Category Archives: Science News

How to distort 0.004% of the statistics

This is the second guest post by Professor Robin Lovell-Badge, who is head of the division of Stem Cell Biology and Developmental Genetics at the Medical Research Council National Institute for Medical Research in London. After an earlier post which debunked myths about the nine-out-of-ten drug failure rate, Prof. Lovell-Badge has taken on the claim that “only 0.004% of all animal experimentation is of any direct benefit to human health”. In this post Prof Lovell-Badge explains how this statistic was derived, and why the claim is not supported by the evidence. This post is also appearing on other websites including www.understandinganimalresearch.org.uk.

A new statistic is doing the rounds in the animal rights camps. It asserts that “only 0.004 per cent of all animal experimentation is of any direct benefit to human health”. A damning claim if it were true.

The claim originates from a 2003 comment article by William Crowley who was commenting on a paper from Contopoulos-Ioannidis, Ntzani and Ioannidis. Let us look at both.

Contopoulos-Ioannidis, Ntzani and Ioannidis – Translation of Highly Promising Basic Science Research in Clinical Applications, 2003

In this paper, the authors screened all articles published between 1979-83 in six highly cited basic science journals for the words: therapy, therapies, therapeutic, therapeutical, prevention, preventative, vaccine, vaccines, or clinical. From these they retained all those which suggested there might be a future clinical application.

“[They] only considered technologies that were still at an experimental stage (molecular, cellular, animal, and early non-random humanized studies) that did not have prior application on humans for a specific promise”.

And

“[They] excluded articles that did not describe a clear clinical promise in the abstract; editorials; commentaries; reviews; news articles; articles that focused on mechanism of action, pathophysiology, or diagnosis; and articles on agricultural or veterinary applications”.

Conclusions:

  • 25,190 papers were screened.
  • 562 included the words mentioned above (therapy, therapeutic… etc.)
  • 101 suggested future clinical application (and thus were further investigated)
  • 27 promising technologies have resulted in at least one published trial (by October 2002).
  • 19 have one published positive trial.
  • 5 technologies were licensed, 4 more have shown limited clinical use
  • 1 has shown extensive clinical advantages (angiotensin-converting enzyme inhibitors).

Study fails to show 0.004% of animal experiment are of benefit to human healthThat only 27 of the 101 papers led to a clinical trial is not a surprise, as the results reported in these papers would have been very early stage findings, and many would have been weeded out in subsequent basic research and pre-clinical evaluation before ever getting to human clinical trials.

If we look at the types of studies which resulted in positive trials, we find that of the 19 out of 101 papers that lead to a positive trial (18.8%), the  rate was the same for animal studies (12 out of 64, which also equals 18.8%) as for non-animal methods (7 out of 37, which is 18.9%).

Furthermore, in concluding the authors make the telling observation that:

“[B]asic research often leads to subsequent clinical breakthroughs simply by answering fundamental questions instead of targeting specific clinical problems”.

In other words, because Watson and Crick didn’t mention future clinical applicability in their seminal 1953 paper, the screening process used by Contopoulos-Ioannidis et al could not have picked it up had they chosen the year 1953. However, this doesn’t mean there wasn’t future medical applicability. Among a huge host of advances, our understanding of DNA structure has been essential to our understanding of cancer, without which we would not have most of our modern treatments.

Crowley’s comment piece mentions several papers related to the cloning of growth hormones and cytokines which were missed by the original authors’ algorithm, but have still led to trials and successful medical treatments. In Crowley’s words:

“[T]he algorithm used failed to unearth several key articles related to the cloning of growth hormone and cytokines. Not only did their algorithm miss these articles in the very journals they searched, but the proteins described therein have led to successful clinical trials and the subsequent development of therapeutic agents”.

A further flaw is that the analysis only looks at the 20 years after publication date. While they mention that a rotavirus vaccine was withdrawn, they could not know (due to it happening after the article was published) that 2 vaccines have been approved for the rotavirus since –based on the bovine rotavirus research reported in the original paper. Similarly they mention the drug Eflornithine:

“Eflornithine (difluoronethylornithine) may be used to treat trypanosomiasis on special request, but the drug has only been tested in nonrandomized studies for this indication”.

Following successful clinical trials, Eflornithine is nowlicensed to treat Human African trypanosomiasis (sleeping sickness) for which it is an important therapy and it is now also being evaluated in clinical trials in combination with the drug Nifurtimox. These two therapies effectively triple the “extensive clinical advantages” success rate. How many other therapies based on the 101 selected papers that were in preclinical development or early clinical trials at the time when Contopoulos-Ioannidis et al. wrote their paper later went on to clinical success is not known.

Crowley – Translation of Basic Research into Useful Treatments: How Often Does It Occur? 2003

The most relevant part of Crowley’s article is contained in a single sentence:

“Of the 25,000 articles searched, about 500 (2%) contained some potential claim to future applicability in humans, about 100 (0.4%) resulted in a clinical trial, and, according to the authors, only 1 (0.004%) led to the development of a clinically useful class of drugs (angiotensin-converting enzyme inhibitors) in the 30 years following their publication of the basic science finding”.

This one sentence contains at least 4 errors.

First off, Crowley has misread the paper when stating 100 had a clinical trial. 101 papers were assessed to see if they had a clinical trial, but only 27 did. Secondly, it does not make sense to make percentages out of the original 25,190 papers when 99.6% of these were screened out and not investigated for clinical trials. The 25,089 papers that were not examined could have led to 10, 100 or 1,000 successful therapies, but we simply don’t know because they never looked. Thirdly, to say that only 1 led to the development of a clinically useful class of drugs is also incorrect, since we have found that at least 7 led to licensed drugs that proved useful in the clinic, of which at least 2 (angiotensin-converting enzyme inhibitors and rotavirus vaccine) have extensive clinical advantages. So, of the 27 which had trials, 7 (26%) led to the development of a medical application. Finally, to say a “basic science finding” in reference to the starting pool of  25,190 papers was also incorrect, since while many will have reported basic science findings, this group of papers will also have included review articles, applied and translational science papers, commentaries, editorials and clinical trial reports.

