Gene Knockouts and Their Relevance to Human Biology

Scientists aim to identify genes that were not previously implicated in human disease with the Human Knockout Project.
Courtesy: http://www.dermamedics.com/science_id35.html

         When scientists aim to uncover the function of a gene, where do they start? They know that genes make up the chromosomes that occupy the nucleus of every cell, but how can this feat be achieved? The classical method for elucidating a gene's function is by "knocking out," or eliminating, the function of the gene. Scientists can prevent a gene from being expressed by introducing mutations, or changes to the genetic sequence, in the gene of interest. They can also introduce a foreign gene into the gene's chromosomal location to prevent it from being converted into messenger RNA, which would in turn prevent protein production. These knockout experiments have been performed in several organisms such as worms, yeast, flies, and mice, and initiatives such as the Knockout Mouse Project (KOMP) venture to collect information detailing the physical effects that result from the ablation of individual genes.

         Due to ethical issues, these initiatives were not implemented in humans. However, Dr. Daniel McArthur at Harvard University has circumvented this roadblock. He is deeply intrigued in the existence of healthy "human knockouts," people that lack function of individual genes without illness, so he began the Human Knockout Project. This endeavor involves the study of naturally occurring mutations in humans that result in the loss of genetic function. This allows Dr. McArthur's group to avoid many of the ethical issues that surround human genetic research. Dr. McArthur stresses that in addition to the necessity for understanding the effects of genetic mutations in essential genes, it is as important to study mutations in genes that lack deleterious effects. This knowledge could lead to the elucidation of genes that are known to improve responses to cancer treatment, for example, and methods to decrease or eliminate the function of these genes can be pursued in humans.

          The Human Knockout Project is a creative way to address the relevance of individual genes to human disease. Oftentimes, scientists tend to have a linear methodology for studying the role of genes in disease, usually focusing on genes that confer harmful effects upon elimination. But as Dr. McArthur eloquently described, we forget that the loss of a subset of genes can bestow beneficial effects on an organism, and ultimately this may revolutionize the current mode of thinking when treating disorders such as Alzheimer's and diabetes. With the implementation of the Human Knockout Project, it is possible that additional efforts to understand the function of human genes can be formulated and carried out in an ethical manner.

I'm a Scientist and I Still Won't Eat Cultured Meat!

         In August 2013, the world marveled at a discovery made by Dr. Mark Post's lab at Maasstricht University in the Netherlands. His lab cultured meat in the laboratory with the use of stem cells obtained from a cow's shoulder. These stem cells were stimulated to differentiate, or convert themselves, into muscle cells. Upon differentiation, the newly generated muscle cells formed a strand, and 20,000 muscle strands were assembled to make a meat patty. This meat patty was cooked and sampled by individuals at an event in London, and while the reviews were not negative, its taste-testers did note that it lacked the flavor associated with the conventional burger.

          Dr. Post manufactured this patty to demonstrate that meat could in fact be made in a laboratory setting, and he hoped that this would be a starting point for ending world hunger in an environmentally conscious manner. Poverty is prevalent in many countries, and the current methods of meat production are believed to be leaving a large carbon footprint. However, is this really the answer? One caveat of the "lab burger" is that it was made with fetal calf serum, so as of now the patty cannot be made without pre-existing animal products. Another drawback is that stem cells have not been successfully isolated from other meat sources such as chickens and pigs, meaning that the types of meat that can be made in the laboratory may be limited.

          Besides the methods utilize to make the meat patty, another important factor to consider is the taste. Does the lab-made patty taste like that from a grass-fed cow? One of the taste testers noted that the texture of the patty was reminiscent of meat, but the taste was bland. Scientists noted that the stem cells utilized to produce the meat were not able to differentiate into fat cells, which may be the reason for the decreased taste of the patty.

          I think that it is amazing that meat can indeed be made in a laboratory, and it is a testament to the advancements that have been made in understanding the differentiation process of stem cells. However, I would not feel comfortable eating a beef patty made in a lab because I love juicy burgers. Dr. Post's group as well as others may encounter great difficulties in recapitulating the taste of farm-raised beef, so the taste is definitely a deterrent. Also, the idea of my food being cultured in a lab is not very pleasant. I've dealt with many chemicals and animal samples in my thesis lab, and I do not want my food being anywhere near that vicinity. I can appreciate the advances being made in the field of stem cell biology, but I rather keep those and my dietary sources separate.

The first lab burger at its grand debut in London.
Courtesy: Natt Garun, http://www.digitaltrends.com/cool-tech/unsurprisingly-300k-lab-grown-burger-tastes-horrible-heres-what-to-eat-instead/#!Qij7k 

The Difficult Plight of the Bee

        What often comes to mind when we think of spring? Usually, it's the cessation of frigid temperatures, the increasing amount of daylight, and of course, the flowers! Flowers have had a longstanding association with the re-emergence of life after a long winter. This relationship evolved from the knowledge that flowers can give rise to fruit and other crops, which are harvested later in the calendar year. Due to this fact, flowers hold great significance in societies around the globe. Since the pollination of flowers triggers fruit formation, the bee is integral for the maintenance of the world's food basket. In addition, bees produce honey, a common flavor enhancer of teas and other confections that we enjoy. Therefore, bees infiltrate many aspects of everyday life.

         Unfortunately, bees have been facing major hardships in the past few years. They have been dying in large numbers with each passing winter, but scientists were unable to pinpoint the cause for this phenomenon. Bees have increasingly been experiencing colony collapse disorder (CCD), in which many worker bees abandon a colony and are found dead elsewhere. This leads to a significant decrease in the number of worker bees maintaining the colony, which often leads to its extinction. Some possible reasons for high death rates among bees were increasing bacterial infection, pesticide use, and even a virus. Nevertheless, the cause of the bees' demise remained unknown.

