Chronic pain is a problem which many Americans currently live with. Further, chronic pain management has led to the uprising of increased opioid use in the last few decades. Which has become a major problem. Especially, with regard to the unusually large amount of pain managing medication illegally entering the United States -- such as 'Fentanyl' -- which can be read about here. With pain management in mind, researchers have been searching endlessly for a cure or treatment which will reduce addiction issues. A possible solution might just have been found. In the blog post below, the new research is highlighted.
For most people, pain eventually fades away as an injury heals. But for others, the pain persists beyond the initial healing and becomes chronic, hanging on for weeks, months, or even years. Now, we may have uncovered an answer to help explain why: subtle differences in a gene that controls how the body responds to stress.
In a recent study of more than 1,600 people injured in traffic accidents, researchers discovered that individuals with a certain variant in a stress-controlling gene, called FKBP5, were more likely to develop chronic pain than those with other variants [1]. These findings may point to new non-addictive strategies for preventing or controlling chronic pain, and underscore the importance of NIH-funded research for tackling our nation’s opioid overuse crisis.
The research team, led by Samuel McLean at the University of North Carolina, Chapel Hill, first found evidence of an association between the FKBP5 gene and chronic pain in 2013 [2]. Those studies of about 1,000 white men and women found at least six different FKBP5 variants. They also showed that each variant could be used to predict the severity of a person’s pain after a car accident or other trauma. In fact, those who carried one particular gene variant, the less common DNA spelling at a location called rs3800373, were especially prone to chronic pain long after the traumatic event.
That is promising news, but what about other races, ethnicities, and cultures? Are the results just as promising for those populations too? Actually, yes. Again, from the Director's web page:
In the follow-up study now reported in the Journal of Neuroscience, the team took advantage of the recently completed NIH-funded Project CRASH . This multi-state project evaluated the recovery process of more than 1,600 white and black Americans who were seen in an emergency room within 24 hours of a traffic accident [1]. Each study participant provided a blood sample and answered questions about their pain just after the crash and then again six weeks later. The researchers also received permission to review data from participants’ medical records detailing the nature of their injuries and treatment.
The new evidence confirms that people who carry the pain-susceptibility variant at rs3800373 are more likely to develop chronic pain after a trauma. That’s true across gender and in people regardless of their race. Though the frequency of this variant is still unclear, the researchers estimate that about 33 percent of Americans have it.
Great. When can we expect a drug? Where do people with chronic pain go to now? What methods exist for those who suffer from chronic pain?
With opioid use at an all time high, other methods are being sought out to reduce chronic pain among those who suffer. Alternative methods include: physical therapy, yoga, mind-body therapies, complementary methods (acupuncture, meditation, etc.), and medical interventions.
For more information regarding the management of chronic pain, visit either: (1) Harvard Health and/or (2) WebMd. Keep checking back to see updates on the research listed above regarding new technology/research surrounding the treatment of chronic pain.
If you have ever had to clean the drain in your sink or the film of dirt off of the shower wall, chances are that a bacteria colony did reside there at one time. You know what I am talking about...That build up of film on your shower door/wall which progressively gets more opaque and changes color if left untouched by a sponge with cleaner. Bacteria colonies arise all over the place. How do bacteria colonies grow? How do individual bacteria in colonies communicate with each other? Scientists have made progress into unveiling the details below.
In the video shown below -- which is 10 seconds in length, the growth of bacteria is shown along with the immediate conversations between them in a community setting:
Scientists have often wondered how bacteria communicate when in a colony setting. This step represents an advance in the detection of communication. A step in the right direction to say the least. Exciting as the results may be, the researchers now have their hands full in pushing the project further.
Of the many unanswered questions that exist around the current election cycle, very few are as important than questions surrounding current scientific research and the funding for the future.
Why should the public vote/influence an increase in science funding?
Why do I suggest the importance of such research is so high?
The range of issues that are tied to science funding is enormous. Most people do not realize what issues are encompassed by science funding. If you (the reader) are one that ties research funding only to important issues like - space or defense - then I ask you to please read everything below. The reason is that the range of issues affected by science include climate science (flooding from Hurricane Matthew) to research into better treatments for eradicating the Zika Virus or Ebola Virus.
Additionally, what about the homeless problem that plagues the United States which includes many victims to serious mental health issues and impact the veterans among others roaming the streets without help. Before you go to the voting polls tomorrow, please read the information below which might or might not influence your vote. Either way, after reading the blog post below, you will definitely be better informed. Last but not least, I will provide direct evidence of the wonderful job that artists such as Beyonce, Jay Z, and Leonardo DiCaprio are doing to elevate science and the need to get out and vote -- which is super inspirational.
Note: various words or phrases are hyperlinked to earlier posts on the subject or other research articles. Please read widely and inform yourself on Science Issues.
Pending Issues Which Need To Be Addressed
Just look at the current state of affairs around the nation and the world along with the issues raised in the blog post below. Then we can talk about the importance of such issues. Currently, the entire East Coast of the United States is recovering from the dramatic flooding and winds which struck when Hurricane Matthew swept through and wreaked havoc on the region.
Any discussion of the funding for the destruction and the recovery?
Has the East Coast rebuilt all of the damaged structures?
Not in the least. Why not? If the same lack of attention toward science research into the issues exist today, where will we be as a nation in 4 or 8 years? This is why the issues of science are serious and need to be entertained before we head to the voting polls next week. At this point, you might be wondering the following question:
What are the most critical issues at hand that are associated with science for the candidates to express their views toward?
A recent article from the website "BioscienceTechnology" titled "Coalition Presses US Presidential Candidates to Address Science Issues" offered commentary on the "Top 20 Questions" from the nonprofit organization "ScienceDebate." The author chose to offer up six of the 20 questions as necessary to provide an example. The six sample questions are shown below:
1) Many scientific advances require long-term investment to fund research over a period of longer than the two, four, or six year terms that govern political cycles. In the current climate of budgetary constraints, what are your science and engineering research priorities and how will you balance short-term versus long-term funding?
