Advancement of biomedical science

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Theme: "How have animals contributed to the advancement of biomedical science over the past 10 years?"

In Lancet, which is known to be one of the world's most famous medical journals, it is said that, “The use of animals in medical research and safety testing is a vital part of the quest to improve human health. It always has been and probably always will be, despite the alternatives available… Without animal testing, there will be no new drugs for new or hard-to-treat diseases… Rather than apologies for medicine as it is pursued today, society should be seeking to strengthen it. Animal research is an essential part of compassionate humanistic endeavor.” The statement concisely summarizes the importance of animal testing in the progress of science. In fact, it has become a rather standardized process in which scientists develop brand new technologies, test them using animal models and then implement them in a large scale to benefit the humanity.

The idea of animal testing is not a new idea to us at all. As long as 2300 years ago, the Greek physiologist Erasistratus carried out the earliest recorded physiology research in pigs to study the functions of the heart and respiratory systems. About 400 years later, Galen published the first textbooks on anatomy, based on dissections on pigs and apes. They laid the foundation of anatomy in today’s scientific world using animal experimentation. Until today, animal models are still crucial to the development of new surgical techniques and the invention of cutting-edge medical devices. However, much more animals are being used in biomedical research than experimental surgery nowadays. The Biomedical science continued to evolve after Claude Bernard established the discipline based on animal experimentation and Louis Pasteur, one of the three founders of microbiology, used animal experimentation to validate his experimental method. The 20th century is a time period in which a myriad of achievements in biomedical science were accomplished. The fundamental research and discoveries in immunology, organ transplantations, physiology, and cardinal diseases were mostly done with the help of animal experimentation. Then, in our century, with the help new technologies such as Magnetic Resonance Imaging (MRI), scientists are now able to get more accurate data in animal models with fewer animals and all these data are contributing to the breakthroughs in biomedical science.

To understand how animals have contributed to the advancement of biomedical science, we need to know why they are important and necessary in the first place. Firstly, animals are the best surrogates of human beings in scientific experiments. Even the most advanced electronic simulation could not generate satisfactory results as comprehensive as scientists could have attained in animal experimentation. This is due to the nature of Biology. Biology is different from other major sciences such as Physics and Chemistry because it is more complex and less predicable. A theory may have been tested hundreds of times and be regarded as a truth; still, it could generate different results in different organisms. Thus, scientist could not rely on the prediction attained in electronic simulation. As they need sound and robust data to validate their hypotheses, scientists need to carry out experiments in surrogates of human beings, who must be very similar to humans in various aspects such as cell structure and organ systems. In this sense, animals are the best choices for scientists to obtain helpful and accurate results.

Apart from moral considerations, animals are better subjects of experimentation as they have a generally sorter life span compared to human beings. Thus, scientists can study the effects of certain drugs or surgical techniques in a long run instead of obtaining results only valid in short periods of time. In addition, animals are able to reproduce in a faster rate and more offspring for experimental use.

Lastly, as previously mentioned, the final testing of any new drugs or surgical techniques has to be conducted on a living organism instead of an electronically simulated system. Alternative methods such as cell culture and electronic simulations may be effective and accurate in early stages of testing. However, they could not predict exactly the complicated reactions which occur in a complex living animal body system. Thus, animal experimentation is irreplaceable provided the current technology level.

With the help of animal experimentation, scientists have developed many life-saving drugs or techniques in the past century. For example, the Polio vaccine, chlorpromazine, German measles vaccine, antibiotics, medicines for once incurable diseases such as diabetes and kidney failures; surgical techniques such as replacement of heart valves, cardiac pacemakers, transplantations; medical techniques such as CT scanning and MRI scanning. These developments have saved thousands of lives despite the fact that many people are not aware of what animals have contributed in the process. So, in this brand new century, what animals have contributed to us and what is promised to bring more benefits to us?

