Tag Archives: basic research

Undermining a cornerstone of medical research – examining a biased commentary on animal studies

Medical sociologist, Pandora Pound, and epidemiologist, Michael Bracken, recently wrote an opinion piece entitled “Is animal research sufficiently evidence based to be a cornerstone of biomedical research?” for the British Medical Journal. The article was chosen as the editor’s choice, leading to an editorial by the editor in chief, Fiona Godlee.

BMJ Pound and Bracken

Pound and Bracken criticise the poor quality and reporting of many animal studies, asserting that this is leading to ineffective drugs going on to clinical trials before failing.

Pound and Bracken make some suggestions for improvement, concluding:

In addition to intensifying the systematic review effort, providing training in experimental design and adhering to higher standards of research conduct and reporting, prospective registration of preclinical studies, and the public deposition of (both positive and negative) findings would be steps in the right direction. Greater public accountability might be provided by including lay people in some of the processes of preclinical research such as ethical review bodies and setting research priorities. However, if animal researchers continue to fail to conduct rigorous studies and synthesise and report them accurately, and if research conducted on animals continues to be unable to reasonably predict what can be expected in humans, the public’s continuing endorsement and funding of preclinical animal research seems misplaced.”

While some aspects of the article are reasonable, the overall impression the reader is left with is that animal research doesn’t work and can’t work in its current form. Their bias is obvious to those who are familiar with the arguments of those who argue against animal research. When they’re not incorrectly conflating basic science* with animal research (most basic biomedical research does not involve animals, e.g. human genetic research), Pound and Bracken argue that “lack of translation” is (apparently) not just from poor research practises, but also due to fundamental differences between humans and other animals, writing:

Even if the research was conducted faultlessly, animal models might still have limited success in predicting human responses to drugs and disease because of inherent inter-species differences in molecular and metabolic pathways.”

However, the bulk of the supporting literature they present to support this statement is – unlike most of the claims made in their commentary – not in the form of peer reviewed scientific research papers or meta-analyses but rather commentaries and books written by (other) opponents of animal research, including a certain Dr Greek whose misleading claims we have discussed several times on this blog (most recently here). For a commentary that sets great store by its evidence-based credentials this is, to say the least, disappointing.

Indeed, in their 2004 publication on whose anniversary this commentary was published, Pound, Bracken and their co-authors found that in all 5 cases where a therapy appeared to be successful in pre-clinical animal studies but later failed in human studies, more rigorous meta-analysis of the pooled pre-clinical animal studies showed that the treatment was not in fact successful in them, and that for one therapy (thrombolysis for stroke) such rigorous analysis would have enabled a serious side effect observed in clinical trials to be identified in the pre-clinical animal studies. In short, their own work shows that animal studies can predict the human outcome when their results are analyzed properly..

Other investigators who have examined failed therapies in cancer, ALS and stroke, have come to the same conclusion that too many therapies in some areas of research have failed in clinical trials not because of species differences, but because they never actually succeeded in animal studies, with most of the apparent successes being false-positive results due to flaws in experimental design and biases in reporting and publication. The authors all agree on a number of steps that need to be taken to avoid false-positive results being taken through to clinical trials, including better study design, requirement for independent replication of results in several animal models of the condition in question, publication of negative results (where the candidate therapy doesn’t work), meta-analyses of animal studies before beginning human trials.

An excellent analysis of animal models of stroke by van der Worp et al (2010) covers many of these issues, but also advises that to avoid false negative results in the clinical trials – where poor trial design leads to the erroneous conclusion that a therapy doesn’t work when in fact it does – human trials should match as closely as possible the conditions e.g. time to drug administration, dose, type of injury) of the successful animal studies.

The “rapid responses” to Pound and Bracken’s piece shows that many scientists who specialize in translating research from bench to bedside are alert to the flaws in their analysis.

To quote the response by Andrew Whitelaw and Marianne Thoresen, Professors of Neonatal Neuroscience at the University of Bristol:

The reader was left with impression that there were no examples in recent years of animal research leading directly to major advances in human health.

Three life-saving treatments in neonatal medicine would never have been given ethical approval for clinical trial if there had not been high quality animal models showing efficacy.

Rather than unselectively condemning the whole of biomedical animal research, we suggest that a more critical approach by funding bodies and journal editors could reduce bad research while supporting the good.