In short, strict screening methods meant that 99.6% of papers were ignored (including all those looking at diagnosis of human conditions, and all veterinary research), leaving a sample size of 101. There was no evidence in the original article that the remaining 25,089 papers resulted in no future medical benefits (they simply were not checked). Of the 101 analysed papers (those which were likely to be looking at future benefit), 27 (26.7%) had trials. 7 (6.9%) resulted in a licensed application and 2 (2%) resulted in a widely used treatment.

Of course just because Contopoulos-Ioannidis et al. only found clinical trials for 27 of the 101 papers they examined does not mean that clinical trials of therapies based on any of the other 74 papers did not take place subsequent to the publication of their study, we have seen that this happened at least twice in the group of 27 papers that they focused on. Unfortunately since they don’t give any details about these 74 papers it is impossible to determine how often this happened.

The Claim:

Finally let us remind ourselves of the claim:

“[O]nly 0.004 per cent of all animal experimentation is of any direct benefit to human health”.

The evidence for this claim that we discuss above does not support such a conclusion. As we saw, the research it is based on includes all manner of research, animal and non-animal (both of which showed the same rate of success in trials that were assessed) – so to make any judgements about animal experiments in particular is unfounded. The claim also assumes that only research that purports to have clinical application (and includes one of four words, or derivations thereof) can have clinical application; however, Crowley points out examples of  successful treatments which originated from papers not mentioning the specific words the original authors screened for.

So the claim that the animal rights activists are making is a misrepresentation of an incorrect interpretation of a study that already had very serious limitations.

In essence, the original statement made by those opposed to animal research is not just inaccurate, it is meaningless.

Professor Robin Lovell-Badge
Head of the Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, London

Animal rights activism and medicine 100 years ago

There is a rather interesting book, Animal Experimentation and Medical Progress by William Williams Keen, published in 1914, which describes some of the incidents in the animal research debate during the early 1900s.  What is  striking about this book is that it illustrates very clearly how little (if at all) the arguments and tactics of animal rights proponents have changed over the last 100 years.

Consider the kind of letters that scientists received because of their work with animals:

letter2

Sometimes, animal rights activists also felt it was also important in making their point to include other members of the scientist’s family in their missives.

letterThe language is nearly identical to the anonymous emails or web-postings attacking scientists today.

A century ago those opposed to the use of animals in medical research were already using deceptive, calumnious imagery, suggesting animals underwent surgical procedures without anesthetic,  which evoked the following, unanimous response from the English Royal Commission:

Image

And a hundred years ago, the scientific  community was already expressing  disbelief and regret at the lack of understanding of the work, and the activists’ willful ignorance of those that denied its benefits –

faseb_v2Scientists were not alone in their outrage.  One hundred years ago medical professionals from all over the world were prompted to issue a  statement at the International Medical Congress supporting animal research:

Image

Of course, Charles Darwin himself, had these famous words to offer some 30 years earlier:

Fortunately, some things have in fact changed over the last 100 years.

Back then we did not have antibiotics, nor vaccinations for terrible childhood diseases.  We do today.  Vaccines that save more than 3 millions people per year, and prevent millions of others from suffering from disease and permanent disabilities.

Back then X-rays machines were just being created, the machines were bulky and access was extremely difficult.  Today X-rays, doppler ultrasound, positron emission tomography, magnetic resonance imaging, are all widely available providing some of the most useful diagnostic tools.

1901 Bayer Heroin ad

Back then Heroin was used in children’s syrup to treat cough and bloodletting was still used to treat fever and inflammation. Today, effective pain relievers and anti-inflammatories are widely available in the pharmacy at the corner.

Back then premature babies almost invariably died.  Today, the development of lung surfactants is saving the lives of babies across the world every day.

And the list of the benefits of animal research goes on and on…

Perhaps it can all be summarized by the fact that that back then life expectancy in the US was 52 years.  Today, we are living an average of 80 years.  In other words, in merely 3 generations, we increased our life expectancy by 60%.  This is time we all now enjoy with our loved ones, children and grandchildren.  Thanks to science.  Thanks to scientists. Thanks to responsible, animal research.

That is why one cannot help but keep repeating Darwin’s famous words “…he who retards the progress of physiology is committing a crime against mankind.”

First human stem cells created through cloning…thank Mitalipov’s macaques!

Today is one of those days that will go down in medical and scientific history, the day that scientists at Oregon Health and Science University led by Professor Shoukhrat Mitalipov announced that they had successfully created pluripotent human stem cells by cloning  skin cells. This is the first time that this has been accomplished in human cells, and is a major milestone in the developing field of regenerative medicine. It is also an achievement that rests on over a decade of careful studies of somatic cell nuclear transfer (SCNT) – the cloning technique they used - in monkeys by Professor Mitalipov and his colleagues.

A donor egg moments after injection of the skin cell nucleus. Image courtesy OHSU photos

A donor egg moments after injection of the skin cell nucleus. Image courtesy OHSU photos

An article on the ONPRC News highlights the importance of research in monkeys to overcoming the barriers that had foiled previous attempts to clone primate cells.

The Mitalipov team’s success in reprogramming human skin cells came through a series of studies in both human and monkey cells. Previous unsuccessful attempts by several labs showed that human egg cells appear to be more fragile than eggs from other species. Therefore, known reprogramming methods stalled before stem cells were produced.

To solve this problem, the OHSU group studied various alternative approaches first developed in monkey cells and then applied to human cells. Through moving findings between monkey cells and human cells, the researchers were able to develop a successful method.

The key to this success was finding a way to prompt egg cells to stay in a state called “metaphase” during the nuclear transfer process. Metaphase is a stage in the cell’s natural division process (meiosis) when genetic material aligns in the middle of the cell before the cell divides. The research team found that chemically maintaining metaphase throughout the transfer process prevented the process from stalling and allowed the cells to develop and produce stem cells.”

While this announcement, coinciding with publication of a scientific paper reporting their work that is published in the prestigious journal Cell (1), was a surprise, the fact that the team was led by Professor Mitalipov was not. Professor Mitalipov is one of the leading experts in reproductive biology, cloning and stem cell biology, and it was only back in March that we discussed how the technique of spindle-chromosomal transfer that he developed to prevent mitochondrial disease had been approved for human trails by the UK’s Human Fertilisation and Embryology Authority.