The most noted use of animal experimentation in biomedical research is studies of cancer therapy. Cancer is a type of disease caused by an uncontrolled division of abnormal cells in a part of the body. According to American Cancer Society, there were 1437180 new cases of cancer in the year of 2008 alone and 565650 deaths were incurred. The best animal model for cancer research has been mice. There are several reasons. Firstly, mice are highly available, easily handled, and reproduced in short periods of time. Secondly, mice share a 99% of their genes of humans and develop nearly all the cancers human beings could potentially develop. The mice also have similar genes responsible for the development of the cancers in human beings. Thus, scientists have been able to study the relationship between certain genes in mice and occurrence of cancer, and then apply the knowledge to human beings. Using the novel technologies of gene modification, they add or delete certain genes in mice and study the effect of these modifications on cancers, leading to many new discoveries of cancers. Lastly, nude mice could be produced in laboratories, which lack thymus and thus have a defective immune system. In this way, human tumors could be transplanted in mice without being rejected, and cancer drugs or other therapies could be tested on them.1

The most recent development in cancer therapy is in the treatment of breast cancer. Aromatase inhibitor could inhibit the enzyme aromatase which synthesizes estrogen. By doing so, cancer cells are deprived of estrogen and their growth is almost stopped. Professor Angela Brodie of the University of Maryland developed this amazing drug which was reported to bring a 50% decrease in the rate of breast cancer recurrence after one year of treatment. In his experiment, nude mice were used in whom carcinomas were induced. He discovered that aromatase inhibitor greatly reduced the tumor progesterone receptor concentration, which is related to growth of tumor. In addition, he found that a combination of the then most successful drug tamoxifen and aromatase inhibitor did not bring better healing effect than armoatase inhibitor alone. This is very important in the treatment of cancer as it not only developed a new effective drug but also study the effects of combinations of different therapies, all with the help of animal experimentation.

Similarly, animal research has also contributed to the treatment of colon cancer, which caused second highest number of deaths in the year of 2008. A novel surgical technique or rather an innovative equipment, microwave probe was developed using pig us the animal model. Colon cancer is usually easy to control unless metastasis occurs and it spreads to the liver, making surgery nearly impossible. The microwave probe is used by inserting it into the targeted tumor and killing the cancer cells by heating them to a very high temperature. The pig model was used because the size of its liver is comparable to that of the human beings and more importantly, it is clearly not ethical or justified to use humans even the patient is perceived to be incurable. In the experiment2, eight female swine were used to study the outcome of the surgery and determine the suitable duration and power of microwave exposure. In the latest news viewed in “Science Daily”, it is stated that “The treatment of more than 100 patients with liver cancer has resulted in curing or extending life for many of them, whose life prognosis was less than twelve months”. 3This great achievement could have been possible without the fundamental experiment conducted on the pig model.

The second area where animal research is essential is the studies of Acquired Immune Deficiency Syndrome (AIDS), which caused by the virus, Human Immunodeficiency Virus (HIV). AIDS is a disease in which the body’s immune system is significantly compromised and resistance to infection and malignancy greatly reduced. HIV is identified as a retrovirus, which is a RNA virus capable of replicating themselves by integrating its DNA copy into the host cell. In this way, the virus could bypass the scrutiny of immune system without being detected. HIV could remain benign for many years until its symptoms are expressed, and by then, the virus would become unstoppable. Since it was identified by scientists, mice and non-human primates have been used in the research of the pathology of the diseases and the struggle to find a cure for it. In the beginning, scientists did not expect primates to be helpful in the research as HIV did not induce similar symptoms in chimpanzees. However, following studies showed that there was a similar virus, namely, the Simian Immunodeficiency Virus (SIV) could cause similar adverse effects in macaque monkeys. 4At the same time, the virus was found to be sensitive to the same drugs as HIV. This discovery was later validated as scientists determined that the HIV and SIV are related to similar genes and both work by attacking a kind of immune cells called T help (CD4). By studying the development of the disease in non-human primates, scientists were able to identify the three main ways in which HIV and SIV are transmitted. (Sexual transmission, perinatal transmission and exposure to contaminated blood) With the help of these discoveries, doctors were then able to develop relevant methods to prevent to transmission of the disease with precautions, drugs and vaccines. For example, in the year of 2002, researchers in Beth Israel Deaconess Medical Center developed a “humanized, nondepleting anti-CD4 antibody which blocks virus entry inhibits virus replication in rhesus monkeys chronically infected with simian immunodeficiency virus”. 5 Briefly speaking, this study showed us that it is possible to use antibodies to hold back the replication of SIV virus and thus possibly HIV virus. Since the non-human primates were able to withstand the drug, it is high possible that this kind of drug could be used in treatment of human beings in hospitals.

