Tag Archives: dog

Veteran speaks up for the importance of allowing canine research to continue at the VA Medical Center

On July 26, 2017, the House of Representatives passed an amendment (proposed by Rep. Brat) to a spending bill that would ban all medical research at the Department of Veterans Affairs that could cause pain to dogs. The spending bill itself has not yet passed, however if such a bill was to be passed with the amendment, and also approved by the Senate, it would do huge damage to important medical research conducted by the VA.

The following article by Sherman Gillums Jr was originally published in The Hill on August 8, 2017 under the title “Devaluing human life is no way to thank wounded veterans for their service“. It is reproduced here with permissions from both The Hill and the original author. Sherman Gillums Jr. is a retired U.S. Marine officer who suffered a spinal cord injury in 2002 while serving on active duty. His career with Paralyzed Veterans of America started in 2004 after he completed rehabilitation at the San Diego VA Spinal Cord Injury & Disease Center. He is an alum of University of San Diego and Harvard Business School.

For a veteran facing a lifetime of paralysis after suffering a spinal cord injury, hope is often the last thing to die. Yet, the recently introduced House bill, H.R. 3197, threatens to crush what little hope to which I, and the approximately 60,000 veterans living with spinal cord injury, cling. The act proposes to reduce investment in medical research, and the reason is as simple as it is controversial: animal research.

Introduced by Rep. Dave Brat (R-Va.), the Act follows reports of experimentation on dogs at the McGuire VA Medical Center in the congressman’s home state. Purportedly disturbing reports revealed that animals were being given amphetamines and suffering heart attacks, among other research-based details that aren’t easily digestible by those outside of the scientific community. The mainstream gut reaction that followed these revelations was easy to predict. When contemplated in a vacuum, the thought of animals experiencing induced pain would bother any reasonable person. However, I do not enjoy the luxury of contemplating these thoughts in a vacuum.

My thoughts immediately shift to the 23-year old soldier I met on a spinal cord injury unit in San Diego. He had a freshly severed spinal cord, fixators that held the bones in his legs together, and chronic pain that often kept him awake all night, despite medication. He also had a two-year old daughter, Marianna, who knew nothing about an explosive device, or how the one that hit her father would change her life forever. Then the two thoughts clashed and bred possibilities— hope —that sprang from what research might offer to him and his daughter. A hope that may now be dying for him, me and those 60,000 other veterans who could benefit from that research.

dog, animal testing, animal experiment

“VA’s canine research that spurred the development of the cardiac pacemaker and artificial pancreas the Food and Drug Administration approved just last year, which serves to benefit both veterans and those who have never worn the uniform” [This image was not part of the original article]

When House members voted on July 26, 2017 to ban all VA medical research that causes pain to animals, specifically targeting VA’s canine research program, it was the first step toward a complete devaluation of the lives of catastrophically injured veterans. Brat declared, “From what I read, the type of work that [VA researchers] were doing was on the level of torture.”

I understand how reading a report like that would spur intense emotion and abstract horror. But if the congressman had put down the report and accompanied me to a VA hospital, he would have discovered that the price of military service is not abstract. He would have seen firsthand what it’s like to care for a paralyzed veteran with a failing heart on a VA spinal cord injury unit; or another on the polytrauma unit who needs a new pancreas, among other missing body parts that need to be replaced. After that reality check, I’d have asked the congressman, to consider these facts: It was VA’s canine research that spurred the development of the cardiac pacemaker and artificial pancreas the Food and Drug Administration approved just last year, which serves to benefit both veterans and those who have never worn the uniform. Non-VA canine research has also led to the discovery of insulin, new tests and treatments for various types of cancer and has played an important role in ushering in advancements in heart surgery procedures. While that reality may be inconvenient, it’s like freedom and democracy; it all comes at a price. I’d rather that price involve as little human suffering as possible. It’s apparent, however, not everyone agrees.

I would like to leave the legislative debate to the congressman and his colleagues, but it’s the ideology behind this bill that troubles me.  Those participating in the debate over the VA’s animal research program appear to fall into two camps: those who believe we should do everything we can to improve the lives of seriously injured veterans, and those who refuse to stare the ugly consequences of war in the face. It is not that simple though. The U.S. military faces the ugliness for its citizens, which includes our public servants.  Now that those citizens are faced with the aftermath, some are having second thoughts.