The key publication by Professor Mitalipov and his colleagues was in 2007 (2) when they reported that they has successfully produced two rhesus macaque embryonic stem cell lines through SCNT.  In their 2010 commentary “Cloning of non-human primate: the “road less travelled by” “ Professor Mitalipov and his co-authors describe this study and  subsequent modifications that they made to the SCNT technique to further improve its efficiency in primates. Their many modifications covered changes to the way in which the nuclei of the cells were visualised and manipulated, changes in the conditions under which the donor nucleus and enucleated egg are fused, and precise regulation of the reactivation of the fused cell. One key innovation was the use of the coat protein from the Sendai (HVJ-E) virus to improve the efficiency of cell membrane fusion between the skin cell nucleus and egg cytoplasm while prolonging the activity of a protein called  maturation-promoting factor (MPF) that keeps the egg in the correct cell cycle stage to allow the introduced nucleus to integrate. Avoiding premature activation of cell division in the egg turned out to be even more difficult  in human cells. Initially the technique they had used successfully in macaques failed to yield stable stem cell lines from cloned human cells, and the problem appeared to be that the eggs were still activating too quickly following fusion, but as Professor Robin Lovell-Badge of the MRC National Institute for Medical Research explained to the Science Media Centre earlier today, they were able to make an additional tweak to their method, by adding a shot of caffeine to the mix.

The idea of using caffeine came from previous experiments they had performed with monkey eggs. Caffeine inhibits certain protein phosphatase enzymes that are involved in the degradation of “maturation promoting factor (MPF)”, a factor that is essential for controlling the cell cycle machinery in the egg.”

It is worth noting that they found that while they could produce embryonic stem cell lines using this technique, macaque embryos created using it failed to develop normally when implanted into female macaques, indicating that while this technique is viable for therapeutic cloning it cannot be used for reproductive cloning.

Professor Mitalipov discusses the first macaque stem cells produced through cloning in 2007.

The potential uses for stem cells produced through this therapeutic cloning technique are myriad; the fact that you can take a person’s own adult cells and convert then into pluripotent cells that can differentiate into any cell type makes them ideal for many transplant purposes, ranging from bioengineered replacement tissues to genetically engineered cell transplants to cure inherited disorders, and of course stem cells created from cloned adult cells from people with a wide range of diseases can be used to create a huge range of in vitro disease models to improve our understanding of the biological process at work and hasten the development of new therapies.

Of course there is already another technology that allows scientists to reprogram cells to a pluripotent state, in 2006 induced pluripotent stem (iPS) cell technology burst onto the scene and quickly became the methodology of choice for many stem cell researchers, with the first clinical trial in human patients expected to start later this year. Has human therapeutic cloning missed the boat?  In an excellent commentary in Nature News on today’s announcement David Cyranoski points out that there is evidence (from studies comparing  SCNT with iPS cells in mice) that cells produced through SCNT are more completely reprogrammed to an embryonic state than iPS cells. So, it is likely that each technique will have its advantages and disadvantages depending on the goal of the research…and in scientific research it is always a good idea to have more than one horse in the race.

We congratulate Professor Mitalipov and his colleagues at OHSU on another stunning scientific achievement, one that will advance medicine, and no doubt be read about by students for many years to come!

Speaking of Research

(1) Tachibana M. et al. “Human Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer” Cell, published online 15 May 2013 DOI:10.1016/j.cell.2013.05.006

2) Byrne J.A. et al. “Producing primate embryonic stem cells by somatic cell nuclear transfer.” Nature. 2007 Nov 22;450(7169):497-502. PubMed:18004281

A new drug to treat type II diabetes: Thank the…Gila monster?

Earlier this week Lyxumia (generic name Lixisenatide), a new drug that helps to control type II diabetes, was launched in the UK. In addition to being an effective and saft therapy for type II diabeted, including in some patients that do not respond to current first-line therapies, Lyxumia is relatively inexpensive when compared to current therapies for type II diabetes, which will help to save the health services money that can be invested in other therapies.

Lyxumia belongs to a new class of drugs known as the glucagon-like peptide 1 receptor agonists that work by increasing the secretion of insulin in response to consumption of food, and is administered by a once daily injection.That animal research played a key role in the development of the glucagon-like peptide 1 (GLP-1) receptor agonists for treating diabetes should not be a surprise, but when I took a quick look at the paper (1) reporting the preclinical development of Lyxumia (them called ZP10A)  I got a surprise.

The low half-life of native GLP-1 (90-120 s) (Deacon et al., 1995; Egan et al., 2003) has led to extensive research to find new compounds with pharmakokinetic properties suitable for development of a drug candidate. Exendin-4 was first isolated from the salivary gland of the Gila monster (Heloderma suspectum), and characterization showed that the peptide was structurally related to, but distinct from GLP-1 with a sequence homology of only 52%. Further characterization of exendin-4 showed that the peptide is a potent agonist for the mammalian GLP-1 receptor  with a longer in vivo half-life and prolonged duration of action compared with GLP-1 (Raufman et al., 1992; Young et al., 1999). Recent studies have shown that administration of exendin-4 induces pancreatic endocrine differentiation, islet proliferation and an increase in β-cell mass (Edvell and Lindström, 1999; Xu et al., 1999), indicating that exendin-4 may exert insulinotropic effects on the β-cells (Greig et al., 1999; Parkes et al., 2001).

Yes, you read it correctly, the development of effective GLP-1 receptor agonists started with a discovery made by a scientist studying venom peptides found in the the saliva of a large lizard!

The Gila monster - an unlikely ally in the fight against diabetes. Image courtesy of Jeff Servoss

The Gila monster – an unlikely ally in the fight against diabetes. Image courtesy of Jeff Servoss

This should actually not come as so much of a surprise, venom is an incredibly rich source of bioactive molecules, and scientists around the world are studying the venom of a bewildering array of animals in order to identify everything from better painkillers to therapies for Parkinson’s disease. Recently EU recognized the value of such research by setting up the VENOMICS project to provide tools and resources to the scientists engaged in it.

