Tag Archives: polio

Research Roundup: Mouse model of bipolar disorder shows promise, fighting cancer with Polio and more!

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • Genetically modified mice show promise for studies of bipolar disorder. Human bipolar disorder is characterised by alternation between manic (hyperactive) and depressive (hypoactive) states, but many of its symptoms can be alleviated by treatment with lithium. A new study from Johns Hopkins University discovered that mice engineered to lack the protein ankyrin-G show manic-like states, characterised by over-excited activity and reactions, which could be ameliorated by lithium treatment. Moreover, repeated stress resulted in alternation between “mania-like” and “depression-like” status, reminiscent of human bipolar disorder. Ankyrin-G is a neuronal protein involved in the initiation of action potentials (electrical pulses used by neurons to communicate messages). “To our knowledge, this is the first robust mouse model of bipolar disorder based on a genome-wide significant risk factor for the human disorder”, said Christopher Ross, M.D., Ph.D., professor of psychiatry and behavioral sciences at Johns Hopkins.  This research was published the journal PNAS.
  • Turning “bad” fat into “good” fat could treat obesity. There are two types of adipose tissue in mammals: white fat and brown fat. Brown fat is considered “good” because, unlike white fat, it is metabolically active and burns calories to generate heat. In contrast, white fat simply stores energy and deposits around the waist, hips, and thighs. Scientists discovered that blocking a protein called PexRAP caused white fat in mice to be turned into “beige” fat, a new type of fat in between white and brown. Beige fat acts more like brown fat and may protect against obesity. Mice that were born without the PexRAP protein had more beige fat, were leaner than their littermates, and burned more calories even when they consumed the same amount of food. If PexRAP can be blocked in human fat cells, people with obesity, which represent 9% of the US population, may have an easier time reaching a healthy weight. This research was published in Cell Reports.

  • Blocking a signaling molecule in brain cells can stop the spread of aggressive brain tumors. Certain human brain cancers called high-grade gliomas are incredibly deadly with five year survival rates for some types around 10 percent. Researchers at Stanford University have uncovered a molecule that when deleted can halt the progression of these tumors. This signaling molecule, called neuroligin-3, had been shown in previous experiments to cause gliomas to grow. Working off of this knowledge, scientists put glioma cells in the brains of mice that had the neuroligin-3 gene and those whose gene had been deleted. They discovered that the cancer cells grew in the brains with neuroligin-3, but growth was halted in the neuroligin-3 deficient mice. Two inhibitors of neuroligin-3 had already been developed and so the researchers tested in mice whether either or both of these drugs would similarly halt the progression of the tumors. And they did. The senior author on the article, Michelle Monje, MD, PhD, stated, “We have a really clear path forward for therapy; we are in the process of working with the company that owns the clinically characterized compound in an effort to bring it to a clinical trial for brain tumor patients.” This research was published in the September 20th edition of Nature.
  • Fighting cancer with Polio.  In recent years, scientists have invested their interest in modified viruses, such as oncolytic viruses, which are optimized to kill cancer cells without damaging healthy tissue surrounding the cancer cells. One of these viruses is an engineered version of poliovirus, however it has been unclear how this virus manages to kill the cancer cells without harming the healthy tissue. This week, a study published in Science Translational Medicine, determined that the modified poliovirus, PVSRIPO, actually stimulates the natural immune system to specifically target the cancer cells. Normally, the immune system slows some types of tumor growth and inhibits tumors from becoming problematic, but when the immune system is suppressed this system no longer works. PVSRIPO seems to overcome immunosupression and may open doors to further cancer research targeting immunosupression.

Molecular model of poliovirus. Photo credit: Karsten Schneider/Science Photo Library