2) Mental illness is among the most painful and stigmatized diseases, and the National Institute of Mental Health estimates it costs America more than $300 billion per year. What will you do to reduce the human and economic costs of mental illness?
3) Strategic management of the US energy portfolio can have powerful economic, environmental and foreign policy impacts. How do you see the energy landscape evolving over the next 4 to 8 years, and, as President, what will your energy strategy be?
4) Public health efforts like smoking cessation, drunk driving laws, vaccination, and water fluoridation have improved health and productivity and save millions of lives. How would you improve federal research and our public health system to better protect Americans from emerging diseases and other public health threats, such as antibiotic resistant superbugs?
5) Science is essential to many of the laws and policies that keep Americans safe and secure. How would science inform your administration’s decisions to add, modify, or remove federal regulations, and how would you encourage a thriving business sector while protecting Americans vulnerable to public health and environmental threats?
6) Evidence from science is the surest basis for fair and just public policy, but that is predicated on the integrity of the evidence and of the scientific process used to produce it, which must be both transparent and free from political bias and pressure. How will you foster a culture of scientific transparency and accountability in government, while protecting scientists and federal agencies from political interference in their work?
The author seem to want to suggest that the above issues just did not impact science funding, but were of significance to the public at large. I found the paragraph below fascinating:
“Some politicians think science issues are limited to simply things like the budget for NASA or NIH, and they fail to realize that a President’s attitude toward and decisions about science and research affect the public wellbeing, from the growth of our economy, to education, to public health,” Rush Hold, CEO of the American Association for the Advancement of Science, said in a prepared statement. He said that Americans should have the opportunity to know where Presidential candidates stand on these issues.
All issues that are researched from a scientific standpoint are important. Just because the public does not see the ramifications of such research does not disqualify funding. Of course, there are certain areas that are of immediate importance than others.
Science Lessons For Next President
According to a recent article in the Journal "Science" titled "Science lessons for the next president" there are certain issues that need definite support. Here is a short video of the issues stated succinctly (less than 4 minutes in length):
Below are the critical science lessons that are of upmost importance for the next President:
1) "Pathogens Change Faster Than Our Defenses"
Our ability to stay ahead of deadly pathogens relies on our ability to understand how to dismantle a virus or deadly bacteria. I wrote a blog about new research that recently was uncovered in which scientists discovered a site (a part of the molecule) that is responsible for disabling the effectiveness of the antibiotic. Meaning, if a target molecule hits this site, then the antibiotic is rendered ineffective (useless) and will not work.
More money should be devoted toward understanding and developing ways to counter that pathway toward disabling the antibiotic -- which is commonly termed as "Antibiotic Resistance." Additionally, this relies on funding to develop drugs that will be effective and can be tuned to treat evolving pathogens. In a blog post that I wrote recently, there was a short video outlining with an explanation the drug development process which is worth looking at and reading. If you are still not convinced after reading the blogs, then read below the excerpt from the Journal 'Science' on critical issues which offers an alternative explanation of the importance of such research:
Importance:
Why it matters: Evolving pathogens can threaten our food and water supplies, natural resources, and health. In the United States, 2 million people develop antibiotic-resistant infections each year, and 23,000 die. Globally, the World Health Organization estimates that in 2015 there were 580,000 new cases of tuberculosis resistant to the two most powerful drugs used against this disease. Increasing drug resistance in malaria, HIV, and other major diseases threatens to undermine control efforts. And recently emerged threats, such as the Zika and Ebola viruses, are certain to evolve in ways that can be hard to predict. To develop treatments, scientists often must work with the most dangerous pathogens in laboratories, and sometimes even engineer new strains; this creates the possibility of accidental or intentional releases that could have dire consequences.
With the emergence of stories surrounding the spread of diseases throughout the world, research into these diseases is critical. The issues above are due to evolving chemical systems that are natural and are constantly challenging us to keep ahead of the game to fight new pathogens. If we switch gears and look at issues that are brought on by our own actions, we find challenges that definitely need to be addressed immediately. One such issue is 'genetic engineering.' The question is raised below:
What about potential problems brought by our own actions?
2) "CRISPR Raises Tough Ethical Issues"
Recently, the field of 'genetic modification' has been getting alot of attention and rightly so. The prospect of changing an organisms "genetic code" seems strange and straight out of a science fiction book. Although, if I were to tell you that certain foods you eat have been genetically modified and you still love them -- what would you do? Furthermore, if the so called 'genetic modification' was to help the crop avoid destruction -- i.e., preserve a given crop in order to provide you food, would your opinion change? The current benchmark (among other methods) is the rising CRISPR-Cas9 method. You can read more about the method on the 'Wikipedia' page if you wish. In order to understand the importance of funding such research along with the potential implications, lets turn to the same article from the Journal 'Science' with the following explanation shown below:
Importance:
Why it matters: A powerful tool for basic research, CRISPR could also lead to new treatments for genetic disease in humans, pest-resistant crops with higher yields, and disease-resistant livestock. But uses of CRISPR could also raise profound ethical and regulatory concerns. It could allow the creation of human embryos with modified genes in their germ line—eggs and sperm—meaning the changes would be passed on to future generations. And, in an approach known as gene drive, CRISPR could be used to permanently alter the genome of an entire species in ways that could shift its evolutionary path and ecological role, or even wipe it off Earth. In principle, gene drive could give an endangered species a boost, wreck the genetic defenses that allow some weeds to resist herbicides, or drive a disease-carrying mosquito to extinction.
The promises are huge as well as the payoffs if the CRISPR method is perfected. And I say "perfected" -- why? Because, according to a certain part of the science community, the method does not work "perfectly." Professor Karmella Haynes at Arizona State University is performing research that investigates which environments where the CRISPR method works well. The method does not work well in human embryo cells. The DNA is coiled differently (slightly as a defense mechanism) which presents a large challenge. Of course, in the popular science news, positive results are published rather than discouraging results. Nonetheless, the method is still a strong method.