Lyxumia itself was created as a synthetic analogue of exendin-4, and following   in the db/db mouse model of diabetes the team at Zealand Pharma concluded that:

[T]hese studies demonstrate that ZP10A is an effective antidiabetic compound that effectively improves FBG and glucose tolerance, resulting in a long-term improvement of total glucose control. Furthermore, the sustained effect on glucose metabolism, and pancreatic expression of insulin even after discontinuation of ZP10A treatment indicates that ZP10A preserves β-cell function in diabetic db/db mice. Therefore, it is concluded that ZP10A is not only a promising candidate for the treatment of human type 2 diabetes but also it has the potential to prevent the progression of the disease.

On the basis of these very promising results ZP10A underwent further preclinical evaluation in collaboration with Sanofi-Aventis before entering into successful clinical trials.

The availability of a new and cost effective therapy to help people to manage type-2 diabetes is very welcome, but the story of the development of the Glucagon-like peptide 1 receptor agonists reminds us that new therapies can lurk in the most unlikely – and indeed most unpleasant – places!

Paul Browne

1) Thorkildsen C, Neve S, Larsen BD, Meier E, Petersen JS. “Glucagon-like peptide 1 receptor agonist ZP10A increases insulin mRNA expression and prevents diabetic progression in db/db mice.” J Pharmacol Exp Ther. 2003 Nov;307(2):490-6. Epub 2003 Sep 15.

Treating Progeria; How GM mice give hope to some very special children

Something big is going on right now in the world of research.

Something very specific for some very special children with a very rare disease. It may not be widely known by name but I am sure you have seen these children. The disease is called Progeria. From the Progeria Research Foundation’s website, we learn:

Hutchinson-Gilford Progeria Syndrome “Progeria” or “HGPS” is a rare, fatal genetic condition characterized by an appearance of accelerated aging in children*.  Its name is derived from Greek and means “prematurely old.”  While there are different forms of Progeria, the classic type is Hutchinson-Gilford Progeria Syndrome, which was named after the doctors who first described it in England: in 1886 by Dr. Jonathan Hutchinson, and in 1897 by Dr. Hastings Gilford.

Progeria affects approximately 1 in 4 – 8 million newborns.  There are an estimated 200-250 children living with Progeria worldwide at any one time.  It affects both sexes equally and all races.  Since The Progeria Research Foundation was created in 1999, we have discovered children with Progeria living in over 40 countries.”

Most of us will have come across a picture of one of these children in the papers, on TV, or on the internet. We remember them because they look different from other kids their age. If you ever get the privilege to chat with them, you will find that are some of the wisest people you will ever meet. To speak with them is truly inspiring because of their personalities and outlook on life. It is also heart wrenching because we know most will never reach their twenties.

About eight years ago I was working as a veterinary technician in a research facility. During that time a new investigator moved his lab into our facility, and we received his colony of mice a few weeks before he arrived. After we had cared for the mice for a few days, we started to see some very strange things. The weanlings were sometimes very small, and occasionally they were also thin. It was strange to see mice that were so young but  looked like such old men. The reason was simple, these mice had been genetically modified to carry the same defective Lamin A gene that is responsible for Hutchinson-Gilford progeria syndrome in children. The ‘sick’ mice we saw were actually mice with Progeria!”

GM mice aided the development of a therapy for Progeria

GM mice aided the development of a therapy for Progeria

Several years later Dr. Stephen G. Young and colleagues at UCLA  published a study that detailed what they found within this small population of mice (1). Once a GM model of mice had been developed, cells from these mice were studied (2). When a farnesyltransferase inhibitor  was used in vitro on these cells, it showed this drug was a possible treatment for this terrible disease. Once this was learned, they went on to the next step which was to test farnesyltransferase inhibitor in vitro on cells from actual Progeria patients (3). When these studies looked very promising, confirming that the process occurring in the mouse and human cells were very similar, the GM mice were once again indispensable for the first in vivo study to determine if farnesyltransferase inhibitors could improve the health of mice with Progeria (1). This is the part that cannot be replicated by any calculations, test tube chemicals or computer programs. Without in vivo studies, it is impossible to know what a treatment will do in a living creature. The mice that were born with Progeria were given a farnesyltransferase inhibitor. Would they get better or would they stay the same? Once the study was complete, all results were compared and this therapy looked very promising indeed!

Professor Young gave a talk on his progeria research to the Congressional Medical Research Caucus in 2009, in which he discusses his group’s GM mouse studies in much more detail, and you can watch the video here.

From there, a drug needed to be developed that could be evaluated in children with Progeria. This is a process that can often take many years, but fortunately some farnesyltransferase inhibitors designed as cancer treatments looked promising (see more about it here). lonafarnib was selected for clinical trials in progeria because it had already been assessed in pediatric cancer clinical trials where it had a demonstrated an acceptable safety profile. This is how decades of drug development happened in less than 10 years.

Researchers were able to move many steps ahead, much closer to the Progeria clinical trials that were needed. Remember, the one thing these children do not have is time. They grow old and die, sometimes as young as seven, and very rarely live past twenty. Most die in their teens. If a completely new drug had been needed, nearly every child alive with the disease that day would have passed away by the time it was ready for a clinical trial.

I think it is very important to explain briefly genetic disease and the role GM play in finding treatments and cures. Francis Collins is a well known and oft cited geneticist and physician, and currently Director of the National Institutes of Health, who gave a TED talk in April 2012 about this very topic.  Dr. Collins has long been interested in Progeria, he led the team that first identified defects in the Lamin A gene as a cause of Hutchinson-Gilford progeria syndrome in 2003, and later in 2008 published a study that examine the effect of farnesyltransferase inhibitors on cardiac defects in a mouse model of Progeria (cardiac defects are the most common cause of death in children with Progeria).


At the most basic, a genetic disease is caused when there is a faulty gene somewhere in the genetic code. While the *reason* the gene is broken may be a mystery, there are roughly 4,000 genetic diseases that scientists at least know what gene is causing the problem, which is the case for Progeria. Scientists know what is causing the problem, but how do you fix it? Dr. Collins has a vision of accelerating the transition from the bench to the bedside, and the example of progeria shows that one of best tools for finding the treatments and cures is Genetically Modified mice. Our GM mice.