          Interestingly, a new study from the University of Maryland is providing more insight into the underlying cause of colony collapse disorder during the winter. Dennis vanEngelsdorp and his entomology lab have found that bees are dying from the Varroa mite, a parasite which prefers worker bees as its host. The Varroa mite is opportunistic in that it invades eggs newly laid by the queen bee, before worker bees are able to seal them for their protection. The mites then feast on the blood of the developing bees as well as the worker bees caring for them, which leads to deformities in young bees and the death of their caretakers. With this finding, scientists are hopeful that the death rate of bees can be controlled with pesticide applications.

           Nevertheless, several questions remain. Increased bee death has been observed during the summer months as well, leading scientists to believe that other environmental causes may exist. vanEngelsdorp postulates that pesticide applications and the loss of plants may be contributing to bee death. Because bee pollination is responsible for producing most of the world's food, the increasing rate of bee death is problematic. With time, due diligence in recognizing Varroa mite infestation should allow bee populations to retain their colonies and continue to provide us with the many fruits and vegetables we need to survive.

Bees have been dying from an unknown cause.
Courtesy: www.britishscienceassociation.org

Synthetic Biology: Innovation or Mad Science?

   

The four bases that make up DNA may not be the only ones with the ability to support life.
Courtesy: http://plus.maths.org/content/dna

           Every introductory course in biology teaches students about the building blocks of deoxyribonucleic acid, or DNA. DNA holds the key to life because it holds the instructions needed to make proteins, which facilitate and carry out chemical reactions necessary for life. DNA is composed of units called nucleotides, which consist of three phosphate groups, a 5-carbon sugar, and a nitrogen-containing base. Four nitrogen-containing bases comprise the genetic code: adenine, guanine, cytosine, and thymine. These bases pair with each other, adenine to thymine (A-T) and guanine to cytosine (G-C), to form the characteristic double helix structure of the DNA molecule. These bases have remain fixed for the entire course of evolution, meaning no additional bases have been found in any existing organism. Due to this observation, scientists have been in concordance that only these four bases can support life.

          However, this long-standing dogma may not necessarily be true. A recent report in Nature describes the generation of Escherichia coli (E. coli) cells that carry a third pair of bases in its DNA. Romesburg and colleagues at the Scripps Research Institute in La Jolla, California, have incorporated an unnatural base pair that can be replicated effectively in bacterial cells without compromising their growth. The Romesburg group utilized two compounds, d5SICS and dNaM, to form a new pair of bases, and they were able to introduce these bases into E. coli cells by expressing a gene that encodes a special nucleotide transporter found in algae. Once these synthetic bases were in bacterial cells, they were observed to contribute to the propagation of a plasmid (a circular piece of DNA) containing the unnatural base pair formed by d5SICS and dNaM. Bacteria carrying this modified plasmid were able to divide normally, suggesting that the introduction of the d5SICS and dNaM base pair was not toxic to bacterial cells. These results indicated to the Romesburg group that it was possible to introduce an unnatural nucleotide base pair into an organism without deleterious effects.

          This newest breakthrough in the field of synthetic biology is a step forward for scientists looking to re-engineer cells for various purposes. Some researchers have praised this study as a stepping stone for one day enabling cells to produce biofuels or medicines that have been historically expensive to produce. It is the hope that one day scientists will be able to produce environmentally safe energy alternatives and other necessary products from organisms, eliminating the need to spend millions to obtain these materials utilizing conventional methods.

          On the other hand, another faction believes that these studies may be used for malicious or unnecessary purposes. Some people believe that scientists are going too far in creating organisms that produce substances that they would not normally produce. In their eyes, scientists are "trying to play God" and are engaging in "mad science." However, these individuals often forget that scientists are far removed from re-engineering animals, or even humans, with foreign DNA, and that many ethical safeguards exist to prevent the misuse and abuse of these new technologies. The aim of synthetic biology is not to employ animals and humans as guinea pigs for radical experiments, but the aim is to formulate novel methods for generating biological materials that are scarce or costly to manufacture. This newest advancement in the synthetic biology field should make this goal more attainable in the near future.

MERS: The Next Global Epidemic?

           The Severe Acute Respiratory Syndrome, or SARS virus, made headlines as a formidable public health threat in 2003. According to the Center for Disease Control and Prevention (CDC), the SARS virus was initially discovered in Asia when several individuals were experiencing severe cases of pneumonia. Unfortunately, this illness was observed to be highly contagious, and it was later attributed to a new viral strain that was subsequently called SARS. This virus spread across four continents and killed 775 people until it was contained several months later. Since the SARS outbreak, public health officials and scientists have worked tirelessly to prevent another viral outbreak.

           These efforts have now been put to the test. A SARS-like virus was identified in late 2012 when a Qatari man exhibited severe respiratory illness in an English hospital. This virus noticeably affected many individuals in Saudi Arabia and other Middle Eastern countries, leading to its name "Middle Eastern Respiratory Syndrome," or MERS, virus. Many comparisons have been drawn between MERS and SARS, mainly due to the similarities in symptoms. However, scientists studying MERS have noticed that it does not spread as easily as SARS because it has not resulted in as many cases. This may be due to a reduced ability of the virus to spread from human to human, but the virus is known to infect humans through animal contact since camels have been characterized as the main vehicle for MERS in the Arabian Peninsula. Scientists studying the genetic makeup of MERS have not been able to detect significant genetic changes that would shed light on the increasing number of MERS cases, but they are hoping that increasing awareness will drive individuals to become more cognizant of possible sources of infection.