The above-mentioned process is commonly known as toxicity testing, which is usually conducted by pharmaceutical companies before a novel drug is brought into clinical use. Again, animals have been playing a very important role in this area. Just like the rhesus monkeys used in the experiment of anti-CD4 antibody, there are many other animal models available. Generally, rodents such as mice are preferred in early stages of testing because their availability and high reproduction rate. However, in the studies of AIDS, scientists were constantly hindered by the difficulty of making rodent models. Until the year of 2006, a group of researchers in University of Maryland found that Sprague-Dawley rats, which are genetically modified to carry HIV-1 receptor complex on CD T cells and macrophages, could be used as a potential preclinical testing model. This is because they discovered that inhibitors targeting virus entry successfully inhibit HIV-1 infection in the mice model. The discovery is promising as it proved that transgenic mice can now be used in testing of the efficacy of anti-HIV drugs in a faster and reliable manner, at the time reducing number of primates required in this kind of testing. Once again, all these advancements could not have been made without the contributions of animals such as mice and non-human primates.

Quite similarly, the use of animal models has always been an essential and irreplaceable element in the study of cognitive neuroscience. Basically, the aim of the neuroscience is to study the structure and the function of the nervous system and brain. Thus, it is obvious that neuroscientists need a very detailed and accurate structure map of the nervous system and brain in human beings. However, it is clearly unethical to do such experiment on a living human being and is pointless to perform it on a cadaver as the results would be inaccurate. Consequently, an anatomical scrutiny has to be performed on the brain of animals who have very similar brain structure and nervous system, and that makes macaque the best choice available. According to Professor R.E. Passingham in Oxford University, UK, “There are already underway studies comparing connections as established by diffusion weighted imaging in the macaque and human brain, and so far no major differences have been observed.” 6 The macaque thus plays a very important role in neuroscience as the fundamental model to interpret results of brain imaging from human beings.
The most prominent example of animal research in neuroscience is probably the studies of Parkinson’s disease. “Parkinson's disease is a neurodegenerative disease whose primary symptoms are tremor, rigidity, bradykinesia (slowed ability to start and continue movements, and impaired ability to adjust the body's position) and postural instability.”7 Using rats as the animal model, the Nobel Prize-winning Swedish scientist Arvid Carlsson discovered that dopamine in the 1950s; and then the Czech neurologist Oleh Hornykiewicz identified the substantia nigra degenerates in the case of PD and ceases the production of dopamine using primates as models. Consequently, they identified levodopa, which is the substance from which dopamine is produced as an effective treatment of Parkinson’s disease and the hypothesis was well supported by experimental data from primates. In 1990s, a novel technology called Deep Brain Stimulation (DBS) was firstly used on human beings, which involves the implantation of a medical device called a brain pacemaker to send electrical signals to targeted parts of the brain. Its implementation was only approved after successful operation in monkeys and other non-human primates. In 2008, scientists from the University of Cincinnati and University Hospital used rat models to prove that DBS could reduce the loss of brain cells by up to 50 percent. 8 There are even more promising techniques being developed using animal models. In this year, the researchers in Duke University developed a novel technique called spinal cord stimulation, which was proven to be more effective and less invasive then the traditional method DBS. Mice and rats models with chronic dopamine deficit were exposed to different levels of electric stimulation on their spinal cord. They found that “When the device was used without additional medication, Parkinsonian animals were 26 times more active. When stimulation was coupled with medication, only two L-DOPA doses were needed to produce movement compared to five doses when the medication was used by itself.” 9 It can be clearly seen how important animal research is in all these biomedical advances. Moreover, with the help of animal experimentation, more novel techniques or therapies would be developed, just like the spinal cord stimulation technique.