In the case with Progeria, researchers were able to create the same disease in mice that was found in humans, effectively mirroring the disease. By doing this, they are able to study not just the disease itself, but study treatments on a live organism with the disease. With GM mice, researchers are able to find treatments and cures at an unprecedented pace. As Dr. Mark Kieran, who led the first clinical trial of  lonafarnib to treat progeria (4), said:

PRF (Progeria Research Foundation)provides a model for disease research organizations, and is a good example of successful translational research, moving from gene discovery to clinical treatment at an unprecedented pace,”

There are over 4,000 genetic diseases known to us right now, yet only 250 of them have treatments. If we can find help for these people so quickly, why are there so few cures? One reason is that in many cases there are still no mouse model available to study. In our case of Progeria, a mouse model of the disease was developed which sped up research by years or even decades. Without GM mice, this treatment would not be available now. Progeria clinical trials moved very quickly compared to most treatments and it was announced in September of 2012. Finally, these children had a treatment! While this is not a cure, it is a huge step forward. With early diagnosis and treatment, these children have a much better chance at a normal life!

Because of the extremely rare occurrence of this disease, these children can be hard to find, especially in less developed countries where they may have never seen this disease before. In 2009, the Progeria Research Foundation  (PRF)launched the “Find the Other 150” campaign. As of September 2012, they were aware of 96 of the estimated 200-250 children living with Progeria. If you are aware of any of these children, please visit www.FindTheOther150.org to find information on how to participate in future studies.

I have spent nearly a decade in this field now. I will always remember those mice and those children. To see a treatment developed and to even have played a small part it helping it happen is humbling. Will I make headlines? No. Will my name ever be in a published paper? Probably not. Will I make millions off any of the discoveries I participate it? Never. I went into this field knowing full well I will never get rich or retire early and wealthy. That is not why I am here.  I choose to do what I do because of people out there like these Progeria kids. I do this for them, and all the millions of cancer patients out there like my late husband. I do this so we can find a cure.

And to know I had even a tiny part in making that cure happen, that, is priceless.

Pamela Bass

1)  Yang SH, Meta M, Qiao X, Frost D, Bauch J, Coffinier C, Majumdar S, Bergo MO, Young SG, Fong LG.”A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation.” J Clin Invest. 2006 Aug;116(8):2115-21

2)  Yang SH, Bergo MO, Toth JI, Qiao X, Hu Y, Sandoval S, Meta M, Bendale P, Gelb MH, Young SG, Fong LG.”Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation.” Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10291-6. Epub 2005 Jul 12.

3) Toth JI, Yang SH, Qiao X, Beigneux AP, Gelb MH, Moulson CL, Miner JH, Young SG, Fong LG. “Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes.” Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12873-8. Epub 2005 Aug 29.

4) Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland R, Snyder BD, Fligor B, Bishop WR, Statkevich P, Regen A, Sonis A, Riley S, Ploski C, Correia A, Quinn N, Ullrich NJ, Nazarian A, Liang MG, Huh SY, Schwartzman A, Kieran MW. “Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.” Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16666-71. doi: 10.1073/pnas.1202529109. Epub 2012 Sep 24.

IVF pioneer Sir Robert Edwards dies aged 87

We are saddened to learn that IVF pioneer Professor Sir Bob Edwards has died at the age of 87, following a long illness. The University of Cambridge announced his death earlier today, noting that through his work Professor Edwards had improved the lives of millions of people around the world. Speaking about his former colleague, Professor Martin Johnson, Emeritus Professor of Reproductive Science at the University of Cambridge noted that Professor Bob was not only a scientific pioneer, but recognized the importance of explaining your research to the public:

Bob Edwards was a remarkable man who changed the lives of so many people. He was not only a visionary in his science but also in his communication to the wider public about matters scientific in which he was a great pioneer.”

Professor Sir Robert Edwards, Nobel Laureate and IVF pioneer

Professor Sir Robert Edwards, Nobel Laureate and IVF pioneer

With his colleague Dr Patrick Steptoe, Professor Edwards performed the first human in-vitro fertilization procedure, which resulted the birth of Louise Joy Brown in 1978.  35 years later more than 4 million children have been born through IVF around the world, and in 2010 Professor Edwards was awarded the Nobel Prize in Physiology or Medicine “for the development of in vitro fertilization”. Unfortunately, as the University of Cambridge statement notes, Professor Edwards was already in poor health when the prize was announced.

The developments for which Edwards and Steptoe were responsible attracted much publicity, some of it, not least from the Vatican, highly critical.

Formal recognition therefore came late, but when it did come, it was decisive, with the award of the Nobel Prize for Physiology or Medicine in 2010 ‘for the development of in vitro fertilization.”

For Professor Edwards the Nobel Prize came late, but for his colleague Dr. Steptoe, who had predeceased him in 1988, it came too late. Dr. Steptoe was not alone in this. When Professor Edwards was awarded the Nobel Prize in 2010 we published a blog post welcoming the award and discussing the key contribution of animal research to the development of IVF, noteing that Dr. Min Chueh Chang – whose studies in rodents and rabbits led directly to the techniques used by Professor Edwards and Dr. Steptoe – was also denied a share in the 2010 Nobel prize as he had died in 1991. Knowing this adds to the poignancy of a moment when we remember the achievements of some of the greatest scientists of the 20th century.

Today our thoughts are with Professor Edwards’ family, friends and colleagues, but we also remember those other scientists and surgeons who worked with him to usher in a revolution in medical care that has brought happiness to millions of people across the globe.

Speaking of Research

An Ongoing Conversation with Robert Streiffer on Science and Ethics

I would like to thank Prof. Robert Streiffer for taking the time to comment on an earlier post of mine regarding the ongoing dialogue on the ethics of animal research at UW-Madison.

I had originally drafted an email to him with a reply, which is now reproduced below.  I am sure the readers will forgive the informal language.  Excerpts from his original comments are in italics.  His full commentary can be found here.

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First, I noted that most people who support animal research think that utilitarianism does not correctly capture our obligations to human beings. 

I think we agree that most people, whether they support animal research or not, reject utilitarianism as correctly capturing our obligations to other human beings.

For example, it is difficult to find anyone to agree it is ethically permissible to harvest the organs of one healthy human being to save the lives of  five others waiting for transplants, even if such an act is one that maximizes the total well-being of the human population.