As an example, here is a short video of a reporter trying to perform the CRISPR method and failing shown below:
The above video shows the extent to which science is a profession of tireless effort. Time is put into get results and verify the methodology of a given experiment. Often, people think that scientists have an easy job -- but in fact, the development of research that is reproducible and clear to the public is a difficult task which takes time and money.
Certain areas require more time than others to delve into a given research inquiry. How about the atmosphere? The time scale of global warming is seemingly long. Although, according to current reports, action is needed immediately. The danger associated with the lack of immediate action is catastrophic. I find the fact that certain politicians are in denial a terrible observation and can only exacerbate the problem and solution.
3) "Sea Levels Rising"
As a nation, the United States public has been engulfed by the current chatter on the television along with the myriad devices that each of us carry around. Not too long ago, their were three presidential debates. Did you watch the debates? Were you able to watch the debates? Why do I ask such questions?
Because, while some were watching the debates, other East Coast residents were in the midst of cleaning up their lives which were ripped apart by Hurricane Matthew. The depth of the destruction along with the cost of the damage to the U.S. has not yet been realized. What is realized is that there have been some crazy weather patterns lately. Further, the seas have been rising. Both situations are not good indicators for the future. The amount of rain that dropped during Hurricane Matthew was insane compared to other large storms around the globe. You can read about the comparison here.
In order to fully understand the importance of such rising sea levels, lets turn to the article (series) we have been citing about the six lessons for the next president. Here is the "importance" stated below:
Importance:
Why it matters: Nearly 40% of the U.S. population lives near the coast, and shorelines host extensive infrastructure—including roads, rail lines, ports, military bases, and energy, water, and sewer plants—that will cost billions of dollars to protect or replace. Already, shorefront communities in hot spots of sea level rise, such as Hampton Roads, Virginia, and Miami Beach, Florida, are seeing tidal floods—even on sunny days—that clog traffic, poison lawns, and corrode utilities. Key ecosystems are also at risk of inundation, such as wetlands and aquatic grass beds that help protect coastlines from storms and provide important nursery grounds for economically important fish. This rising stage also allows stormwaters to surge deeper and higher inland, exacerbating their damage.
Based on the destruction that we have seen this year in the United States as a result of a rising sea level (flooding rain), there is no question that the above research is vitally important. One candidate (Donald Trump) would like to take funds away from research concerning global warming and fight ISIS. Ask yourself if this is a good idea? Is that where you want your money spent? Money is already available for the Department of Defense for such adventures. If any money should be diverted toward research in defense, then how about toward mental health for veterans returning from war with invisible wounds?
4) "Brain Health Should Be Top Of Mind"
Dr. James Watson once posed the following question regarding the human brain:
Can the brain understand itself?
The above question at first sight appears to be quite simple. Yet, over the decades that have past coupled with the advancing digital age, science still appears to be in the dark age to an extent. At the other end of this logic, the computational power needed to understand the brain is said to not yet exist. If the second statement is correct, then we need not stop funding research just yet.
Each and every one of us has either experienced or been touched by a person with a mental health issue. Even if we did not realize it at the time. Mental health is an extremely complicated issue that plagues parts of the entire population from the homeless to the ultra rich. Mental Illness is blind to income and wealth. With the new initiative to study the brain put forth by President Obama, we are headed in the correct direction. He has the BRAIN initiative - which can be understood in greater detail by reading more about here. Why is the health of the brain so important? Here is an excerpt from the article in 'Science' below:
Importance:
Why it matters: Brain health touches us from cradle to grave, and when brain disease strikes, the costs—personal and budgetary—are staggering. By 2025, at least 7 million Americans are expected to suffer from Alzheimer's disease, which causes memory loss, personality changes, impaired reasoning, and, eventually, death. This year alone, treating and caring for Americans with Alzheimer's and other less common dementias cost $236 billion, with government health programs shouldering two-thirds of the cost. At the other end of life, the prevalence of autism, a disorder of language and social communication, rose by 123% between 2002 and 2012. That year, one in 68 U.S. children was affected; costs to each affected family are estimated at about $60,000 annually.
Other brain health issues abound. Learning disabilities are a big issue in classrooms; mental illness is common in the homeless, in addicts, and in prison inmates; and concussions have become a major concern in sports. The military faces the burden of treating traumatic brain injuries and the psychological aftereffects of combat. Effective diagnostics and treatments could make a huge difference.
As I mentioned above, the amount of computational power needed to fully understand the brain is just being realized. Think about current research just published which shed light on the way proteins behave in their natural environment -- inside a human cell. If research carried out at the current level sheds light on the onset of diseases, then imagine the requirement to understand diseases inside the entire brain (different parts of the brain acting together). The point is that research into the disease causing aspects of the brain as well as our ability to comprehend the world around us is extremely important.
With the rise of the machine in understanding the world around us come other advances of the same technology. Artificial intelligence has been speculated to be around and supposedly proposed to play a large role in our lives in the coming decades. For now, what about simple machines -- drones? self driving cars, etc?
5) "Machines Are Getting Much, Much Smarter"
Elon Musk has been in the news lately for a variety of reasons. His space initiative has cost the private sector of the space industry a pretty penny. He has shown a complete lack of regard for the loss of life in his Tesla cars while operating on autopilot. How? He cannot admit that his technology is not nearly where technology needs to be at in order to let everyone have an autonomous car. I write about this here. In order to have completely autonomous cars, advancements in artificial intelligence will have to be taken toward a whole new level. Currently, we are not there yet. Science can shed light on potential issues that prevent us from proceeding to 'go' just yet -- which are shown below:
Importance:
Why it matters: Although experts say we are still decades away from machines that truly think like humans, narrower applications of AI are already having an impact on society. Products and services from self-driving cars to systems that guide medical care and treatment could bring major benefits, including increased labor productivity, lucrative new markets, and fewer deaths from traffic accidents and medical mistakes. But AI brings worries, too. It will enable employers to automate more tasks and displace workers, and economists predict that some low-wage jobs will be among the first to be eliminated, possibly increasing economic inequality. Letting machines make their own decisions also raises profound ethical, legal, and regulatory questions. Who is responsible if an autonomous car crashes, a piece of software wrecks an investment portfolio, or a sensor switches a stoplight to green at the wrong time? The stakes are even higher on the battlefield, where the military is exploring the possibility of fielding autonomous lethal weapons that would make their own decisions about when to fire.