  • Ethical concerns growing after genome editing of human embryos. This week the journal Nature published results of experiments that used CRISPR-Cas9 to modify the DNA of a human embryo. They found that the gene OCT4 could steer cell fate as a fertilized egg starts to divide and proliferate. Another study, published just last month in Nature, used the same CRISPR-Cas9 method to correct specific genetic mutations in early stage human embryos. Both studies provide important insights into the biology of human embryos, and may pave new methodologies for in-vitro fertilization (IVF). Concerns are growing however because such gene-editing methods could lead to permanent modifications, and we do not yet understand the safety, accuracy, and feasibility of genome editing as a clinical tool. Thus, although this research is exciting and promising, much basic research and ethical discussions are necessary before we can take advantage of it.
  • A new antibody is able to attack 99% of HIV strains, according to studies in primates. The collaboration between NIH and the pharmaceutical Sanofi involves combining three “broadly neutralising antibodies” to create a “tri-specific anibody” which is able to tackle 99% of HIV strains. Dr Fauci, noted, “Combinations of antibodies that each bind to a distinct site on HIV may best overcome the defences of the virus in the effort to achieve effective antibody-based treatment and prevention.” Twenty-four monkeys were involved in the experiments, and none of those that received the antibodies developed an infection when they later received the HIV virus. Clinical trials are now planned for next year. This research was published in Science.

Last surviving member of Pittsburgh polio vaccine team dies at 96

Dr. Julius S. Youngner, the last surviving member of the team that developed the Salk polio vaccine in the 1950s, died in his home on April 27 at the age of 96.

Yougner - Image by University of Pittsburgh

Dr. Julius Youngner. Photo courtesy of University of Pittsburgh

Dr. Youngner, like many scientists, pursued a passion to help people via his love of the scientific method.  His own experiences as a child recovering from numerous infectious diseases, including severe pneumonia that almost killed him at age 7, inspired him to pursue a career in science — specifically, virology.

His interest in infectious disease led him to join Dr. Jonas Salk’s vaccine team at the University of Pittsburgh in the quest to fight polio. Polio crippled an average of 1,000 children every day in more than 125 countries during its peak.  The polio vaccine ended this serious illness that plagued the United States from the late 1800s to the mid-20th century.

Dr. Youngner made three critical advances in the polio vaccine research, much of which relied on research with animals. He first devised a way to break down monkey cells so the team could grow large quantities of poliovirus in the lab. He then developed a way to inactivate the virus so it could be safely injected as a vaccine, and finally, he developed tests to determine the vaccine’s effectiveness in the first human patients. The number of polio cases went from an average of 35,000 a year before the vaccine to fewer than 2,500 two years later. Today, polio is virtually eradicated in the United States and much of the world.

Since his polio work, Dr. Youngner made other major advances in virology and immunology, continuing to rely on animal models. Youngner was the first to demonstrate that non-viral agents could trigger interferon infection in animals, and his research team devised a novel approach to antiviral therapy. By demonstrating that the live, attenuated virus vaccine for influenza A interacts with wild-type influenza to confer protection, rather than inducing a protective immune response, Youngner and his team demonstrated that this type of vaccine, tested in animal models, has the potential for significantly reducing morbidity and mortality associated with influenza.

A comprehensive obituary of Dr. Youngner, including his work on the Manhattan Project and his feud with Dr. Jonas Salk, was published on April 28 by the Pittsburgh Post-Gazette.

Albert Sabin and the monkeys who gave summer back to the children.

Albert Sabin has been called “the doctor who gave summer back to the children.”*

Because of his decades of research to develop the oral polio vaccine, children today know nothing of the fear that polio brought to the United States every summer well into the 20th century.  Swimming pools and movie theaters were closed and children were kept inside their homes by frightened parents.  Worldwide, the disease killed millions of people and left legions of others permanently disabled.

Albert Sabin administering the vaccine that saved millions from polio.

We’ve just celebrated the 50th anniversary of the introduction of Dr. Sabin’s vaccine. Estimates suggest that in just its first two years of worldwide use, the vaccine prevented nearly 500,000 deaths and five million cases of polio.  Today, the world is on the brink of realizing Dr. Sabin’s lifetime dream: the eradication of polio from the planet.

The development of the oral polio vaccine required years of extensive research with rabbits, monkeys and rodents.

Animal rights activists long ago seized on a single phrase by Dr. Albert Sabin, and have been using it ever since to try to support their outrageous claim that the developer of the oral polio vaccine(OPV) opposed the use of animals in research.

That phrase, “The work on prevention (of polio) was long delayed by an erroneous conception of the nature of the human disease based on misleading experimental models of disease in monkeys” spoken by Dr. Sabin during a congressional hearing in 1984, has been used in animal rights publications and comments for over two decades.

Dr. Sabin, a member of the Board of Directors of the pro-research Americans for Medical Progress until his death in 1993, spent years working to correct the record.  Here is a letter he wrote to the editor of the Winston Salem Journal, published in 1992.