In my view, human rights and obligations towards each other derive from our ability to adhere to a mutually agreed social contract, respecting the interest of others even when the resulting behavior goes against our own interests or against optimal utility. Non-human animals (and a handful of humans) cannot participate as full moral agents in our community, and thus cannot have rights as properly understood.  Of course, we owe all living beings moral consideration by the fact they can experience suffering.  But the only meaningful question that can be posed is how we should treat them.  (A question only humans ask.)

Second, I pointed out that even though supporters of animal research sometimes describe themselves as utilitarians-when-it comes-to-animals-but-rights-theorists-when-it comes-to human-beings (whom I refer to as “hybrid utilitarians”), they are probably not accurately characterizing their own views. 

Some scientists may have studied the ethical objections and the moral literature more than others.  Some may be able to explain their position using the language of moral philosophy; others may not.

However, I think a similar characterization applies to those that oppose the use of animals in research.  Indeed, it is rare for many of them to accurately represent their views. Consider for example PeTA, an animal rights organization which paradoxically cites the work of utilitarian philosophers as the basis for their position, leaving out all references to animal rights theorists.  An organization that objects to the use of animals to improve devices that restore hearing in humans, but allegedly kills thousands of dogs and cats every year.  Or consider Mr. Marolt, who appears well educated on these issues, but when given the opportunity to explain his objections to animal research in public, he simply relied on his “moral intuitions.”

Let me clarify my own view — suppose we met individuals from other species that could participate as full moral agents in a community of equals, with all the rights and obligations that come with such participation.  Should we welcome them?  Sure, I don’t see why not.  I stand ready to include hypothetical beings such as James Rachel’s super-chimp, or Asimov’s bicentennial man, or Aliens, as equals within our moral community.

As for your own view — I would be interested to learn where you stand.  It seems you have described the various positions held by various people, but you have never offered your own position on these issues.

For example, I expect that when they reflect on their obligations to their own pets, they probably believe that there are ways in which it would be wrong to treat their pets even though doing so would maximize utility.

Harming a pet would cause not only harm to the animal, but to a human being or family that cares deeply about it. That harm, which comes from a special relationship between the animal and other human beings, ought to count as well.  Thus we do not owe the same moral consideration to a rat in the New York subway system and one that is the dear pet of a human family. Do you think their moral status ought to be the same?  Different?  Why?

But Ringach never specifies how the sliding-scale framework adjudicates a conflict of interest between individuals who don’t have rights and who possess the same degree of moral status, and so, for all he has said, the sliding-scale framework could still take a utilitarian form with respect to such conflicts. If it does, such a framework would still be subject to a concern similar to the one I raised about utilitarianism and hybrid utilitarianism.

In scientific research, the conflict of interest is not between individuals who possess the same degree of moral status. It is between humans, who display a proven ability to learn about the processes of life to alleviate the suffering caused by disease, and the interest to well-being and life the animals used for such experimentation.

Ringach is correct that discussing examples of actual research that Marolt would find ethical would have helpfully highlighted some common ground and led to a more productive and balanced discussion. I will try to keep this in mind for future reference.

I believe this is an important point.  The starting point of the debate is usually framed with the question of “how can one morally justify the use of animals in scientific research?”

This implicitly assumes the other side has absolutely nothing to justify for their own position — which I think is wrong.  An equally valid question that needs to be asked is what moral justification the opponents have to call for the abolition of all animal research, as we believe their call for inaction is not harm-free.

I would note, though, that this point needs to be applied in a fair way: many animal researchers are reluctant to publicly discuss examples of actual research that they find unethical, even though doing so would also help highlight common ground and lead to more productive and balanced discussions. 

A fair criticism.

I think moral boundaries are dynamic and what we learn about animal behavior/minds and the availability of new experimental methods (such as the introduction of anesthetics) make some forms of experimentation that were accepted in the past unacceptable today.  As a specific example, I can offer the work of William Harvey on the circulation of blood and respiratory system.  I think most scientists and members of the public would agree such experiments on dogs, which form the basis of much of today’s internal medicine, would not be morally acceptable today.

As for scientists’ reluctance to participate — you must acknowledge it is not entirely self-generated.  As you know, some animal activists, including individuals in your UW forums, have publicly justified for the use of violence against those they disagree with.  It should not come as a surprise that scientists may be hesitant to engage with these individuals.  Do you feel there is value in engaging with them?

The first key point I was making is that there is a distinction between knowledge and benefit per se and that research, in the first instance, produces knowledge, not benefit. The phrases “in the first instance” and “per se” are important here. While knowledge often leads to benefits, research can produce knowledge without producing any benefit at all. 

Understood.  But benefits always derives from knowledge, even if the knowledge is obtained from something as basic as trial-and-error.  There are no benefits without knowledge.  And there is no knowledge without science.  Here is a nice piece by Isaac Asimov that is germane to the topic of benefits derived from basic research.

However, the second key point I made is that, when one is evaluating research that harms and kills animals, the moral threshold is higher than it is with other academic pursuits: that kind of research cannot be justified merely on the grounds that it produces knowledge if that knowledge is “totally unrelated to anything practical” (by which I meant “totally unrelated to improving individual well-being”). 

Devoting resources to any one scientific project may harm others indirectly.  One may argue, for example, that in spending so much effort and funds to discovering the Higgs one is indirectly harming other human beings.  After all, the same resources could be used to provide food and housing to the under-served in developing countries. Thus, the decision to fund this basic question into the structure of matter is not truly harm-free, as you seem to imply.

My own view is that immediate benefit is not necessarily the most desirable goal in allocating resources. Understanding the fundamental laws of physics may not feed people tomorrow, but will certainly generate incalculable benefits in the future. One has only to look  at the history of science to verify such claim.  Who can deny the benefits of basic biology, the physics of semiconductors, lasers, or quantum mechanics? Who doubts that today’s basic science is bound to produce manifold benefits for our children and grandchildren?

Ringach’s objections to this point, examples of basic research leading to medical imaging technology, are logically irrelevant, since the basic research that led to their development was not totally unrelated to anything practical: it ultimately led to beneficial technologies. None of Ringach’s examples are of the right form to constitute an objection to either of the two key points I was making at this point in the dialogue.