             Due to the sharp increase in cases, the general public does not know whether MERS should be raising alarms. Because this virus is contagious, people should adhere to stringent hygienic practices. Simple efforts like covering the face after a sneeze, hand washing, and taking a sick day may curb the spread of viruses such as MERS. At this point in time, an effective vaccine cannot be developed due to the MERS virus belonging to the coronavirus family, a notoriously difficult virus subtype to target. Furthermore, we will have to rely on old-fashioned sanitary measures to protect ourselves and others from another potentially devastating virus.
           

The recent series of MERS infections closely resemble those of 2003's SARS virus.
Courtesy: Reuters

Biomedical Research and the Male Scientist

Mouse behavior in a study may depend greatly on the sex of the researcher.
Courtesy: http://www.allaboutvision.com/conditions/amd_news.htm

           Many scientific fields focus on disease studies in order to develop effective therapies. Before potential remedies are supplied to human subjects, their efficacy and safety must first be tested on animals. Mice have served as suitable subjects for new drugs and treatment options that may potentially alleviate or eradicate human disease; thus, an overwhelming majority of biomedical research projects utilize mice. In these studies, variables need to be considered in order to accurately assess whether the experimental group is truly responding to the administered treatment. Such variables may include the health of the mice, the time of day that the treatment is administered, and the treatment dosage.

            Nevertheless, there may be an additional factor that biomedical researchers are not considering: the sex of the researcher. A report in Nature Methods details this discovery. Jeffrey Mogil's lab specializes in projects relating to pain perception in mice at McGill University in Canada. Interestingly, Mogil noticed that something was amiss with the recent set of experiments done by his students.  A pain-inducing agent was injected into the hind paws of mice, and facial grimaces were measured post-treatment. However, mice showed a significant reduction in facial grimaces in the presence of male researchers compared to that of no researcher, and the number of facial grimaces was not affected by the presence of female researchers. It was hypothesized that the smell of males influence this trend because placing a male's shirt in close proximity to a cage was able to exert this same effect, and surprisingly, this effect was nullified by the placement of a female's shirt nearby. Upon further analysis, the scent of male researchers and males of other species increased the levels of corticosterone, a stress-related hormone, in the blood of mice. This revelation led Mogil's group to postulate that the male scent induces a stress response in mice, which can alter the outcome of administered treatments.

             Though the idea that mice behavior exhibits a sex bias can be comical, this possibility raises a number of concerns. For example, some people wonder whether all past biomedical experiments employing mice are now invalidated. This finding does not necessarily prove this notion for a number of reasons. First, this set of experiments was done solely to measure pain responses; this study does not address sex bias in other types of mouse studies, such as those involving drug responses. Also, some physical characteristics of mice are known to be dependent on genetic background. This means that a particular stimulus may elicit a different behavior in a mouse with brown coat color compared to one with black coat color. Mouse behavior may also exhibit a more pronounced sex bias in response to pain versus other stimuli. Furthermore, we are reminded that there are subtle aspects of scientific studies that may influence their outcome, and we should identify and consider these factors more heavily when evaluating the data of future experiments.

The Mysterious Y Chromosome

        One key difference distinguishes men from women: the Y chromosome. This name is a misnomer, since this chromosome resembles a chromosomal fragment rather than the letter Y. Despite the Y chromosome's small size, its biological function is essential to the survival of species. Several genes on this chromosome are important for initiating the development of male sex organs. For example, the SRY (Sex-determining factor Y) gene is responsible for stimulating the formation of testes during embryonic development.

         Questions surrounding the evolution of the Y chromosome have lingered in the minds of scientists since its discovery in 1905. It has been estimated that the Y chromosome lost 97% of its genes during the course of evolution, and researchers believe that there must be a reason why the remaining 3% of genes on the Y chromosome were retained. Until recently, it was unknown whether these genes possessed a selective advantage over the genes that were no longer present. A study in Nature has conducted rigorous genetic analysis of the Y chromosome to gain a better understanding of the genes that have weathered time. David Page's group at the Massachusetts Institute of Technology (MIT) found that the genes that have been shielded from decay are required to maintain proper levels of proteins essential for viability. In other words, loss of these genes on the Y chromosome would result in deficiencies for proteins involved in important biological processes, which can lead to the death of an organism. Thus, this research group concluded that genes found on the Y chromosome play a role in supporting basic cellular processes as well as determining male sex characteristics.

          This finding is intriguing because it sheds light on possible variables that might not be considered in human diseases and disorders. For instance, loss of the Y chromosome can result in developmental disorders such as Turner syndrome, in which an individual has one X chromosome but lacks another functional X or Y chromosome. These individuals appear to be female but often fail to develop mature ovaries, leading to decreased fertility. Turner syndrome also results in other maladies such as hearing loss, scoliosis, and short stature. It is possible that a deficiency in gene dosage due to the lack of an X or Y chromosome is responsible for sex-independent characteristics of this disease. Many of the genes on the Y chromosome are expressed throughout the body, so they will most likely function in capacities that are independent of male sex organs. Furthermore, future studies should investigate the various functions of these genes in male cells and how they contribute to supporting the lives of male organisms.

A human X chromosome (in red) and Y chromosome (in blue).
Courtesy: SPL, http://www.bbc.com/news/health-24991843

The Ferocity of Amoebae at the Microscopic Level

An amoeba (in green) is eating a human cell (in pink).
Courtesy: Katy Ralston; http://www.npr.org/blogs

