On April 23, surgeon and researcher David Gorski MD, PhD published “The problem with preclinical research? Or: A former pharma exec discovers the nature of science.” (Gorski 2012) In his blog, Dr Gorski discusses the topic of basic science research in light of some articles in Nature that I considered in Trouble in Basic Research Land. I have discussed Dr Gorski several times in this blog and elsewhere (here, here, and here for example). I have stated that while I disagree with Dr Gorski regarding animal models, I find his blog to be otherwise excellent. His April 23 blog nicely illustrates his thinking and reasoning that leads to my disagreement with him regarding animal models. I covered much of what I am going to say in our PEHM article: Is the use of sentient animals in basic research justifiable? So, I will attempt to make the following as brief as possible.
My issue boils down to what I perceive as a double standard among basic biomedical researchers. Of course, this is accompanied by numerous fallacies both stated and implied. Basic research in the biomedical sciences is very unrewarding in terms of patient-relevant information obtained per dollar spent. Therefore, when this is mentioned, basic researchers always fall back on the excuse that they are conducting basic research and should not be judged by the same standards used to evaluate applied research. Now, this is true as far as it goes and if that were all the basic biomedical research community claimed, then I would not be writing this essay. Dr Gorski himself expresses the problem: “These days, everybody touts ‘translational’ research, meaning research that is designed to have its results translated into human treatments. It’s darned near impossible these days to get a pure basic science project funded by the NIH; there has to be a translational angle. Often this leads basic scientists to find rather—shall we say?—creative ways of selling their research as potentially having a rapid clinical application, even though they know and reviewers know that such an application could be a decade away.”
Freeman and St Johnston state the same in Dis Model Mech 2008: “Many scientists who work on model organisms, including both of us, have been known to contrive a connection to human disease to boost a grant or paper.” (Freeman and St Johnston 2008)
Yep, that's my issue. Fraud. The researcher applying for the grant and the committee that will ultimately fund the grant both know that the research will probably not (it has approximately a 0.004% chance (Crowley 2003)) lead to anything clinically useful and that if it is lucky (and luck is the right word as any modality that fails 24,999 times out of 25,000 is in the realm of luck not science) that patients will not benefit for decades. Yet, these same people testify before congress, write articles for both lay and science audiences, and state in interviews that their research is predictive for humans. Even if they do not explicitly state that such research is predictive and hence necessary for medical advances they certainly imply it and fail to correct others who state it explicitly. (I have given examples of this multiples times, for example here, here, and here.) But when the extremely poor results from basic biomedical research are made available for the taxpayer to see, the researchers fall back on the following, again from Dr Gorski: “Real scientists know that cutting edge (or even not-so-cutting edge) scientific and medical research isn’t like that at all. It’s tentative. It might well be wrong. It might even on occasion be spectacularly wrong. But even results that are later found to be wrong are potentially valuable.” (I question the valuable part of that statement but will leave it for another essay.)
Compare Dr Gorski’s statement with the following three examples of NIH grant applications we used in our book Animal Models in Light of Evolution.
Grant Number: 5R01MH057483-06
Project Title: Dopamine deficit and schizophrenia
Abstract: . . . In the monkey, we have found that subchronic exposure to PCP induces a decrease in dopamine function in the prefrontal cortex (PFC), which persists for more than a month. Demonstrates, neurochemical and anatomical specificity. This PCP-induced PFC dopamine deficiency correlates with cognitive impairments in the monkey, which resemble those occurring in schizophrenia. . . . These data will aid in the development of novel strategies for ameliorating the neurochemical and behavioral deficits in this potential animal model, and in the cognitive dysfunctions associated with schizophrenia and other psychiatric disorders. (Emphasis added.)
Grant Number: 1U01AA014829-01
Project Title: Testing fasd therapeutic agents: neonatal rodent models
Abstract: The long-term goals of this component are to use rodent models of binge alcohol exposure during the 3rd trimester equivalent to screen and identify molecular agents that may be effective in preventing prenatal alcohol-induced brain damage and neurodevelopmental disorders . . . . A key advantage of integrated approaches across the Consortium is that as promising candidate molecular agents emerge, these animal models can provide in vivo tests of their therapeutic effectiveness. (Emphasis added.)
Grant Number 1R41AI071451-01
Project Title: Novel Model to Predict Safety and Efficacy of Microbicides
Abstract: Genital herpes is 1 of the most prevalent sexually transmitted infections (STI) worldwide and is associated with substantial morbidity . . . A major limitation in the development of this novel class of drugs is the absence of a small animal model to predict safety and effectiveness. Preliminary studies indicate that the cotton rat will fill this niche.
These examples could be easily multiplied.
