No link found between gender and performance in physics courses

Dew et al. Gendered performance differences in introductory physics: A study from a large land-grant university. Physical Review Physics Education Research, February 2021.

A new study discredits the stereotype that male students perform better than female students in science, more specifically in physics. Researchers from Texas A&M University analyzed the grades of more than 10,000 students enrolled in four introductory physics courses over a decade-long period and found no evidence that male students consistently outperformed female students in these courses. Their analyses showed that exam success and final grades were largely independent of student gender. In addition to multiple statistical analyses of course-level data, researchers distributed questionnaires to students to see how the results aligned with student perceptions. Interestingly, student responses showed that female students had lower perceptions of their performance than their male classmates. The only class where female students perceived their performance as equal to their male classmates was algebra-based mechanics, in which females outperformed males. This study can be another step in breaking up the preconceived notion of a societal bias based on gender in physics. Moreover, it may help to fight against gender stereotypes that negatively impact so many female students and harm women in STEM (science, technology, engineering, and math) related courses.  All students should have equal opportunities and chances for success.

Air pollution may cause chronic heart disease in children

Prunicki et al. Air pollution exposure is linked with methylation of immunoregulatory genes, altered immune cell profiles, and increased blood pressure in children. Scientific Reports, February 2021.

Exposure to air pollution has been linked to various diseases in adults, but no study had yet extensively investigated its long-term impacts on children. A new study suggests that children exposed to air pollution, such as wildfire smoke and car exhaust, for as little as one day may become more prone to heart disease in adulthood. Researchers investigated air pollution’s effects at the single-cell level in a group of 221 school-aged children (6–8 years). They focused on Fresno, California, a city with some of the country’s highest air pollution levels due to industrial agriculture and wildfires. Using a combination of continuous daily pollutant concentrations measured at central air monitoring stations in Fresno, daily concentrations from periodic spatial sampling, and meteorological and geophysical data, the research team estimated average air pollution exposures for 1 day, 1 week, and 1, 3, 6, and 12 months prior to each participant visit. When combined with health and demographics questionnaires, blood pressure readings, and blood samples, the data showed that polluted air can alter gene regulation in cardiovascular and immune systems of children in a way that can impact long-term health. In particular, exposure to fine particles, carbon monoxide, and ozone over time is linked to increased DNA methylation, a form of epigenetic alteration of DNA molecules that can change their activity without changing their sequence. This inheritable change in gene expression may be passed down to future generations. Researchers also found that air pollution exposure leads to an increase in monocytes, white blood cells that play a key role in the buildup of plaques in arteries and could possibly predispose children to heart disease in adulthood. According to the World Health Organization, air pollution is one of the leading causes of death in children. Children typically breath faster than adults, making them more susceptible to health problems by rapidly inhaling low quality air. With air quality deteriorating globally, we all need to be more careful and conscientious to protect kids from air pollution.

Sleep memories

Clawson et al. Causal role for sleep-dependent reactivation of learning-activated sensory ensembles for fear memory consolidation. Nature Communications, February 2021.

Sleep is very critical for brain functions. Inadequate sleep can impair our abilities to concentrate, think clearly, and process memories. Past studies showed that regions of the brain that are highly active during intensive learning surprisingly show more activity during sleep. However, which biological purpose this “reactivation” of memories during sleep serves remains unclear. To address this question, researchers studied how memories associated with a specific sensory event are formed and stored in mice. They specifically examined how a fearful memory formed in relation to a particular visual stimulus in the brain. By focusing on a specific set of neurons in the primary visual cortex, researchers were able to create a visual memory test. When they ran this test in various conditions, the mice with regular sleep learned to fear the specific stimuli that had been paired with a foot shock. However, the mice with disrupted sleep had no fear association with the visual stimulus. These sleep-deprived mice seemed to process the fact that they should be afraid, but there may have been a lost connection regarding what they were supposed to be afraid of. These observations suggest that sleep-associated reactivation of the neurons encoding that stimulus is required for them to make an accurate fear association with a visual stimulus. These findings have important implications for anxiety and post-traumatic stress disorders. In the absence of sleep, the brain seems to manage processing the fact that we should experience emotions, but we may be unable to link those emotions to exact causes accurately. That specification process may be one that goes awry with such anxiety-related disorders.

In 1981, scientists discovered ways to derive embryonic stem cells from early mouse embryos. Since then, they have been the subject of intense scrutiny, controversy, and advocacy.

They are unique cells, which can be derived from human embryos and can be differentiated into virtually any kind of different cells. In humans, there are about 200 different types of cells including bone, muscle, and nerve cells, and within these cells there are about 20 different types of structures or organelles. Essentially, stem cells can be derived from human embryos, and with the right enzymes, can be stimulated. For instance, bone cells can originate from osteocyte cells, or liver tissues can come from hepatocytes.

Stem cell types and research

There are three types of stem cells:

• Embryonic stem cells
• Adult stem cells
• Induced Pluripotent Stem Cells (iPSC)

Embryonic stem cells are derived from human embryos. Adult stem cells are undifferentiated cells (meaning “clean slates” with the potential to change into another cell variant) found throughout the body after development; they multiply via cell division to replenish dying cells and regenerate damaged tissues. Induced Pluripotent Stem Cells (iPSC), which were discovered in 2006, are derived from skin or blood cells that have been reprogrammed back into an embryonic-like pluripotent state that enables the development of an unlimited source of any type of human cell needed for therapeutic purposes. While these types of cells are interesting and certainly worthy of research, this article will focus on embryonic stem cells as they are consistently the most well-known and discussed type by the general public.

Embryonic stem cells are potent and often sought after due to their abilities to proliferate without limit and contribute to any cell type. However, with great power comes great responsibility and stem cells are no exception. Poorly processed cells have been documented to mutate into cancerous tumors that can wreak havoc upon people’s bodies. Bearing this in mind, scientists also do not believe that this should derail stem cell therapies considering that there are DNA tests to check if stem cells will turn out to be problematic or not.

The stem cell project is regularly a subject of ethical debate in both the academic and public sectors. Most embryonic stem cells are derived from embryos that develop from eggs that have been fertilized in vitro—in an in vitro fertilization clinic—and then donated for research purposes with the informed consent of the donors. People willingly donate their eggs for this research, and this process does not constitute child-killing since the eggs are near their zygote phase, not a whole mature embryo. Scientists obtain those types of cells from an embryo which has not yet completed its formation to develop into a human being. Researchers then use these cells for various treatment and research purposes. It is important to stress that they are not derived from eggs fertilized in a woman’s body and that they are produced in a plastic laboratory culture via clinics in vitro.

Some examples of embryonic stem cells being used in research include the following:

1. UCLA stem cell gene therapy cures bubble baby disease

Researchers at UCLA (University of California, Los Angeles) have developed a cure for babies born with Bubble Baby Disease, a rare and life-threatening condition that can be fatal within the first year of life, by using stem cells from multiple patients and gene therapy to correct the genetic mutation of these patients.

2. Asterias biotherapeutics restores some independence to those suffering from paralysis caused by spinal cord injuries

Asterias Biotherapeutics spent much of 2016-2017 developing a stem cell therapy to restore upper body motor function to quadriplegic spinal cord injury victims. Through lengthy and rigorous testing in human clinical trials, the therapy was found to be safe for use in people with all patients treated reporting at least some improvements. Asterias is now expanding its clinical trials to include patients with sub-acute injuries.

3. UC Irvine scientists engineer stem cells to destroy cancer

In a study conducted by University of California, Irvine researchers, a stem cell-based technique was devised to find and destroy breast cancer cells that had already metastasized. The cells “feel” the stiffness of the surrounding tissues and destroy the cancer-causing cells.