        We've all heard the headlines detailing fateful encounters with a dreadful foe, the amoeba. An amoeba is a single-celled organism that can infect a host and cause serious illness, sometimes to the point of death. Amoeba infections tend to be rare, but their effects can be damaging. For example, Naegleria fowleri, an amoeba that is commonly found outdoors in untreated water, can infect humans through the nose. Remarkably, 90% of infected individuals are asymptomatic, but inflammation of the brain can develop in the few cases that do present symptoms. Scientists discovered that this amoeba secretes enzymes that digest brain tissue, which the amoeba then utilizes as sustenance.
         If this occurrence sounds like the makings of a horror film, this is just the tip of the iceberg. Another subtype of amoeba, called Entamoeba histolytica, populates the intestine upon infection and results in severe cases of food poisoning. The mechanism by which E. histolytica causes disease has remained unclear until now. A recent report in Nature describes the methods utilized by this amoeba to antagonize human cells. Dr. William Petri's group at the University of Virginia uncovered the devastating events by imaging E. histolytica activity under a microscope. To the groups' amazement, the amoeba chewed on human cells and regurgitated the cellular debris. Upon making this observation, Petri's group was perplexed. Why would the amoeba destroy human cells in this manner without digesting their material? Their hypothesis states that the amoeba is solely attempting to break through the intestinal wall, rather than consuming intestinal cells. With this revelation, Petri hopes new tactics can be developed to combat the cellular carnage that E. histolytica and similar amoebae  inflict.
        It is common to observe bacteria and other parasites exhibiting aggressive behavior toward each other, but to visualize an amoeba eating a human cell and merely spitting out the remnants evokes a different sense of fear. We like to consider ourselves near the top of the food chain, so to see a microscopic organism challenge that notion is difficult to accept. This story reminds us that vigilance is essential to remaining in good health. So don't forget to boil that water for your neti pot and remember to wash food items in clean water!
        
            

Fertilization Really Isn't Magic!

         The creation of a new life first requires the fusion of an egg with sperm. This initiates a cascade of events that drives the division of the newly fertilized egg. Though this phenomenon is considered to be a fundamental part of biology, there are many aspects of fertilization that are unknown. For example, the mechanism for sperm-egg partnering has been nebulous for many years. In 2006, a breakthrough was made in which a protein called Izumo1 was discovered on the surface of mouse sperm. Inoue and colleagues at Osaka University in Japan found that male mice lacking this protein were sterile. Interestingly, sperm lacking this protein were observed to bind to an unfertilized egg, but they were unable to undergo fusion. These results led the group to conclude that Izumo1 was necessary for sperm-egg recognition, but it also raised a new question surrounding the identity of Izumo1's binding partner on the surface of the egg.

         A new report in Nature has proposed an answer to this question. A study from Dr. Gavin Wright's laboratory at the Sanger Institute in Cambridge, England, have identified a protein on the surface of the egg called Juno. This protein binds to Izumo1, and it is essential for egg-sperm recognition since fertilization does not occur in female mice lacking this protein. An intriguing facet of this report is the disappearance of Juno protein from the egg surface after fertilization. This occurrence may be responsible for limiting eggs to one fertilization event since it takes place within forty minutes of fertilization. These findings led Wright's group to conclude that Juno is the long-lost partner of Izumo1, and the presence of these proteins in humans indicates that identical interactions occur during the inception of human life.

        Both these studies raise a new set of questions. How does binding of Izumo1 to Juno lead to the surface of the egg becoming more permeable? Which signaling events are taking place in the cell to remove Juno from the egg surface after fertilization? More work will have to be done to fully understand all events occurring during the fusion of egg and sperm. It will also be useful to determine whether a reduction of either protein in humans can serve as an underlying cause of infertility. Conversely, it may be possible that an increase in Juno protein on the egg surface can facilitate fertilization. It's a wonder that these protein-binding events spur the wonderful journey that we call life! 

A fertilized human egg after in-vitro fertilization.
Courtesy: Advanced Fertility Center of Chicago; http://www.advancedfertility.com/embryos.htm

Cancer Cells: The Epitome of Greed

         Regulatory networks exist within cells to control behaviors that may potentially become pathogenic, such as migration and division. When these systems are defective, cancer cells arise and wreak havoc in an organism.  Cancer cells have broken free of regulatory constraints to divide uncontrollably and compete with normal cells for nutrients, interfering with tissue function and leading to organ failure. Cancer cells are a unique challenge for treatment because they can evade detection by the immune system, and their elimination can have deleterious effects on neighboring normal cells.

         Over several decades, researchers have studied methods to halt cancer cell growth. One facet of cancer cell physiology was highlighted in the 1920s when Otto Warburg, a German biochemist, noticed that cancer cells consumed significantly more glucose than normal cells. In order for cells to carry out the processes required for life, they must consume and dissemble glucose in a series of steps to extract energy. Increased metabolism in cancer cells indicated to Warburg that the abnormal division rate of cancer cells was driven by their insatiable need for glucose. Fifty years later, attention shifted to genetic alterations that were conducive to cancer progression, and researchers at that time believed that Warburg's observation was a consequence rather than a causative agent of cancer.

         However, the spotlight has once again turned to the metabolic properties of cancer cells due to a recent discovery described in Nature. This report states that cancer cells are highly dependent on a mutation within the enzyme called isocitrate dehydrogenase 2, or IDH2. This enzyme is a component of the citric acid cycle, which facilitates the generation of adenosine triphosphate (ATP), the main energy source in cells. Mutations within this enzyme are significant because they are hypothesized to re-route the metabolic process by favoring a faster, less efficient method of producing ATP in cancer cells. In light of this result, a drug called AG-221 was developed to combat the activity of the abnormal version of IDH2 in cancer cells. Clinical trials for AG-221 have shown great promise in acute myeloid leukemia (AML) patients, raising the possibility that the reliance of cancer cells on particular metabolic pathways can provide drug targets for cancer treatment.

       Metabolism has become a hot topic in the realm of cancer biology because it is a feature of all cells. Every cell in the body must incorporate glucose for ATP production, but cancer cells take advantage of this process to support their constant growth and proliferation. The identification of compounds that block the utilization of alternative metabolic pathways in cancer cells can serve as an innovative method of combating cancer's devastating effects. Nonetheless, more research is needed to ensure that these compounds have a minimal effect on healthy tissue and that these compounds are not a short-term fix. Cancer cells notoriously accumulate additional genetic mutations to circumvent cancer therapies, and this has hampered the formulation of effective anti-cancer drugs. Despite the uncertainties that remain, this new finding sets the stage for a greater emphasis on differential requirements between cancer cells and their normal counterparts, which will increase our knowledge of the aberrations that surface when a normal cell becomes cancerous.