I also note that what basic researchers perceive as the problem with basic research and what the scientists that use the results from that very research see as the problem could not be more different. The basic research community essentially says that models, be they in vitro or animal, are all we have to work with and therefore society must settle for the inefficient process. What is left unsaid is the fact that most of these models are animal-based even if they are classified as in vitro. The tissue or cells came from a nonhuman.
Scientists in the pharmaceutical industry or in related fields, on the other hand, say the following. Markou, Chiamulera, Geyer, Tricklebank (of Eli Lilly), and Steckler (of Johnson and Johnson) state: “Despite great advances in basic neuroscience knowledge, the improved understanding of brain functioning has not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system disorders. This situation has been partly attributed to the difficulty of predicting efficacy in patients based on results from preclinical studies. . . . Few would dispute the need to move away from the concept of modeling CNS diseases in their entirety using animals. However, the current emphasis on specific dimensions of psychopathology that can be objectively assessed in both clinical populations and animal models has not yet provided concrete examples of successful preclinical-clinical translation in CNS drug discovery. . . . Since the founding of the American College of Neuropsychopharmacology (ACNP) in December 1961, there have been tremendous advances in neuroscience knowledge that have greatly improved our understanding of brain functioning in normal and diseased individuals. Unfortunately, however, these scientific advancements have not yet led to the introduction of truly novel pharmacological approaches to the treatment of central nervous system (CNS) disorders in general, and psychiatric disorders in particular . . .” (Markou et al. 2009)
Cook et al: “The primary purpose of preclinical therapeutic efficacy testing is to predict whether a particular compound will be successful in the clinic. Despite encouraging preclinical results, unfortunately most drugs are found to be ineffective late in their development, with only a small percentage (5%) of patients in Phase I clinical trials responding (Roberts et al. 2004). Apart front using inaccurate tumour models, there are many other reasons why preclinical studies fail to predict clinical activity. Species-specific PK, its addition to differences in drug delivery, and tumour heterogeneity might all contribute to discordant results. Such failures are costly to scientists and drug companies and of great consequence to the patients that optimistically enrol in experimental clinical trials.” (Cook, Jodrell, and Tuveson 2012)
Giri and Bader: “Clearly, drug testing on animals is unrealistic and causes unforeseen reactions in human clinical trials.”(Giri and Bader 2011)
Geerts, of In Silico Biosciences in 2009: “The tremendous advances in transgene animal technology, especially in the area of Alzheimer's disease, have not resulted in a significantly better success rate for drugs entering clinical development. Despite substantial increases in research and development budgets, the number of approved drugs in general has not increased, leading to the so-called innovation gap. While animal models have been very useful in documenting the possible pathological mechanisms [basic research] in many CNS diseases, they are not very predictive in the area of drug development. . .” (Geerts 2009) Note that the basic research referred to is being done on the premise that it will lead to drugable targets. That is the whole point of the research!
In an editorial introduction to one article by Ellis and Fidler and another by Van Dyke (Van Dyke 2010), Nature Medicine stated: “The complexity of human metastatic cancer is difficult to mimic in mouse models. As a consequence, seemingly successful studies in murine models do not translate into success in late phases of clinical trials, pouring money, time and people’s hope down the drain.” (Ellis and Fidler 2010)
Ellis and Fidler: “Preclinical models, unfortunately, seldom reflect the disease state within humans (Fig. 1).” (Ellis and Fidler 2010)
Littman and Williams of Pfizer writing about using humans as models for other humans in Nature Reviews Drug Discovery 2005: ”Humans are the ultimate ‘model’ because of the uncertain validity and efficacy of novel targets and drug candidates that emerge from genomics, combinatorial chemistry and highthroughput screening and the use of poorly predictive preclinical models . . .” (Littman and Williams 2005)
An editorial in Nature Reviews Drug Discovery 2005: “Clearly, one part of the problem [of drug research] is poorly predictive animal models, particularly for some disease areas and drug classes with a novel mechanism of action, a topic we continue to cover in our ongoing 'Model Organisms' series. But arguably the best 'models' for drug discovery are human subjects and as the need to have proof of concept or mechanism for a drug before moving on to larger, more costly clinical trials has never been greater, more big-pharma companies are now embarking on programmes in experimental or translational medicine.” (Editorial 2005)
Horrobin: “First, there must be a recognition that in the last analysis the human disease itself must be studied in human subjects. It is at least arguable that if we devoted as much effort to the human disease as we do to unvalidated models, then we might be much further forward in understanding.” (Horrobin 2003)
Heidi Ledford, writing for Nature: “In April this year, Nobel laureate Sydney Brenner brought the crowd to its feet at the American Association for Cancer Research meeting in San Diego, California. Brenner pioneered the use of the nematode Caenorhabditis elegans as a simple model for studying growth and development. But in his talk, he championed experiments on a more complicated creature: Homo sapiens. ‘We don't have to look for model organisms anymore because we are the model organism,’ he said.” (Ledford 2008) (Emphasis added.)