Embryonic stem cells can remain undifferentiated when they are grown in a well taken care of culture that is under stable conditions. Problems primarily begin to arise if cells are allowed to clump together to form embryoid bodies in which they begin to differentiate, or change into more specific cell variants, spontaneously. Although spontaneous differentiation is a good indication that shows which cultures of embryonic stem cells are healthy, the process is uncontrolled and, therefore, an inefficient strategy to produce cultures of specific cell types.

The ability of stem cells being able to differentiate into hundreds of other types of cells continues to amaze scientists as this is no small discovery. Researchers believe that the possibilities with stem cells are near endless, especially in regard to “regenerative medicine,” the process of “replacing, engineering, or regenerating human cells, tissues, or organs to restore or establish a new function.” It is even believed that even whole organs could be synthetically grown by using them.” Additionally, stem cells have the potential to rebuild healthy tissues, help people with heart disease, diabetes, ALS, Alzheimer’s disease, liver disease, Parkinson’s disease, cancer, and many more illnesses.

In a stem cell transplant, embryonic stem cells are first specialized into the necessary adult cell type. Then, those mature cells replace tissue that is damaged by a disease or injury. This type of treatment could be used to:

• Replace neurons damaged by spinal cord injury, a stroke, Alzheimer’s disease, Parkinson’s disease, or other neurological problems.
• Produce insulin that could treat people with diabetes and heart muscle cells that could repair damage after a heart attack
• Replace virtually any tissue or organ that is injured or diseased.

Sometimes scientists use stem cells as a drug. For example, it is possible to inject a stem cell into joints to reduce swelling and pain, or in order to promote the healing processes of soft tissues. Stem cell therapy is performed by injecting the patient’s own stem cells to stimulate the body to repair and replace damaged tissue in any joint or soft tissue structures – such as knees, shoulders, hips, wrists, ankles, elbows, tendons, ligaments and non-healing bone fractures. Cellular Dynamics, a large biotechnical company, sells human heart cells called cardiomyocytes that are derived from induced pluripotent stem (IPS) cells. Pharmaceutical companies are adapting to this new and innovative trend on a day-to-day basis. Stem cells can also be used to test the quality and safety of investigational drugs by testing them on stem cells that have been transformed into tissue-specific cells. Researchers are able to monitor the side effects before exposing the drug to a patient and thus have a greater expectancy of how their body may respond to the drug. This allows us to test for cures for potentially fatal diseases in ways that would otherwise be risky or unethical.

With all of the aforementioned advantages, stem cells are a fairly new, but exceptionally promising, research area. For some people, it may seem unethical to use stem cells on the grounds that extracting stem cells damages the blastocyst, which is a structure formed in the early development of mammals, more specifically the sixth or the eighth day of the development of an embryo. In 2006, President Bush vetoed the Stem Cell Research Enhancement Act stating that the federal government should not support “the taking of innocent human life.” Although stem cells are very promising for science and can open new doors to many new treatments in the medical field, it looks like there are still differences of opinion on their ethical use. This is perhaps because there is need for more convincing evidence or people are not informed accurately on the details of this research area.

References

• https://stemcells.nih.gov/info/Regenerative_Medicine/2006Chapter1.htm
• https://www.healthline.com/health/stem-cell-research
• https://www.statnews.com/2017/04/26/stem-cells-cancer-mutations/
• https://plato.stanford.edu/entries/stem-cells/
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398703/
• https://www.mayoclinic.org/documents/the-amazing-stem-cell/doc-20249792
• https://www.unmc.edu/stemcells/educational-resources/history.html
• https://www.cirm.ca.gov/patients/power-stem-cells
• https://www.nature.com/news/stem-cells-take-root-in-drug-development-1.10713
• https://hsci.harvard.edu/examining-ethics-embryonic-stem-cell-research#:~:text=Opponents%20argue%20that%20the%20research,taking%20of%20innocent%20human%20life.%E2%80%9D

It is uncommon that we observe the background details of a well-produced film or notice the subtle masterpieces behind a state-of-the-art play. Aside from those that are very observant, these elements usually only come into view when production experiences a horrible mishap, perhaps if an actor’s costume is ruined or they forget their lines. The same can be said for the quiet mechanisms and systems, which our lives are dependent on, on a daily basis, namely our organs and their exceptionally complex makeup that we often take for granted. This issue aims to take a deep look at some of the processes that affect us every day that we usually do not think about.

Modern medicine is perhaps one of the greatest blessings of our time, as synthetic drugs are able to cure complex diseases in previously unknown ways. These medicines undergo intense research, testing, and scrutiny before being released to the general public. We quickly rush to the doctor’s office and pop a few pills when we feel ill, yet we rarely ponder over highly exhausting and costly process of developing these drugs.

Our hearts never rest from the moment we are born to the day we die. This organ we don’t usually think about pumps onwards multiple times per minute and allows us to perform our daily functions. In her piece in this issue, Ceyda Sablak reminds us how delicate the anatomy of this organ is and why we should maintain a healthy, balanced life of physical and spiritual activity, as many spiritual masters have seen a connection between our biological heart and our spiritual well-being.

Stem cell research has been a common point of discussion, debate, and controversy in the past few decades. Researchers argue that they possess an almost endless number of possibilities while advocates argue that they are derived in an unethical manner. The science behind them is fascinating, and the potential that they possess is undoubtedly inspiring.

Lastly, it turns out that our tears are integral to keeping our eyes healthy and itch-free. A lack of tears can result in a multitude of annoying and harmful disorders that can severely affect a person’s life. Searches have been underway to find the perfect “alternative tear” for those that suffer from tear related disorders. Who would have thought that something so simple contributes so much to our normal happiness and peace?

The single biggest problem regarding mathematics and the sciences is motivating younger students to study them.

While the United States excels at welcoming people from all over the world to travel to the U.S. and study science and math, the number of aspiring mathematicians at universities is decreasing. About only 2% of all students in America that pursue a bachelor’s degree are in the fields of mathematics or other physical sciences. On top of that, roughly 48% of students studying a STEM field in a bachelor’s program, and 69% of students pursuing an associate’s degree, changed majors or exited college before earning their degree [1]. One possible explanation for this is the reputation that math has for being boring, uninteresting, and complicated. However, there could hardly be a better time to become a mathematician.

I was watching a documentary about deserts with my 2 year old. At first, she found the documentary to be boring because the desert appeared to be bland and void of life. Then, the screen started showing the lively and colorful aspects of a desert including its oases, various cacti, and small creatures. She was shocked that the arid desert could possess so much color, life, and intrigue. It reminded me of my feelings towards mathematics. For some people, mathematics seems like a dry and dull subject that makes little sense. However, it too becomes full of life and color once one looks in the right places and from the correct perspective.

Ten years ago, the Wall Street Journal ranked jobs based upon a number of parameters such as salary, freedom, the possibility of promotion, and ease of employment. It may surprise you to find out that being a mathematician was ranked as the number one job in the world! [2] Career Cast, a company that started as a spin-off for this kind of ranking in 1988, also ranked mathematician as the number one job in 2014 [3].

In job advertisements, the definition of a mathematician is somebody who applies mathematical theories and formulas to teach or solve problems in a business, educational, or industrial setting. In other words, a mathematician is someone who insists on solving problems, which is what mathematics was invented for. However, a crucial point is missing from this description. There are mathematicians who not only teach or apply mathematics but do math, generate math, and change math.

If a mathematician is one of the best jobs in the world, how many mathematicians are there around the world? Thankfully, it is in the hundreds of thousands: almost 250,000, and it is growing every year, particularly in India and China [4]. These countries encourage their children to participate in STEM fields from a young age and place a very high emphasis upon education that can help foster a love for STEM careers at a young age.