Leukemia cells take advantage of metabolic pathways to support their high division rate.
Courtesy: Charles Hess, MD and Lindsey Krstic, BA; University of Virginia 

Guess That Bacterium!

Salmonella, a potentially dangerous bacterium, is often associated with raw eggs.
Courtesy: Bill Marler, www.marlerblog.com

      Food poisoning is an unconvenient part of life. Though foods can be prepared with the proper guidelines, bacteria and viruses can sometimes evade these safeguards and cause illness upon ingestion. In the case that infections spread through a population, it is the Center for Disease Control and Prevention (CDC) that conducts investigations to identify the sources of foodborne illness.

      For potentially serious outbreaks, whole genome sequencing has recently been adopted to identify causative pathogens. Whole genome sequencing allows for the elucidation of all DNA sequences within an organism, and this method has been a useful tool for distinguishing organisms within a species. Recently, the CDC has embarked on a project to identify several strains of Listeria involved in outbreaks this year. This work will be carried out with whole exome sequencing, and this venture is exciting because Listeria strains responsible for these cases may be detected more accurately. The probability that two bacterial strains will be 100% genetically identical is extremely low; therefore, this testing option may distinguish pathogenic bacteria and viruses more effectively.

       If this project is successful, the CDC will have a robust protocol for identifying the sources of illness within the population. In addition to recognizing bacterial and viral agents efficiently, whole genome sequencing can illuminate the diversity that exists between strains and the mechanisms by which this diversity arose (e.g. genetic mutations). Though this prospect is a step forward in understanding the genetic landscape of pathogens, we should still enjoy that next burger safely!

   

The Publishing Predicament

        The postdoctoral fellow waits anxiously at his computer as time ticks away. His fifth year in the lab is quickly coming to an end, and he has worked tirelessly to produce a cohesive story from his research project of three years. It took a year to prepare the final manuscript, and he is waiting on the email containing the verdict of his last submission attempt. Unfortunately, the paper had already been rejected from four journals, and he is slowly losing hope of his work being published in a highly respected journal. He plans on applying for faculty positions in the fall, but he senses a long journey lies ahead because he lacks one thing: a publication in Cell, Science, or Nature.

        Unfortunately, this situation is not uncommon for those looking to gain tenure-track positions in academia or research scientist positions within industry. Universities and institutions scrutinize the number of publications a candidate has authored in addition to the journals in which those publications appear. As a general rule of thumb, a candidate must have at least one publication in Cell, Science, or Nature. These journals are considered to be elite since they often publicize the most novel and provocative findings. In line with this reputation, these journals are highly selective, often rejecting 90% of submissions.

         Though these three journals are highly respected by the scientific community, researchers know that every piece of scientific work must be evaluated for its merit. In the search for novel discoveries, journals sometimes overlook the scientific reasoning that accompanies the work, leading to errors and faulty logic that may derail the research of others in a particular field. This problem has recently been highlighted by Randy Schekman, one of two scientists recognized for the 2013 Nobel Prize in Physiology or Medicine. In an article for The Guardian, he suggested that researchers boycott submissions to Cell, Science, and Nature and instead publish in open-access journals. Though the journals try to provide the scientific community with novel science, he argued that they often fail to recognize major flaws, which can later lead to retractions.

        Journal editors require a set of criteria for identifying reports that will further scientific progress, and novelty has become a convenient measuring stick. But it has become increasingly clear that this cannot be the main criterion for assessing the quality of scientific work. A new system must be adopted in which the merit and clarity of scientific work is more heavily considered. Not only will this change allow for more young scientists to continue their research pursuits in academia, but it will also encourage them to take more care with their work and present arguments that are sufficiently supported by their experimental results. No consensus has been reached concerning how this change can be effected, but the future of science depends on emphasizing the inherent quality of scientific reports rather than the journals choosing to publish them.

       

                      Randy Schekman, a 2013 Nobel laureate, has called for an end to the elite journal culture.
                          Courtesy: http://newsroom.ucla.edu/portal/ucla/randy-schekman-molecular-biologist-248784.aspx

         

  

Acid Bath Stem Cells: Fact or Fiction?

      Three months ago, the scientific community was rattled by two papers published in Nature. These papers, with Haruko Obokata listed as first author, claimed that subjecting adult mouse white blood cells to acidic conditions converted them into embryonic stem-like cells. Embryonic stem cells have the ability to produce multiple cell types in an organism, and scientists have attempted to find alternative methods for their isolation since the primary method involves the destruction of fertilized embryos. Thus, the publication of these papers excited researchers with the prospect of a relatively easy protocol for creating stem-like cells.

       Unfortunately, the inability of researchers to reproduce Obokata's experiments have raised questions about the validity of her results. Several figures in the papers appeared to be modified or mislabeled, sparking an investigation for scientific misconduct by the RIKEN Center for Developmental Biology. Yesterday, the committee ruled that Obokata was indeed guilty of scientific misconduct due to several inconsistencies in her 2011 paper as well as those found in her most recent publications.

       This situation is a cautionary tale to those that fail to scrutinize sensationalist scientific reports. The results from Obokata's papers seemed reasonable upon second glance, but the idea that adult cells can be converted into stem-like cells with pH stress was outlandish. Editors of scientific journals, in the quest to publish the most novel and insightful papers, can get carried away with a provocative study that may be shown to be fraudulent or non-reproducible in the future. Therefore, the old adage still rings true: "If it seems too good to be true, it probably is."