Nowadays, nearly every people is benefiting from the numerous vaccines available in all kinds of medical institutions. However, few of us realize what animals have contributed to make the development of vaccines possible. The study of animal models is fundamental in the understanding of how vaccines work and how they are developed. Similar to toxicity testing, the use of models was usually in the testing of efficacy and potential adverse effects in animals before clinical use of the vaccines. Nowadays scientists are even more privileged with the help of gene therapy as they can insert human genes causing certain diseases into animals to induce similar symptoms in the animals. In this way, more accurate and reliable information could be obtained since the experiments conducted on animals could almost accurately predict the efficacy of the vaccines if they were used in humans. Currently, there are many vaccines being developed with the help of animal models. Cervarix, a vaccine against Human Papillomavirus (HPV) 16 and 18 was developed using primates and rabbits as experimental model. Rabbits played the most important role in its development as there is a virus, the cottontail rabbit papilloma virus (CRPV), which is very similar to HPV in many aspects. 10 Using the rabbit as the fundamental model and the CRPV as the substitute virus model, important discoveries about HPV were made and the vaccine was developed. Alzheimer’s disease, which causes progressive mental deterioration due to degeneration of the brain, is being studied using rhesus monkeys as models. In a journal published in 2004, the scientists did a controlled experiment to access the effect of a vaccine- aggregated Abeta in two groups of rhesus monkeys. It was showed that the group vaccinated benefited from the vaccine obviously as the degeneration of their brain was almost prevented. The result was very promising as it not only once again showed that the use of animal model was relevant and at the same time, it opened future opportunities of new vaccines of the disease to be used on human beings.11

While we are overjoyed at the current success of biomedical science, it is also crucial for us to aware that there are still many troublesome diseases that scientists are struggling to handle with them. Alarmingly, these diseases are usually prevalent in less developed countries, depriving normal lives of thousands of people everyday, for example, tuberculosis and malaria. Tuberculosis is a deadly infectious bacterial disease characterized by the growth of tubercles in the tissues, especially in the lungs. Based on the annual report of the World Health Organization, there were about 9.27 million new cases reported across the globe in the year of 2007 alone. Among these patients, 1.32 million died and an additional 456000 TB deaths incurred among HIV-positive people. Currently, the main treatment of it is dependant on the use of antibiotics and vaccine. Worryingly, both methods are not risk-free. The vaccine, Bacillus Calmette-Guérin , only provides weak protection and it is not effective in prevention of pulmonary TB in adults. However, a new vaccine is being developed which has showed impressive results in animals. The secA2 mutant TB vaccine, developed by researchers at the Albert Einstein College of Medicine of Yeshiva University, was proven to be more effective then the only TB vaccine we have now. In the experiment they conducted with laboratory animals, those vaccinated with the secA2 vaccine had significantly less bacteria left after two month of observation compared to those vaccinated with BCG. 12 Similarly, the research of malaria, yet another endemic disease across the world, is dependant of the use of animal experimentation to find a reliable vaccine. Malaria is infectious diseases characterized by intermittent and remittent fever. It is caused by a protozoan parasite which attacks the red blood cells and is transmitted by mosquitoes in many tropical and subtropical regions. According to the World Health organization, “there were 247 million cases of malaria in 2006, causing nearly one million deaths, mostly among African children.” Sadly, there is no effective vaccine of malaria yet. The development of vaccine for malaria has long been the headache of scientists. Once again, the application of animal research is now proving yet another promising potential vaccine for human beings. According to the latest in July of 2009, researchers at the Johns Hopkins Malaria Research Institute have developed a potential transmission-blocking vaccine which was proved to be effective in mice and non-human primates. In their experiments, they produced a malarial protein, namely, the Pfs48/45, which could effectively stifle the development of the parasite, thus preventing the malaria from developing. The vaccine was tested on mice and non-human primates. The results were promising with an over 90 percent transmission-blocking immune response. 13 From the several vivid examples above, it could be clearly seen that animal research is extremely important in the field of vaccine production. Only with the help of animal models, a fundamental understanding of the diseases could be obtained and vaccines produced. Furthermore, without testing the potential vaccines on animals, nobody would dare to use them on human beings for the fear of causing unpredictable adverse effects.