The VA has a responsibility to consistently find new and better ways of treat America’s heroes. Animal research helps the department do that. The program has helped save and improve countless lives, and it will continue to do so—unless ideology, and in some cases extremism on the issue of animal rights, succeed in forcing the public’s attention away from VA waiting rooms, inpatient wards, and rehabilitation gyms across the country. This is where the price of wars across several eras can be seen almost daily, as well as where medicine and science find their ripest opportunities.

Medical and scientific experts in America, as well as across the globe, agree animal research is essential. That’s because only animal research will provide the answers needed to develop revolutionary new treatments. Whether we like it or not, canine research is especially vital to potential medical breakthroughs because of unique traits shared by humans and dogs. In fact, CNN recently highlighted in a February 2017 story how canine research is leading to better results than traditional cancer research efforts.

Despite the hyperbole used by legislators to invoke disturbing images, VA is conducting research that is vital to seriously disabled veterans.  That is what cannot be forgotten or eclipsed by words hyperlinked to extreme ideologies. Canine studies address a host of medical problems afflicting them, and it advances treatments that heal them, or at the very least, mitigate their suffering and give them a better quality of life. I’ve seen it for myself, as Paralyzed Veterans of America has collaborative partnerships with Yale University and New Haven VA Medical Center to further the treatment advances that make veterans’ sacrifices endurable.

The research conducted at these facilities includes exploring cures and treatments for fatal lung infections affecting those with spinal cord injuries, dysfunction in brain circuits that control breathing, and whether service dogs reliably reduce the symptoms of post-traumatic stress disorder. Orthopedics research conducted with animals is especially important to many VA patients, as it has been essential to the design and testing of new prosthetic devices for veterans who have lost limbs.

Much of the animal research VA is doing aims to benefit a small group of veterans with specialized needs — those who’ve sustained serious injuries in the line of duty. As a veteran who represents tens of thousands within this group, veterans who stand to benefit from VA’s animal research efforts, I am compelled to challenge those who are fighting to shut this vital program down. I ask them, instead, to take a step back and look at things from our perspective.  We are veterans who live with severe disability, many still in the prime of our lives. Our lives after service will never be the same as our lives before service, but advances in research will help us experience lives with less pain—and more hope.

It is my sincere hope there will come a time when we don’t need animals for research. Unfortunately, that time has not arrived, and because of the incredible complexity of human anatomy and our still-limited understanding of how it works, animal research will be needed for the foreseeable future. To those who remain unconvinced, I’ll close with two questions: What wouldn’t you do to find a cure for spinal cord injury, cancer, chronic lung infection, orthopedic deterioration, or other serious afflictions associated with military service? Then, what would you do if it was your son or daughter who served and returned home profoundly broken by battle, illness or disease?

For many veterans and their families, these questions are not philosophical. Because for them, hope is indeed the last thing to die. It is now up to Congress to decide whether that hope will be put completely out of its misery.

Sherman Gillums Jr

Pioneering non-beating heart transplant success – thanks to animal research!

Yesterday a team led by Consultant Surgeon Stephen Large at Papworth Hospital near Cambridge in the UK announced the successful transplant of a non-beating donor heart to heart failure patient Huseyin Ulucan, the first time such an operation has been performed in Europe.

Current practice is for donor hearts are obtained when the donor has been declared brain dead, but their heart is still beating, and the heart is then cooled and transferred to the recipient.  The technique used in Mr Ulucan’s operation involves re-starting the heart in the donor five minutes after death and perfusing it and other vital organs with blood and nutrients at body temperature using the Transmedics Organ Care System (OCS). In this case the donor heart was kept nourished and beating for three hours before being transplanted into Mr Ulucan. The main importance of the technique it that it has the potential to substantially increase the  number of donor hearts available for transplant, though it also enables the surgical team to assess the health of the donor heart more thoroughly.


The Transmedics Organ Care System.