Mouse embryo supposedly created by Obokata's stress-induced cells, which expressed green fluorescent protein (GFP).
Credit: Nature News http://www.nature.com/news/acid-bath-stem-cell-study-under-investigation-1.14738

Embryonic Stem Cells, Retroviruses, and You

        The human cell contains roughly 25,000 genes, so it is natural to believe
that the majority of the human genome contains protein-coding genes. On the contrary, protein-coding genes only make up about 2% of our genomes. If protein-coding genes constitute a small percentage of the human genome, what is the function of the other subset of genes occupying our cells? Ninety-eight percent of our genomes contain non-coding DNA, which includes DNA sequences that regulate the expression of coding genes, pseudogenes (genes that no longer encode protein due to the acquisition of mutations over time), and transposons (DNA sequences that migrate through the genome). Scientists hypothesize that these non-coding sequences

Embryonic stem cells in the process of generating multiple cell types.
Courtesy: University of California, Merced 

  

originated from retroviruses. Retroviruses are a unique class of virus that convert their RNA sequences into DNA with the aid of an enzyme called reverse transcriptase. They also possess enzymes that facilitate the incorporation of their newly converted DNA into the genome of their host, ensuring that their genetic material will be replicated during the lifetime of the host cell. Retroviruses have received much negative attention due to the devastation caused by HIV, the most infamous retrovirus of all.

         However, retroviruses may have contributed to our evolution. A new study published in Nature Structural and Molecular Biology suggests that a retroviral infection may have bestowed pluripotency (the ability of a cell to generate multiple cell types) on primate embryonic stem cells. This study, led by Huck-Hui Ng's group in Singapore, discovered that sequences belonging to the human endogenous retrovirus H, or HERVH, could be detected in human embryonic stem cells. When mutations were introduced into these sequences, human embryonic stem cells no longer had the capacity to generate multiple cell populations, leading Ng and colleagues to conclude that HERVH infection played an important role in the origins of cell pluripotency.

       Interestingly, these scientists suggested that stem cells from non-primates do not rely on HERVH for pluripotency. This idea implies that primate and non-primate stem cells rely on different evolutionary sources for their pluripotency, and the next logical question concerns how this phenomenon occurred. These studies highlight a crucial role that environmental agents play in our evolution, and it will be fascinating to learn of other important cellular functions that may be dependent on virus-host interactions.

Designer Bags and Designer Chromosomes

      Imagine your pet carrying a genome assembled by a group of scientists. This situation probably sounds like the beginning of a science fiction movie, but it may become a reality. A new report in Science describes the creation of a synthetic chromosome in baker's yeast (Saccharomyces cerevisiae).

      Jef Boeke's group at New York University generated a synthetic version of chromosome 3, one of the smallest chromosomes in the genome of baker's yeast. In creating this chromosome, they eliminated transposons (DNA sequences
that have the ability to move around the genome) and introns (non-coding
regions of DNA). Boeke's group also designed custom DNA sequences

Electron micrograph of human chromosomes.

Courtesy: Andrew Syred, York University, Canada

that they incorporated into the yeast chromosome with the aid of homologous recombination, which involves the exchange of native yeast DNA sequences for the custom-made counterparts. Yeast cells carrying this chromosome were able to mate and behave normally, which indicates the artificial DNA is not deleterious to the cells. Additionally, artificial DNA incorporated into this synthetic chromosome allowed yeast cells to undergo genetic recombination, which can add or delete specific segments of DNA.

      Craig Venter announced his team's creation of the first synthetic bacterium in 2010, and this innovation quickly grasped the attention of the public. With the advent of these synthetic organisms, scientists have claimed that the formulation of vaccines, medications, and biofuels can be less expensive and time-consuming. It may take several years for scientists to engineer these organisms, but this possibility opens the door for additional advantages of these systems to be explored.

The Nose Knows More Than We Think

         The intoxating smell of bacon permeates the kitchen. The spring flowers bloom and envelop the atmosphere with their natural scents. Smoke from a nearby bonfire on the beach signals the beginning of summer. These stimuli are sensed by the nose, which houses specialized structures that sense odorants (molecules that produce smells) and relay information to the brain through their association with brain cells. Our noses are able to detect a wide range of smells, and several publications have estimated that the human nose can detect 10,000 different scents.

          However, a report in Science estimates that one trillion scents can be detected by the human nose. Researchers at Rockfeller University developed a set of criteria that allowed for the generation of various odor combinations, which they provided to subjects. The ability of the subjects to discriminate between different odor mixtures was measured, and the quantifications from these experiments were used to calculate their estimate.

          This article noted that one trillion is the lower limit of odors our noses can discern, meaning that the actual number may be much higher. This piece of news intrigued me and led me to think of physical properties that confer this capability. How many different olfactory receptors (proteins that bind odor molecules and facilitate the transfer of odor information to the brain) do we have? Do olfactory neurons, the cells through which olfactory receptors transmit signals, function as small or large groups? How would this activity be controlled? Our olfactory systems may be more complex than we previously believed.

          Furthermore, it will be interesting to determine the mechanism through which olfactory receptors process different odor molecules to allow for the brain to distinguish smells. Studying the means by which this sensory information is sorted and interpreted by the brain will also provide more insight into the development of this amazing ability. Until then, happy smelling!

The scent of a rose is composed of 275 odor components (Bushdid et al., Science 2014).

Courtesy: http://www.varietybackyard.net/ho-to-deal-with-some-common-diseases-of-roses/

Does Lupus Provide the Basis for the Next HIV Vaccine?