The basic mathematical question upon which 3D imaging depends was the reconstruction of 3D shapes from an object’s shadows (or projections) obtained from various angles.  The problem was originally posed and solved by Radon in the 1910s, way before the development of 3D imaging methods.  The work was originally, totally unrelated to anything practical.  Nevertheless, as I said, his results form the basis for all tomography-based imaging techniques today.

Science would be trivial (and our ethical decisions much easier) if one had an oracle that told you which lines of research would ultimately lead to benefits.  We don’t. That’s just not how science works.

In my remarks, I also acknowledged the difficulty in evaluating, before the fact, whether specific animal research will be related to improvements in individual well-being. Even if some animal research, tragically, didn’t result in any knowledge at all, that alone wouldn’t show that the original decision to pursue the research was unjustified. In some cases, it would have been reasonable at the onset of the research to think it would ultimately contribute to benefits significant enough to justify the research, even if eventually it did not.

Exactly right… but this is true for all scientific research, not just biomedical research.  Indeed, your comment shows the limits of demanding an ethical justification for every single study.  We cannot be sure that any one individual experiment will yield an important benefit.  Instead, one must look at the field as whole, realize the benefits it has already produced, and accept the scientific consensus that if we stop the research, no benefits will be forthcoming in many areas of biomedical research.

Ringach notes that I voted against Ned Kalin’s protocol on the grounds that the value of the data did not justify the harms to the animals, especially given other research avenues that would also benefit those suffering from anxiety disorders, even though they would not directly answer Kalin’s specific scientific question. 

I do not want to misinterpret your position, so please correct me if I am wrong.

I presume that by “other research avenues” you mean research that does not involve animals in research, such as prevention programs. Perhaps you consider it is your responsibility, as an IACUC member, to evaluate not only the use of animals in a given scientific protocol, but to consider if there are other ways the same resources could be used to benefit patients suffering from anxiety that do not directly involve harming animals in research.

If so, I think you are effectively setting public policy from your IACUC.  It is clear the medical leadership at NIH already decided that there is a good justification to understand the biological basis of  psycho-pathology, including anxiety disorders.  This is why they established a study section on this topic and devoted funds to answer these questions.  At the same time, we should all note that they have also decided to devote resources to human-based studies and prevention work in these same areas.

You may have good reasons to disagree with NIH’s research portfolio and distribution of funds in general, and you are free to engage them in this discussion.  However, in my opinion, an IACUC rejecting a study invoking such disagreement as a justification seems inappropriate.

Of course an institution can decide not to engage in studies they disagree with.  Some, for example, do not engage in non-human primate research. However, such institutional policies should be made clear to scientists and NIH ahead of time, so everyone knows the kind of work an institution supports and which it does not.  Scientists should not need to find out what these are from their IACUCs protocol reviews.

Again, thank you for clarifying your position and continuing this conversation.

Extending a Public Conversation on the Ethics of Animal Research

The following is commentary by Prof. Robert Streiffer on a previous post by Dario Ringach. It was originally published on a UW-Madison website but  was subsequently removed.  It is being republished here with his permission, with Dario’s reply to it being published on SR tomorrow.

On March 11, 2013, Rick Marolt and I engaged in a public conversation about the ethics of animal research. Dario Ringach, a professor of neuroscience and psychology at UCLA and contributor to the blog, Speaking of Research, posted an entry with questions and comments about the exchange. I wanted to take this opportunity to extend the public conversation by responding to Professor Ringach. I appreciate Ringach’s attention to our exchange on this significant issue, but some of his criticisms are based on misinterpretations of what I said, and so I welcome this opportunity to clarify my remarks (some of which were probably quite cryptic), respond to some of his criticisms, highlight areas where he and I agree, and acknowledge one issue where I overstated my concern. (I should note that I am only considering Ringach’s remarks as they concern my part of the conversation.)

Ringach’s comments relevant to my remarks are in the sections of his post entitled “The good,” The curious”, “Mind the gap,” “the bad,” and “the inconsistent,” and I will address them in that order.

The Good
Let me begin by expressing my appreciation for Ringach’s expression of support for the event. I think that engaging in this kind of public dialogue about the ethics of animal research helps overcome the polarization of the debate, and helps improve peoples’ understanding of both the scientific and ethical aspects of animal research. In addition, participating in these kinds of public discussions is a core part of the service component of my job as a professor at a public university. So, I am grateful for Ringach’s supportive words on this point.

The Curious:
Ringach is puzzled by the fact that Marolt and I spent such a long time discussing utilitarianism. I agree that the discussion of utilitarianism went on for too long. The intention was to start with utilitarianism and then to spend more time exploring other frameworks. However, contrary to what Ringach claims, we did not assume that scientists are always utilitarians, or that the only justification for animal research must appeal to utilitarianism. First, I noted that most people who support animal research think that utilitarianism does not correctly capture our obligations to human beings. Second, I pointed out that even though supporters of animal research sometimes describe themselves as utilitarians-when-it comes-to-animals-but-rights-theorists-when-it comes-to human-beings (whom I refer to as “hybrid utilitarians”), they are probably not accurately characterizing their own views. For example, I expect that when they reflect on their obligations to their own pets, they probably believe that there are ways in which it would be wrong to treat their pets even though doing so would maximize utility.

Nonetheless, both utilitarianism and hybrid utilitarianism are commonly invoked or are implicitly presupposed in attempts to justify animal research, and so do merit discussion.

As an example of one non-utilitarian view, Ringach’s cites his own article, “The Use of Nonhuman Animals in Biomedical Research.” The “sliding-scale” framework he presents there is certainly not utilitarian. It accords rights to individuals that are “able to participate as autonomous rational agents in our moral community,” it accords a higher degree of moral status to individuals with a higher degree of “cognitive, affective, and social complexity” (although he later modifies the framework so that an individual’s moral status is affected by his or her relational properties), and it requires that the interests of individuals with a higher moral status be given priority over the interests of individuals with a lower degree of moral status. But Ringach never specifies how the sliding-scale framework adjudicates a conflict of interest between individuals who don’t have rights and who possess the same degree of moral status, and so, for all he has said, the sliding-scale framework could still take a utilitarian form with respect to such conflicts. If it does, such a framework would still be subject to a concern similar to the one I raised about utilitarianism and hybrid utilitarianism.