The technique they used was developed by Cardiothoracic Transplant Registrar Simon Messer, who developed it with Consultant Surgeon Ayyaz Ali, and commented:

Using techniques developed to recover the abdominal organs in non-heart beating donors, we wanted to apply similar techniques to hearts from these donors.

“Until this point we were only able to transplant organs from DBD (Donation After Brain-stem Death) donors. However, research conducted at Papworth allowed us to develop a new technique not used anywhere else in the world to ensure the best possible outcome for our patients using hearts from non-heart beating donors.”

This approach, known as normothermic donor heart perfusion, is an example of a technique that is showing great promise in surgery, in 2013 we discussed how the normothermic transplantation technique using the OrganOx system – developed through research in pigs – had been used successfully in a liver transplant operation, and large scale clinical trials are now underway.

In a review entitled “Normothermic donor heart perfusion: current clinical experience and the future” published in 2014 (1) Simon Messer and colleagues highlights the role of research in animals including dogs, pigs and monkeys in demonstrating that Donation After Cardiac Death (DCD) heart transplantation is possible, and that normothermic donor heart perfusion improves the success rate.

DCD heart transplantation has been shown to be possible in animal models [32-34] and in humans [35, 36] provided that the warm ischaemic time could be kept below 30 min. However, we suspect that the only safe way to adopt DCD heart transplantation into routine clinical practice is by ex vivo functional and metabolic assessment following appropriate reconditioning. Normothermic blood perfusion has been shown to be superior to cold storage in preserving DCD hearts in dogs [37]. In the pig, reconditioned DCD hearts were shown to have comparable function to BSD donor hearts [38]. In an asphyxiation pig model, DCD hearts exposed to 30 min of warm ischaemia were evaluated on the OCS using lactate assessment. Four of seven transplanted DCD hearts were subsequently weaned off cardiopulmonary bypass on low dose inotrope [39].”

In a key paper published in 2013 (2) – reference 38 above – an Australian team assessed whether the Transmedics OCS system could be used to successfully transplant non-beating hearts in pigs, concluding that:

The Transmedics OCS provides an excellent platform to assess DCD heart recovery following warm ischemia. Using a clinically applicable model, we have shown that DCD hearts with WIT ≤30 mins appear to be a viable source of additional organs in cardiac transplantation and warrant human studies.”

Pigs are a excellent species for many transplant research studies. Image courtesy of Understanding Animal Research.

Pigs are a excellent species for many transplant research studies. Image courtesy of Understanding Animal Research.

Results such as this led to Simon Messer and colleagues concluding in their 2014 review (1) that:

It is estimated that use of DCD hearts may increase the number of heart transplants by 11–15% [40]. We believe that functional assessment during ex situ normothermic donor heart perfusion must be made prior to transplantation in this setting. In Papworth Hospital, we are currently investigating whether DCD human hearts can be assessed on the OCS using pressure volume loop measurements.

In conclusion, cold ischaemic preservation for the donor heart has been universally adopted into clinical practice over the last 45 years. However, the diminishing pool of ideal donors coupled with the drive to further improve heart transplant outcomes mandate a rethink in this area. Normothermic donor heart perfusion is the logical next step and from the clinical experience to date, appears to hold promise.”

We congratulate Stephen Large, Simon Messer, Ayyaz Ali and colleagues at Papworth Hospital for taking this next important step successfully, and we wish Huseyin Ulucan a full recovery and long life.

Yesterday’s announcement was a reminder that more than 50 years after Norman Shumway’s pioneering heart transplants studies in dogs, animal research remains crucial to progress in this important field of medicine.

Paul Browne

1) Messer S1, Ardehali A, Tsui S.”Normothermic donor heart perfusion: current clinical experience and the future.” Transpl Int. 2014 May 23. doi: 10.1111/tri.12361. PubMed:24853906

2) Ali AA, White P, Xiang B, et al. “Hearts from DCD donors display acceptable biventricular function after heart transplantation in pigs.” Am J Transplant 2011; 11: 1621. Link


Peritoneal Carcinosis and HIPEC: A second chance for patients, thanks to animal research

When we hear the phrase ‘animal research’ we tend to think about the development of new drugs for the clinical practice, or studying molecular pathways involved in the progression of disease; but we must also remember that the techniques used in the operation room are a consequence of biomedical research, including the use of animals. It is not just the creation of these techniques but also for the prior steps necessary for us to consider a surgical technique as an option when faced with a disease. An example of this is research into a type of cancer known as Peritoneal Carcinosis (PC) and the development of a technique, known as HIPEC, that may dramatically improve the prognosis for patients with this type of cancer.

