Tag Archives: nobel prize

Nobel Prizewinner John O’Keefe warns of threat to science from overly restrictive animal research and immigration rules

In an interview with the BBC yesterday 2014 Nobel laureate  John O Keefe has warned of the dangers posed by regulations that restrict animal research and the free movement of scientists across borders.

“It is an incontrovertible fact that if we want to make progress in basic areas of medicine and biology we are going to have to use animals.

“There is a worry that the whole regulatory system might begin to be too difficult, it might be constrictive.”

Professof John O'Keefe, 2014 Nobel Laureate in Medicine or Physiology. Image: David Bishop, UCL.

Professof John O’Keefe, 2014 Nobel Laureate in Medicine or Physiology. Image: David Bishop, UCL.

His concerns are well founded. Our post yesterday discussed the key role of recordings of single neuron activity in rats to the discoveries made by John O’Keefe, May-Britt Moser and Edvard Moser. The post also discusses two other advances made through basic research in animals whose impact in medicine has been recognized by awards, deep brain stimulation in Parkinson’s disease, and infant massage in preterm babies. Nevertheless in many countries around the world there is increasing pressure from animal rights groups on politicians to restrict, and even ban, animal research. Scientists have a key role to play in ensuring that important basic and translational research, and we welcome John O’Keefe’s statement,  it’s an example that scientists around the world should follow.

The issue of immigration is another important one for science, and John O’Keefe knows this better than most. Born in New York, he completed his PhD at the University on Montreal under the supervision of renowned Psychologist Ronald Melzack, before moving to the UK to undertake a postdoctoral fellowship, and credits the research environment in the UK and at UCL for giving him the opportunity to make his discoveries, and later May-Britt and Edvard Moser spent time as postdoctoral researchers at his laboratory.  For science to flourish scientists must be free to travel to centres of excellence in other countries, to learn skills and establish collaborations that are key to success in many fields of research in the 21st century. This freedom is under threat from narrow-minded isolationism in many countries, for example earlier this year Switzerland found its position as a leading scientific nation undermined by a new immigration law that threatens its ability to recruit talented scientists from abroad, and has disrupted its participation in a key EU research programmes.

John O’Keefe’s warning is a reminder that the threats to scientific research can come from many directions, and of the need for supporters of science to be ready to take action to defend the freedoms on which science is built.

Speaking of Research

Nobel Prize 2014: Fortune favours the prepared mind

Speaking of Research congratulates John O’Keefe, May-Britt Moser and Edvard I. Moser on being awarded the 2014 Nobel Prize in Physiology or Medicine “for their discoveries of cells that constitute a positioning system in the brain”.

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By recording the activity of individual nerve cells within the brains of rats that were moving freely through their environment, they have shown how specialised nerve cells work together to execute higher cognitive processes.

In 1971 John O’Keefe identified the first component of the system, by identifying cells in the hippocampus that were only activated when a rat was in a certain position in its environment. These cells were activated when the rat visited the same location, but different nerve cells were activated when the rat visited a new location, these “place cells” were not merely registering visual input, but were building up an inner map of the environment. John O’Keefe is now a professor at University College London, where he studies the neural basis of cognition and memory in humans and animals.

Professor John O'Keefe UCL Institute of Cognitive Neuroscience. Image: David bishop, UCL

Professor John O’Keefe, UCL Institute of Cognitive Neuroscience. Image: David Bishop, UCL

In 2005 May-Britt Moser and Edvard I. Moser identified a second part of the system, a group of nerve cells in the an area of the brain adjacent to the hippocampus named the entorhinal cortex which were activated when a rat passed multiple locations arranged in a hexagonal grid. Each of these “grid cells” was activated in a unique spatial pattern and together they allow the rat form mental representation of a coordinate system that allows the rat to navigate through space. If you would like to learn more about their work at the Norwegian University of Science and Technology in Trondheim, Alison Abbott has written an excellent article in Nature News on the studies that led to the discovery of grid cells and their ongoing research in this field.