Although mathematics is the science in which theorems last for a long time, it is also a field that is being renewed constantly. There are not many other subjects in which knowledge can last thousands of years and always remain both correct and relevant. For instance, the theorems of Euclid, a Greek mathematician who lived in the third century BC, are still accurate today. If we look at the modern applications of computer science and mathematics we see that people are still applying the contributions of Laplace about the central limit theorem, using the contributions of Shannon in sampling, and applying Fourier’s ideas about signal analysis and signal processing. Paradoxically, mathematics is ancient and contemporary at the same time.

In 2014, Emmanuel Candes of Stanford University gave a short speech about how he had collaborated with medical doctors and mathematicians, and used Fourier’s ideas in analysis and data processing, to drastically reduce the time needed to develop a scan [5]. His machine was a significant evolution for the medical field. In experiments, it was shown that to reconstruct images with the best accuracy, they need to have only 2% of the Fourier transform. Candes managed to reduce this time by a factor of eight by knowing only a very small portion of the Fourier transform. Netflix also uses this technology for reconstructing missing information and predicting the preferences of users for movies.

However, the life of a mathematician is not always full of success. The field is full of uncertainty, intense problem solving that can often take weeks or even months, and waiting. Most of a mathematician’s time as a researcher is spent in failure. That is an objective fact. A common motto is, “Every day is a failure. This is our life.” But when we look back on the amount of time that is spent solving these problems, everything pays off. Every year, the number of new theorems added in mathematics runs into the thousands. Failures are not actually failures, but merely bumps along the path of progress.

Another common problem that befalls mathematicians is that they will be expected to perfectly predict what will happen should their discovery work as intended. This is especially true of work done under the auspices of government agencies, since they will often not grant money without a very clear path towards a desired outcome. Things do not always go as planned, and thus it can be challenging to argue that a desired result will occur 100% of the time.

Despite these drawbacks, one of the most exciting aspects of mathematics is the potential to discover something revolutionary and groundbreaking. History has shown that the ideas and discoveries of one individual can make a tremendous difference in the world. By encouraging and enabling more and more students to study math and science, we thus increase the odds that more discoveries, be they groundbreaking or not, will continue to be made in the future.

Alan Turing was a mathematician who had an outsized impact on human history. He was instrumental in cracking the secret codes that were used by the Nazis during the Second World War. Some have argued that World War II would have lasted at least two more years without Turing’s intervention. In particular, the Normandy operation would have been impossible. What was Turing’s motivation? It was not patriotism, honor, or a strong duty to his country. It was simple: his main motivation was solving riddles and difficult problems. He lived for the thrill of solving his next big challenge.

Paul Erdos, a Hungarian, was the most productive mathematician of the 20th century. Erdos had no home, no car, no bank account, and no salary. He lived with just one suitcase and his ideas. He worked on theorems his entire life. When he got some money from some reward, he would always use part of it to put a reward on another theorem.

Leo Szilard was another revolutionary mathematician. He was the first person to understand the concept of chain reactions between atoms. His inspiration came from a public lecture, in which famed physicist Ernest Rutherford said, “It would be moonshine talking if you are willing to extract energy from the atom.” Rutherford acknowledged that energy existed within atoms but thought it was impossible to do anything with it. Szilard felt that Rutherford was wrong and decided to prove it. He worked and thought for days. And one day, while he was crossing a street in London, he was struck with an idea about the principle of chain reaction and exponential growth of atomic energy. This lead to him eventually meeting with Albert Einstein and the subsequent development of the Manhattan Project.

Steps in developing ideas

But how do scientists find those perfect ideas? What are the steps? Henri Poincare gives us some hints about how the ideas were coming to him. Poincare, who was always considered a genius, experienced many discoveries after working very hard on the problem and he had a lot of failures. He said: “Disgusted from my failure, I went to spend a few days near the sea thinking anything else. And one day, while walking on the cliff, the idea came to me. And as before, it was very brief, sudden, with immediate certainty, that arithmetic transforms of indefinite ternary quadratic forms are identical to those of non-Euclidean geometry.”

So, under which circumstances does a big idea come? In popular culture, we have those myths like Newton saw an apple falling down and changed the world. But in real life, it’s not the way it happens. For Poincare’s example, the cliff has nothing to do with quadratic forms. Poincare was saying that he worked very hard and then he decided to rest a little bit, and finally, he had the enlightening moment. What is important here is if the brain had not been prepared by hard work, the illuminating idea wouldn’t have struck.

So what is the process of discovery?

Of course, a publication will be the last step for the discovery of an idea. Because publication means that the idea is out and going to be seen and read by the world. But before that, we have many steps or ingredients which make our idea stand up on its feet.

1. Fecundation

The first step is fecundation. In other words, conversations and discussions you have with your colleagues. Your interaction has a potential to bring about a new phase, a new idea out of different projects. It may take months or years to decide what you want to prove.

2. Documentation

Documentation is built upon previous research and insights. We may need to document things from several centuries ago or from recent times. Nowadays, all information is stored in computers and the internet, which makes this step easier than before.

3. Motivation

Motivation is the most important ingredient when we pursue a discovery. Psychologists believe that childhood experiences play a big role. For instance, both Szilard and Turing’s lives were strongly influenced by a book they read before they found their ideas. In the case of Turing, the book Natural Wonders Every Child Should Know was his inspiration. When I was a child, I watched “Donald in Mathmagic Land” and thought it was fascinating. It might have played a big role in my choice to become a mathematician.

4. Ecosystem

A discovery or an idea never arrives on its own. A scientist is never alone and there is a whole ecosystem around them. For instance, at one point in history, Persepolis was the most innovative city in the world. Then it was Paris, and then Budapest. Today, we have the well-known Silicon Valley.

If you are working in a lab, you need to have an atmosphere where people can meet, discuss, and be creative. A good idea comes from teamwork.

5. Constraints

The next ingredient that you need for a good idea is constraints. Without constraints, discovering new ideas is not as likely as when there are. Rigorous findings come about mostly with constraints. One of the most famous problems in mathematics is the Riemann hypothesis, which was tested in thousands of experiments. After those experiments, the proof was only a set of logical rules with constraints. Constraints usually help generate authentic results and artistic quality as in rhyming poems.

6. Intuition

Intuition usually comes together with hard work, yet it is not easy to understand its process.

In addition to these six ingredients, whether one has good fortune or not also plays an important role. It is human condition that things may not come out as we like although we might have done everything necessary.

Henri Poincare says, “Thought is only a flash between two long nights, but this flash is everything.” Yet, a big idea might take years of work. Still, even after working so hard, our knowledge is like a tiny island in an ocean of unknown. We know almost nothing, but this is such a precious nothing, because that that knowledge came out of the richness of the thought of many people and their efforts. There are still so many ideas just waiting for us to discover them.

Mathematics, like many scientific fields, is an infinite universe with an infinite amount of problems waiting to be discovered and solved. Their applications within our world are endless, and the possibilities to use these results to create real change in our world are also endless. One tends to ask, is math a stand-alone, abstract concept while its vast horizons of knowledge explains the intricacies of our universe, or does it imply an infinitely bigger wisdom from which this abstract knowledge rises from and that relates to our existence? We must continue to motivate students to study math so that they may fall in love with it and continue to develop humanity.