In many of the examples given above, many studies involved transgenic animals. So, how are they made available? The answer lies with the use of the technique of gene engineering. Using this technique, scientists are able no insert or transfer genes from an organism to another unrelated organism so that it could process new traits from the original organism. With the help of this technique, a new branch of biomedical science has evolved- gene therapy. Gene therapy refers to the insertion of genes into diseases-causing cells or tissues to replace the deleterious genes. It is the ultimate goal of medical treatment since it solves the root of the problem and virtually eliminates the disease instead of just suppressing it. The development of gene therapy has been closely related to the animal research. Sickle cell anemia is a hereditary disease in which a mutation in the hemoglobin gene leads to distortion of red blood cells into a crescent shape. The ability of the red blood cells to bind with oxygen is significantly lowered and life expectancy of patients is reduced. The current treatment of the disease is either ineffective or very painful. Thus, the use of gene therapy is expected to be a perfect tool to solve the crisis. In 2006, scientists did an experiment on mice with sickle cell disease and obtained impressive results. They used the technique of gene engineering to transfer a correcting gene for the disease into the bone marrow of the mice and then transplanted the bone marrow back to the mice. In up to ten month of testing, the mice with the transplanted genes have the antisickling protein in up to 52% of their total hemoglobin and 99% of their blood circulating red blood cells. Now, after many rounds of testing in animals, the technique is being carefully applied to humans in clinical trials. 14 Transgenic animals are not only being used as animal models in experiments; they are now contributing in an even more significant field- the production of human proteins, human replacement valves or even whole organs. Instead of producing medicines using chemicals, biomedical research now opens the opportunity to produce human proteins in animals to be used as drugs. In the latest news, the US government has approved “the first drug made using genetically engineered animals”. The drug, namely, Atryn, is made from human proteins obtained in the milk of genetically modified goats. 15 The drug is used in the prevention of blood clots in patients with a disorder known as hereditary antithrombin deficiency. In the production process, human antithrombin genes are inserted into the embryos of the goats, enabling them to produce milk contains the desired proteins. Similarly, some scientists are now using transgenic hens to produce a protein called ovalbumin. The whites of the legs laid by these transgenic hens contain a great amount of the protein and these transgenic hens now provides the main source for the production of this pharmaceutical protein. 16
The last example of animals’ contribution to the advance of biomedical research, which is also the latest developed technology, is the application of knowledge pertaining to the stem cells in cell therapy and regenerative medicine. What are stem cells? We can use a simple analogy to illustrate the difference between normal cells and stem cells. If we regard cells as the building blocks of human bodies, then stem cells are the magic ones which could develop into any type of blocks eventually. The use of stem cells has the potential to revolutionize the current medical industry as it provides opportunities to treat currently incurable diseases such as brain damage, muscular dystrophy and spinal cord damage. Because of the ability of the stem cells to develop into all the 210 distinct types known in human body, it is possible to transplant stem cells to any damaged tissues or organs to repair them. Although there are not yet very effective therapies developed, the application of stem cell therapy still has a very promising future. Currently, a group of scientists at the University of Missouri are using pigs as their models to study the potential use of stem cell therapy in the future. In their experiments, the pigs were genetically modified by inserting genes in to cells in connective tissue of the pigs. They successfully obtained stem cells in their experiments and are currently researching on how to guide these stem cells to develop into specific types of cells desired. 17 If the research progresses smoothly, it will not be amazing for us to view in the future that severely damaged tissues or even organs be regenerated using this technology. This will no longer be our imagination in the science fiction but really happen in our lives. There are also other similar potential treatments such as the repair of spinal cord injury, skin burns and scars. Among them, the development of repair of spinal cord injury has shown the most impressive progress. In 2009, a new study has shown that transplantation of stem cells into the damaged region of spinal cord in animal models could reverse the paralysis resulted and brought new hopes for the patients who have been diagnosed to be permanently disabled due to spinal cord injury. Again, all these advances and future promises would be impossible without the help of the animals along the way of researches.