They ought to know, as basic and applied research in animals was crucial to the development of techniques that use cooling and xenon gas to protect babies from brain damage following oxygen starvation during birth.

Dr Thomas Wood, is more succinct:

[T]he overriding message of the article is somewhat confusing – demanding that we optimise and streamline animal research is very different from suggesting that it is useless, but both of these ideas are presented side-by-side.”

Prof Malcolm Macleod, a neurologist at the University of Edinburgh, and a frequent critic of poor design in some animal studies, agrees with many of Pound and Bracken’s criticisms, but in a more balanced manner, noting:

When conducted to the highest standards, animal research can indeed inform the development of human medicines. Given that there are many diseases for which we do now have treatments, it is perhaps self evident that the diseases which remain are more challenging, probably requiring research that is done to a higher standard – there is less signal, and more noise.”

Professor Macleod is one of Europe’s leading experts on the development of therapies for stroke, and is one of the leaders of the EuroHYP-1 trial of therapeutic hypothermia in adult patients with acute ischaemic stroke, a trial he advocated after undertaking a rigorous meta-analysis of studies on this therapy in animal models of ischaemic stroke.

Dr Charles M Pearman discussed how basic science makes up the building blocks that lead to human medicine:

Much clinical research is performed by standing on the shoulders of giants. A phase III drug trial comparing two antihypertensives will have much greater direct impact on clinical decision making than any individual animal model based basic science study. However, hundreds or thousands of such “low impact” works are needed to develop the drugs in questions. The authors reference Wooding et al. who themselves acknowledge this and conclude that clinically motivated basic biomedical research should be encouraged.

Basic biomedical research may try and may fail. Without it, however, there will be no successes to base clinical triumphs upon.

There have been many other comments, Prof Fernando Martins do Vale discusses why some of Pound and Bracken’s criticisms may not have much of an impact on results. Prof Robert Perlman argues that evolutionary differences between species can inform animal research. And Dr Vanitha A J explains that much cancer research has been effectively translated from animals to humans, noting in particular recent progress in cancer immunotherapy.

Another, separate, but strong response to Pound and Bracken’s paper was from Dr Liz Harley at Understanding Animal Research. Harley notes that many of the criticisms made in the original opinion piece are already being addressed by the industry. The UK Government’s delivery plan, “Working to Reduce the Use of Animals in Scientific Research”, explicitly mentioned the problems of poor experimental design and outlined several initiatives aimed to improve current practices. While Pound and Bracken call for a lay person to sit on ethical review bodies, they fail to note this is standard practice in the UK, while US regulations demand a lay person unaffiliated with the university stand on their Institutional Animal Care and Use Committees. Clearly Pound and Bracket do not do their homework sufficiently.

We finish with a quote from Prof Martins do Vale:

But the existence of bias and errors does not invalidate Science; on the contrary, as Karl Popper said, the awareness of errors is the first step for their correction and scientific progress.”

Pound and Bracken’s article opens up some important questions, but their biased interpretation risks throwing out the baby with the bathwater as they use flaws in experimental design to try and argue for a fundamental flaw in animal research. Their attempts to use legitimate concerns over experimental design to attack animal research are in fact a dangerous distraction from ongoing efforts to address problems that affect all areas of biomedical research (and indeed any areas of research where scientists have looked for them) from the most fundamental in vitro molecular biology studies right through to clinical trails.

Speaking of Research

* Confusion over what is meant by basic research is a theme throughout Pound and Bracken’s piece, it’s notable that many of the examples of “basic” research they mention are in fact applied or translational research, and that they focus on a paper on translation of basic research published by Contopoulos-Ioannidis et al. in 2003, a paper whose serious flaws in both design and conclusion we have discussed previously.

To learn more about the role of animal research in advancing human and veterinary medicine, and the threat posed to this progress by the animal rights lobby, follow us on Facebook or Twitter.

Don’t let medical progress go over the cliff, contact your representative today!

In this blog we frequently discuss threats to medical research, ranging from harassment of individual scientists by animal right extremists, to spurious complaints by animal rights groups, to legislative proposals that may harm medical research.  The threat we wish to draw your attention to today is somewhat different, as it impacts not only on medical research but on all areas of scientific research in the US, but it is one which demands urgent action.