References

1. United States, Congress, Chen, Xianglei, and Matthew Soldner. “STEM Attrition: College Students’ Paths Into and Out of STEM Fields.” STEM Attrition: College Students’ Paths Into and Out of STEM Fields, National Center for Education Statistics, Nov. 2013. nces.ed.gov/pubs2014/2014001rev.pdf.
2. Needleman, Sarah E. “Doing the Math to Find the Good Jobs.” The Wall Street Journal, Dow Jones & Company, 7 Jan. 2009, www.wsj.com/articles/SB123119236117055127.
3. “Jobs Rated 2014: Ranking 200 Jobs from Best To Worst.” CareerCast.com, CareerCast.com, 9 Mar. 2017, www.careercast.com/jobs-rated/jobs-rated-2014-ranking-200-jobs-best-worst.
4. “Mathematics Genealogy Project.” Welcome! – The Mathematics Genealogy Project, genealogy.math.ndsu.nodak.edu/
5. Emmanuel J. Candes. “Mathematics of sparsity (and a few other things), August 14, 2014, Seoul. ICM2014 VideoSeries PL3. https://www.youtube.com/watch?v=W-b4aDGsbJk

There are many ongoing studies into fasting, a practice prescribed across many religions. Increasingly, there is evidence to support that intermittent fasting is beneficial to human health.

The opposite of fasting – overeating – has been revealed to be a major culprit in many illnesses, including cancer, obesity, and heart disease. For many years, the medical consensus was that fasting, i.e. prolonged hunger, too, could have deleterious effects on the human body. From kidney failure to loss of muscle, fasting was believed to be harmful – thus calling into question the benefits of this widespread religious commandment.

People of faith – including Muslims – have long believed that God wouldn’t recommend a practice that was harmful to the body. The hardships and troubles that accompany a religious practice are not too extreme for people aware of their servitude to God: they regard their trials as a testament of their faith. Part of that faith is the certainty that God wouldn’t recommend a harmful or unbearable practice.

In this article, we will share with you two unknown benefits of fasting that have been recently discovered.

Regenerating stem cells

There is a substantial body of evidence showing that staying hungry during certain periods of the day heals the body’s metabolism, hastens loss of fat, decreases oxidative stress,* and improves the functions of the tissues that make up various organs including the liver, the intestines, and the brain. The first of the two new discoveries about the underlying processes, however, provides a missing piece of the puzzle by helping us understand the incredible changes hunger triggers in stem cells.

Researchers at MIT, Duke University School of Medicine, and Whitehead Institute for Biomedical Research in Cambridge published an article recently on stem cells, indicating that part of stem cell’s mystery could lie in the oxidation (burning) of fat in the mitochondria [1]. Omer H. Yilmaz and his fellow researchers found that a 24-hour fast hastens fat breakdown in intestinal stem and special progenitor cells of rats.

To run the study, Yilmaz and colleagues let the mice go hungry for 24 hours to study the state of their stem cells. They found that the functions of intestinal stem cells increased, and fat metabolism quickened, in both young and aged mice, even during early periods of hunger. They saw that the body’s tapping into fat for its energy needs maintained the health and strength of the intestinal stem cells. Moreover, they noticed that if the aged mice did not fast, they started to lose their ability to break down and use fats for energy expenditure.

The researchers obtained more interesting results as the studies progressed. It was found that a single period of hunger for 24 hours boosted renewal of intestinal cells – and the stem cell functions increased even more significantly in aged mice. Another interesting finding was that mice with damaged intestines that were fasted recovered faster than those that were fed.

“My lab is really interested in understanding how diet, in general, can be used to improve tissue function,” Yilmaz said. “One of the tissue types I study is the intestine. In my lab we study the intestine because it’s one of the largest organs in the body. It’s also a tissue that experiences rapid cellular turnover.” [2]

The intestine is lined by a single layer of cells, Yilmaz explains, that turns over every 5 to 7 days. The workhorses of the intestinal lining and this cellular turnover are intestinal stem cells. These cells must retain a high level of function or cellular health in order to replenish the intestinal epithelium on a regular basis. Intestinal stem cells are particularly important in terms of repairing intestinal damage caused by gut infections and chemotherapy, for example.

The single layer of epithelial cells needs to be renewed every 5-7 days: the aids and enzymes secreted in the intestine for digestive and absorptive activities damage cells despite the protective mucus layer, and some other cells already burst and die as they empty their secretions. Moreover, some medications, particularly chemotherapy, cause the destruction and breakdown of the epithelial cell layer. However, fast-multiplying stem cells replenish the epithelial cells. Stem cells are very active and young and have the ability to divide and multiply continuously.

Dr. Yilmaz also says:

“As we age, stem cells in the intestine as well as in many other tissues of the body, including in the blood and nervous systems, become less functional. We believe that reduced adult stem cell function contributes to some of the decline of function associated with old age. My lab is very interested in studying low-calorie interventions to delay this decline. As a field, we’ve known for over 100 years that low-calorie states such as fasting or caloric restriction can have positive effects on tissue health and aging. We’ve seen evidence that fasting during times of intestinal infections that lead to diarrhea may promote healing of the intestinal lining, for example.” [2]

This quote emphasizes the importance of the issue. Yilmaz adds that despite all this knowledge, the cellular mechanisms of this renewal have not been discovered, and he and his team are working to find out how fasting and hunger enable this recovery.

Stem cells become happy in fat!

The researchers discovered through the experiments that the stem cell function could be brought about in hungry mice by the burning (oxidation) of fatty acids in intestinal cells. When they stopped the fat metabolism through genetic engineering, they noticed that the benefits of fasting on intestinal stem cells were negligent.

In the present dietary conditions, we obtain nearly 60-70% of our energy from carbohydrates or sugar, 20% from fats and 10% from amino acids. Yet an interesting finding revealed by Dr. Yılmaz and his research team is that we essentially obtain much greater energy from using fats once we fast. According to their experiments on mice, during fasting, the intestinal stem cells in both young and aged mice switch from carbohydrates to fats as the primary source of energy, and this shift enables improvement in stem cell functions.

It is not yet known what underlies the fat metabolism that boosts stem cell functions in response to fasting, but it is observed that stem cells work better when they burn fat. The ability to metabolize fats efficiently decreases with age.

It is likely that this hastened metabolism – encouraged by certain diets, like the keto diet, where the amount of fat ingested is raised to 70% and carbohydrate intake is limited to 5% – helps with epileptic seizures and similar neurological disorders: the ketone bodies generated during metabolism of fats are used as energy sources by the brain.

According to Dr. Yilmaz, if fasting can improve the functions of intestinal stem cells through metabolism of fats, the key is the mitochondria, the powerhouses of the cell responsible for this function. Fat metabolism, or the immediate breaking down or “burning” of the fat entering the cell, is carried out in the mitochondria. Disrupted energy generation associated with aging and decreasing mitochondria can be a reason for the brain’s susceptibility to age-related illnesses. Positive developments in brain functions can therefore be viewed in connection with the correlation between fasting and the oxidation of fatty acids.

Cleaning by fasting

Just like the spring cleaning in our homes, our cells need a thorough cleaning to function properly. Wrongly folded protein particles, remains of damaged organelles, broken molecular pieces, and aged cells that can no longer divide should be disposed out of our cellular structure. Fasting perfectly performs the task of cleaning these wastes and clearing the area in the cell.

“Everything has zakat (a means of cleaning), and the zakat of the body is fasting.” (Ibn-i Majah, Siyam: 44)
“Fasting is a protective shield.” (Bukhari, Sawm: 2)

What is autophagy?

Autophagy is the compound of two ancient Greek words: auto (self) and phagos (eating). What is meant by “self-eating,” is the breaking down and recycling of protein waste and old, impaired molecules by intracellular digestive organelles called lysosomes. In this way, proteins or cellular organelles are digested and taken out of circulation. We can liken autophagy to garbage collection.

Japanese researcher Yoshinori Ohsumi’s study, which brought him the 2016 Nobel Prize for Medicine, found that the autophagy that occurs inside the cell due to fasting or starvation plays an important role in preventing ageing, infections, and tumors. If autophagy breaks down, many illnesses may be triggered, including cancer. Conversely, if autophagy activity is regular, tumors may be suppressed – depending on the stage of development and type of tumor. Cancer research has long focused on channeling these autophagic activities. Restriction of food intake through fasting shows promise: it may protect normal cells while triggering autophagy and thus increasing the effect of cancer treatments. Autophagy might offer solutions or treatment options for other illnesses, too, including inflammatory diseases [3], neurodegeneration [4], metabolic and cardiovascular diseases [5], obesity [6], and metabolic disorders.