Winston-Salem Journal

March 20, 1992

The Correct Conclusion

In a recent letter to the Journal (“Misrepresenting Research,” Feb. 20), Dr. Stephen R. Kaufman, the chairman of the Medical Research Modernization Committee, correctly quoted my 1984 testimony before Congress but he drew wrong conclusions from it.  Dr. Kaufman was also wrong when the said “the polio vaccine was based on a tissue culture preparation … not animal experimentation.”

On the contrary, my own experience of more than 60 years in biomedical research amply demonstrated that without the use of animals and of human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans but also among animals.

In my 1956 paper in the Journal of the American Medical Association (Vol. 162, p. 1589), I stated that during the preceding four years “approximately 9,000 monkeys, 150 chimpanzees and 133 human volunteers were used thus far in studies of various characteristics of different poliovirus strains.”  These studies were necessary to solve many problems before an oral polio-virus vaccine could become a reality.

Albert B. Sabin, M.D.

Washington”

It is true that in the early years of polio research some lines of inquiry eventually proved unsuccessful. An overreliance on a strain of the virus known as the MV strain that had become adapted to survive only in nervous tissue, and the fact that the Rhesus macaque, while a good model for many aspects of polio, cannot be infected through ingestion via the mouth, led to the incorrect assumption that polio could only infect nerve cells (despite evidence to the contrary from both clinical studies and laboratory studies with other polio strains and monkey species).   These mistakes were unfortunate, though understandable given the fact that virology as a science was in its infancy.

However, these failed attempts do not cancel out the fact that animal research, and research using monkeys in particular, was absolutely crucial to the development of vaccines for polio.  Without it the polio vaccine would certainly not have been developed by the end of the 1950’s, and we might even still be waiting for it.

These vital contributions made by animal research to the development of polio vaccines were not limited to the work of Albert Sabin, and include:

  • The discovery by Karl Landsteiner and Erwin Popper in 1908 that polio was caused by a virus, a discovery made by inoculating macaque monkeys with an extract of nervous tissue from polio victims that was shown to be free of other infectious agents.
  • The subsequent discovery by Simon Flexner  that blood serum from infected macaque monkeys could protect against polio infection.
  • The discovery by Carl Kling and colleagues in 1911, following an earlier discovery that polio virus could be isolated from the lymph nodes of the small intestine of monkeys, that polio virus was present in the throat and intestinal tissues of people who dies from polio. Soon afterwards they isolated virus from the intestines of patients suffering from acute polio, and importantly from family members who did not display the symptoms of polio, establishing that healthy carriers played an important role in spreading the disease. In these studies the presence of polio was demonstrated by injecting filtered fluid from the patients into monkeys, the only method then available to confirm the presence of polio (Introduction to Epidemiology, fifth edition, by Ray M, Merill, Jones and Bartlett Learning).
  • The discovery in the early 1930’s by the Australian scientists Macfarlane Burnet and Jean Macnamara that antibodies against one strain of polio did not always protect macaque monkeys against infection with another strain.
  • The discovery by John Enders, Thomas Weller and Frederick Robbins that the polio virus could be grown in a number of tissue types, not just nerve tissue as previously assumed, a discovery that required the use of mice and monkeys to prove that the cultured virus was indeed polio and still capable of causing paralysis.
  • The determination in 1949 by David Bodian and colleagues at Johns Hopkins University that there were three major families of polio virus, referred to as types 1, 2, and 3, and that a separate vaccine would be necessary for each to give broad protection against polio.
  • The discovery by David Bodian and colleagues in the late 1940’s and early 1950’s that the polio virus entered the body through the mouth, and then needed to pass into the blood stream before it could infect nervous tissue, and that if you could block the infection in the blood you could prevent the virus from entering nerve tissue and causing paralysis. The work of Enders and Bodian paved the way for the development of vaccines by Salk and Sabin.
  • The evaluation by Jonas Salk and his colleagues at the University of Pittsburgh  of vaccine candidates produced by inactivating the virus with formalin under a range of conditions, until a vaccine was identified that was effective and safe enough for human trials.
  • The evaluation by Albert Sabin of hundreds of polio virus strains in hundreds of monkeys and scores of chimps before identifying attenuated strains that were capable of efficiently entering the body through the digestive system and provoking an adequate immune response to protect against the different pathogenic strains of polio while not causing the disease themselves.