As the end-of-year deadline for agreement on a new federal budget looms ever closer, and discussions in the US Congress continue, the danger of going over the “fiscal cliff” is increasing, an event that would trigger  sequestration — automatic spending cuts scheduled to take effect in January 2013.  These cuts, amounting to about 600 billion in non-defence spending would reduce funding for research agencies by $3.9 billion in 2013 alone. These agencies include those charged with protecting the health of US citizens and developing innovative new therapies to treat disease, the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), and the National Science Foundation (NSF), and provide funding for many of the exciting research projects that we have discussed on this blog over the past few years.

saveresearchheader

The impact of such cuts, coming after almost a decade of stagnant funding levels – in reality funding decreases in most agencies once you adjust for inflation and a sharp increase in administrative costs over the same period – would be devastating for biomedical research in the USA, as the report “Sequestration: Health Research at the Breaking Point” from Research! America makes all too clear. The leadership of Research!America, a not-for-profit public education and advocacy alliance whose members include many research institutions, charities and scientific associations, noted that this would:

  • Result in the loss of 33,000 NIH-funded jobs and a $4.5 billion decline in economic activity.
  • Eliminate NSF funding for more than 19,300 researchers, students and technical support personnel.
  • Eliminate 2,500 specialized disease detectives in state and local health departments funded by the CDC, severely limiting efforts to identify and stop food borne outbreaks.
  • Mean the loss of $111 million in FDA user fees that are vital for its evaluation activities, delaying patient access to new medical treatments.

What is not so easy to calculate is the longer-term impact when promising young researchers leave science due to career insecurity, when great new ideas go unstudied, when fewer opportunities exist to capitalize on scientific and technical advances, and when new therapeutic ideas don’t get developed to the point where they can be tested in the clinic. The Federal Government provides about 60% of funding for basic research, so it is clear that Research! America’s use of the term “devastating” to describe the impact of the cuts is fully justified. Indeed, investments in science and engineering have produced more than half of U.S. economic growth since WWII, with government funding fostering new knowledge, industrial innovation, and the training of future scientists and engineers, which explains why a recent Pew Research centre poll found that a clear majority of Americans oppose cuts in funding for scientific research.

Unfortunately there are those who see this crisis as an opportunity to renew their ongoing attacks on science. In particular the animal rights group PeTA – using the kind of misleading propaganda we have grown very used to -  is urging it’s supporters to write to their senators and congressional representatives to ask then to cut all funding for animal research (Warning: PeTA Website). Such campaigns make it even more crucial for scientists and those who support science to make their voices heard by the politicians who are currently debating the budget.

So what can we all do about this?

Well, you can head over to the Advocacy and Action page at Research! America, where they have loads of information on how you can contact your Senator, Congressional Representative and President to let them know that while reducing the deficit is important it must not come at the cost of scientific advancement, future economic prosperity, health or human lives. They even have an online tool to help you compose messages to tell our politicians that we need cures, not cuts!

A new campaign SaveResearch.org has united dozens of research charities and scientific organizations to campaign against the cuts, and has lots of suggestions for action, including this research advocacy toolkit that offers lots of helpful advice and tips.

And if you are a scientist the American Association for the Advancement of science has a great resource where you can leave a message or video  that they will take to Capitol Hill and the White House.

You might even take up the suggestion made by the editors of Nature to put on your lab coat and march on Capitol Hill.

Whatever you decide to do, doing nothing is not an option. We in the scientific community – and all those who support scientific research – need to make sure that our political representatives hear our voices, and act now before the damage is done!

Speaking of Research

 

 

Animal rights activists protest Curiosity driven research

The last couple of days was nothing but jubilation at NASA/JPL after the landing of the rover Curiosity on Mars.  President Obama congratulated scientists on the occasion by stating:

The successful landing of Curiosity — the most sophisticated roving laboratory ever to land on another planet — marks an unprecedented feat of technology that will stand as a point of national pride far into the future.”

However, the atmosphere changed dramatically this morning. As JPL scientists came to work, they were perplexed to be greeted by a group of noisy animal rights protestors at the entrance to the Jet Propulsion Labs in Pasadena, California.

Michael Bunkie, from Stop Alien Exploitation Now, told a group of reporters gathered at the scene that:

 These experiments have been done before and nothing came out of them. How many times do we have to land on Mars to just look at rocks?  I mean, all of them look the same! We already have space junk on Mars.  Why do we need more? This is clearly duplicative research done at the taxpayer expense and it must stop.”

Mr. Bunkie said he will FOIA every employee at NASA to obtain more information on what he called “an outrageous waste of resources.”