        The immune system allows our bodies to maintain their integrity by eliminating deleterious foreign agents. The immune cells that mediate this process are highly effective and specific, contributing to the powerful nature of the immune response. However, the deregulation of immune cell activity has severe consequences. For instance, lupus is a disorder that stems from the production of self-reactive antibodies (antibodies that recognize the body's proteins). In normal individuals, immune cells that produce self-reactive antibodies are eliminated. However, individuals affected with lupus fail to clear these cells, resulting in autoimmune responses throughout the body that result in widespread inflammation, pain, and tissue destruction.

         Though the damage inflicted by lupus is extensive, one facet of the disease has been highlighted as a possible treatment option for human immunodeficiency virus (HIV) infections, which kill immune cells and dampen the immune response. Through studies of a young woman affected by both lupus and HIV, researchers at Duke University identified broadly HIV-1-neutralizing antibodies (BnAbs). These antibodies were considered unique due to their ability to recognize HIV proteins, and their presence in the woman may have alleviated the detrimental effects of HIV infection. Wonder and amazement filled many people upon the reception of this news, and some have proposed that further studies of these antibodies may lead to the formulation of new HIV vaccines.

         The findings of this study shed new light on lupus and the process that immune cells utilize to produce antibodies, but many questions remain unanswered. First, it is unclear whether BnAb production is dependent on the production of self-reactive antibodies. The authors of the study observed that BnAbs can bind to human proteins and double-stranded DNA, which suggested that BnAbs were self-reactive. This result highlighted a similarity between BnAbs and antibodies found in lupus patients, leading Duke researchers to postulate that BnAbs and self-reactive antibodies are produced by the same population of immune cells. Second, a normal immune system eliminates cells that produce BnAbs, and it is unknown whether the immune system can be coaxed into producing these antibodies safely. Stimulating a person's immune system to generate these antibodies may also encourage the production of self-reactive antibodies, which will be a dangerous side effect. Thus, more work is required to understand how these antibodies are created and the conditions that favor their production. Scientists must also consider the high mutation rate of the HIV virus, so major hurdles obstruct the possibility that this study will lead to a functional HIV vaccine.

Diagram depicting CH98 (green and blue), a broadly-reactive antibody, bound to the HIV protein gp120 (gray).

Courtesy: Bonsignori et al., The Journal of Clinical Investigation 2014

The Funding Conundrum

          Reused pipette tips were once a odd occurrence in the lab, but they're increasingly more common. The eppendorf tube quality, which was once adequate, are now replaced with shoddy counterparts that fail to close properly and are prone to nail chipping. The purchase of an essential antibody for that dream experiment is now arduously negotiated with the principal investigator, though this practice was virtually nonexistent several years ago. These are all measures that have been taken by labs to cut costs, and unfortunately more drastic steps may quickly follow due to significant funding cuts at the National Institutes of Health (NIH).

Courtesy: http://report.nih.gov/success_rates/

          The NIH is the major funding agency for biomedical research, and principal investigators rely greatly on NIH grants to support their research projects and staff. The sequester of 2013 resulted in a

5.5% NIH budget decrease to $29.15 million, which greatly reduced the number of funded research grant proposals in 2013 by roughly 650. The approval rate for grant applications in 2013 was estimated to be 14%, exponentially decreasing the chances that a grant application will be funded. Thus, a proportion of researchers looking to renew their grants were denied and many early career scientists requesting financial support for their projects were turned away.
 

         The scientific community is wading through dark times as a result of this drop in funding. Labs are closing left and right, while those that remain are forced to cut down on resources that are essential for their research. For example, a lab heavily dependent on microscopy for its projects may be forced to decrease microscopy hours. This would negatively impact research quality and progress. Postdoctoral researchers planning to apply for faculty positions are now forced to rethink their options as the possibility of reaching that goal dwindles, and graduate students with the same aspirations are facing the same grim reality.

         Scientific research faces an uncertain future. No substantial remedy for the NIH funding situation has been proposed, and it is possible that more cuts will be made to the budget. The ramifications of this dilemma ripple through the research hierarchy, and talented scientists that may have successfully led their own labs are increasingly drawn toward other career paths. Though the government struggles to maintain our country's infrastructure, officials need to ensure that biomedical research is sufficiently funded. The etiologies of many developmental disorders and diseases remain unclear, and treatment alternatives as well as prophylactic therapy for these maladies depend on the work of research scientists. It is our hope that Congress keeps these considerations in mind as we move forward.  

Happy Pi Day!

             Combine the world's favorite irrational number and a sweet confection of the same name and what do you get? Pi Day! Today is March 14, or 3/14, so I'll shed some light on the history of this popular constant.

            The origins of pi (or 3.14159...) lie in the detailed calculations of the Babylonians and Egyptians, who noted that an approximate ratio of 3:1 described the relationship between a circle's circumference and diameter. The first approximation of pi was achieved by the Greek scholar Archimedes. Unlike his unsuccessful predecessors, he chose to utilize the perimeters of polygons to estimate a value for pi. This involved inscription and circumscription of hexagons followed by a doubling of the sides four times to generate a 96-sided polygon. This significant breakthrough sparked the curiosity of a French mathematician named Françiose Viéte. He adapted the methodology of Archimedes to calculate a pi value of 3.1415926535, the first numerical approximation. Several other gifted mathematicians followed suit and estimated the value of pi to a total of 35 digits. Ludolph Van Ceulen of Germany devoted his life to elucidating the full value of pi and successfully derived the 35-digit value. The symbol for pi (π) which we hold so dear, was introduced by Leonhard Euler in 1737.

          Circles can represent a multitude of ideas. For example, they are believed to symbolize eternity, or the absence of a beginning or end. As the significance of the circle will continue to live on in cultures across the world, the concept of pi will certainly follow in the same footsteps.

courtesy: www.rebloggy.com

Embryonic Development of C. elegans

      In about a month, I will be educating kids about the link between genes and behavior at Science Saturday! I belong to a group of students and postdoctoral fellows that will construct booths to show kids that science is fun. And in the process, we will expose them to a multitude of scientific areas. This is an event put together by two science outreach groups at Rockefeller University and it's going to be amazing.