Preclinical studies have shown that dietary restrictions by fasting contribute to the increase of a person’s lifespan and slow the development of age-related diseases such as cancer and neurodegenerative and cardiovascular diseases [7].

* Oxidative stress: The damage caused as a result of excessive proliferation of free oxygen radicals released from foods that spike blood sugar (with high glycemic index) as metabolic waste. A good example of oxidative stress is the browning of certain foodstuff such as apples, bananas, etc. sometime after they are peeled.

References

1. Yilmaz, Omer H. et al. 2018. “Fasting Activates Fatty Acid Oxidation to Enhance Intestinal Stem Cell Function during Homeostasis and Aging.” Cell Stem Cell, Vol. 22, Issue 5, May 3, pp. 769–778.
2. Paige Brown Jarreau. 2018. “Eating (Or rather, Fasting) Our Way to Rejuvenated Stem Cells?” in Life and Tech @ LifeOmic. June 7. A Medium Corporation.
3. Cadwell K. 2016. “Crosstalk between autophagy and inflammatory signaling pathways: balancing defence and homeostasis.” Nat Rev Immunol.16 (11): 661–75.
4. Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A et al. 2017. “Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities.” Neuron. 93 (5):1015–34.
5. Bravo-San Pedro JM, Kroemer G, Galluzzi L. 2017. “Autophagy and Mitophagy in Cardiovascular Disease.” Circ Res. 120((11)):1812–24.
6. Lavallard VJ, Meijer AJ, Codogno P, Gual P. 2012: “Autophagy, signaling and obesity.” Pharmacol Res. 66 (6):513–25.
7. O’Flanagan CH, Smith LA, McDonell SB, Hursting SD. 2017. “When less may be more: calorie restriction and response to cancer therapy.” BMC Med. 15(1):106.

Embryonic stem cells are cells in the early stages of embryonic development when a fertilized egg cell is divided first into two cells and then into four, eight, and sixteen. Each grows into a brand new cell type and multiplies as per the codes present in its DNA program as tissues form and organization starts. 

After twenty years of research and accompanying debates on the human embryo, we are finally on the threshold of both reshaping our present concepts in biology and moving on to clinical case studies. The first human embryonic stem cells were produced in 1998. Studies researching the question, “Can we treat diabetes by reprogramming the DNA in these cells at the beginning of life?” switched first to how human genes worked and which genes are responsible for the development of particular tissues and then to the embryonic stem cells for these areas and ultimately to replacing or reprogramming a “faulty or deficient” gene.

The most controversial topics in genetics and embryonic studies are related to bioethics. Many scientists are grappling with questions like whether is it ethically correct to intervene with the genetic programming of a fertilized human egg (zygote)? If so, what should be the limits? Are we trespassing a divine domain?

Embryonic stem cells have been an excellent source of information that we lacked throughout history about how living organisms started to develop. Like astronomers who trace their knowledge to the Big Bang in order to obtain fundamental information about the origin of the universe, biologists have been researching how the molecules in a single cell went through sequential and planned changes, how they transformed and acquired new functions that triggered the mind-blowing developments in diverse, miraculous living organisms. Scientists have found out how primordial embryonic cells transformed into more than 200 cell types that constitute various tissues and organs. The number of studies has skyrocketed about which molecule types can be used to regenerate the damaged tissue, say, after a traffic accident. Embryonic studies that focus on the regeneration or reparation of medulla cells (spinal cord) have been a source of hope for some patients with permanent paralysis because of a broken back injury or severed spine in a traffic accident or those who are still stranded in wheelchairs. Similarly, the preliminary findings of research into Parkinson’s and diabetes are extremely promising, and a new study reports of two blind people with macular degeneration (which causes blindness) who have been treated.

Initial studies

In 1981 researchers successfully obtained stem cells from a rat embryo culture. They soon realized that the cells held a secret potential: they could grow into 200 different types of cells. Later Wisconsin-Madison University biologist James Thomson derived stem cells from primates for the first time. Three years afterwards, Thomson derived the first human embryonic stem cells from donated but unused embryos.

The increasing number of research studies into embryonic stem cells sparked off intense debate both in religious circles and among the science community that care passionately about the sanctity of humans. Allegedly, lab studies were conducted on human embryos without restrictions, which were grown until tissues and organs formed but were then killed. In 2001, the US president George W. Bush slashed federal funds, stating that stem cell research was not strictly ethical. Deriving embryonic cells was banned in many countries including Germany and Italy. In other countries, however, studies went full speed ahead. Indeed, reports flooded in about stem cells grown by researchers in Australia, Singapore, Israel, Canada and the USA into nerve cells, immune system cells, and heart cells.

Before long, a new idea emerged about transferring new cells into the egg cell – like nuclei of body cells used in cloning Dolly the sheep – to produce various tailor-made, fully DNA-compatible tissues and organs, as they had the same genome as the donor’s. It became a topic of everyday conversations that spare organs could be cultivated for the human body just like spare parts of cars or other machinery were produced to replace a faulty or damaged part. In fact, if it were not for claims such as “creating a new human” there would be no objections against producing a kidney, lung, or heart from the DNA of a patient and thus overcome the major problem of tissue rejection in transplantation of organs.

If faulty or defective genes could be removed and replaced by healthy genes in the DNA of stem cells, many incurable genetic diseases could easily be fixed and many prospective parents who avoid having a child because of a defective gene they carry would welcome the development enthusiastically.

We are on the threshold of reshaping our present concepts in biology and moving on to clinical case studies. Embryonic studies have been a source of hope for even patients with diseases like paralysis and blindness.

Just in time and in the right amount

Embryonic stem cells are cells in the early stages of embryonic development when a fertilized egg cell is divided first into two cells and then into four, eight, and sixteen. Each grows into a brand new cell type and multiplies as per the codes present in its DNA program as tissues form and organization starts. It is most mysterious and miraculous that the molecules that lead a stem cell to transform into a new type of cell are synthesized at exactly the right moment and in the precise amount.  Scientists are currently trying to figure out which molecule leads a cell to become a nerve, muscle, or bone cell when attached to it. They are likely to decode the molecules by monitoring the tissues that remain undeveloped because of missing genes resulting from DNA mutations observed in certain genetic diseases.

The new field that has developed in the last two decades called regenerative medicine is predicated on tapping into the potential of stem cells by repairing missing or faulty tissues, or completing a link in the chain necessary for the functioning of a dysfunctional metabolic process. In 2006, stem cell biologist Shinya Yamanaka of Kyoto University in Japan successfully transformed adult rat cells into an embryonic state. The following year, human body cells were transformed into embryonic stem cells. The ensuing research has led to the acknowledgement that it was theoretically possible to transform stem cells into any cell type, a promising cure for diseased embryos that have genetically missing parts.

The major problem, however, is keeping these delicate cells alive in a culture medium. In 2007, Yoshiki Sasai discovered a molecule called rock inhibitor that nourished the cell colonies he grew. The success rate in generating new cell colonies rose to 27%. Parmar from Swedish Lund University heralded “a new golden era” by producing new neurons from embryonic stem cells for the treatment of Parkinson’s.

As new techniques were developed for producing cells fast and reliably, these cells turned out to involve a very low risk of developing cancer. “We don’t yet know how this hidden power and balance that can be transformed into any cell type is controlled,” states Hiromitsu Nakauchi, a stem cell biologist at Tokyo University who researches making blood platelets out of stem cells derived from the embryo or somatic cells.

Experiments are underway that aim to treat disorders by activating stem cells stored in the body that have not yet differentiated through the help of proper stimulating molecules. 