Advancing forward, a fair amount of research needs to be conducted. From the machine programming and execution standpoint, current research is quite advanced. Just this week, research about a world record was set for NASA surrounding the precision of a satellite with GPS technology. A satellite traveling at a distance of 43,500 miles travels the slowest, whereas at a distance of just under 5 miles from Planet Earth -- the satellite can travel at speeds of 22,000 miles per hour. The precision offered in orbit has allowed very precise 3-dimensional images of different aspects of Earth. This is just one of many reasons why space funding is extremely important. Better precision, better time, new technologies.
Although, with space research comes risk. Over the decades, risk has been studied and worked on by scientists over various scales within various problems. From the small scale - quantum error correction to the enormous scale of space flight - risk remains a crucial area of need to study in greater detail.
6) "We Aren't So Great At Assessing Risk"
Communicating risk to the public without posing great fear is extremely complicated. In many areas of research, communication of results is equated with great fear surrounding the research which leads to reductions in funding and possible cancellations of investigations all together. This highlights the demand to understand how to greater understand risk and the ability to convey risk to the greater public. Two areas seem to be polarized with regard to risk: 'genetic engineering' and 'climate change'. These two areas stand at opposite ends of the spectrum, but are equally important. In the area of 'genetic engineering' - the scare lies in the unknown product and effect toward civilization. Whereas in the other area -- climate science, the scare lies in the incomprehensible. Thinking on the global scale couple with temperatures rising to the point of civilization not being able to occupy the Earth is unfathomable and science fiction -- as far as some are concerned.
Therefore, understanding how to communicate and assess risk is crucial. Science says:
Importance:
Why it matters: Misperception of risk can push a president to overreact to lesser threats and underreact to greater problems, or to embrace policies that may make people feel good but end up being costly and ineffective—or even counterproductive. And how a president communicates with the public about risk can mean the difference between sowing panic and maintaining calm. Talking realistically about risks in advance—as opposed to promising absolute protection—may help prepare people for the inevitable disasters and minimize calls for a policy response that's out of proportion to the actual threat. To do this effectively, the president will have to maintain the public's trust, which is much harder to earn than it is to lose. Understanding the basic psychology of risk can help avoid missteps.
Again, transmitting the unfathomable to the public is complicated. The best hope is that the communicator is a good communicator (patient, humble, and intelligent) with a great audience (patient, humble, and intelligent). Yes, each of us need to do our part to achieve transmission of information (i.e. communication) between one another. Hollywood does this quite well. Science is a work in progress.
Celebrities Elevate STEM and Voting!
Beyonce (the singer) recently promoted the presidential candidate Hillary Clinton along with her husband Jay Z. With good reason. It has taken over a hundred years to achieve equality (and we are still fighting for it) - a work in progress. Having the first female president would be a major step in the right direction. Furthermore, this would reinforce the idea that any woman can go as far as she is willing to work to go. My wife is a scientist and I encourage her to be the best she can be -- break all barriers.
Although, the fields -- Science Technology, Engineering, and Mathematics (STEM) still need more women and minorities engaging in them for careers. Each of us is smart in our own unique way. There are plenty of women and minorities out there to help take science and society to the next advanced level. Having celebrities elevate science is critical. Science usually gets a bad rap. Why? Movie portrayals (such as "The Accountant") portray scientists as strange with disorders but super smart. Not all are strange. I promise.
Recently, the actor Leonardo DiCaprio became the 'Messenger of Peace' for the United Nations -- an honor he holds dearly and sincerely. He speaks about the role in a documentary he recently released investigating the state of global warming and explored all possible solutions. We need more people like him with the unparalleled ability to communicate to a large audience the importance of research and world problems. Here is the video below (just over an hour and a half in length) - but worth watching before or after the election:
I think that I have provided you (the reader) with an eyeball full of information to think about before you hit the voting polls. Get out and vote. Listen to the stars, listen to your family, just be sure to vote. Exercise your place in our democratic society. Yes, your vote does count.
Conclusion ...
Science funding impacts all areas of our lives. If you do not believe me, just try to think of an area which has nothing to do with science. Leave the answer in the comments below and I will try to provide a rebuttal to your answer. There is no rebuttal for the issues that can be solved with science but lack funding. We need all of the help that is possible to educate the public about the importance of science. How do you help?
The most important learning begins at home. What about science do you not understand? Why don't you care? What kind of world are you leaving to your children? These questions do have answers. The unknown is centered around how those answers will surface in the days and years to come. Whether we find out the answers through your vote, your children, your family, the answers will become apparent. Why not educate yourself and others on critical issues for a better society?
I hope that each of you go out and vote tomorrow. Further, I hope that each of you are inspired to educate yourself more after reading this post. Until next time, Have a great day!!!
How do chemists discover new drugs? Obviously, in the laboratory! Is that all one can say about the process? Certainly not. There is a process by which discovery happens. The process may vary depending on which laboratory a chemist works in. Although, the process does not vary so greatly as to eliminate a general procedure or process a drug takes from laboratory to the marketplace. In the blog below, I introduce the general process by which drug discovery proceeds. I want to highlight the word "introduction" since depending on your level of understanding, the process can be described in different ways.