May-Britt Moser, Edvard Moser, and the rats that they use in their groundbreaking neuroscience research. Image Geir Mogan/ NTNU

May-Britt Moser, Edvard Moser, and the rats that they use in their groundbreaking neuroscience research. Image Geir Mogan/ NTNU

These place and grid cells have since been found to be present in all mammals, including humans, and equivalents are present in other vertebrates. In humans, the hippocampus and entorhinal cortex are frequently affected in the early stages of Alzheimer’s Disease, and it is hoped that understanding how the positioning system discovered by this year’s Nobel laureates in Physiology or Medicine will help us to understand the mechanism underpinning the loss of spatial memory that often leaves patients unable to recognize and navigate through familiar environments.

This year’s Nobel Prize highlights once again the continuing importance of animal research in pushing the frontiers of Neuroscience, and in particular the critical importance of techniques that use implanted electrodes to record the activities of individual nerve cells.

In an interview following the Nobel Prize announcement John O’Keefe stressed the continuing importance of animal research and warned of the danger to science from excessively strict animal research regulations.

Lasker Awards recognize pioneers of Deep Brain stimulation

The Nobel Prize is of course not the only award that recognizes excellence in scientific and medical research, and since the 1940’s the Lasker Foundation has granted awards to recognize excellence in basic and clinical medical research. In 2014 the Foundation has awarded its Lasker-DeBakey Clinical Medical Research Award to Alim Louis Benabid and Mahlon R. DeLong for “the development of deep brain stimulation of the subthalamic nucleus, a surgical technique that reduces tremors and restores motor function in patients with advanced Parkinson’s disease.”.

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The development of deep brain stimulation of the subthalamic nucleus is a classic example of the intellectual cross fertilization between laboratory and clinical research that drives medicine forward, as Dario Ringach described on this blog a couple of years ago in “A Brief History of Deep Brain Stimulation”.

In the award description the Lasker Foundation again highlights the synergy between animal and clinical research.

First it looks at how Mahlon DeLong recognized the significance of the accidental discovery that a chemical called MPTP could induce Parkinson’s disease like symptoms, a discovery that would allow him to resolve long-standing questions concerning the role of different regions of a part of the brain known as the basel ganglia in Parkinson’s disease.

DeLong seized upon the opportunity. A part of the basal ganglia called the subthalamic nucleus drives the inhibitory output signal, and in 1987, DeLong reported that MPTP triggers neurons in the subthalamic nucleus of monkeys to fire excessively. Perhaps, DeLong reasoned, the overexuberant signals quash motor activity in PD. If so, inactivating the subthalamic nucleus might ameliorate some of the illness’s worst symptoms.

Next, he did an experiment that would transform PD treatment. He administered MPTP to two monkeys; as usual, they gradually slowed down until they sat motionless, their muscles stiffened, and they developed tremors. DeLong then injected a second toxic chemical that inactivated the subthalamic nucleus. Within one minute, the animals began to move. Gradually, their muscles loosened and the tremors ceased. These findings strongly supported the hypothesis that hyperactivity in the subthalamic nucleus underlies PD symptoms.”

On the other side of the Atlantic in Grenoble, Alim-Louis Benabid realized that DeLong’s findings could used to greatly improve a new therapy for Parkinson’s disease that he had pioneered.

Although the technique quelled tremors, Benabid knew that this symptom was not the one that most debilitated people with PD. Perhaps high-frequency stimulation of brain areas other than the thalamus (i.e., the subthalamic nucleus) would alleviate the more troublesome aspects of the illness such as slowness of movement and rigidity, he reasoned.

In this state of mind, Benabid read DeLong’s report that damage to the subthalamic nucleus wipes out multiple symptoms of PD in animals. This site was not an attractive target: Lesioning procedures and spontaneous lesions had established decades earlier that, when things went wrong, violent flailing could result. By that time, however, Benabid had performed high-frequency stimulation of the thalamus and other brain regions’ in more than 150 patients. He was confident that he would cause no harm in the subthalamic nucleus; if necessary, he could remove the electrode.

In 1995, Benabid reported results from the first humans who received bilateral, high-frequency stimulation of the subthalamic nucleus—three people with severe PD. The treatment suppressed slowness of movement and muscle rigidity.”