What is the definition of Peritoneal Carcinosis? We describe this medical condition as the presence of neoplastic nodules caused by the spreading of a primary or secondary tumor in the peritoneal cavity. The peritoneal cavity, also called the abdominal cavity, is the largest body cavity and contains many of the major organs – such as the liver, kidneys, stomach and intestines – surrounded by a protective membrane known as the peritoneum.

Although PC is sometimes seen in primary tumours, such as peritoneal mesothelioma or Pseudomyxoma peritoneii, it is more frequently observed as a metastatic diffusion of gastroenteric (stomach and colon, primary) or gynaecologic (ovarian) tumors. In the second situation, we could see it as an advanced manifestation present at the same time as the primary neoplastic disease or appearing in the years following treatment of the tumour. This condition is often associated with a poor prognosis (about 6 months), depending on the site to which it spreads, the involvement of abdominal organs (like colon or liver) and how aggressive is the tumor at the moment of diagnose.

Peritoneal Carcinosis viewed by laparoscopy. Image: www.cancersurgery.us

Peritoneal Carcinosis viewed by laparoscopy. Image: http://www.cancersurgery.us

In the past, physicians have had only two options when combating the disease: systemic chemotherapy or palliative surgical therapy to debulk the tumor masses- removing as much as possible of tumors which cannot be entirely removed –  and prevent severe conditions such as bowel obstruction. Recently, surgical research developed another therapeutic approach, known as Cytoreduction (CR) associated with Hyperthermic intraperitoneal Chemotherapy (HIPEC). This technique consists of a two-part operation: during the first part, the surgeon debulks as much of the neoplastic nodules in the peritoneal cavity as possible, and in the second stage the peritoneal cavity is washed with a hyperthermic chemotherapy solution, where a solution containing a high concentration of chemotherapy drugs is heated to above body temperature (usually 41.5°-42.5°C) which increases absorption of the drugs by the target tumor and therefor their effectiveness.

The role of the hyperthermic solution and the possibility of using a high-dose of chemotherapic agent was developed through research in rodents and dogs: these studies demostrated that the peritoneal barrier itself is not a barrier that prevents substances from pass through it. This is in agreement with observations made during surgery in human patients, when we remove the peritoneum (for example, when we debulk a neoplastic nodule on a peritoneal surface with a technique known as peritonectomy) the rate at which drugs are cleared from peritoneal cavity is not significantly affected. [1]

Studies in dogs and subsequently in human volunteers demonstrated that the high concentration of chemotherapeutic drugs in the peritoneal cavity is not related to a high concentration of these in the blood stream [2]. In particular a key study undertaken in dogs by Rubin et al. [3], consisted of studying the effects of removing portions of the perotineum such as the the omentum, the mesentery or the small bowel on the clearance of substances like glucose, urea and insulin from the peritoneal cavity. Surprisingly, this experiment indicated that these operations do not influence the clearance of these substances. On the base of these observation, clinical studies were started on clearance of drugs from the peritoneal compartment:. These clinical studies demonstrated that the process observed in dog with other substances occured also with drugs and that, in some cases, the concentration of a drug within the peritoneal cavity could be extremely high without having effects on the concentration in the bloodstream.

A natural consequence of this evidence is that we can use a high-dose chemotherapy drug against these nodules without having systemic adverse effects on the patient, a problem frequently observed in conventional systemic chemotherapy. These studies also led researchers to reconsider the spreading of a tumour in the peritoneal cavity not as a systemic dissemination but as a local disease, and that treatment might be able to cure it rather than just have a palliative impact. If the peritoneal barrier can selectively allow only some molecules to pass through, it could have also an active role on slowing the diffusion of metastatic cancer cells.

This evidence, together with the property of hyperthermia in helping drugs to penetrate cancer cells [4], and avoid the normal defences that a tumor cell has, led to development of this ambitious surgical technique.