Miraculous differentiation

As the techniques for producing and feeding stem cells got easier, researchers aimed at growing and forming tissues and organs. A connective tissue or an outer covering like the skin that lacks a shape but takes the shape of the underlying muscles and bones can be produced even in a Petri dish and then transplanted to a burned or missing area of the skin. The present aim is the production of organs such as the kidney or the heart that has a particular shape and is made up of a number of different tissues. If the correct signal molecules responsible for cell division and differentiation can be identified and readily used where necessary and at the right amount, then organs including any type of tissue can be produced. Researchers like James Wells at Cincinnati Children’s Hospital in Ohio have tested the damage of drugs on intestines by using the partial intestines they developed from stem cells rather than administer them to normal humans, thereby hailing the imminent age of intestine transplants.

In 2004, the doctors who did tube baby experiments for a patient in Chicago known to have a genetic disorder started to produce a series of stem cells from generated embryos. They made models at the cellular level of the emergence of such genetic disorders as thalassemia, Huntington’s disease, Marfan syndrome, and muscle dystrophy. In 2007, they used embryonic stem cells to suppress molecular changes that trigger mental disorders caused by a genetic disorder called fragile X syndrome.

Research shows that multipotent (mesenchymal) cells stimulated at the outset of tissues are even more promising than embryonic cells with respect to diseases because it is easier to repair damaged or missing tissue by guiding them. However, it is essential in a genetic disorder that cells derived at the beginning of the embryonic stage should be used in order to replace faulty genes with healthy ones and address the disorder at its outset.

Experiments are underway that aim to treat disorders by activating stem cells stored in the body that have not yet differentiated through the help of proper stimulating molecules. In this way, as many as ten illnesses are likely to be treated, some of which include diabetes, macular degeneration in the eye, and neurodegenerative diseases such as Parkinson’s.

Douglas Melton from Harvard Stem Cell Institute in Cambridge has worked for fifteen years to transform embryonic stem cells into insulin-producing β-cells. He has produced pancreatic cells that sense glucose and produce insulin and he hopes to transplant them to end the dependence of patients of diabetes type-1 on insulin shots. The last obstacle remains to be the introduction of these cells to the system so that they are not destroyed by the patient’s immune system.

Clinically, it is believed that stimulated multipotent cells have a greater advantage than embryonic cells because the produced cells and tissues have the same DNA as the patient and thus do not cause any immune reaction when they are transplanted. The problem for many genetic disorders including type-1 diabetes is that the patient has the same mutation in his or her genes, and a method should be devised for cleaning and replacing these cells.

Another problem is the cost. It is reported that preparation of a series of multipotent cells will cost about one million dollars. However, the cost is expected to decrease and cells will be developed for the treatment of Parkinson’s disease, which is caused by a loss of neurotransmitter substance, which enable communication between nerves, and dopamine.

Treatment of macular degeneration is a popular target in this field. Patients gained the ability to read, though slowly, one year after the transplantation of part of stimulated multipotent cells to a damaged retina.

Such research studies normally cause some opposition. Playing with genes and embryos involve certain ethical and health risks. Yet, as reported in a Prophetic tradition, with all our God-given abilities like intelligence, curiosity, and willpower, humans can, and hopefully will, find cures for all diseases. Research into stem cells has the potential to provide many breakthroughs in these efforts to find healing for every human. Scientists and ethicists have to work together to determine our direction not to cause any unintended harm to any single soul while moving forward with this research.

Sight is one of the most miraculous things for which we can never be thankful enough. Our eyes serve as windows connecting our inner life with the outer world. In “Retina the Mind-Boggler,” Dr. Serranur explains the intricacies of the eye’s physiology. Despite many theories and scientific advances, we still don’t completely know how sight works. Scientists do know that the retina plays a crucial role in this very complex structure – so important, in fact, not every eye surgeon dares touch it.

Stem cell research has expanded our understanding of biology and medicine to once-unimaginable levels. Among the treatments for which the initial findings are promising are paralysis, Parkinson’s, diabetes, and even blindness. Despite these groundbreaking discoveries, many are not sure about how far we should go in genetic programming. Dr. Yorulmaz elaborates on this dilemma in “Embryonic Stem Cells.”

The question of how to handle refugees has been a critical issue throughout human history. Despite many regulations, international legal conventions, and technological progress, refugees still pose intractable questions to governments around the world. Last summer, when Dr. Sophia Pandya was visiting Greece to observe the situation of refugees there, the country suffered one of the deadliest wildfires of the twenty-first century, in which a hundred people died and more than a thousand buildings were destroyed. Greece has been the crossroads for many refugees, including, yes, many Turkish citizens, especially in the last few years. The Erdoğan regime’s clampdown on the Hizmet Movement and many others who oppose his autocracy has forced tens of thousands of Turkish citizens to flee their homes and seek asylum in Europe, the US, and elsewhere. Hundreds of thousands of people have been detained in these purges; thousands more are waiting their turn, as their freedom to travel has been illegally curtailed by the Turkish government. What is their crime? Association with a group that opposes autocracy and supports democracy. For many fleeing injustice, Greece has become the last chance for freedom. What Dr. Pandya saw there was representative of what the Hizmet Movement has been doing for decades: Turkish refugees reached out to victims of the wildfires and distributed food and other aid. This was their way of responding to the hospitality of Greek people, who opened their homes to refugees when, as described in this issue’s lead article, they were forced to flee “dark-spirited night demons who were overwhelmed by hatred, rancor, and enmity, and dejected souls growling with wrath.”

Astronomers have discovered a planet with the longest known orbital period. Exoplanet Kepler-421b has been identified through the Kepler observatory, a space-based telescope. It circles its star once every 704 days. More than 1800 exoplanets have been discovered so far, but compared to Kepler-421b, those had much shorter orbital periods, like a few weeks or even a few days. The host star for Kepler-421b is much like the sun, but it is little bit smaller and relatively cooler. With an orbital distance of 177 million kilometers, Kepler-421b gets about one-fourth the light from the host star as the Earth receives from the sun, which makes the exoplanet as cold as -100 °C. The unusual orbit places Kepler-421b beyond the “snow line,” which is accepted as the dividing line between rocky and gaseous planets. Outside of the snow line, water condenses into ice grains that stick together to build planets known as “gas giants.” Since gas giant planets are very close to their stars, theorists believe that many exoplanets migrate inward early in their history. However, Kepler-421b is the first example of why such migration may not be necessary.

Sunflowers’ internal clock

Plants are known to grow toward the sun to maximize the amount of energy they absorb. Sunflowers (Helianthus annuus) show the most fascinating behavior during summer, when they follow the sun as it rises in the east every morning and sets in the west every evening. In a recent study, scientists challenged the obvious explanation for this plant’s behavior: are flowers solely responding to sunlight or are there other unknown mechanisms at work? They designed a clever yet simple experiment where they grew sunflowers in chambers with a fixed overhead light that was continuously on. Surprisingly, for several days, the sunflowers under constant light kept moving as if the sun were rising in the east and setting in the west. This unexpected result suggests that sunflowers were not responding only to the direction of the light but also to an internal biological clock. Furthermore, they discovered that sunflowers bend when one side of the stem grows faster than the other. For example, the west side of the stem seems to grow faster to bend the plant towards the east in the morning. Scientists now hope to understand how an internal biological clock in sunflowers has the opposite effects on opposite sides of the stem. Sunflowers are not the only plants performing this diurnal dance; other agriculturally important crops such as soybeans and cotton exhibit the very same behavior. Solar tracking is known to boost plant yield and discovering the mechanisms of how plants track the sunlight might have important implications for improving global agricultural yields.