While DBS of the subthalamic nucleus is not a cure for Parkinson’s disease, it can relieve many of the major symptoms, and has benefited tens of thousands of patients around the world whose symptoms are not adequately controlled by first-line therapies. Currently DBS is also being explored as a therapy for several other neurological conditions, including depression and chronic pain.

From Golden Gongs to Golden Geese

What would you think if you read that scientists had received tens of thousands of taxpayer dollars to massage newborn rat pups?

You might think that it is exactly the sort of research that opponents of basic science like to parade as examples when accusing the NIH of wastefulness. However, as usual the truth turns out to be quite different.

In September the 18th Saul Schanberg, Tiffany Martini Field, Cynthia Kuhn and Gary Evoniuk ,  were among the 8 recipients of the Golden Goose Award at a ceremony at the Library of Congress in Washington, D.C., an award established “to demonstrate the human and economic benefits of federally funded research by highlighting examples of seemingly obscure studies that have led to major breakthroughs and resulted in significant societal impact”.

The work began in 1979 with a problem. Cynthia Kuhn and Gary Evoniuk needed to separate newborn rat pups from their mothers as part of their NIH funded research project to investigate the factors influencing two key growth markers, ornithine decarboxylase and growth hormone , but they found that despite being kept fed and warn the pups failed to thrive. What happened next was a classsic example of how careful observation and outside-the –box thinking advances science:

A series of experiments ruled out factors such as nutrition, body temperature and maternal pheromones. The researchers then made the key observation: the rat mothers spent a great deal of time grooming and vigorously licking their pups. Wondering whether the act of stimulation through licking was making the difference, the researchers simulated the mother’s tongue with a small brush and stroked up and down the rats’ tiny backbone. This was the missing link. Enzyme and growth hormone levels rose and the rat pups thrived again.

Field, a psychologist at the University of Miami Medical School who was conducting her own research on how to help premature infants survive and grow, learned of Schanberg’s groundbreaking work and wondered whether it had implications for human infants. In 1986, Field published her own landmark study drawing from Schanberg, Kuhn and Evoniuk’s work with rat pups. Funded by the National Institute of Mental Health (part of NIH), Field’s study demonstrated that using similar tactile stimulation in preterm human infants had immediate positive effects. Premature infants who were massaged for 15 minutes three times a day gained weight 47 percent faster than others left alone in their incubators (standard practice at the time), were more alert and responsive, and were released from the hospital an average of six days sooner than the premature babies who were not massaged.”

Since their discovery tactile stimulation of preterm babies, in the form of infant massage, has become standard practice in many neonatal intensive care units around the world. It has been demonstrated to greatly improve the outcome for babies born prematurely millions of lives around the world, and saved billions of dollars in healthcare costs in the United States alone.

It’s yet another example of how “Off the wall” scientific research can deliver the goods!  Spending on basic scientific research is a crucial long-term investment, one whose precise outcomes are never certain, but which will pay off in both advancing knowledge and improving our future health, well-being and prosperity!

Paul Browne

Reprogrammed frog and mouse cells win the 2012 Nobel Prize

This morning the Nobel Assembly announced that the 2012 Nobel Prize in Physiology or Medicine will be shared by John B. Gurdon and Shinya Yamanaka for their “discovery that mature cells can be reprogrammed to become pluripotent”.  Animal research played a key role in the research honoured by the prize, specifically the studies of frogs undertaken by Professor Gurdon and studies of mice performed by Professor Yamanaka.

Sir John Gurdon. Image: Nobel foundation.

Professor Gurdon’s key work showed in a series of studies undertaken at the University of Oxford in the late 1950’s and 1960’s that if the nucleus of a specialised cell from a frog of the species Xenopus laevis - initially from late embryonic cells and subsequently adult intestinal and skin cells – was transferred into an egg whose nucleus had been removed, it could give rise to normal frog that could themselves produce offspring. This demonstrated for the first time that the nucleus of an adult cell is totipotent, and that in under certain conditions it could give rise to all cell types, including eggs and sperm, that are required in a healthy adult.