The results of this combined technique is clear. Against primary tumors this technique shows a high survival-rate after 5 years (reaching 96% in some studies [5]). Against secondary spreading of gastroenteric or gynaecological tumours it shows a lower efficacy that may be related to the more diverse biological characteristics of the tumor cells, to the physiopathological features (diffusion, tumor already treated with chemotherapy etc.) and also to the characteristics of the patient (such as clinical status, age, concomitant diseases) [6],[7],[8],[9]. The 5-years survival rate for PC from colorectal cancer, for example, according to studies conducted by Dr. Paul Sugarbaker of the Washington Cancer Institute, one of the most important researcher on this field, is around 40%, when the cytoreduction is complete and the disease is not so diffuse in the peritoneal cavity. [7] Also, this surgical approach can be uses a second time, in case of a recurrence of PC, and, ultimately, as a palliative treatment to delay complications and reduce suffering of the cancer patients.

These numbers could seem low but we have to consider that we’re facing a disease that is often fatal within six months if left untreated. This technique gives patients another chance until very recently, they did not have. Why? Because of research that was built up, in part, thanks to animal research

These results are a direct effect of research in the fields of surgery and oncology, from the including the development of more effective chemotherapic agents, research that, as we have said many times, requires the study of animals for everything from the basic understanding of the processes involved to the preclinical testing a new therapy’s effectiveness and safety profile.

Marco Delli Zotti

[1] Michael F. Flessner “The transport barrier in intraperitoneal therapy” Am J Physiol Renal Physiol 288:F433-F442, 2005. http://www.ncbi.nlm.nih.gov/pubmed/15692055

[2] Pierre Jacquet, Andrew Averbach, Arvil D. Stephens, O. Anthony Stuart, David Chang, Paul H. Sugarbaker “Heated Intraoperative Intraperitoneal Mitomycin C and Early Postoperative Intraperitoneal 5-Fluorouracil: Pharmacokinetic Studies” Oncology 1998;55:130–138 http://www.ncbi.nlm.nih.gov/pubmed/9499187

[3] Rubin J, Jones Q, Planch A, Rushton F, Bower J. “The importance of the abdominal viscera to pertioneal transport during peritoneal dialysis in the dog.” Am J Med Sciences 1986;292:203– 208. http://www.ncbi.nlm.nih.gov/pubmed/3752166

[4] Elwood P. Armour, Donna McEachern, Zhenhua Wang, et al. “Sensitivity of Human Cells to Mild Hyperthermia” Cancer Res 1993;53:2740-2744. http://www.ncbi.nlm.nih.gov/pubmed/8504414

[5] Yan TD, Black D, Savady R et al. “Systematic review on the efficacy of cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei.” Ann Surg Oncol 2007;14:484-92 http://www.ncbi.nlm.nih.gov/pubmed/17054002

[6] Franco Roviello, Daniele Marrelli, Alessandro Neri, Daniela Cerretani, Giovanni de Manzoni, Corrado Pedrazzani, MD, Tommaso Cioppa, MD, Giacomo Nastri, MD, Giorgio Giorgi, Enrico Pinto
“Treatment of Peritoneal Carcinomatosis by Cytoreductive Surgery and Intraperitoneal Hyperthermic Chemoperfusion (IHCP): Postoperative Outcome and Risk Factors for Morbidity” World J Surg (2006) 30: 2033–2040 http://www.ncbi.nlm.nih.gov/pubmed/17006608

[7] Paul H. Sugarbaker “Review of a personal experience in the Management of Carcinomatosis and Sarcomatosis” Jpn J Clin Oncol 2001; 31(12)573-583 http://www.ncbi.nlm.nih.gov/pubmed/11902487

[8] Zanon C, Bortolini M, Chiappino I et al. “Cytoreductive surgery combined with intraperitoneal chemohyperthermia for the treatment of advanced colon cancer.” World J Surg. 2006 Nov;30(11):2025-32. http://www.ncbi.nlm.nih.gov/pubmed/17058031

[9] Bijelic L, Jonson A, Sugarbaker PH “Systematic review of cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis in primary and recurrent ovarian cancer.” Ann Oncol 2007;18:1943-50 http://www.ncbi.nlm.nih.gov/pubmed/17496308

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Paralysed dogs walk again thanks to nasal cell transplants…and Professor Raisman’s rats.

