BSR 1.01 - Standards and Research Types - v4_08.13.23.pdf

BASIC SCIENCE RESEARCH Standards and Research Types Block 1 Mark Pierre S. Dimamay, PhD | August 4, 2023 BSR 1.01...

BASIC SCIENCE RESEARCH Standards and Research Types Block 1 Mark Pierre S. Dimamay, PhD | August 4, 2023 BSR 1.01 OVERVIEW where drug was tested on rodents but not on I. Types of Medical Research II. Scientific Fraud humans and led to pregnant women giving birth to A. Basic Science Research A. Definition babies with birth defects) Animal Welfare B. Types ↪ A way of respecting human life B. Clinical Research C. Causes But, this DOES NOT exempt researchers from C. Clinical Trials D. Examples complying with animal welfare laws. D. Translational Research III. Research E. Research Standards A. Research - Why Do It? ANIMAL WELFARE B. Who Should Do Research? Five (5) Basic Freedoms ⭐ C. Potential Ethical ○ Reference parameters for animal welfare in an animal Concerns facility ○ These are: I. TYPES OF MEDICAL RESEARCH Freedom from thirst, hunger, and malnutrition A. BASIC SCIENCE RESEARCH Freedom from physical discomfort and pain Characteristics: Freedom from injury and disease ○ Investigates mechanisms and how they relate to Freedom to conform to essential behavior patterns diseases Freedom from fear and distress ○ Fundamental theoretical or experimental investigation to Living conditions required for laboratory animals: advance scientific knowledge ○ 24/7 air-conditioning Immediate practical application is NOT a direct ○ Regularly cleaned shelter objective ⭐ ○ Food, water, and toys ○ Differs from all other forms of research in being totally Recognize the animals’ facial features to determine if they unpredictable are in pain or not ○ Requires: ○ Find an alternative method or apply analgesia if research Long term commitment by the researchers and by methods inflict pain the funding agency, as well as infrastructures ○ Consistency of baseline is done by using the same Good training in research techniques and in fields lineage of the animal that are certified clear of outside medicine pathogens (e.g. mice, swine, etc.) ○ No initial connection between the research and its medical application Explains why pharmaceutical companies hesitate on investing on studies that will not provide a clear return of investment (ROI) Example: Watson and Crick’s discovery of the structure of the DNA ↪ Led to the elucidation of the central dogma of molecular biology, resulting in the association of DNA mutations and disease [Trans 2026] Example: Paul Berg, Herbert W. Boyer, and Stanley N. Cohen’s invention of recombinant DNA technology ↪ Led to the development of the biotechnology industry in the production of recombinant protein products for treatment of human protein deficiencies [Trans 2026] Most common examples: ○ Cloning of a gene To study a virus ○ Bioinformatics approaches In-silico approaches to sequence genome and Figure 1. This image shows the different facial features according to the level of pain the mouse is experiencing. determine lineage ○ Developing a prototype diagnostic test 3 R's (Reduction, Refinement, Replacement) of Russell Can be done even without human samples and Burch ○ Screening for bioactive compounds ○ Principle that guides the use of animals in research, Usually from plants ○ Animal studies ⭐ testing, and teaching ○ Protocols are reviewed by an Institutional Animal Care Studies using laboratory animals are still considered and Use Committee (IACUC) basic science research since giving patients a drug Flow of permit: Clearance from institution → that has not been tested in animals puts patients at Clearance to Animal Welfare Division of the higher risk of danger (e.g. Thalidomide disaster Philippine Bureau of Animal Industry Page 1 of 5 | TH: ASUNCION, C.| BSR TG 1 | ABESAMIS, BERNARDO, BORJA  BSR 1.01 Standards and Research Types Reduction ↪ Appropriate sample size calculations must be made to, as much as possible, reduce the number of animals to be used Refinement ↪ Procedures to be done with the animals should minimize harm and distress Replacement ↪ Research should be done to show that there is no in vitro model that can replace the use of an animal B. CLINICAL RESEARCH Characteristics: ○ Epidemiological and behavioral studies Determine the prevalence, incidence, distribution of Figure 2. Research and Development Process of Clinical Trials disease, the factors that affect health, how people make health-related decisions D. TRANSLATIONAL RESEARCH ○ Outcomes and health services research Mantra: “Bench to bedside and back” Seeks the most effective and efficient interventions, Combination of basic clinical research ⭐ treatments, and services Links the scientific advances to patient care ○ Patient-oriented research Requires good communication between the laboratory and Involves a particular person or group of people or clinic uses materials from humans ○ To translate basic biomedical research into effective new ↪ Studies to understand pathogenesis or therapies mechanisms of human disease ○ To bring clinical observations