The very first Xenopus frog produced by somatic nuclear transfer to reach sexual maturity. Image: J.B. Gurdon

In 2009 Sir John wrote an account of his research on nuclear transfer in Xenopus for Nature Medicine, which can be read online without subscription, after he and Professor Yamanaka were presented with the  Albert Lasker Basic Medical Research Award in 2009.

Professor Shinya Yamanaka. Image: Nobel foundation

Almost 4 decades later Professor Yamanaka, then at the Kyoto University Institute for Frontier Medical Sciences, made another great step forward by proving that it was possible to transform adult mouse cells into a pluripotent stem cells without nuclear transfer. By inserting 4 genes whose expression is associated with the embryonic state into the adult cell, his team were able to create the first induced pluripotent stem (iPS) cells, cells that could give rise to any tissue in the body.

Earlier this year in a post congratulating Professor Yamanaka’s on winning the 2012 Millenium Technology Prize I noted that:

The work briefly described above was a technological tour-de-force where Prof. Yamanaka and his colleagues selected 24 genes which had previously been identified as having key roles in mouse embryonic stem cells, and developed a screening method using skin fibroblast cells derived from mice that had be genetically modified with an antibiotic resistance gene that was only expressed in embryonic cells, so that only cells that were in an embryonic state would survive in a culture containing the antibiotic. Different combinations of these 24 genes were screened for their ability to induce to the production of colonies of embryonic -like cells from adult fibroblasts.  They eventually identified just 4 genes – Oct3/, Sox2, Klf4 and c-Myc – that together could reprogram adult mouse fibroblast cells to a pluripotent embryonic-like state (1), and subsequently demonstrated that these iPS cells could give rise to a wide variety of  tissue types when incorporated into mice, either by subcutaneous injection into adult mice or incorporation into early mouse embryos. By modifying their method slightly to also include expression of an important developmental gene named Nanog  they were then able to generate chimeric mice (mice whose tissues are made up of a mixture of cells derived from their own embryonic stem cells, and cells derived from iPS cells) which were capable of transmitting the iPS cells to the next generation of mice (2).

Soon after this Prof. Yamanaka succeeded in generating iPS cells from human fibroblasts, using the same techniques used for the mouse cells, and a whole new and exciting field of biomedical research was born.

1)      Takahashi K, Yamanaka S. “Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.” Cell 2006 Vol. 126(4):663-76. PubMed: 16904174

2)      Okita K., Ichisaka T., Yamanaka S. “Generation of germline-competent induced pluripotent stem cells.” Nature Vol. 448:313-317 (2007). PubMed:17554338””

It’s worth remembering that this breakthrough did not come out of thin air, and built on years of research that followed the pioneering work of Martin Evans and Gail Martin who demonstrated that cells derived from mouse embryos could be cultured and give rise to all tissue types…the first embryonic stem cells.

The field of iPS cell research has progressed swiftly since the first mouse iPS cells were produced just 6 years ago, and the techniques used to produce the cells have been refined to address early concerns that the inserted genes might give rise to tumors, but as Prof Yamanaka outlined in a recent review of progress in the field there is still a lot of scope for improvement.  Nevertheless iPS cells are already showing promise in a variety of medical research applications – for example to create nerve cell lines from Parkinson’s disease patients in order to study the processes that trigger the degeneration, or  to evaluate the toxicity of new drugs – and are expected to join  human embryonic stem cells as key components of regenerative medicine.

This year’s Nobel Prize in Physiology or Medicine highlights once again the key role played by animal research in making groundbreaking discoveries that give rise to new fields of medicine, and we offer our heart-felt congratulations to John Gurdon and Shinya Yamanaka.

 

Addendum: In a statement to Reuters on the problem of the unproven stem cell therapies being offered for a myriad of disorders by private health clinics around the world - and widely touted on the internet -Professor Yamanaka highlighted the key role played by animal research in ensuring that real stem cell therapies are safe and effective:

Yamanaka, who shared the Nobel Prize for Medicine on Monday with John Gurdon of the Gurdon Institute in Cambridge, Britain, called for caution [on stem cell therapies - PB].