This morning the BBC News carried a report on a medical breakthrough – and it is not a term  I use lightly – that has enormous implications for people who have been paralysed following spinal cord injuries.  A team at the University of Cambridge led by Professor Robin Franklin  Department of Veterinary Medicine, along with colleagues at the MRC Centre for Regenerative Medicine in Edinburgh succeeded in restoring the ability to walk with their hind legs to dogs which had been paralysed by spinal injury.  To do this they removed a special type of cell called the olfactory ensheathing cell (OEC) from the nasal passageways of the dogs, grown them in culture until a sufficient number had been produced, and then transplanted them at the site of injury.  Many of the dogs which received the transplant were subsequently able to walk with their hind legs if supported by a harness, and some even able to walk without being supported by a harness, whereas dogs which received a control injection did not recover the ability to move their hind legs.

This is a major medical advance, and the first time that cell transplantation has been demonstrated to reverse paralysis in a real-life situation where the injury involves a combination of damage to the nerve fibre and to surrounding tissues, and there is a significant delay between injury and treatment, and while the therapy did not completely restore function it marks a very significant step towards a therapy that can be evaluated in a human clinical trial. It also of course is a very promising therapy for dogs that have suffered spinal injuries, for example after being hit by a car, and as such is an excellent example of the One Health concept which seeks a closer integration of human and veterinary medicine.

As with many breakthroughs this one did not happen overnight, indeed it is the result of decades of research.  The story really begins in 1985 when Professor Geoffrey Raisman at University College London (for a good overview of his work see the UCL spinal Repair Group homepage) was studying the unique ability of nerve fibres in the olfactory system to grow and make the connections with central nervous system – an ability that other adult nerve cells lack and which is probably retained in the olfactory system due to the importance of preserving the ability to smell despite exposure of nerve cells in the nasal passages to toxins in the environment (a good sense of smell being crucial to survival for many mammalian species). He found that in a part of the brain termed the olfactory bulb of mice and rats a specific type of glial cell, cells that act to support and regulate the activity of the nerve cells along which nerve impulses travel ,  were responsible for creating the pathway along which the olfactory nerve fibres could regenerate (1).

Studies in rats were key to unlocking the potential of olfactory ensheathing cells in repairing spinal injuries. Image courtesy of Understanding Animal Research

This discovery suggested that if these specialised olfactory ensheathing cells (OECs) were transplanted at the site of spinal cord injury they might promote the growth of a bridge of nerve cells that would reconnect the severed pathway and restore function.  In a  series of experiments in rats Professor Raisman and colleagues demonstrated that OEC transplantation could repair a variety of different types of spinal cord injury, in order to restore function, for example to improve the ability to breath and climb following spinal cord injury (2) and to restore the ability of rat paws to grasp in order to climb following lesion of the spinal nerve that runs from the spinal cord down through the arm (3). Other scientists provided additional key information, for example scientists at the University of New South Wales in Australia demonstrated that OECs could be isolated from the nasal mucosa as well as from the olfactory bulb (4), and that these can also repair spinal cord injuries, an important step since obtaining OECs from the nasal mucosa is far more straightforward and safer than harvesting them from the brain. These discoveries, and the refinement of OEC transplant techniques over the past 2 decades by scientists such as Prof. Raisman, paved the way for the “real life” veterinary study reported today.  A human clinical trial of this technique cannot be far off, though it is worth noting Prof. Raisman’s words of caution to the BBC concerning what has been achieved and what is still to be done:

“This is not a cure for spinal cord injury in humans – that could still be a long way off. But this is the most encouraging advance for some years and is a significant step on the road towards it…This procedure has enabled an injured dog to step with its hind legs, but the much harder range of higher functions lost in spinal cord injury – hand function, bladder function, temperature regulation, for example – are yet more complicated and still a long way away.”