back to the lab ↪ Studies on interventions for disease or E.g. therapeutics ○ Development of diagnostic tests ↪ Studies to develop biomedical devices or new Translatable to patient testing technology related to disease Development of a test to determine the type of COVID-19 variant C. CLINICAL TRIALS ↪ Some medicines do not work on other variants of Controlled studies involving human subjects COVID-19 Designed to prospectively evaluate the safety and ○ Stem cell work effectiveness of: Growth of eye epithelial cells to be transplanted to ○ New drugs or devices patients with ocular surface injuries ○ Behavioral interventions Safety – from adverse events E. RESEARCH STANDARDS Informed Consent – to safeguard the rights and welfare of Good Laboratory Practice research participants Good Clinical Practice Important to have good clinical practice certification before Good Manufacturing Practice conducting any form of clinical study Biosafety and Biosecurity Clinical Trial Phases II. SCIENTIFIC FRAUD Phase 1: Safety of the healthy subjects A. DEFINITION ○ Most difficult of the phases Used to describe intentional misrepresentation of the ○ First time to try the drugs on human subjects following parts of scientific research: ○ Done on a smaller population of healthy volunteers to ⭐ see if it is safe ○ Methods ○ Procedures ○ Need a community where healthy volunteers can be ○ Results enrolled from Scientific fraud is when the following behaviors occur during Problems: the proposing, performing, or reviewing scientific research, ↪ Those from the community without work are or reporting research results: usually not healthy ○ Fabrication ↪ When healthy subjects are enrolled → need ○ Falsification better compensation to support participation ○ (E.g. some will use the compensation to start ○ Plagiarism ⭐ Even paraphrasing can be fraudulent; ensure proper drinking and will become unhealthy) credits to authors when citing literature Phase 2: Safety of the patients ○ Drug is tested on a larger population of sick patients Scientific fraud is unethical and often illegal ⭐ ○ Testing efficacy and safety of patients ⭐ ○ When discovered and proven → fraud can end the scientific careers of researchers who engage in it Phase 3: Testing on a larger population ○ Usually randomized and blinded ○ To eliminate the placebo effect ○ Next step is to get the approval from the Food and Drug Administration (FDA) Page 2 of 5 | TH: ASUNCION,C.| BSR TG 1| ABESAMIS, BERNARDO, BORJA  BSR 1.01 Standards and Research Types B. TYPES Research work will help save the lives of patients, even Misdemeanors those that you do not see ○ Improper credit to colleagues ○ Improper credit to collaborators B. WHO SHOULD DO RESEARCH? ○ Re-publishing content The question is – whether all MDs or merely a few should Smallest publishable unit perform research ○ Plagiarism Not all MDs can do basic research ⭐ ○ Unethical use of peer review ○ Not enough funding Felonies ○ Vast majority of MDs would rather spend a major part of ○ Misrepresenting Results their time in active medical practice Cooking: Selecting and retaining results that fit the Should all MDs do some research? data Why do research when the practice of medicine it’s already a Trimming: Adjusting data to make it look extremely noble profession? accurate ○ Your sphere of influence becomes bigger Forging: Fabricating data or entire experiments Clinicians who are Nobel Peace Prize awardees Why would anyone commit scientific fraud? ○ Arvid Carlsson (2011) ○ “Nobody arrives at fraud as the first thing they ever do. Studied dopamine treatment for Parkinson’s Disease They got there by doing little things and getting away ○ Robert Lefkowitz (2012) with it.” - Paul Friedman, Univ. of California at San Diego Discovered a family of G-coupled protein receptors (GCPR) that is important as drug targets C. CAUSES ○ Barry Marshall (2008) ⭐ Stiff competition for research funds Studied H. pylori and found out that they were Pressure to publish responsible for causing peptic ulcers ⭐ Fight for recognition ○ Shinya Yamanaka (2010) Difficult experiments that cannot be repeated due to lack of Researched stem cells funds Discovered that mature fibroblast cells could be Conflicts of interest reprogrammed to become immature stem cells EXAMPLE OF SCIENTIFIC FRAUD C. POTENTIAL ETHICAL CONCERNS [Dimamay,2023] Scientific fraud is not limited to researchers. Beware of Table 1. Potential ethical concerns in research ⭐ predatory journals that will publish papers for a fee but Issues Description/Example there is no peer review Patients who have been given candidate “Who’s afraid of peer review?” by John Bohannon vaccines are deliberately infected with the ○ An article written by John Bohannon from Science virus to test if the vaccine works wherein he investigates how many open-access journals Example: Edward Jenner deliberately do not perform peer reviews on submitted research infecting a young boy with cowpox and papers smallpox to test his vaccine ○ Bohannon submitted 304 different but similar generated Example 2: SARS-CoV-2 vaccine trials versions of a fake study to many open access journals where people volunteered to be These papers were submitted under different Human deliberately infected randomly generated names and affiliated institutions Challenge Weigh benefits and risks first ○ Despite the obvious scientific flaws in the data plots and Studies ○ If the risk of getting the disease is experiments that could easily be pointed out by any very high and is incurable, ethics credible peer reviewer, Bohannon found out that 60% of committee will not allow the study the 255 papers that underwent the editing process were (e.g. Ebola) accepted by these open-access journals Depends on the country where study will be done, ethics committee, how fast a cure Who’s Afraid of Peer Review. Scan the QR code is needed, and the availability of facilities or click this link: Who’s Afraid of Peer Review? that can treat any adverse effects from the study A baby is born with nuclear DNA from the mother and father as well as mitochondrial III. RESEARCH Three-Parent DNA from a healthy female donor A. RESEARCH - WHY DO IT? Baby Does the donor of the egg have any Excitement of discovery parental rights to the child? Pursuit of prestige Does this commoditize eggs? Need for publication Patients that have their genes tested for Career advancement diseases (e.g. Parkinson’s, Huntington’s, Travel opportunities etc.) may have their psyche and quality of Other benefits Susceptibility life affected ○ A critical or scientific attitude is developed Screening ○ Some patients had bouts of ○ Special interests and skills are developed depression after finding out about ○ Chance to study a subject in depth their susceptibility ○ Obtaining a higher degree Reproductive Clones can be used as organ donors Clinical work will help you save the lives of the patients you Cloning (underground science) see Page 3 of 5 | TH: ASUNCION,C.| BSR TG 1| ABESAMIS, BERNARDO, BORJA  BSR 1.01 Standards and Research Types CRISPR-Cas9 as a tool to alter/edit mutated A. The researchers genes to become “normal” B. The journal publishers Can be used as weapons in the battlefield by In vivo Gene C. Both A and B modifying vectors to cause complications Editing D. Neither A nor B (e.g. aerosol that can render opponents motionless, unconscious, breathing Research problems) Process of infecting self for experiments _____6. Which of the following is not a reason to pursue Self Example: Barry Marshall experimented on research? Experimentation himself to prove H. pylori as a cause of A. Career advancement gastric ulcers B. Get more money How personalized should you get? C. Pursuit of prestige Customized approach achieved via trial and D. Travel opportunities error Personalized Helps to avoid wasting money on drugs that _____7. What did Shinya Yamanaka win a Nobel Peace Prize Medicine will not work award for? Example: Use of biopsy samples to test A. Discovery of reprogramming of mature fibroblasts to which chemotherapeutic drugs will work or immature stem cells not before using it on a cancer patient B. Discovery of H. pylori as the cause of peptic ulcers C. Discovery of family of GCPR that can be used as drug IV. REVIEW QUESTIONS targets D. Dopamine treatment for Parkinson’s Types of Medical Research _____1. Rose wants to fully understand the characteristics of _____8. Which of the following ethical concerns refers to the basic science research. The following statements can help birth of a child with mitochondrial DNA from another female strengthen her knowledge on this topic EXCEPT: who is not his/her mother? A. Uses theoretical approaches A. In vivo gene editing B. Uses experimental approaches B. Reproductive cloning C. Uses practical approaches C. Human challenge studies D. NOTA D. Three-parent baby _____2. Bernard plans to study laparotomy through mice models. ANSWERS However, he wants to ensure that his experiment is still in line 1: C 2: C 3: B 4: D 5: C 6: B 7: A 8: D with animal welfare laws, particularly the 3 R’s. What could be his next step? RATIONALE A. Use as many mice as possible to finish the experiment 1: Basic science research applies theoretical or experimental faster investigations to advance scientific knowledge. Immediate B. Implement more invasive instrument attachment practical application is NOT a direct objective of basic science techniques for remarkable results research. C. Administer inhaled anesthetic agents during the 2: A does not follow the Reduction principle while B and D experiment does not follow the Refinement principle. Only C shows an D. Employ maximal restraints on mice for a smoother attempt to refine the experiment and cause less harm on the experiment animal models. 