Dr. Maximus Ego, a retired physician and long-time scientific advisor to Bunkie, added:

“There is really nothing we can learn on Mars that will help humans.  Chaos theory and the Heisenberg uncertainty principle guarantee that even if life originated first on Mars, nothing we learn about its evolutionary history will be applicable to us.  I have published a 300-page long proof of this obvious statement (available from Amazon for $12).  After all, they are Martians and we are humans. Isn’t this obvious to NASA and its so-called scientists?”

When asked about the potential benefits of the research claimed by the space agency Dr. Ego added:

Gimme a break! This is clearly curiosity-driven research.  Nothing else, nothing more. They even named the rover ‘Curiosity’!  It is unacceptable for them to keep misleading the public by saying the questions at hand have any significance for advancing well-being on Earth. This type of research is worse than the discovery of the Higgs Boson!”

As JPL scientists quickly walked past, Dr. Ego ran after them screaming “I challenge you to a debate! Come on, I challenge you to a debate!  Do you know what a hypothesis is? Do you?!” 

Meanwhile, Rick Bungled, of the Alliance for Microbial Ethics, stood by silently holding a sign that read “How like us are they?”  When asked about its meaning Mr. Bungled explained:

How can we be invading Mars when we know there is a chance there might be life there? We must give these hypothetical organisms the benefit of the doubt, and assume they are sentient and conscious life forms just like us. For humans to gratuitously invade other planets is nothing more than a sign of our decadence. We have already destroyed Earth and now we are going to destroy the rest of the Universe. Humans are nothing but evil monsters (except me, of course). The Universe would be a better place if we all killed ourselves (I mean, if you killed yourselves).”

Nearby, Dr. Andrew Smoothtalk, from the Humane Planetary Society, said his organization held a much more moderate position.

“Of course we support science.  But we are now in the 21st century and have developed advanced computers, such as IBM’s Watson which can defeat you at Jeopardy. Clearly, we have the technology to simulate the origin of the solar system. We could send a virtual rover to a simulated Mars and explore simulated life in this simulated planet. We could even give scientists 100 bonus points for a good landing!  Given these new methods, which these NASA scientists are completely unaware of, we think time has come for NASA to switch these type of space exploration with more cost-effective methods than studying the real thing”  Waving out a piece of paper he pulled form his pocket he exclaimed “Here, I have with me a pledge that NASA can sign which already counts with the support of about 800 Raelians.”

NASA/JPL reacted to the criticism by circulating an email to the press this morning stating that they have serious and important work to do and are not planning on wasting precious time in responding to the activist’s allegations.

A masked activist, after being told of the NASA statement, said the activist will continue their relentless work to make space exploration stop “by all means necessary” — and walked away with a Molotov cocktail under his arm.  “To educate the neighbors” — he clarified.  Mr. Bungled, standing next to him, sighed deeply and explained that “the continued refusal by scientists to engage with activists can only lead to violent actions by the underground. Don’t tell us we didn’t warn you.”

Disclaimer: Although this may look like a real story you might have read over the past year or two,  it is in fact satire. Any resemblance to actual living persons is…err…purely coincidental and not to be taken (too) seriously.

Speaking of Research

So, what can a growing fly teach us about skin cancer?

Back in April we welcomed launch of the Golden Goose Awards , an annual prize awarded to honor federally funded research  “whose work may once have been viewed as unusual, odd, or obscure, but has produced important discoveries benefiting society in significant ways.”.

The Golden Goose award was developed in response to attacks on basic research by politicians who fail to appreciate the value of basic research, and it is not difficult to imagine that a research project begun back in the 1980’s which sought to determine the role of a gene named “hedgehog” during embryonic development in fruit flies would have been greeted with derision by the usual suspects .

D. melanogaster, an organism whose small size belies its huge contribution to medical science. Image courtesy of André Karwath.

Any such derision would have been badly misplaced. An article posted last week on the Cancer Research UK Science Update blog reveals how studying the hedgehog gene in the fly Drosophila melanogaster ultimately led to the development ofVismodegib, a drug recently approved for the treatment of advanced basal-cell carcinoma by the FDA, noting that:

 For us, the hedgehog’s tale is a testament to the beauty and potential of basic biology. It’s certainly not the first time that our basic research has helped set the stage for a new drug that can help cancer patients, and – given the progress we’re continuing to make in our research centres across the country – we doubt it will be the last.”