It is hardly surprising that those close to Albert Sabin are disgusted with the way in which his views are misrepresented by animal rights activists. Writing for the Wall Street Journal two years after his death Albert Sabin’s widow, Heloisa Sabin, discussed the value of animals to his research.

ANIMAL RESEARCH SAVES HUMAN LIVES

The Wall Street Journal, October 18, 1995

by Heloisa Sabin

Mrs. Sabin is honorary director of Americans for Medical Progress.

That scene in “Forrest Gump,” in which young Forrest runs from his schoolmate tormentors so fast that his leg braces fly apart and his strong legs carry him to safety may be the only image of the polio epidemic of the 1950s etched in the minds of those too young to remember the actual devastation the disease caused. Hollywood created a scene of triumph far removed from the reality of the disease.

Some who have benefited directly from polio research, including the work of my late husband, Albert Sabin, think winning the real war against polio was just as simple. They have embraced a movement that denounces the very process that enables them to look forward to continued good health and promising futures. This “animal rights” ideology — espoused by groups such as People for the Ethical Treatment of Animals, the Humane Society of the U.S. and the Fund for Animals — rejects the use of laboratory animals in medical research and denies the role such research played in the victory over polio.

The leaders of this movement seem to have forgotten that year after year in the early ’50s, the very words “infantile paralysis” and “poliomyelitis” struck great fear among young parents that the disease would snatch their children as they slept. Each summer public beaches, playgrounds and movie theaters were places to be avoided. Polio epidemics condemned millions of children and young adults to lives in which debilitated lungs could no longer breathe on their own and young limbs were left forever wilted and frail. The disease drafted tiny armies of children on crutches and in wheelchairs who were unable to walk, run or jump. In the U.S., polio struck down nearly 58,000 children in 1952 alone.

Unlike the braces on Forrest Gump’s legs, real ones would be replaced only as the children’s misshapened legs grew. Other children and young adults were entombed in iron lungs. The only view of the world these patients had was through mirrors over their heads. These, however, are no longer part of our collective cultural memory.

Albert was on the front line of polio research. In 1961, thirty years after he began studying polio, his oral vaccine was introduced in the U.S. and distributed widely. In the nearly 40 years since, polio has been eradicated in the Western hemisphere, the World Health Organization reports, adding that with a full-scale effort, polio could be eliminated from the rest of the world by the year 2000.

Without animal research, polio would still be claiming thousands of lives each year. “There could have been no oral polio vaccine without the use of innumerable animals, a very large number of animals,” Albert told a reporter shortly before his death in 1993. Animals are still needed to test every new batch of vaccine that is produced for today’s children.

Animal activists claim that vaccines really didn’t end the epidemics — that, with improvements in social hygiene, polio was dying out anyway, before the vaccines were developed. This is untrue. In fact, advanced sanitation was responsible in part for the dramatic rise in the number of paralytic polio cases in the ’50s. Improvements in sanitation practices reduced the rate of infection, so that the average age of those infected by the polio virus went up. Older children and young adults were more likely than infants to develop paralysis from their exposure to the polio virus.

Every child who has tasted the sweet sugar cube or received the drops containing the Sabin Vaccine over the past four decades knows polio only as a word, or an obscure reference in a popular film. Thank heavens it’s not part of their reality.

These polio-free generations have grown up to be doctors, teachers, business leaders, government officials, and parents. They have their own concerns and struggles. Cancer, heart disease, strokes and AIDS are far more lethal realities to them now than polio. Yet, those who support an “animal rights” agenda that would cripple research and halt medical science in its tracks are slamming the door on the possibilities of new treatments and cures.

My husband was a kind man, but he was impatient with those who refused to acknowledge reality or to seek reasoned answers to the questions of life.

The pioneers of polio research included not only the scientists but also the laboratory animals that played a critical role in bringing about the end of polio and a host of other diseases for which we now have vaccines and cures. Animals will continue to be as vital as the scientists who study them in the battle to eliminate pain, suffering and disease from our lives.

That is the reality of medical progress.”

 

Animal rights activists are free to express their opposition to the use of animals in research, but they cannot do so by blatantly robbing society of scientific achievements.  This one fact is clear — if our critics had their way, today millions of children would be dead or disabled from polio and other infectious diseases.

* Of course Jonas Salk is equally, if not more, deserving of this accolade.