Among scientists that actually have to produce clinically relevant results, it is a given that research has to switch from being animal-based to being human-based. Among scientists that rely on animal models to pay their mortgage, it is a given that the universe will end if animal models are not funded more vigorously than they currently are. This is illustrated by Susan Fitzpatrick of the James S. McDonnell Foundation, who wrote a letter published in The Scientist in January 2011, in which she stated: “I earn my living thinking about science funding, and I have tried to draw attention to the detrimental warping the current system exerts on academic norms and values. More than a decade ago, I floated an idea akin to the one in this Opinion by many of my friends and colleagues, mostly successful biomedical researchers at prestigious research universities who are well-funded by NIH. Many think it a good idea as long as the ‘everyone has enough but no one is huge or overly rich’ rubric is only applied to others. Whining for dollars is the #1 academic indoor sport, and no one does it better than biomedical researchers! The roots of this problem deserve serious outing: overbuilding, the addiction to discretionary funds brought to institutions via indirect cost recovery, and the overproduction of trainees. A smaller, leaner basic biomedical enterprise, unfettered and allowed to study serious biology, will probably accomplish much more than the bloated work-fare program we currently are trapped in.” (Fitzpatrick 2011) (Emphasis added.)
I have other issues with various aspects of Dr Gorki’s essay but will leave those for another time. Dr Gorski is correct when he says research is difficult and that basic research will turn out to be wrong most of the time. But spinning and outright fraud should not be tolerated, especially when lives are at stake.
Let me state emphatically that I support basic research. Basic research has led to our understanding much of the material universe. However, conflating basic research in the biomedical sciences that uses animal models and that is masquerading as applied research, with basic research in physics, chemistry, and basic biomedical research that relies on human tissue is a fallacy and is done for a purpose. Money. Like Dr Gorski said, it is almost impossible to get an NIH grant without lying.
Cook, Natalie, Duncan I. Jodrell, and David A. Tuveson. 2012. Predictive in vivo animal models and translation to clinical trials. Drug Discovery Today 17 (5/6):253-60.
Crowley, W. F., Jr. 2003. Translation of basic research into useful treatments: how often does it occur? Am J Med 114 (6):503-5.
Editorial. 2005. The time is now. Nat Rev Drug Discov 4 (8):613.
Ellis, L. M., and I. J. Fidler. 2010. Finding the tumor copycat. Therapy fails, patients don't. Nat Med 16 (9):974-5.
Fitzpatrick, Susan. 2011. Funding Biomedical Research. The Scientist (January):13.
Freeman, Matthew, and Daniel St Johnston. 2008. Wherefore DMM? Disease Models & Mechanisms 1 (1):6-7.
Geerts, H. 2009. Of mice and men: bridging the translational disconnect in CNS drug discovery. CNS drugs 23 (11):915-26.
Giri, Shibashish, and Augustinus Bader. 2011. Foundation review: Improved preclinical safety assessment using micro-BAL devices: the potential impact on human discovery and drug attrition. Drug Discovery Today 16 (9/10):382-397.
Gorski, David. 2012. The problem with preclinical research? Or: A former pharma exec discovers the nature of science. Science-Based Medicine, April 23 2012 [cited April 23 2012]. Available from http://www.sciencebasedmedicine.org/index.php/the-problem-with-preclinical-research/.
Horrobin, D. F. 2003. Modern biomedical research: an internally self-consistent universe with little contact with medical reality? Nat Rev Drug Discov 2 (2):151-4.
Ledford, H. 2008. Translational research: the full cycle. Nature 453 (7197):843-5.
Littman, B. H., and S. A. Williams. 2005. The ultimate model organism: progress in experimental medicine. Nat Rev Drug Discov 4 (8):631-8.
Markou, A., C. Chiamulera, M. A. Geyer, M. Tricklebank, and T. Steckler. 2009. Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34 (1):74-89.
Roberts, T. G., Jr., B. H. Goulart, L. Squitieri, S. C. Stallings, E. F. Halpern, B. A. Chabner, G. S. Gazelle, S. N. Finkelstein, and J. W. Clark. 2004. Trends in the risks and benefits to patients with cancer participating in phase 1 clinical trials. JAMA : the journal of the American Medical Association 292 (17):2130-40.
Van Dyke, T. 2010. Finding the tumor copycat: approximating a human cancer. Nat Med 16 (9):976-7.