I encourage you to read the full CRUK Science Update Blog post “High-impact science: Hedgehogs, flies and skin cancer – the story of vismodegib” , it’s an excellent example of how research on flies, rodents and a range of other organisms combined with studies of cancer genetics in humans to enabled the development of an innovative therapy.

Paul Browne

The Golden Goose Awards

Politicians sometimes deride research based on the what they perceive as being “silly” titles of federal funded grants.  If they spot a title that deals with “games”, for example, they may assume it deals with some sort of amusement of little value to society, instead of a deep, powerful branch of mathematics that describes the behavior of competing rational agents with much relevance to voting, economics, cooperation, and so on.  Animal rights activists also enjoy the hobby.  The latest example is IDA’s list of “ridiculous research” ,whose claims were sadly repeated by far too many news journalists who were clearly too lazy check if they were accurate.  There were some honorable exceptions, notably an excellent editorial entitled “When the facts ruin a good spin” in the Times Union, which discusses a project on the role of music as a conditioning stimulus for drug use ends with a statement with which we heartily agree:

What’s “ridiculous,” to borrow the press release’s language, is that we fall for it, over and over, egged on by politicians eager to score easy points. And what’s “wasteful” is the time and energy that could be so much better spent on something other than a cheap shot.”

Back in 1976 the House Committee on Appropriations asked the National Science Foundation “Why does the Foundation persist in supporting research whose results have no apparent value to the American people?”  The NSF responded in part that:

Basic research seeks an understanding  of the laws of nature  without  initial  regard  for specific  utilitarian  value. Ultimately, however, it  is of the  most important  practical significance, because in a broad sense it is the foundation upon  which rests  all technological development.  Applied research builds on the results of basic research, seeking detailed  information  about  a specific situation  whose general laws have  been  discovered by  basic  research.  The  final step  toward  utilization  of research-development is  the systematic  application  of knowledge to  the  design  of  end products. [...]

As we  increase  our  knowledge  of nature  and  mankind,  in order  to adjust  nature  to our survival, safety,  comfort and convenience, we must  depend  upon  scientific research  to clarify the  relationships  of many, many things.  Thus,  we study  atoms,  even  though  they  will never  be seen  by an  unaided  human  eye.  We study  stars  too  faint  to  be  seen without  a  telescope  and  with  wavelengths  which  can  only be  detected  with  radio  receivers  or  photographic  plates. To  understand  geology, we must  look  at  geologic formations  and processes in many  parts  of the world where different  conditions have existed.  To understand  more about the  phenomena  of life, we must  study  the  behavior  of viruses,  single  cells,  plants,  and  animals  of  many  species.

A book was compiled covering various areas of research with Isaac Asimov writing an essay defending the value of basic research.

Thus, it was with some surprise and delight that we read in the news about Rep. Jim Cooper (D-Tenn) understanding the value of basic research.  The Washington Post reports that:

On Wednesday afternoon, Cooper rose to the defense of taxpayer-funded research into dog urine, guinea pig eardrums and, yes, the reproductive habits of the parasitic flies known as screwworms–all federally supported studies that have inspired major scientific breakthroughs.

Together with two colleagues he created the Annual Golden Goose Awards to honor federally funded research  “whose work may once have been viewed as unusual, odd, or obscure, but has produced important discoveries benefiting society in significant ways.”

Studying dog urine, among other stuff deem crazy by animal rights cranks, led to major medical discoveries

The article goes on to describe how research on dog urine led to an understanding of the effects of hormones on the human kidney, how studies in the guinea pig led to a treatment for hearing loss in infants, and how studies on the screwworm led to the effective control of the a deadly parasite that targets cattle.  All these provide additional examples refuting the notion that learning about life processes from animals cannot yield knowledge applicable to human health.

The Golden Goose Award has the backing of the American Association for the Advancement of ScienceAssociation of American Universities (who in 2011 published a series of “Scientific Inquirer” articles skewering dubious politically-motivated attacks on basic science) and the Progressive Policy Institute, who are to be congratulated for this excellent initiative to highlight the importance of basic research.

At the press conference to launch the award Rep. Robert Dold told reporters that “When we invest in science, we also invest in jobs. Research and development is a key part to any healthy economy,” while  Rep. Charlie Dent (R-Penn.) added “It’s critical, and the federal government has an important role to play,” who went on to describe how injecting horses with snake venom might “seem peculiar” but led to the discovery of the first anti-venom.