Friends linked by genes

It is a common observation that close friends look alike. Even centuries ago, Plato noted the tendency that good friends usually have similar appearances. Recently, a group of geneticists took this idea even further and suggest that people on average tend to choose friends who are genetically similar. The study provided convincing evidence that we have more DNA sequences in common with the people we pick as friends than we do with strangers in the same population. Researchers performed a genome-wide analysis of approximately 1.5 million markers of gene variations from 1,932 subjects of the Framingham Heart Study, which is one of the most comprehensive genetic databases. They identified 1300 pairs of non-relative friends and compared their genetic information to each other. The analyses showed that friends share similar genetic variations (around 1% genomewide), to the degree that it is as if they have the same great-great-great-grandparent – in other words, as if they were fourth cousins. Notably, friend pairs seem to have the greatest similarity in the genes that are responsible for a sense of smell and they show the most difference in immunity-related genes. Friendship entails spending a lot of time together and looking out for each other. Odors are strong behavioral cues in human psychology and people with similar olfactory preferences might like to prefer living or hanging out in similar environments. Likewise, it is potentially a big advantage that friends don’t get infected from the same microbes at the same times, so that one of them can take care of the other. As much as these anthropological implications are merely speculations with many caveats – and despite there being many obvious social, ethnical, and cultural factors that help determine friendships – the genetic basis of friendship and other social interactions may hold answers to at least some of the mysteries of human behavior.

The findings in mice imply that humans might also possess similar characteristics. This increases the possibility and brings hopes of having a baby even at older ages along with treatments in the future, just like in the miraculous story of Prophet Abraham and Sarah as narrated both in the Qur’an (ad-Dhariyat 51:24-30) and the Bible (Genesis 21:7), showing us one aspect of the possibility and ultimate limits of knowledge and technology that humans can attain one day so that these miracles can become true, though to some extent, with the advancement of medicine.

Bone borne eggs

An interesting study showed an unexpected source of oocytes in the bone. Study by Tilly’s group at the Harvard Medical School in 2004 showed that cells in the bone marrow of mice could be a source of oocytes that are developing in the ovaries [1, 2]. Their first observation was the expression of genes related to egg cells in the bone marrow samples of mice. To test the possibility of bone marrow cells as a source of new oocytes, they chemically generated infertile mice. Treating mice with two chemotherapy drugs called cyclophosphamide and busulfan causes infertility. Once they treated the mice with these drugs, the mice had extensive damage in their ovaries along with an end in new oocyte production in their follicles. Ovarian follicles are spherical aggregations in the ovaries which periodically produce oocytes. Remarkably, when they transplanted bone marrow from female donors, they found a number of oocyte containing follicles (about several hundred). Interestingly, the appearance of those oocytes were rapid and thought to be due to circulating oocytes originating from the bone marrow and developing as they travel through the blood stream. Although they don’t have the evidence that those cells could be fertilized, findings could lead to fundamental changes in the current understanding of the female reproductive system.

Tilly and colleagues also report that bone marrow and blood transplants could also induce the development of oocytes in a genetically infertile mice model (which has a mutation in ATM gene) [3]. This mutant mice lack follicles and developing oocytes and are unable to produce mature germ cells (egg producing cells). Their study shows that bone marrow or blood transplant from healthy donors induces production of oocytes in this mice model. They conclude from those studies that bone marrow could be a source of germ cells to the ovaries throughout adult life. Their findings are somewhat supported by the clinical studies on cancer patients who were expected to be infertile but they could have babies after bone marrow transplant.

Another study on the circulating cells for female fertility used parabiotic (the union of two mice through an exchange of blood) mice model. This study by Eggan and colleagues tested the capacity of circulating bone marrow cells to generate ovulated oocytes and could not show any contribution of bone marrow cells to ovulated oocytes [4]. Blood or bone borne oocytes are highly debatable but bone marrow cells, at least, might have a role in enhancing women’s fertility. This might lead to the treatment of infertility. In addition, it might bring new opportunities for those dreaming of having a baby even at a late stage, but requires much additional research to be realized.

Lab & bone borne sperms

Sperm formation is known to continue throughout adulthood. It involves various steps of cellular differentiations. Maturation of sperms in the body takes more than a month in most mammals. Trials to mimic this complex process in petri dishes failed to demonstrate the production of normal, fertile sperms.

Scientists had dreamed of growing sperms in petri dishes for years. Recently, researchers in Japan developed a technique that allowed production of fertile mammalian sperms in a petri dish [5]. Attempts to make such mature sperms usually failed due to meiosis, a specific type of cell division that halves the number of chromosomes. Meiosis is very essential step for sperm cells to get ready to fuse with an egg. Ogawa and colleagues demonstrated that meiosis of sperm cells lay in a simple change to standard petri conditions. They tried various petri conditions but they ended up with a special serum free medium that is commonly used for growth of embryonic stem cells. Several weeks later, they observed formation of mature sperm cells and even half of them had flagella, a tail-like structure that sperm cells use to swim. Injection of those sperms into egg was also able to produce offspring. In addition, when they used frozen testis tissues of newborn mice, they could grow sperms as well. This discovery in reproductive biology is likely to be beneficial not only for people having infertility problems associated with sperm maturation but also children that undergo cancer therapy which destroys fertility. It is known that chemotherapy impairs fertility. Adults could freeze their sperm before such treatment, but young boys can’t. This new discovery offers such patients hope. In addition, this finding opens new avenues for protection of endangered animals that might die before reaching sexual maturity. It is a matter of time for the same technique to be applied to humans and other species.

There are also reports suggesting the generation of male germ stem cells (sperm producing cells) from bone marrow [6, 7]. Mesenchymal stem cells, which are derived from the bone marrow, have shown to differentiate into male germ cells. Studies testing the effect of retinoic acid and testicular extracts showed to induce human bone marrow stem cells to differentiate into male germ cells as shown by male germ-cell specific marker expressions. Another approach tested the possibility that bone marrow-derived stem cells would differentiate into germ cells when transplanted into the mouse testis. Using GFP positive bone marrow cells transplantations, it has been demonstrated that bone marrow-derived stem cells can also be induced to differentiate into germ cells. Interestingly, there seems to be a connection between bones and fertility.

Bones and fertility

The Qur’an tells the story of Prophet Zachariah, peace be upon him, when he secretly prayed to God to ask for a successor. He said “My Lord! My bones have grown feeble and my head glistens with gray hair from old age…” (Maryam 19:4). His prayer was accepted and the angels came with the glad tidings of his son, John. He was surprised as to how he could have a son while his wife was barren and that he had already reached infirmity in old age. It has been said by scholars that weakness of bones here refers to weakness in engaging in sex due to old age and gray hairs as a sign of infertility. It is also worthy to mention another verse where the creation of human is described as happening from a lowly fluid that gushes forth the vertebra and rib bones: Let human, then, consider from what he has been created. He has been created from some of a lowly fluid gushing forth. It proceeds (as a result of incitement) between the (lumbar zone in the) vertebra and the ribs (At-Tariq 86:5−7). As commentator Ali Unal explains, these verses refer to both the mechanism of the ejection of the seminal fluid and where it is emitted [8], which is a relatively recent discovery in biology. Remarkably, the Qur’an mentions two major bones where this fluid is emerging. Our current knowledge in medicine do not say anything about the role of ribs in reproduction or fertility but both the Islamic and Judeo-Christian traditions mention the creation of Eve from Adam’s ribs, peace be upon him. Could this refer to the relation between bones and fertility? God knows best. Lastly, it is of importance to note that one of the symptoms of menopause is the loss of bone mass. Isn’t it amazing how mysterious events regarding bones and fertility are taking place beyond our control and knowledge?

Ali Fethi Toprak is a PhD candidate at University of Texas Southwestern Medical Center.