“This type of practice is an enormous problem, it is a threat. Many so-called stem cell therapies are being conducted without any data using animals, preclinical safety checks,” said Yamanaka of Kyoto University in Japan.

“Patients should understand that if there are no preclinical data in the efficiency and safety of the procedure that he or she is undergoing … it could be very dangerous,” he told Reuters in a telephone interview.

Yamanaka and Gurdon shared the Nobel Prize for the discovery that adult cells can be transformed back into embryo-like stem cells that may one day regrow tissue in damaged brains, hearts or other organs.

“I hope patients and lay people can understand there are two kinds of stem cell therapies. One is what we are trying to establish. It is solely based on scientific data. We have been conducting preclinical work, experiments with animals, like rats and monkeys,” Yamanaka said.”

 

Paul Browne

 

 

 

The new face of transplant surgery, thanks to animal research

Yesterday the University of Maryland Medical Center (UMM) announced most extensive full face transplant completed to date, including both jaws, teeth, and tongue. In a marathon 36-hour operation the surgical team led by Professor Eduardo Rodriguez were able to transplant a face of an anonymous donor onto their patient Richard Lee Norris, who had been injured in a gun accident 15 years ago.  The operation was the culmination of years of clinical and animal research undertaken at UMM under the leadership of Professor Stephen Bartlett, and funded by the Department of Defense and  Office of Naval Research due to its potential to help war veterans who have received serious facial injuries.

This successful operation, termed a vascularized composite allograft, was made possible not only by the selflessness of the family of the anonymous donor, but also by the years of animal research undertaken by Professors Rodriguez and Bartlett and colleagues. For example, a key factor in the success of this operation was that they transplanted high amounts of vascularized bone marrow (VBM), which came inside the transplanted jaw, a technique that was developed by the team after observing that tissue rejection following composite tissue allotransplantation in a cynomolgus monkeys was greatly reduced when VBM was included in the transplant. This discovery will also help to reduce the amount of immunosuppression that Mr. Norris and future patients require following facial transplants.

Of course this is far from the first contribution that animal research has made to transplant surgery, from the development of the techniques of kidney transplant through research in dogs by Joseph Murray and colleagues, to the careful experiments in dogs conducted by Norman Schumway and Richard Lower that led to the first successful heart transplants, to the studies in mice and rats that identified the immunosuppressive properties of the drug cyclosporin that transformed the transplantation field in the 1980′s, animal research has made a crucial contribution to this field. Indeed, in his 1990 Nobel Lecture Edward Donnall Thomas stressed the importance of animal research to his Nobel prize winning discoveries concerning bone marrow transplantation.

Finally, it should be noted that marrow grafting could not have reached clinical application without animal research, first in inbred rodents and then in outbred species, particularly the dog.”

Animal research continues to make key contributions to transplant science, and we have had several opportunities to discuss its role in the development of lab-engineered tissues for transplant, such as the artificial trachea and bladder, on this blog.

Yesterday’s news from the University of Maryland is another reminder that animal research is still crucial to advances in transplant surgery. It is also worth remembering that when animal rights groups attack animal research conducted by the Department of Defense, it is work such as that which led to yesterday’s breakthrough that they are attacking.

Paul Browne

Of Mice, Rice, Flies and Men

Animal rights activists often argue that animal models are irrelevant for human medicine, because they are ‘so different’ from us. But in fact some basics are shared across wildly distant species – something that the Nobel Committee acknowledged last year when they gave the Prize for Medicine and Physiology to Bruce Beutler and Jules Hoffmann for discovering the ‘early warning’ signals that set off immune responses in flies, mice and humans.

On Jan. 25 both Beutler, who works at the University of Texas in Dallas, and Hoffmann of the University of Strabourg, France, were at the University of California, Davis talking to a packed house about their work. Joining them on stage was UC Davis plant pathologist Pam Ronald, who studies rice, and Luke O’Neill of Trinity College Dublin, Ireland, who talked about human medicine.