In this respect it is worth noting the other approaches to repairing spinal cord injury, for example using other glial cell known as astrocytes and the use of electrical stimulation have produced promising outcomes in animal studies and early human clinical trials. Indeed, a clinical study of electrostimulation that we discussed last year reported “improved autonomic function in bladder, sexual and thermoregulatory activity that has been of substantial benefit to the patient”. In the future these different approaches may be combined to maximize the benefit to the patient, but it is still far too early to say which techniques will best complement each other. One thing we can be sure of is that turning these very promising technologies into effective treatments – perhaps even cures – for paralysis will require further research, both in the lab and in the clinic.

Paul Browne

1)      Raisman G. “Specialized neuroglial arrangement may explain the capacity of vomeronasal axons to reinnervate central neurons.” Neuroscience. 1985 Jan;14(1):237-54. PubMed: 3974880

2)      Li Y, Decherchi P, Raisman G. Transplantation of olfactory ensheathing cells into spinal cord lesions restores breathing and climbing.” J Neurosci. 2003 Feb 1;23(3):727-31. 12574399

3)      Ibrahim AG, Kirkwood PA, Raisman G, Li Y. “Restoration of hand function in a rat model of repair of brachial plexus injury.” Brain. 2009 May;132(Pt 5):1268-76. Epub 2009 Mar 13. PMID: 19286693

4)      Lu J, Féron F, Mackay-Sim A, Waite PM. “Olfactory ensheathing cells promote locomotor recovery after delayed transplantation into transected spinal cord.” Brain. 2002 Jan;125(Pt 1):14-21. PMID: 11834589

Lasker Awards 2012: How animal research empowered the pioneers of liver transplantation

As a medical student in 1950 one of my patients was a boy of my age dying of kidney failure and I was instructed to make him comfortable for he would be dead in two weeks. I asked if he could have a graft of a kidney and I was told “no” and then when I asked “why” the subject was dismissed with the words “it can’t be done.””

These are the opening words of the acceptance remarks of Sir Roy Calne, Professor Emeritus at Cambridge University, after it was announced last month that he and Professor Thomas E. Starzl, of the University of Pittsburgh, would share the 2012 Lasker-DeBakey Clinical Medical Research Award For the development of liver transplantation, which has restored normal life to thousands of patients with end-stage liver disease”.

It’s an award that is well deserved by both Calne and Starzl, since not only did their work help to prove within a few years that kidney grafts “be done” (for which Joseph E. Murray, E. Donnall Thomas were awarded the Nobel Prize in Physiology or Medicine in 1990) but they then went on to show that the liver, considered to be a more difficult organ to transplant due to its greater complexity, could also be transplanted. As a consequence of the work of Calne and Starzl more than 50,000 people are alive today who would otherwise died from end-stage liver failure. The Lasker Foundation have produced an excellent video to accompany the awards, which includes interviews with both scientists, and can be viewed on their website here.

Image courtesy of the Lasker Foundation

And how did animal research contribute to the development of liver transplant surgery?  Well, the truth is that it would take too long to detail in this post all the key contributions that operations performed on dogs by Thomas Starzl made to the development of the surgical techniques required, and the animal studies undertaken by both Calne and Starzl that allowed them to develop the first immunosuppressant therapies to prevent rejection.

To learn about how they moved from the lab to the clinic and then back to the lab again you can read the award description, which also highlights how transplant survival improved dramatically after the introduction of improved immunosuppressants. These included Cyclosporin A, discovered through studies of immunosuppressant activity in mice by Jean-Francois Borel at Sandoz Laboratories, and Campath-1H/Alemtuzumab, a humanized rat monoclonanal antibody whose development by Hermann Waldmann and colleagues at Cambridge University was prompted by studies in mice, dogs and monkeys, and whose subsequent development relied heavily on studies in mice.

Image courtesy of the Lasker Foundation

If you would like to know more, Professor Calne has written a lively essay on his work transplants entitled “It can’t be done”, while Professor Strazl’s perspective on their work and the insights into the functioning of the immune system that they gained is titled “The long reach of liver transplantation”. Both essays are well worth reading, and highlight an important fact; animal studies alone can’t perfect a therapy, and neither can clinical studies, it is the close interplay between the two that leads to breakthroughs in medicine.