References

1. Johnson, J., et al., Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature, 2004. 428(6979): p. 145-50.
2. Vogel, G., Reproductive biology. Controversial study finds an unexpected source of oocytes. Science, 2005. 309(5735): p. 678-9.
3. Johnson, J., et al., Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell, 2005. 122(2): p. 303-15.
4. Eggan, K., et al., Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature, 2006. 441(7097): p. 1109-14.
5. Sato, T., et al., In vitro production of functional sperm in cultured neonatal mouse testes. Nature, 2011. 471(7339): p. 504-7.
6. Hua, J., et al., Derivation of male germ cell-like lineage from human fetal bone marrow stem cells. Reprod Biomed Online, 2009. 19(1): p. 99-105.
7. Lue, Y., et al., Fate of bone marrow stem cells transplanted into the testis: potential implication for men with testicular failure. Am J Pathol, 2007. 170(3): p. 899-908.
8. Unal, A., The Qur’an with Annotated Interpretation in Modern English. Vol. Qur’an 86:5−7, 51;24−30 and 19:4. 2009.

Hierarchy of hematopoietic stem cells

The blood system, also known as hematopoietic system, has enormous regenerative capacity to maintain functional mature blood cells that arise from highly proliferative but short-lived progenitor cells. Those progenitors in turn are generated from very rare blood stem cells called hematopoietic stem cells (HSCs). HSCs are one of the most studied stem cells in our body which has greatly shaped our thinking on the features of adult stem cells. These stem cells are kept at the bone marrow in close proximity to bone cells and other supporting cells forming the specialized home known as niche. In several aspects, a niche resembles a cellular stronghold that a queen lives in a safe and protected environment.

The interaction of stem cells with the niche is crucial as this prevents exhaustion of stem cells from uncontrolled cellular divisions and proliferation. While active progenitors account for the generation of mature blood cells, hematopoietic stem cells function as a reserved cell population. Interestingly, we observe the importance of the balance between those two cell populations in the aging process. Although the number of HSCs increases in aged animals, there is a decline in self-renewal of HSCs.

Other protective mechanisms include the low proliferation rates of HSCs in a relatively quiescent state, residing in a low oxygen environment [3], a relatively low degree of metabolism and preferential use of glycolysis as energy source, and additional protection mechanism against oxidative stress.

Low in oxygen but a good place to be!

Stem cells as the cell bank of the body are protected against internal and external insults by a number of mechanisms. Stem cell niche not only provides an environment that they can survive but also poses the lesser degree of internal and external insults. Those possible stresses on cells include, but not limited to, UV exposure, radiation, toxic chemicals, and free oxygen species that cause various damages in the cell including mutations in DNA (Fig. 3). Cells respond to those external and internal issues by various ways such as senescence (loss of stem cell activity), cell death or DNA repair. For example, blood stem cells mainly house in the bone marrow next to osteoblastic lining (blood-forming cells) and endothelial cells where they form the hypoxic (low oxygen tension) endosteal region. This hypoxic niche of HSCs provides lower levels of oxygen so that there are lower levels of free oxygen radicals that mainly arise from electrons leaking from mitochondria during oxidative phosphorylation. In addition, it has been shown that HSC express higher levels of hypoxia inducible factor-1α, a master regulator at low oxygen tension with hundreds of downstream targets regulating various aspects of metabolism including defense against oxidative stress and survival at low oxygen environment. It has also been shown that hypoxia increases self-renewal abilities of HSCs, thus keeps them healthy and functional for longer periods.

Protection from detrimental effects of reactive oxygen species (ROS)

Excess amounts of reactive oxygen species are detrimental to cells. ROS are found to cause hematopoietic stem cell defects as shown in mouse lacking FoxO and Atm genes. In those mutant mice, the hematopoietic defects could be rescued by the use of an antioxidant N-acetyl-cysteine. Anti-oxidants are one of the scavengers that diminish unwanted effects of reactive oxygen species. A number of fruits and vegetables such as beans, blueberry, strawberry, and apple are known with their high content of anti-oxidants. It is amazing to observe anti-oxidants being placed into our sustenance just as much as in some special genes (such as SOD2 and Hypoxia Inducible factor-2α) that provide additional protection for cells. Amazingly, stem cells show high levels of ROS scavenger genes.

Low metabolism provide protection for stem cells

Recent studies demonstrate that hematopoietic stem cells have lower rates metabolism as measured by lower oxygen consumption, lower ATP content and higher lactate production (an end product of cytoplasmic glycolysis) [4]. This means that stem cells produce and consume lesser energy (ATP) compared to more differentiated cells and the by-products of the energy production are kept lower. As higher energy demand brings higher rates of internal insults like production of ROS which is associated with aging and cellular damages, HSCs are granted with another protective mechanism by preferential use of glycolysis (anaerobic) instead of oxidative phosphorylation (aerobic).

Hematopoietic stem cells are quiescent

Another defense mechanism is the quiescence of stem cells which is associated with slow cell-cycle progression. Quiescence of stem cells means that they are kept at a resting, inactive state thus sustaining a self-renewing HSC compartment for life. Because when cell divides, they have to undergo thousands of chemical reactions including making a copy of the three billion letter long DNA, which puts cells at risk to get mutations. Thus, they don’t undergo division unless there is a stimulus. In addition, it has been found that HSCs divide only once every 145 days on average.

There are a number of studies indicating that there are signals in the niche that keeps HSCs in a quiescent state. Tie2/Ang-1 signaling, for instance, has been demonstrated to contribute to the maintenance of HSCs by inducing quiescence. While Ang-1 is expressed in the mesenchymal/stromal cells of niche, its receptor Tie2 is expressed at HSCs. In addition, it has been shown that Ang-1 can inhibit HSC division in culture and promote quiescence of HSCs in the bone marrow [5].

It is also reported that the cell adhesion molecules that allow physical interaction between stem cells and their niche components may participate in regulation of stem cell quiescence through a process called contact dependent inhibition of proliferation. For instance, it has been found that cell adhesion molecules such as N-cadherin, β1-integrin, and osteopontin might be involved in the regulation of cell cycle status of HSCs [6].

One advantage of quiescence of HSC comes from the lower susceptibility of slowly proliferating cells to radiation than other cells due to the expression of cell cycle inhibitors like p21 and anti-apoptotic (controlled cell death) machinery like ATM in HSCs. In addition, studies in p21 (a cell cycle inhibitor gene) knockout mice suggest that maintaining cell cycle quiescence is directly linked to self-renewal of HSCs [7].

Toxics are exported from hematopoietic stem cells

There are other issues concerning external insults against toxics and unwanted chemicals. An HSC population described as side population has been equipped with a number of transporters such as ATP Binding Cassette (ABC) transporters, P-glycoprotein (P-gp/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) on their membrane providing high efflux ability [8]. They play an important role in the excretion of drugs and endogenous compounds. Those transporters work actively when there is an entrance or excess of such chemicals thus keeping damage minimal.

HSCs are placed in such an environment that even minimum damages by internal and external insults are prevented by different defense mechanisms including residing HSCs in the hypoxic niche, expression of ROS scavenger genes, preferential use of glycolytic metabolism, quiescence nature of HSCs, and removal of toxins by ABC transporters. It is very wise to home such an important cell in a place where it can prosper with a carefully balanced rate of cell division and metabolism. Hypoxic niche seems key to the protection of hematopoietic stem cells by supporting self-renewal and preservation of hematopoietic functions both at the same time. The presence of these protective systems that are graciously placed in our cells with perfect measurements provides an elusive mechanism to ensure healthy life-long reservoir of HSCs.

Ali Fethi Toprak is a PhD candidate at Southwestern Medical Center, Texas University.

Selected References

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2. Li, L. and H. Clevers, Coexistence of quiescent and active adult stem cells in mammals. Science, 2010. 327(5965): p. 542-5.

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