In a nut shell, although the use of animals may be considered inhumane or even immoral, the use of animal models in biomedical researches is inevitable provided there are no superior substitutes of them. While we as human beings are enjoying the benefits from the advances contributed significantly by the animals, we should be aware of their important roles and respect their contributions in the development of biomedical science. At the same time, we should be thankful for what they have done for us in the past years and be confident about the dazzling opportunities animal researches have provided to us.

References:

1. http://science.jrank.org/pages/382/Animal-Cancer-Tests.html">Animal Cancer Tests - Mice—the best animal model for cancer research

2. Microwave Ablation with Loop Antenna: In Vivo Porcine Liver Model

3. University of Leicester (2009, May 14). Microwave Technique Successful In Treatment of Liver Tumors, Surgeon Shows. ScienceDaily. Retrieved August 30, 2009, from http://www.sciencedaily.com¬ /releases/2009/05/090513121629.htm

4. The SIV-infected rhesus monkey model for HIV-associated dementia and implications for neurological diseases, by DM Rausch, EA Murray and LE Eiden http://www.jleukbio.org/cgi/content/abstract/65/4/466

5. A humanized, nondepleting anti-CD4 antibody that blocks virus entry inhibits virus replication in rhesus monkeys chronically infected with simian immunodeficiency virus. http://www.ncbi.nlm.nih.gov/pubmed/12167266

6. The need for research on non-human primates in cognitive neuroscience http://www.animalresearch.info/en/medical/articles/primates_in_cognitive_neuroscience

7. http://www.neurological.org.nz/html/article.php?documentCode=109508. University of Cincinnati (2008, September 3).

8. Deep Brain Stimulation Halts Cell Loss, Parkinson's Researchers Find. Science Daily. Retrieved August 30, 2009, from http://www.sciencedaily.com­ /releases/2008/09/080902171151.htm

9. Duke University Medical Center (2009, March 21). Novel Spinal Cord Stimulator Sparks Hope for Parkinson's Disease Treatment. ScienceDaily. Retrieved August 30, 2009, from http://www.sciencedaily.com­ /releases/2009/03/090319142357.htm

10. Giri, Isabelle; Danos, Olivier; Yaniv, Moshe (1985), "Genomic Structure of the Cottontail Rabbit (Shope) Papillomavirus", PNAS 82: 1580-1584, doi:10.1073/pnas.82.6.1580

11. Alzheimer's Abeta vaccination of rhesus monkeys (Macaca mulatta), Mech Ageing Dev. 2004 Feb;125(2):149-51)

12. Journal of Clinical Investigation Demonstrates Better Protection than Standard Vaccine Used Worldwide ,http://www.einstein.yu.edu/home/newsArchive.asp?id=364

13. Johns Hopkins University Bloomberg School of Public Health (2009, July 23). Vaccine Blocks Malaria Transmission in Lab Experiments. ScienceDaily. Retrieved August 31, 2009, from http://www.sciencedaily.com¬ /releases/2009/07/090722110850.htm

14. Science 14 December 2001:Vol. 294. no. 5550, pp. 2368 - 2371DOI: 10.1126/science.1065806, Correction of Sickle Cell Disease in Transgenic Mouse Models by Gene Therapy

15. http://www.reuters.com/article/domesticNews/idUSTRE5154OE20090206

16. http://www.pnas.org/content/104/6/1771.full, Oviduct-specific expression of two therapeutic proteins in transgenic hens

17. University of Missouri-Columbia (2009, June 26). Stem Cells Created From Pigs' Connective Tissue Cells. ScienceDaily. Retrieved September 1, 2009, from http://www.sciencedaily.com¬ /releases/2009/06/090625141508.htm

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