better diagnostic tools may allow for improved treatment that reverses or limits pain amplification processes in the CNS before they become well established. Here it is important to recognize that while neurodegeneration as a result of chronic pain is likely to be difficult, if not impossible, to fully reverse, several recent discoveries in this area offer a high degree of confidence that the brain can cope with these problems given the proper opportunities. For instance, recent research in mouse neurodegeneration models indicates that environmental enrichment can enhance cognitive function and even restore certain types of memory deficits. Therefore, appropriate pain control medications coupled with physical and/or mental therapy (e.g. puzzle solving or other types of cognitive challenges) may hold considerable promise for patients experiencing cognitive decline as a result of chronic pain.

The past decade has seen an exponential growth in our understanding of the basic mechanisms which underlie the transition from acute to chronic pain. The molecular mechanisms of this transition share common features with the synaptic plasticity that underlies learning and memory and the recognition that chronic pain can lead to neurodegeneration has shed new light on the myriad of complications that frequently accompany chronic pain. As we continue to gain a firmer understanding of these processes and their respective potential therapeutic targets there is growing hope that we will be able to alleviate the suffering of the millions of people worldwide who experience chronic pain.

NB: Rather than linking to original research papers, I have tried to supply links to reviews throughout to make the information more accessible to readers that may not have direct experience in the pain neuroscience area.

It may seems that the answer is obvious: do high quality research and try to move your work towards the clinic if you are in a position to do so. This is the position that I have taken since I entered the pain neuroscience area back when I was wee PhD student. As of about three weeks ago, I’ve changed my mind.

First, let’s make a few things clear. I still think that ultimately the research has the potential to have the largest impact on patient care. There is a severe lack of efficacious treatment for large swaths of the chronic pain patient population. As we continue to learn more and more about what makes pain become chronic more and more opportunities for intervention arise. Many of these have the potential to be disease modifying, in other words, to reverse chronic pain by targeting its underlying pathophysiology. In the meantime, the more you get involved in patient issues, the more you realize that there are massive numbers of patients that need help right now. I suppose that all of us know this at some level but sometimes events and/or circumstances make it obvious that you need to take another approach.

Two recent events have caused me to undertake a major reevaluation of my overall approach.
1) Mrs Juniorprof is working on her advanced clinical degree. She is writing up her clinical research project. I have been shocked to find, through helping her edit her write-up, that despite thousands of basic research articles on pain sensitization there are very few studies out there which evaluate efficacy of available treatments for stopping the progression of pain disorders in susceptible patient populations. If you consider substance abuse patients the problem gets even worse. A consistent complaint is lack of physician education in the area. Education. Duly noted.
2) At a recent big pain meeting including basic researchers and clinicians I spent most of my time in the physician-type sessions. The disconnect between the basic science and the clinical areas was huge. A canyon in fact. While the basic scientists were discussing novel targets and basic mechanisms the physicians were arguing over opiate use policy and FDA regulations. In discussion periods after presentations several physicians explained that they felt that many patients were too far gone by the time they got to their pain speciality clinics. Again, education. No one is teaching physicians how to manage pain efficiently when it begins, no one is teaching how the basic science indicates that treating pain early is critical to avoid chronic pain and no one is effectively communicating that chronic pain is a disease in its own right. Apparently.

Now, those last statements are obviously a gross generalization. There are fantastic pain service physicians out there. Our hospital has one of the best. But one, quite literally. One pain specialist in a public hospital that serves millions. There are other physicians in the hospital that care deeply about treating pain, I know, I have interacted with many of them. But the fact of the matter is that they have other things to worry about when they see the patient come in on an ambulance after a car accident and more than likely they have never been properly educated in the critical nature of treating pain early to avoid later, lingering medical problems. Treating pain needs to be routine, something they can do without even thinking about it. Education. Its not the fault of any one physician. Its the fault of a training system that does not adequately incorporate what we know about pain into how we do it on a daily basis. Somewhere there is a gap, and we need to fill that gap.

So, eventually one realizes that you can get there from here in the lab but that route is filled with uncertainty and clinical development that is largely outside your control. The fastest way to get there may actually be in the classroom. It may not mean getting adequate treatment to those that are not helped by available therapeutics but it has strong potential to prevent the emergence of new patients by teaching the importance of adequate pain control early on and overcoming some of the myth and stigma that come with the territory anytime pain treatment comes up.