As we congratulate Sir Roy Calne and Professor Thomas Starzl on winning this prestigious award, it is worth remembering that animal research continues to make a crucial contribution to the development of new transplant techniques, from the bioengineered tissues that are beginning to transform transplant surgery, to the spermatogonal stem cell transplants that we discussed on this blog only last week.

Paul Browne

Dogs in Medical Research

A video clip from Understanding Animal Research, a UK organisation which tries to tackle some of the misunderstandings about animal research. This kind of open advocacy which allows people to see the conditions of animals in labs is an important step in winning and keeping public support for lifesaving medical research.

Notice the use of clicker training to get the animals to do simple tasks such as jump on the weighing scales – this reduces any stress that might be caused by trying to force the beagle to do this unwillingly. This is just one of the many enrichment techniques used to improve animal welfare in laboratories around the world.

An excellent example of the value of dogs in biomedical research is provided by a BBC report “‘Heart shrinking’ trial to combat heart failure to begin” on the launch of a multi-centre trial (see clinicaltrials.gov for details) to evaluate whether electrical stimulation of the vagus nerve can reduce cardiac hypertrophy and arrhythmia, and improve heart function in patients with heart failure. The BBC report acknowledges that “The technique is being trialled in humans after it was shown to keep rats and dogs alive for longer” and links to a 2003 paper which found that electrical stimulation of the vagus nerve increases survival in a rat model of cardiac hypertrophy.

This  technique is based on a discovery made in 1984 (1), when scientists showed that an imbalance in the autonomic nervous system – part of the nervous system that acts as a control system functioning and is comprised of parasympathetic nervous system (PSNS) and sympathetic nervous system (SNS) – has a critical role in the induction of lethal ventricular arrhythmias in dogs following heart attack, with an increase in SNS activity leading to abnormal heart rate, heart tissue growth, and heart failure. Over the past decades several drugs have been developed to treat heart failure by reducing heart tissue growth – the ‘heart shrinking’ referred to in the BBC report – and heart rate, for example Ivabradine whose development we discussed recently, but more recently another approach has received attention, modulating the PSNS through stimulation of the vagus nerve in order to rebalance the autonomic nervous system inputs into the heart.

Following a series of studies which demonstrated that stimulation of the vagus nerve could prevent death and improve heart function in a variety rat and dog models of cardiac dysfunction and heart failure (including the study mentioned by the BBC above), scientists demonstrated in that the beneficial effect of vagus nerve stimulation was additive when combined with drugs to treat heart failure in dogs. An open access review of these studies published in 2010 (2) by Professor Peter J Schwartz of the University of Pavia notes that:

An impressive aspect of these experimental studies is that they provide an unusually uniform picture of significant positive effects produced by chronic vagal stimulation in the failing heart. Furthermore, they also provide evidence for the important concept that the mechanism(s) underlying the protective effect of vagal stimulation involve something at least in part independent of the heart rate slowing.”

This result supported a decision to launch the first small phase I clinical trial of this technique in patients with heart failure, led by Professor Schwartz (3), which demonstrated the safety of the technique, and provided early hints of its effectiveness in 8 human patients. The much larger study whose launch was by the BBC uses a device manufactured by Boston Scientific rather than the BioControl Medical device used in the earlier study led by Prof. Schwartz, but is development was equally dependent on the same careful research in dog models of cardiac disease and heart failure.

It’s just one of many examples of why lab such as the one  in the Understanding Animal Research video are so valued by the medical research community.


Tom Holder

1)      Schwartz PJ, Billman GE, Stone HL. “Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death.” Circulation. 1984 Apr;69(4):790-800.PubMed: 6697463

2)      Schwartz PJ.”Vagal stimulation for heart diseases: from animals to men. – An example of translational cardiology.-.” Circ J. 2011;75(1):20-7. PubMed: 21127379.

3)      Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, Campana C, Revera M, Ajmone-Marsan N, Tavazzi L, Odero A. “Long term vagal stimulation in patients with advanced heart failure: first experience in man.” Eur J Heart Fail. 2008 Sep;10(9):884-91. PubMed 18760668

Schwartz, P. (2011). Vagal Stimulation for Heart Diseases: From Animals to Men Circulation Journal, 75 (1), 20-27 DOI: 10.1253/circj.CJ-10-1019