Taking us, once again, to the concluding words of Asimov’s essay:

Unless we continue with science and gather knowledge, whether or not it seems useful on the spot, we will be buried under our problems and find no way out.  Today’s science is tomorrow’s solution — and tomorrow’s problems , too — and, most of all, it is mankind’s greatest adventure, now and forever.

How nerve cells reach their niche.

Developmental biology, the study of the processes through which organisms grow and develop, is an area of biomedical research where modal organisms – ranging from the slime mold Dictyostelium  discoideum to the chicken – play a crucial role, and one that has been honoured with several  Nobel Prizes in recent years.  For example, the 1995 prize for “discoveries concerning the genetic control of early embryonic development” was awarded for studies of the fruit fly  Drosophila melanogaster , and the  2002 prize for “discoveries concerning ‘genetic regulation of organ development and programmed cell death”, was awarded for research undertaken with the nematode worm Caenorhabditis elegans, while the 2007 prize for  “discoveries of “principles for introducing specific gene modifications in mice by the use of embryonic stem cells”” depended on studies of stem cells in the developing mouse embryo undertaken by Martin Evans.

Today on the Neurophilosophy blog Mo Costandi has another great example of how our knowledge of developmental biology is being advanced through animal research. In a post entitled “Astrocytes build blood vessel scaffolds for long distance neuron migrations” he discusses how a research team led by Dr Armen Saghatelyan  used  Green Fluorescent Protein labeling and genetic modification to track the processes that control the migration of nerve cells to their correct location in the developing mouse brain.

It’s fascinating work, and you can read about it on the Neurophilosophy blog here.

 

 

So what does this basic research in developmental biology mean to medicine?

Scientists have known for some time that the brain has a limited ability to repair itself following injury, for example after a stroke, and more recent studies have identified a critical role for adult neuronal precursor cells in this recovery.  But the process by these adult neuronal precursor cells migrate to the site of injury and integrate into the damaged brain circuitry is very inefficient, with only a small number of cells reaching the correct location, so scientists are working on a variety of approaches to boost the brain’s ability to repair itself.

One approach to doing this is the use of exogenous stem cells, such as the human embryonic stem cell derived neuronal precursor cells developed by the UK-based company ReNeuron that entered clinical trials for stroke in 2011.

Another avenue being pursued by several research groups around the world is to improve the efficiency with which the endogenous neuronal precursor cells migrate to and repair damaged regions of the brain. In order to develop therapies that improve endogenous brain repair scientists first need to understand the processes that drive – and limit – neuronal precursor production, migration and integration in the developing and adult brain, so that they can modify and enhance those processes to safely  optimize repair.  The work of Dr Saghatelyan and his colleagues has provided medical science with another important piece of a puzzle that when solved will benefit many thousands of stroke victims around the world.

Paul Browne

A breakthrough against Chronic Lymphocytic Leukemia…thank the mice!

A challenge that science communicators frequently face when discussing the process whereby a scientific discovery eventually leads to a medical breakthrough is the time that this often takes, indeed by the time that the reports of exciting clinical trial outcomes start to appear in the press the role of the scientists who made the initial discoveries is often relegated to a passing comment…if it is mentioned at all. An example of this comes from the Weizmann Wave blog, produced by the Weizmann Institute of Science.

You may remember reports last month on the very promising results of a small clinical trial where a new immunotherapy technique was used to eradicate cancer cells in patients with Chronic Lymphocytic Leukemia (CLL), a blood cancer for which currently available treatments are often inadequate.  That trial, conducted by scientists at the University of Pennsylvania led by Professor Carl June, involved removing T-cells from the patient, treating the cells with a lentiviral vector that encodes for a Chimeric Antigen Receptor which recognises a protein named CD19 that is found on B-cells, including the cancer cells responsible for CLL, and then infusing the transformed T-cells back into the patients.  As the reported in the Los Angeles Times the results were dramatic, within a few weeks of the infusion the modified T-cells expanded rapidly and targeted the cancer cells in all three paients, so that a year later two of the three patients were still in complete remission.

It’s exciting stuff but as the Weizmann Wave reports the Press Release issued by Penn Medicine noted that this was a “cancer treatment breakthrough 20 years in the making” but “didn’t, however, explain those “20 years in the making.””. The Weizmann Wave goes on to discuss the pioneering basic scientific research undertaken by Professor Zelig Eshhar at theWeizman Institute of Science in the late 1980’s, which you can read about here.