That concern notwithstanding, I highly recommend Ringach’s article as a presentation of the pro-animal-research position. It is one of the few papers by a scientist that explicitly and concisely explores not just several of the empirical aspects of the debate but also many of the philosophical aspects as well. And I certainly endorse Ringach’s call for more scientists to publicly discuss their views on the science and ethics of animal research rather than to leave it to others to speculate and hypothesize about what their views are.

Mind the Gap
Ringach is correct that discussing examples of actual research that Marolt would find ethical would have helpfully highlighted some common ground and led to a more productive and balanced discussion. I will try to keep this in mind for future reference.

I would note, though, that this point needs to be applied in a fair way: many animal researchers are reluctant to publicly discuss examples of actual research that they find unethical, even though doing so would also help highlight common ground and lead to more productive and balanced discussions. For example, Ringach’s article which I mentioned above never acknowledges any actual examples of unethical animal research.

The Bad
In this section, Ringach presents what appears to be his most pressing concern. It stems from my concurrence with Marolt’s view that, if all a study does is produce knowledge for a researcher or a community of researchers without that knowledge ever ultimately leading to any further benefits, then the knowledge produced is not a very significant benefit. Ringach says that this view, which he inaccurately summarizes in the words “knowledge is not a significant benefit,” is an “insult to reason” that betrays a misunderstanding of the scientific process and a failure to appreciate negative results in science. Ringach thinks that this view implies that I must not see much value in abstract mathematics, space exploration, physics, or astronomy, and that I must be “oblivious” to the fact that basic research has led to many medical imaging technologies.

I won’t speak for Marolt, but Ringach’s concerns here regarding what I said are based on a fundamental misunderstanding of the two key points I was making and ignores almost the entirety of what I said regarding them. I therefore welcome this opportunity to clarify and expand on my views.

The first key point I was making is that there is a distinction between knowledge and benefit per se and that research, in the first instance, produces knowledge, not benefit. The phrases “in the first instance” and “per se” are important here. While knowledge often leads to benefits, research can produce knowledge without producing any benefit at all. However, this conceptual point does not imply that research that does not produce benefits is not valuable, as there is also a distinction between the concept of a benefit, which I take to be an improvement in individual well-being, and the more general concept of value. It is thus perfectly consistent to say that something is not itself a benefit and that it does not lead to benefits while maintaining that it is nonetheless valuable. Indeed, I explicitly stated that there are significant kinds of knowledge worth spending a fair bit of money on even if they do not actually improve anyone’s well-being.

Nor do these conceptual points imply that basic research has not led to many beneficial technologies. I even mentioned one of Ringach’s examples, space exploration, saying that although it is often used as a stock example of research that doesn’t produce improvements in individuals’ well-being, it actually has produced all kinds of ancillary benefits, and that funding it would be justified even if it hadn’t. Marolt and I did not discuss the other examples of abstract mathematics, etc., but I would make the same two points about those. They often produce benefits in unanticipated ways, and they can be justified by the value of the knowledge they produce even if they did not in fact produce improvements in individual well-being.

However, the second key point I made is that, when one is evaluating research that harms and kills animals, the moral threshold is higher than it is with other academic pursuits: that kind of research cannot be justified merely on the grounds that it produces knowledge if that knowledge is “totally unrelated to anything practical” (by which I meant “totally unrelated to improving individual well-being”). Ringach’s objections to this point, examples of basic research leading to medical imaging technology, are logically irrelevant, since the basic research that led to their development was not totally unrelated to anything practical: it ultimately led to beneficial technologies. None of Ringach’s examples are of the right form to constitute an objection to either of the two key points I was making at this point in the dialogue.

In my remarks, I also acknowledged the difficulty in evaluating, before the fact, whether specific animal research will be related to improvements in individual well-being. Even if some animal research, tragically, didn’t result in any knowledge at all, that alone wouldn’t show that the original decision to pursue the research was unjustified. In some cases, it would have been reasonable at the onset of the research to think it would ultimately contribute to benefits significant enough to justify the research, even if eventually it did not.

I do agree that I was overly dismissive of what can be learned from poorly designed experiments or experiments that fail to produce the intended knowledge. I am appreciative of the audience member who pressed me on this during the Q&A, at which point I did concede that one can learn something even from poorly designed or unsuccessful experiments and that both positive and negative results can lead to benefits. However, I’ve never heard of an IACUC approving research that involves harming and killing animals, when they believe the research to be poorly designed or believe that it would not produce the intended knowledge, merely in the hopes that we might learn something useful. So I don’t think that this concession has much practical import.

The Inconsistent
Ringach notes that I voted against Ned Kalin’s protocol on the grounds that the value of the data did not justify the harms to the animals, especially given other research avenues that would also benefit those suffering from anxiety disorders, even though they would not directly answer Kalin’s specific scientific question. But Ringach wonders how it is then consistent for me to also acknowledge, as I did, that I didn’t fully understand the details of the analyses the researchers were going to perform on the brain tissue of the moneys to establish the molecular pathways involved in anxiety.

Perhaps I am missing Ringach’s point, but it seems to me that there is no inconsistency here at all. Given what Kalin and the other scientists on the Committees said, it seemed reasonable for me to defer to their expertise and assume that the protocol’s proposed analyses would establish which molecular pathways were involved in anxiety. I then had to decide how important I considered that knowledge to be. Just as I don’t need to fully understand how Google Maps produces its maps to evaluate how useful they are, I also don’t need to fully understand how Kalin was going to answer his scientific question to have a view about its importance. I think this is often the situation with individual IACUC members, both scientists and non-scientists alike: they don’t need to understand every single scientific detail of the methods to have a reasonable and informed opinion about the significant of the anticipated findings. (Of course, the committee as a whole needs to have, or have access to, sufficient expertise to evaluate scientific validity of the protocols they review.)

In closing, I appreciate Ringach’s contribution to this particular discussion as well as his work encouraging public dialogue more generally, and I hope that my responses here further advance the discussion.

Robert Streiffer, Ph. D.
Associate Professor of Bioethics and Philosophy
University of Wisconsin, Madison