      For my booth, I will present normal and abnormal strains of a small, transparent worm called Caenorhabditis elegans, or C. elegans. This worm is 1 millimeter in length and can be found in common outdoor areas such as compost heaps and garden soil. Due to its short generation time and relatively small genome, this worm has become popular for genetic studies mainly through the work of Nobel laureate Sydney Brenner.

      By training I'm a developmental biologist, so visualizing the metamorphosis of a fertilized egg into a functional organism is quite breathtaking. Enjoy the video below of C. elegans development! How a fertilized egg develops into a hatching worm within twelve hours is nothing short of awesome!

  )
  courtesy: Hymanlab

Is Tongue-Rolling a Genetic Trait?

          "How many people in this room can roll their tongue?" This question was posed to my ninth grade biology class as an introduction to the subject of genetic traits. I was taught that tongue-rolling, the ability to elevate the lateral edges of the tongue, was a genetic trait; thus, if you were able to roll your tongue, at least one of your parents would be able to do the same. This example was widely utilized in schools to introduce children to the concept of genetic inheritance, but can this trait be  explained by a single gene?

          Several studies in the past 70 years have set out to answer this question. Alfred Sturtevant, of later Drosophila melanogaster (fruit fly) genetics fame, was scintillated by this question and conducted a small survey on those able to roll their tongue (rollers) and those that could not roll their tongue (non-rollers) within families. Before embarking on this project, he hypothesized that tongue-rolling was determined by a single gene with two copies (one inherited from each parent). During his studies, he found that tongue-rolling parents often had children with the same trait. However, he also discovered that parents without the tongue-rolling trait occasionally had children that rolled their tongues, albeit at a lower frequency than parents with the trait. Philip Matlock conducted a similar study in identical twins across a large age range and noted many cases in which only one twin was a tongue roller. The data collected by Sturtevant, Matlock, and others suggest that tongue-rolling cannot be attributed to one gene. In fact, this trait can also be learned because in 1951, Taku Komai's analysis of Japanese children described the increase in tongue-roller frequency from 54% in children from ages 6-7 to 76% in children at age 12.

Courtesy: fakescience.org

        Since there is overwhelming evidence that tongue-rolling is not controlled by a single gene, what are the other possibilities? One is that tongue-rolling is determined by multiple genes, so it would be quite complex to predict who possesses this trait since the identity and quantity of genes responsible for this trait are unknown. Another is that this trait requires an environmental component, and this would be compatible with the observation that non-rollers can learn to roll their tongues. In light of this data, it is inaccurate to state that tongue-rolling is a simple genetic trait. Therefore, it would be more wise for classrooms to revert to pea color and shape as examples of Mendelian inheritance.

The Battle of the Sexes: Revisited

     This divide between the sexes is attributed to sex hormones, namely estrogen and testosterone. Both hormones are present in men and women, but testosterone predominates in males while estrogen predominates in females. Several organs in the body contain cells whose behavior is modulated by biological sex. For example, female muscle stem cells were found to regenerate muscle cells more efficiently than their male counterparts in a mouse model of muscular dystrophy. Though sex can influence cellular behavior in multiple organs, cells within organs that are not known to present sex-specific differences are thought to function similarly in both men and women.

     However, a recent report in Nature challenges this notion. Studies in the Morrison lab at the University of Michigan have focused on identifying sex-specific differences in cell populations that are seemingly unresponsive to sex hormones, and hematopoietic stem cells, or HSCs, first grabbed the lab’s attention. Hematopoietic stem cells reside in the bone marrow and divide to generate red blood cells, which carry oxygen to tissues throughout the body, and immune cells, which recognize and destroy bacteria, viruses, and parasites. These cells often lie dormant until stimulated to divide by external cues, and there has been no previous evidence that these cells exhibit sex-related differences. Surprisingly, data from the Morrison group suggest that HSC behavior is not uniform between males and females. Though HSC number and frequency in male and female mice were comparable, increased HSC division was observed in female mice. Interestingly, HSC division was induced by administration of estrogen to both male and female mice, and this phenomenon did not occur in other bone marrow cell populations or in response to testosterone. HSC number, along with red blood cell and immune cell numbers, were increased in pregnant females compared to non-pregnant females. This effect was abolished when estrogen receptor function was compromised, leading to the theory that female HSCs respond to estrogen and that estrogen can regulate HSC division to accommodate the increased need for oxygen in pregnant females. 

    If these data mirror HSC activity in humans, there are several implications. First, the ability of HSCs to respond to estrogen may be relevant for the health of pregnant mothers and their unborn children. Estrogen levels among women can vary, so those with lower estrogen levels may be predisposed to more physical stresses during pregnancy. Second, there is now the possibility that sex hormones can modulate the onset of blood disorders and other diseases. For example, cytopenias, diseases in which immune cell numbers are greatly reduced, tend to be more common in men. Thus, reduced HSC proliferation in men might contribute to the persistence of these disorders. Third, sex may be an additional variable to consider in the field of personalized medicine, which involves the administration of therapy tailored to an individual’s genetic makeup. In this case, it will be imperative to note the individual’s sex in order to uncover contributing factors to disease and to predict patient prognosis. 

    Evolution allows organisms to meet metabolic needs during fluctuations in nutrient availability or changes in physical state (such as pregnancy). It is remarkable that nature may have designed a system that enables HSCs to divide in response to a sex hormone heavily involved in the reproductive process, and new insights provided by future studies on this topic will be of great interest. It will also be fascinating to discover other stem cell populations that function in a similar fashion. Until then, it is comforting to think that womanhood just got a lot better!