Drug Discovery - General Route
I recently stumbled upon a video made by the 'National Institutes of Allergy and Infectious Diseases' (NIAID) titled "How A Drug Becomes A Drug" which I will show below in a moment. Before I emphasize the importance of viewing the short video (less than 4 minutes), I want to introduce the agency NIAID -- which is a sub-agency of the 'National Institutes of Health'. Here is an excerpt describing the organization taken from the "Wikipedia" page for the "NIAID" below:
The National Institute of Allergy and Infectious Diseases (NIAID) is one of the 27 institutes and centers that make up the National Institutes of Health (NIH), an agency of the United States Department of Health and Human Services (HHS). NIAID's mission is to conduct basic and applied research to better understand, treat, and prevent infectious, immunologic, and allergic diseases.[1]
NIAID has "intramural" (in-house) laboratories in Maryland and Montana, and funds research conducted by scientists at institutions in the United States and throughout the world. NIAID also works closely with partners in academia, industry, government, and non-governmental organizations in multifaceted and multidisciplinary efforts to address emerging health challenges such as the pandemic H1N1/09 virus.
The three main mission areas can be summarized from the "Wikipedia" page as follows:
Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS)
The goals in this area are finding a cure for HIV-infected individuals; developing preventive strategies, including vaccines and treatment as prevention; developing therapeutic strategies for preventing and treating co-infections such as TB and hepatitis C in HIV-infected individuals; and addressing the long-term consequences of HIV treatment.
Biodefense and Emerging Infectious Diseases (BioD)
The goals of this mission area are to better understand how these deliberately emerging (i.e., intentionally caused) and naturally emerging infectious agents cause disease and how the immune system responds to them.
Infectious and Immunologic Diseases (IID)
The goal of this mission area is to understand how aberrant responses of the immune system play a critical role in the development of immune-related disorders such as asthma, allergies, autoimmune diseases, and transplant rejection. This research helps improve the understanding of how the immune system functions when it is healthy or unhealthy and provides the basis for development of new diagnostic tools and interventions for immune-related diseases.
The above mission covers every disease known and unknown. The National Institutes of Health is a huge organization made up of sub-agencies like the NIAID to divide up the mission. As such, the NIAID oversees the funding of drug research to a large extent in order to understand how infectious disease compromise the immune system -- the body at large. Additionally, the NIAID is interested in how drug discovery overcomes infectious diseases that have invaded our body. This includes the research behind the disease at the academic level.
I mentioned above a short video to highlight the general process of drug discovery from the academic level up all the way through to the consumer level -- i.e. the pharmacy. Here is the video below -- which is worth watching:
In the video above, the research is said to start at the basic science level at the university. This is true to an extent. Basic research into disease function and origin typically starts at the university level. Although, I would add that a fair amount of research is done at the industry level too by large drug companies. That research is typically targeted at a specific disease in which the pathway of progression or origin is known. I will explain more about the last sentence shortly.
The drug companies take the research done at the academic (university) level and carry the "small molecule" or "drug target" out to an actual therapeutic that is sold on the shelf of the pharmacy.
Why is this important to know?
Periodically, in the popular news, stories emerge about the over pricing of medication by companies like Turing pharmaceuticals (outrageous pricing) which cause wonder as to why such high prices exist for a given medication. These instances (of over pricing) are minimal compared to the price point needed to make a profit and move onto research more efficient drugs. The point is that research at the companies take time and money along with infrastructure.
The overall benefit of such research could be realized through an "open-access" network of drug targets and therapeutics (proprietary information at the moment) to which other researchers could access at their leisure. Arguments for such a system is that the funding has been provided by a government agency. Whereas arguments against such a system is loss of proprietary information. Tough call. Sorry for the divergence.
The goal of research is to find effective therapeutics (drugs) that treat a large part of the population. Side effects come about as a result of non-target delivery. The drug misses the target of intent or hits additional targets and causes extra problems. This is where the concept of "personalized medicine" comes in and will be discussed in future blog posts. For now, lets focus on designing drugs for a certain disease.
Drug Design 101
In order to design a drug to treat a certain disease or ailment, the pathology of the disease needs to be known. The origin of the disease needs to be known. How did the disease originate in the body?
Is the disease the result of a mutation in the genetic make-up of the person?
Is there a mutation in the DNA of the patient which causes a downstream mutation in the production of proteins?
Is the protein distorted in shape, contour which affects function?
Is the disease caused by an external agent (i.e. virus or bacteria)?
These problems can plague researchers success greatly for years. Luckily, over time, drug companies have built up libraries of "molecules" that serve as "messengers" or "therapeutics" that can hit a specific target that is involved in the process of the disease. Here is an excerpt from the "Wikipedia" page for "drug design" which I think will help you understand the process at the research level in either the university or industry setting:
Drug design, often referred to as rational drug design or simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target.[1] The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques.[2] This type of modeling is sometimes referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design.[2] In addition to small molecules, biopharmaceuticals and especially therapeutic antibodies are an increasingly important class of drugs and computational methods for improving the affinity, selectivity, and stability of these protein-based therapeutics have also been developed.[3]
The phrase "drug design" is to some extent a misnomer. A more accurate term is ligand design (i.e., design of a molecule that will bind tightly to its target).[4] Although design techniques for prediction of binding affinity are reasonably successful, there are many other properties, such as bioavailability, metabolic half-life, side effects, etc., that first must be optimized before a ligand can become a safe and efficacious drug. These other characteristics are often difficult to predict with rational design techniques. Nevertheless, due to high attrition rates, especially during clinical phases of drug development, more attention is being focused early in the drug design process on selecting candidate drugs whose physicochemical properties are predicted to result in fewer complications during development and hence more likely to lead to an approved, marketed drug.[5] Furthermore, in vitro experiments complemented with computation methods are increasingly used in early drug discovery to select compounds with more favorable ADME (absorption, distribution, metabolism, and excretion) and toxicological profiles.[6]
The drug designer is looking for a "biological target" that is involved in either the origin or progression of the disease. As mentioned above, there are two popular processes: computer-aided drug based design and structure-based drug design. Both involve information on the biological target of interest.