Well, this week one of the deans got together with a few of us pain people around these parts and we started to sketch out the beginnings of a “pain course” for medical students in clinical years. The course is going to focus on those issues that come up in the clinical treatment of pain in different settings and discuss the basic science behind the importance of treating pain early on. One fairly innovative part of the course is that it will begin as a small series of lectures, largely composed of clinical and basic findings (not a review of neuroanatomy/physiology — all new material), followed by explanations of current guidelines (WHO and International Association for the Study of Pain) and things to look for as students head out into clerkships. Then, in intersessions, we will reconvene in workshops to discuss clinical practice and observed shortcomings in pain treatment with an eye to how these can be better addressed and what the basic science tells us about what these shortcomings may mean for patients. This will be repeated throughout the clinical year. Hence, the course will comprise a number of lectures and workshops focusing on improving pain management skills in physicians that leave this medical institution. Since a large number of these clinicians either stay in state or return after residency, the overall goal is to begin the process of improving pain management skills in the next generation of clinicians for our area.

Obviously, this is going to take a good deal of work and I’m not sure I’m quite ready to take on co-directing another course but at the end of the day this is the area of science that I have chosen for my career. While I would like to think that the lab work has the greatest potential for immediate clinical improvement, this would be somewhat delusional. The fact is that medical student instruction can have a huge impact on clinical care and classes such as these, that address pain issues, are generally either given the short shrift or not given at all. That won’t be the case around here anymore.

Just posted final grades. The semester from hell is over! I may actually blog again sometime soon. Let’s just say that writing several grants, directing a course (as the more or less solo lecturer), teaching 5 hrs a week to med students and getting 4 papers out the door has been stressful. However, I survived!

Such a sad story.  A young man gets hit in the head by a pitch and dies.  Apparently he turned to escape a wild pitch and it hit him just below the helmet, killing him. This may sound like a freak accident but the fact is that baseball helmets are not constructed to protect a person when they turn (as is the reflex) to avoid a pitch headed for their head. A simple flap attachment to the back of a helmet (similar to the throat protector on a catcher mask) could stop this from happening in most cases.

I played baseball from the time I could walk until my knees became so bad (from football) that I could no longer bend to catch (I was a catcher). I cannot tell you how many times I have seen players get hit in the head with pitches. If you’re lucky, the ball hits your helmet as you turn but all too often it hits just below the helmet, hitting a relatively softer spot very near the brainstem/spinal cord junction where many respiratory control centers are located (among other things). While I never witnessed anyone severely injured by this, I did see several concussions and had one myself that landed me in the hospital for a day.

If Barry Bonds and other players can get away with wearing protective equipment for their lead elbows as they crowd the plate there is no excuse for not adding to the protection offered by helmets through the addition of an extra unit that would protect the base of the skull from wild pitches. Well, forget Barry Bonds, there is no excuse period. I feel terrible for this kid and his friends and family (and the pitcher). This is a tragedy that could have been avoided.

In DM’s thread on a Nature article concerning the bombing of a UCLA researcher whimple asks to hear from pain researchers:

Good idea, let’s throw out pain research based on animal models altogether.

Yes, this is a possibility that some people are willing to consider, the sarcastic tone of the statement notwithstanding. The best refutation would be evidence that pain research based on animal models has directly resulted in improvements in pain management in animals (including humans as animals).

How about it pain researchers? Can you compile a quickie list of such instances? Even stipulating that the ends can be used to justify the means, if causing pain to animals is “bad”, then this research is going to need to demonstrate that it is “worth it”. There’s a lot of arguing over how bad the badness is, but not a lot arguing over how good the goodness is. In the absence of a list of pain research successes, a cynic might suppose this is because there in fact isn’t any good that has resulted from this research.

To which I responded:

“Yo Whimple, pain researcher here to address your points:
1) Go to any pain research conference and you will quickly learn that most pain researchers don’t work with animals, most work with humans. These include physicians doing clinical work, electrophysiologists doing peripheral nerve recordings, fMRI people doing what fMRIers do, psychologists looking at comorbidity, nurses looking at outcomes, etc., and the list goes on and on.
2) Then there are us basic researchers who work with cells, animal tissues, human tissues and so on. Most of this work does not involve causing any pain at all. Genetic studies are done, patch clamp recordings are made, biochemical experiments on all sorts of channels and kinase are performed all with the aim of understanding the physiology of nociceptors and pain transmission neurons. These studies have led to an exponential increase in our understanding of the channels and kinase (and other proteins) that mediate nociception.
3) There are, obviously, preclinical pain models. Some of the first ones (back in 50s and 60s) were extreme and have been discarded on ethical grounds. Most models used now cause a mild pain stimulus (certainly no worse than the shock applied in fear conditioning). Others involve long-term inflammation and largely the same as preclinical models used to study inflammation or arthritis. In other words, these models are not exclusive to pain research as they are co-opted from other areas of research on important human diseases that also involve pain. Nerve injury models are slightly different and somewhat unique to the pain area but let’s remember that this is the hardest type of human pain to treat and it leads to a terrible quality of life…
4) So what are the treatments that have resulted from this work? A) massive improvement in opiate efficacy and safer formulations based on preclinical work. B) new generation neuropathic pain meds including gabapentin, pregabalin and the clinical rationale for the use of 5HT and NE reuptake blockers and improvements on their clinical use based on real basic science. C) anti TNFalpha, anti IL-6 and anti NGF treatments either now coming out or in late trials. Some of these originated in other areas and some originated in the pain area but the rationale for the clinical use is all based on preclinical basic science. That’s just a start to a long list.
5) If you doubt the importance of basic science pain research take a trip to your local university hospital and go talk to the patients in the pain clinic.”