(Watch the presentations here: http://ccm.ucdavis.edu/immunity.html)

L to R symposium speakers Bruce Beutler, Jules Hoffmann, Luke O'Neill and Pamela Ronald, with (far right) symposium sponsor Murray Gardner.

Work in these very different organisms can give insights that advances human medicine. From the basic discoveries in mice, flies and even rice could come new drugs and new approaches to treat heart disease, rheumatoid arthritis, inflammatory bowel disease and other conditions.

Our immune system has two lines of defense. The innate immune system reacts first, attacking invading microbes and triggering inflammation. If that response fails, the adaptive immune system fights back with antibodies and specialized killer cells. Afterward, the adaptive immune system retains a memory that allows a more rapid and powerful response if the same virus, bacterium or parasite comes back.

Only animals with backbones, from fish to humans, have an adaptive immune system. But all animals, including insects, as well as plants, have innate immune systems.

In the 1990s, Ronald (working with rice), Hoffmann (with Drosophila flies) and Beutler (with mice) identified genes for immune receptors that triggered innate immunity in the rice, flies and mice, and found that the genes were remarkably similar despite hundreds of millions of years of evolution.

From this common trigger, plants, insects and animals develop different types of response to invaders.

Activation of the immune system is not always a good thing. It can lead to allergy, inflammatory diseases such as rheumatoid arthritis or autoimmunity, when the body starts attacking its own tissues.

In his talk, for example, Beutler described how his team, working with mice, has isolated genes related to inflammatory bowel disease, while O’Neill talked about the possibility of being able to develop drugs to treat a wide range of diseases linked to inflammation.

The symposium is an annual event sponsored by a fund created by AIDS pioneer and UC Davis professor emeritus Murray Gardner, who previewed in an interview for Sacramento Public Radio Jan. 24 [http://www.capradio.org/168919] At the beginning of the AIDS epidemic in the 1980s, Gardner helped discover viruses similar to HIV in monkeys and cats – animal models that have been of vital importance in discovering drugs to treat and prevent HIV/AIDS.

– Andy Fell

From Science to Miracle in 2 years: The Discovery of Insulin

For more information about the discovery of insulin we recommend you read our more recent post: Animal research and diabetes: Now the truth must be told Part 1 and Part 2

A mere one hundred years ago, when people were diagnosed with diabetes, they were handed down a death sentence.  There was no treatment for the disease.  Children would become skeletons and die of severe weight loss in front of their families.

The first breakthrough in the search for a treatment came in 1879 with the discovery by Von Mering and Minkowski that removing the pancreas in dogs led them to develop all the symptoms of diabetes and die shortly after.  They proposed that the pancreas was involved in the metabolism of sugars.

In 1921, Banting and Best replicated this earlier result and took it a step further – working under the supervision of Macleod they showed that they could restore diabetic dogs to their normal state by injections of an extract of produced by the Islets of Langerhans obtained from healthy dogs.

With this result in a dog model of diabetes they subsequently recruited Dr. Collip, a biochemist, they who helped them extract a reasonably pure formula of insulin from the pancreas of cattle. This painstaking process of refinement of the technique for extracting insulin required many tests in rabbits in order to evaluate the potency and safety of the insulin preparations.

In January, 1922, the first human patient, a diabetic teenager named Leonard Thompson, became the first person to receive an injection of insulin. The improvement was so astonishing, nearly miraculous, that the news about this medical breakthrough traveled the world within days.

An early patient: before and four months after treatment with insulin.

The University of Toronto gave pharmaceutical companies license to produce insulin free of royalties (would this count as an argument against the notion that universities merely seeking financial gain for their work?).  In early 1923, just one year after the first test injection, insulin became widely available and has saved countless human lives since.  Banting and Macleod received the Nobel Prize in Medicine for their work.

This is only one of multiple stories about how animal research has benefited mankind.  This is research that will benefit you, your children, and all future generations.  An honest discussion of the use of animals in scientific research must acknowledge these facts, how we arrived at them, and recognize that despite the difficult ethical decision to use dogs in the discovery of insulin, today millions of humans are alive thank to the work of scientists engaged in biomedical research.

Dario Ringach