What might a biological target look like?
A biological target can vary in definition depending on the nature of the disease. For instance, if the disease involves the distortion or mutation of a protein, then the surface of the protein would be considered the biological target. Specifically, the site of interest for a drug to interact with is referred to as the "active site." Here is an image take from the "Wikipedia" page for "Active Site" to help assist the reader in what that might look like:
Source: Thomas Shafee - Own work, CC
As you can see, the protein appears to be like a "blob" in the image above. The reason for that to emphasize the "binding site" or "catalytic site" not the overall structure which is of little concern to the drug designer. Remember that proteins are made up of amino acids which in turn form large "macromolecules" some of which are referred to as Proteins. I wrote an earlier blog about oligosaacharides are made up of simple sugars.
Starting from the picture above, now, the video below might make sense to watch before we proceed with our discussion of drug design. The video is titled "A Basic Introduction to Drugs, Drug Targets, and Molecular Interactions" and is just over 4 minutes long -- and definitely worth watching.
The video above is more technical than some readers might want to view in order to understand the process. Therefore, we should back off a little on the "technical side" and focus on the "development" side of drug development -- from a simplistic standpoint.
Are you ready to understand drug design from a simple standpoint?
Alright, here we go!
In order to do so, I decided to borrow a few slides from a recent webinar offered online by the American Chemistry Society. The webinar was titled "Crystallography As A Drug Design And Delivery Tool" and was given by Dr. Vincent Stoll of AbbVie -- where he serves as the Director of Structural Biology.
One of the examples that Dr. Stoll used to talk about drug design was binding to the transmembrane molecule B-Cell-Lymphoma-Extra-Large or bcl-xl in the mitochondria. In his talk, he focused on a few binding sites shown in the slide below with a picture:
Specifically, in this case the company wanted to design a drug candidate that would "mimic" the peptide Bak binding. Shown to the right on the slide are the sites or "active sites" that the peptide Bak bind to on the transmembrane molecule bcl-xl. In order to find a drug that will mimic the binding of the peptide, the drug will have to have the ability to bind to multiple sites on the transmembrane molecule.
Fortunately, over time, large drug companies have built up a data base or library of 'molecules' that will bind to similar or exact sites. In the slide below, I show a yellow surface with two molecules hovering above the surface -- slightly bound -- taken from Dr. Stoll's talk:
There is a lot of information on the slide shown above. Let me walk you through the relevant information for drug design 101. First, I mentioned that each drug company kept a library or database with a bunch of 'fragments' that are intended to hit specific targets on biological surfaces. These biological surfaces can be viewed as the picture shown to the right in the slide. They might be a protein surface, or another biological surface of interest to drug manufacturers.
In the case above, the two molecules shown on the yellow surface -- one is a brown color while the other is a green color. The different color is to illustrate that the molecules are fragments designed to hit a specific type of target or active site on a biological surface. In this case, the biological surface is the transmembrane molecule bcl-xl.
Once the fragments have been identified that will occupy and hit the desired targets or active sites, then the challenge is to link the fragments together by chemistry. This step in of itself is often challenging and does not guarantee that the newly formed molecule (of two fragments with a linker molecule) will work. Therefore, in the picture above, there are possible linker molecules that exist within the pharmaceutical database that have been shown to work in other cases.
After linking the two fragments together, the next step is to verify by spectroscopy that the total or linked molecule worked.
How is this accomplished?
In the lab, the substrate or biological surface will have a drop of the linked molecule injected onto the surface. Then the surface which should have the drug bound to the active sites will be investigated using a spectroscopic technique like Nuclear Magnetic Resonance Spectroscopy. Upon confirmation, a number will be reported as shown on the slide that indicates the binding affinity of the molecule onto the surface:
In the slide above, there are a couple of numbers reported that make sense to drug designers but probably not the reader -- you. Do not worry. Over time (through other blog posts) you will come to understand their meaning. What is important to understand at this point is that after linking molecular fragments together, an experiment occurs to understand if the drug or linked molecule is as effective as the fragments are alone.
Furthermore, the pharmaceutical company might understand the chemistry of the active site to a large extent and further modify the linked molecules to make a more "potent" drug or linked molecule. On the slide below, I show from Dr. Stoll's talk such a modification:
Again, the overall take home message is that the molecular modification done to the linked molecule has some effect.
Is that effect better or worse?
Can there be a further modification to the linked molecule or now drug to enhance the ability to mimic the peptide binding?
Who knows. That is why research is continuously pushed forward and costs money to find out.
Conclusion...
In the above paragraphs, my intention was to introduce briefly the process of drug design. As we speak though, changes are being made to parts of the process. Outsourcing of linker molecules is occurring as are mergers and acquisitions of large companies by even larger pharmaceutical companies. Which potentially means that the shared database or libraries of available drug targets is growing. The process is dynamic but slow at the same time.
Discovering the mechanisms of disease and cures as a result is the dream of every drug designer. Progress is unfortunately slowed down by the trial and error process. Research takes time and money to complete. Furthermore, improvements to existing drugs take time. I will leave you with another short video about the progression of the medical research field:
There are many reasons why science outreach is critical in our world today. In the past, the importance has been present. Although, with the explosion of the internet and the devices along with the climate changes that are being seen, science outreach might be at an all time high. Action needs to be taken with the help of a much-needed educated STEM (Science, Technology, Engineering, and Math) population rising up through the educational ranks as we speak. With that in mind, we still have a long way to go. Below are two examples of why we need to communicate science more effectively. These two examples have relevance to the spread of the 'Zika' virus occurring in the United States today.