Of course between the basic research undertaken by Prof. Eshhar and his colleagues in the 1980’s and the clinical trial whose outcome was announced last month there was a lot of work to be done. It would be impractical to describe all the different discoveries that made this immunotherapy possible, but one discovery in particular highlights the importance of animal research to this breakthrough.

There have been previous attempts to use Chimeric Antigen Receptors to target T-cells to attack cancer, but these had disappointing results in clinical trials.  A major improvement made by the University of Pennsylvania team was to include an additional motif – named the CD137 co-stimulatory molecule- which greatly enhances the cancer killing ability of the infused T-cells.  In a recent paper published in the Journal of Cancer the University of Pennsylvania team point out that the decision to include CD137 (called 4-1BB in mice) in their Chimeric Antigen Receptor construct was based on promising results in studies undertaken in mice:

 Our group has tested a CAR directed against CD19 linked to the CD137 (4-1BB) co-stimulatory molecule signaling domain to enhance activation and signaling after recognition of CD19. By inclusion of the 4-1BB signaling domain, in vitro tumor cell killing, and in-vivo anti-tumor activity and persistence of CART-19 cells in a murine xenograft model of human ALL (acute lymphoblastic leukemia) is greatly enhanced”

Indeed, in a paper published by Professor June and colleagues in the journal Molecular Therapy in 2009 they describe this work in much more detail, highlighting just how groundbreaking the results were:

Previous in vitro studies have characterized the incorporation of CD137 domains into CARs.10,11,29 Our results represent the first in vivo characterization of these CARs and uncover several important advantages of CARs that express CD137 that were not revealed by the previous in vitro studies. We demonstrated that CARs expressing the CD137 signaling domain could survive for at least 6 months in mice bearing tumor xenografts. This may have significant implications for immunosurveillance, as well as for tumor eradication. For example, in a mouse prostate cancer xenograft model, survival of CAR+ T cells for at least a week was required for tumor eradication.30

Long-term survival of the CARs did not require administration of exogenous cytokines, and these results significantly extend the duration of survival of human T cells expressing CARs shown in previous studies.17,31 To our knowledge, this is the first report demonstrating elimination of primary leukemia xenografts in a preclinical model using CAR+ T cells. Furthermore, complete eradication was achieved in some animals in the absence of further in vivo therapy, including prior chemotherapy or subsequent cytokine support.

The long-term control of well-established tumors by immunotherapy has rarely been reported. Most preclinical models in a therapeutic setting have tested tumors that have been implanted for a week or less before initiation of therapy.32 After establishing leukemia 2–3 weeks before T cell transfer, we found that many animals had long-term control of leukemia for at least 6 months. The efficacy of targeted, adoptive immunotherapy in this xenograft model of primary human ALL compares favorably to our prior experience testing the antileukemic efficacy of single cytotoxic (ref. 27 and data not shown) or targeted agents,26 where we have observed extension of survival but not cure of disease. Additionally, we have not previously observed the ability to control xenografted ALL for a period of as long as 6 months.”

These results led directly to the clinical trial reported last month.

So there you have it, behind the headlines are years of graft by hard-working and innovative scientists, who utilised a wide range of experimental approaches – among which animal studies figure prominently – to develop a novel therapy for CLL. As Professor Bruce Levine points out in the video above, the key to success is often keeping one hand in the basic research lab and the other in the clinic.

Paul Browne

Addendum: Scienceblogger Erv has written an excellent commentary on this study

Taming the Wolf: a new treatment for Lupus

Earlier today we posted a commentary on PeTA’s misleading propaganda by Professor Anthony Garro of UMass Dartmouth.   At the time I mentioned that it was a pity that Prof. Garro was not able to write more about the role of animal research in 21st century medicine, but a recent story in Nature News provides an excellent example, showing how research on mice and monkeys was crucial to the development of a new drug for lupus.

The autoimmune disease lupus, or to give it its full name Systemic Lupus Erythematosus (SLE), affects over 100,000 people in the United States, causing damage to a variety of tissues in the body and a wide range of symptoms ranging from fever, headache and  joint pains to anemia and renal failure. While there is no cure for lupus it can be treated successfully, though current treatments do not work well for all patients. Continue reading