3: B is the best representation of “cooking”. A shows “forging” Scientific Fraud of data, C represents “trimming”, and D is plagiarism, which is not a felony but a misdemeanor. _____3. Which of the following best represents the definition of 4: D is a scenario where results of the study were “cooking” results? misrepresented, which is a felony, while the other three A. Creating data to better support the study choices are exmaples of misdemeanors. B. Keeping only the results that best fit the data 5: Both researchers and journal publishers are capable of C. Removing outliers from the data set of your committing scientific fraud experiment 6: Getting more money is not a reason to pursue research D. Using results from a different study as your own 7: Choices B, C, and D belong to Barry Marshall, Robert Lefkowitz, and Arvid Carlsson respectively _____4. Which of the following scenarios of scientific fraud are 8: A three parent baby has the nuclear DNA of his/her parents not misdemeanors? but has the mitochondrial DNA of a healthy female donor A. Copy and pasting paragraphs from differnet journals into your own research REFERENCES B. Putting only your name on the article after having Mark Pierre S. Dimamay, PhD. Notes from Research Types collaborated with 2 other colleagues and Standards. C. Rejecting the paper of someone you actively dislike D. Using a multiple regression to make one's results ONLINE SOURCES appear more significant John Bohannon (Science, 2013). Who’s afraid of peer review. https://shorturl.at/lDGZ6 (Accessed on 08/2023). _____5. Who can commit scientific fraud? Page 4 of 5 | TH: ASUNCION,C.| BSR TG 1| ABESAMIS, BERNARDO, BORJA  BSR 1.01 Standards and Research Types SUMMARY What are the types of research? What are some reasons to do research? Types Description Excitement of discovery Fundamental theoretical or experimental Pursuit of prestige investigation Need for publication No initial connection between research Career advancement Basic Science Travel opportunities and application Research Other benefits Unpredictable Needs long term commitment, funding, ○ A critical or scientific attitude is developed training, and infrastructures ○ Special interests and skills are developed Epidemiological and behavioral studies ○ Chance to study a subject in depth Clinical Research Outcomes and health services research ○ Obtaining a higher degree Patient-oriented research Controlled studies involving human Can all MDs perform research? subjects No, only some. Sometimes there is not enough funding for Clinical Trials Evaluates safety and effectiveness of new research and sometimes MDs would prefer to do medical drugs or devices and behavioral practice over research interventions “Bench to bedside and back” Who are some examples of MDs who did research and won Translational Combination of basic clinical research Noble Peace Prize awards? Research Links the scientific advances to patient Scientist Discovery care Dopamine treatment for Parkinson’s Arvid Carlsson disease What are the research standards? Family of GCPR that were important Robert Lefkowitz Good Laboratory Practice as drug targets Good Clinical Practice Bacterium H. pylori were responsible Barry Marshall Good Manufacturing Practice for causing peptic ulcers Biosafety and Biosecurity Mature fibroblasts can be Shinya Yamanaka reprogrammed into immature stem What is scientific fraud? cells Used to describe intentional misrepresentation of the methods, procedures, and results of scientific research What are some potential ethical concerns? Types Scientist Discovery Misdemeanors Felonies Deliberately infecting patients to test Misrepresenting Results Human Challenge a research method Improper credit to Cooking: Selecting and Studies Edward Jenner with smallpox vaccine colleagues retaining results that fit the SARS-CoV-2 vaccine volunteers Improper credit to data Baby with nuclear DNA of a couple collaborators Trimming: Adjusting data to and mitochondrial DNA of donor Three-Parent Baby Re-publishing content make it look extremely Parental rights of donor over child and Plagiarism accurate commoditization of eggs Unethical use of peer review Forging: Fabricating data or Susceptibility Genetic testing and patient’s quality of entire experiments Screening life/psyche after learning results Causes Reproductive ○ Stiff competition for research funds Cloning of humans for organs Cloning ○ Pressure to publish Altering mutated genes to become ○ Fight for recognition In vivo Gene “normal” ○ Difficult experiments that cannot be repeated due to lack Editing Biomedical warfare weapons of funds Self-Experimentat Self-infection for experiments ○ Conflicts of interest ion Barry Marshall with H. pylori How personalized should you get? What are the five (5) freedoms in animal welfare? Personalized Customized approach achieved via Freedom from thirst, hunger, and malnutrition Medicine trial and error Freedom from physical discomfort and pain Freedom from injury and disease FREEDOM WALL Freedom to conform to essential behavior patterns Must watch show recommendations by Doc: Freedom from fear and distress What are the three (3) R’s in animal welfare? Principle Description Reduction Use appropriate sample size calculations Perform procedures with minimized harm Refinement and distress No in vitro model can replace the use of an Replacement animal Page 5 of 5 | TH: ASUNCION,C.| BSR TG 1| ABESAMIS, BERNARDO, BORJA