The adult form of attention-deficit/hyperactivity disorder has a prevalence of up to 5% and is the most severe long-term outcome of this common disorder. Family studies in clinical samples as well as twin studies suggest a familial liability and consequently different genes were investigated in association studies. Pharmacotherapy with methylphenidate (MPH) seems to be the first-line treatment of choice in adults with attention-deficit hyperactive disorder (ADHD) and some studies were conducted on the genes influencing the response to this drug. Finally some peripheral biomarkers were identified in ADHD adult patients. We believe this work is the first systematic review and meta-analysis of candidate gene association studies, pharmacogenetic and biochemical (metabolomics) studies performed in adults with ADHD to identify potential genetic, predictive and peripheral markers linked specifically to ADHD in adults. After screening 5129 records, we selected 87 studies of which 61 were available for candidate gene association studies, 5 for pharmacogenetics and 21 for biochemical studies. Of these, 15 genetic, 2 pharmacogenetic and 6 biochemical studies were included in the meta-analyses. We obtained an association between adult ADHD and the gene BAIAP2 (brain-specific angiogenesis inhibitor 1-associated protein 2), even after Bonferroni correction, with any heterogeneity in effect size and no publication bias. If we did not apply the Bonferroni correction, a trend was found for the carriers allele 9R of dopamine transporter SLC6A3 40 bp variable tandem repeat polymorphism (VNTR) and for 6/6 homozygotes of SLC6A3 30 bp VNTR. Negative results were obtained for the 9-6 haplotype, the dopamine receptor DRD4 48 bp VNTR, and the enzyme COMT SNP rs4680. Concerning pharmacogenetic studies, no association was found for the SLC6A3 40 bp and response to MPH with only two studies selected. For the metabolomics studies, no differences between ADHD adults and controls were found for salivary cortisol, whereas lower serum docosahexaenoic acid (DHA) levels were found in ADHD adults. This last association was significant even after Bonferroni correction and in absence of heterogeneity. Other polyunsaturated fatty acids (PUFAs) such as AA (arachidonic acid), EPA (eicosapentaenoic acid) and DyLA (dihomogammalinolenic acid) levels were not different between patients and controls. No publication biases were observed for these markers. Genes linked to dopaminergic, serotoninergic and noradrenergic signaling, metabolism (DBH, TPH1, TPH2, DDC, MAOA, MAOB, BCHE and TH), neurodevelopment (BDNF and others), the SNARE system and other forty genes/proteins related to different pathways were not meta-analyzed due to insufficient data. In conclusion, we found that there were not enough genetic, pharmacogenetic and biochemical studies of ADHD in adults and that more investigations are needed. Moreover we confirmed a significant role of BAIAP2 and DHA in the etiology of ADHD exclusively in adults. Future research should be focused on the replication of these findings and to assess their specificity for ADHD.
Clozapine is a unique compound that is particularly effective for treatment-resistant schizophrenia (TRS). The use of clozapine is limited, however, due to the 0.8% risk of agranulocytosis,1 which necessitates a strict monitoring of neutrophil counts to detect early neutropenia and prevent progression to agranulocytosis.
First and foremost, I must admit that one of these is an article -- specifically a 'review' while the other is a "news and commentary" -- which means that the formats are quite different. Still, the abstracts are extremely different. Why?
What about if I show you an abstract from a different journal?
Fluorescence microscopy is an essential tool for the exploration of cell growth, division, transcription and translation in eukaryotes and prokaryotes alike. Despite the rapid development of techniques to study bacteria, the size of these organisms (1–10 μm) and their robust and largely impenetrable cell envelope present major challenges in imaging experiments. Fusion-based strategies, such as attachment of the protein of interest to a fluorescent protein or epitope tag, are by far the most common means for examining protein localization and expression in prokaryotes. While valuable, the use of genetically encoded tags can result in mislocalization or altered activity of the desired protein, does not provide a readout of the catalytic state of enzymes and cannot enable visualization of many other important cellular components, such as peptidoglycan, lipids, nucleic acids or glycans. Here, we highlight the use of biomolecule-specific small-molecule probes for imaging in bacteria.
I think that these four abstracts illustrate the point. Right about now, the reader (you) might be thinking the following regarding the three abstracts above:
What do those abstracts mean?
What science is being done?
Why are the words and sentences so complicated?
Am I right? Were you thinking any of the three questions above. I know that I would be -- especially, if I had very little of a science background to serve as a starting point when reading them.
Science Communication Should Be Simple
In a recent TED talk by Tyler DeWitt titled "Hey Science teachers -- Make It Fun" the problem with communicating science is discussed in a simple and elegant manner. Tyler is a graduate student at the MIT.
Below are two avenues by which a virus can infect a cell. Given that the 'Zika' virus is spreading among the United States population, the stories below are completely relevant to current stories in the popular news press. I paraphrased the speech by Tyler DeWitt and used 'still images' from his TED talk below.
Story #1 goes as follows:
The story starts off with a happy little bacterium who is occupying a medium -- say your stomach. Over time the bacterium starts to not feel well as depicted in the slide below:
While pondering over the many reasons which might lead to a cause for the feeling, he looks down to notice the culprit -- a virus who is emerging from his body as shown below:
And with time, the situation is getting very worse while the viruses keep poring out from his body as pictured below:
Now there are two different viewpoints to describe the situation that is occurring. From the standpoint of the bacterium, the situation is worsening exponentially with time hosting an army of viruses. While, from the viewpoint of the virus, each little virus is thinking the following:
"We rock!" From the viruses viewpoint, the first virus managed to get into the host and successfully propagate -- evolve. In order to complete the mission of evolving a number of complex steps had to occur for survival to happen. Lets review them from the standpoint of the virus.
First, the virus had to slip a copy of its DNA into the bacterium as shown below:
In order for the virus to proceed to copy its DNA, the virus had to destroy the DNA of the bacterium as shown below:
After gaining control of the bacterium by destroying the bacterial DNA, the bacterium will not propagate (copy) only the DNA of the virus. The bacterium is serving as the host factory producing multiple copies of the virus as shown below:
The bacterium will continue to make copies of the virus since the 'blue print' has been changed from the bacterium's DNA to the viruses DNA. Manufacturing the virus will not stop until the bacterium bursts due to holding 'too many copies' of the virus as shown below:
The above steps illustrate one avenue by which viruses "infect" bacteria to takeover as a host.