Whimple then returns with:

Juniorprof, good list. Personally, I think if the studies can be done on humans, they should be done on humans. My concern is that animal research slows down human research because it’s so easy to work with mice (or whatever) so people spend a lot of resources on finding effective treatments for mice and doing “basic research” studies with mice, which don’t necessarily (usually?) translate into humans. My big whatif goes something like this:

Suppose researchers were not allowed to work with animal models, but could do human subjects research with all the current legal and ethical limits on human research currently in place still in effect (cell culture work on all species still allowed). Would that slow down the development of useful human clinical treatments, speed up the development of useful human clinical treatments, or would things progress at about the same pace? If we took all the animal model researchers and said, “If you’re going to use animals, they have to be human,” would that wind up being good or bad for science from the point of view of the taxpayer funding the work and waiting for treatments and cures?

Can pain researchers (for example) say, “without studies in animal X, currently useful product Y would have been impossible to develop.” Where “impossible” really means impossible, not just more difficult or costly or slower to get working?

Is it in the taxpayers’ best interest to make animal work easier to do, or would the taxpayers be better off long-term if animal work was more difficult to do? (leaving aside the above extreme example of animal work not being allowed at all) Usually I get jumped on for asking this kind of question, but I think it’s worth discussing since the answer to this question helps determine the “goodness” side of the “animal research bad” (less than / equal to / more than) “animal research good” equation.

To which I added:
“Whimple,
First, I largely agree, I would prefer to do the work in humans too but in many cases it is simply not possible. On the other hand, we have recently developed a new treatment preclinically that we are now trying to take into a trial in humans. We never would have gotten anyone to believe us without the preclinical data but now that we have it a trial is feasible (its a synergistic drug combo wherein both drugs are approved for human use so we can proceed). From a basic science perspective the trial isn’t very interesting at all. From a treatment perspective its interesting and will certainly be exciting if it translates. From a personal perspective, its about the most exciting thing I can think of… taking treatments form the bench to the clinic is why I wanted to enter this field and I can’t wait to work with some humans!

On your other question, are there examples where the clinical never would have been possible without the preclinical the answer is also yes. My example is not a good one because I likely would have been able to instigate a trial but it would have been much more difficult without the preclinical. On the other hand, the anti-NGF treatments for chronic pain are an excellent example of where it would not have been possible. We have known for a long time that NGF is involved in preclinical pain models and in human pain. We have also known that genetic mutations in humans that block NGF signaling (mostly receptor mutations) cause a terrible disease wherein people with the mutation have profound mental retardation, total lack of pain and inability to sweat. While it was the view of most researchers that this was due to a developmental issue, it was not known if blocking NGF signaling later in life would lead to similar deficits and this made any trial on anti-NGF therapies impossible due to very serious safety issues. After decades of preclinical work it is now known that anti-NGF treatments later in life do not cause similar problems and this animal work has made the safety issue a much smaller issue. So, due to literally thousands of papers on NGF signaling in animal models we have a good idea that these treatments will not cause devastating side effects in humans and these therapies are now late in clinical development. If they gain FDA approval I expect that they will become important treatments for chronic pain disorders. That is but one of several examples wherein animal work was absolutely neccessary to develop new pain treatments.”

Perhaps we can continue the conversation here…

Juniorprof got a call from a very generous foundation today to notify him that he will be receiving a Fellowship award for the next three years from said foundation. Juniorprof is very excited! While the money is not huge, it is a start, and this Fellowship carries some degree of prestige in Juniorprof’s area that makes it a real honor to be recognized in such a way. Time for a margarita!!