Is there an alternate way for the virus to invade the bacteria and take over to use as a host?
Yes! There is -- which is outlined below:
The virus starts out as a "secret agent" as shown below:
With the ability to secretly insert its DNA into the DNA of the bacterium as shown. The insertion process has no damaging effect like the first avenue of replication did in the example above. The DNA appears to be normal inside the bacterium as shown below:
As mentioned, the secret agent is able to insert his DNA into the bacterium who is unaware of the insertion and lives life normally. Over time, the bacterium reproduces/replicates itself and makes many copies of the "inserted DNA" which has been silent as shown below:
The silent/inactive inserted DNA is not recognizable to the bacterium until a "signal" is sent among the bacterium and the virus DNA pieces pop out and take control over all of the bacterium -- also shown above. After the virus DNA has taken over the bacterium, the replication process of the virus occurs as shown below:
The bacterium have been turned into virus making factories. Extended copies of the virus are produced in each bacterium until the bacterium bursts and releases all of the copies of the viruses as shown below:
And with that, the viruses have won by dominating and replicating through the bacterium. Shown in the slides (which are still pictures taken from Tyler Dewitt's TED talk) are two different stories.
These two stories represent the two pathways by which a virus can attack cells!!!!
On the left hand-side of the picture above is the first pathway (the lytic pathway) -- where the viruses insert themselves and take control over the cell (bacterium) immediately. Whereas, in the second pathway (lysogenic pathway), the virus inserts their DNA and that DNA stays dormant until a signal is sent.
Was that hard to explain and comprehend or what? All science should be that simple - right?
Virtually, everyone who has graduated high school has been exposed to these two pathways in their biology class. The difference is in the presentation of the material. First, the presentation that each of us experienced was most likely more serious than the cartoon story above and certainly did not use cartoon characters like those presented above.
Why not?
The field of science suffers from a "seriousness" problem. Which is to say, scientists, and the way that science is portrayed is too serious. Science is meant to be fun too. You can have fun doing science. I do it every day!
In the next section before concluding, I will tie together the first two sections. Namely, the seriousness of science -- which is a downfall and -- secondly, the language that is used. Language seems to be the number one 'turn off' for students entering various fields of science.
Science Should Be Simplified!
Many of scientists that I know believe that making science simple is simply impossible. Furthermore, the belief is centered around the idea that "dumbing down" science devalues the field. This belief could not be further from the truth. Let me explain why with more slides from Tyler DeWitt's TED talk above to illustrate my point. There is no need to recreate the wheel.
In Tyler's TED talk, the two stories about the two possible avenues by which a virus can infect a cell were told. And he used cartoons and very creative imagery along with simple words right. Everything he said was easily digestible -- at least for me.
Textbooks often complicate explanations of science as do professional publications (i.e. journal articles -- as shown above). Why do these publications use such complicated language to illustrate a point? Because, that is the way the system is designed to be -- which needs to change.
In the example given in the TED talk above, the simple explanation might be something like: Viruses make copies of themselves by slipping their DNA into a bacterium. How would this look in the formal language inside of a textbook? Here is an example -- a slide from the TED talk above with the informal explanation above and the formal explanation below:
Wow. The two descriptions above look completely different. The first (above) is one that I can relate to and would love to read. Whereas the second (below) is completely a 'turn off' and might very well put me to sleep. Here is the divergence of the majority of people's attention. When the practitioners of science transition from the top to the bottom description -- a large percentage of the audience drops off too.
Why does this transition occur in descriptions?
Because, in the simple description, not every word is accurate. After going through and editing the statement for accuracy -- 100% accuracy, the statement would look like the one shown below with corrections:
And this begs the question of science: can we describe science with slightly inaccurate descriptions? I would argue that the answer is yes. Why? Because, a majority of the undergraduate education uses "toy examples" to illustrate the concepts and theories. For example, in the undergraduate curriculum students learn about "ideal gases" and the ideal gas law. The assumption is that gas molecules are "point particles" and do not "interact." What does this mean?
Throughout the undergraduate degree process -- at least in Chemistry -- students are running calculations using the "ideal gas equation" to arrive at relations between chemical compounds. Real gases do not behave ideally and computational coefficients are added to equations to take into account the 'non-linear' behavior. The non-linear behavior arises when gas molecules react with one another or during the collision -- the molecules temporarily "stick together." These types of properties are extremely complex and cannot be simulated with the limited (and great) computational power that society possesses today. See? This is why simplification can work.
Conclusion...Science Should Be Made Simple!
In order to capture the interests of the widest audience for science, the work has to be made simple. A few professors worry about the simplification process attracting others to science. Who cares if that happens? Would we not want the best minds tackling the problems of society? Yes, we would. Science is meant to be fun -- not just serious without.
With captivating and creative descriptions by enthusiastic scientists like Tyler DeWitt, we have a great opportunity to engage a wider audience into science. Although, if other scientists don't sign onto this line of thinking, the new avenue will run dry and we will be stuck with the same old 'broken' method of communicating science.
The world has changed over the decades. Why shouldn't the communication evolve too to attract the widest array of audience members? Technology is providing a whole new range of possibilities for the classroom to teach the message of science. Why would we want to stick with the same broken method that has accomplished enough for the past few decades -- but is currently in need of an overhaul.
One of the overarching goals of this blog is to simplify science for everyone. If you have an idea that you would like explained on the blog site, please leave a comment. As you can see by reading the first few abstracts (descriptions of science studies in section one), we have a long way to go. Lets all band together and demand a change of our system to move toward a more creative and captivating educational system for all disciplines. Until next time, Have a great day.
