Epigenetics: The Software of the DNA Hardware


Scientists identified the genes of the human genome to understand how the genes influences the function and physical characteristics of human beings.

The Human Genome Project (HGP) was an amazing endeavor to map the full human genome, and so intense an effort that it required an international collaborative research team. One of the ultimate goals of this project was to shed light on human diseases and find the underlying genes causing these health issues. However, the HGP ended up creating more questions than answering them. One thing we found out is that most diseases are complex diseases, meaning that more than one gene causes the disease. Obesity is one such example of a complex disease. This is in contrast to cystic fibrosis which is a disease caused by a mutation in a single gene. To further complicate diseases, there are gene and environment interactions to consider. A gene-environment interaction is a situation in which environmental factors affect individuals differently, depending on their genotype or genetic information. The possible number of gene-environment interactions involved in complex diseases is daunting, but the HGP has given us the information necessary to start better understanding these interaction.

Although the HGP did not end up giving us the answers we were looking for, it pointed us in the direction we needed to take. We needed to consider the role of environmental factors on human health and disease. For not only are complex diseases not fully explained by genetics alone, but another aspect of these diseases remains unexplained by genetics: the health disparities seen within diseases like obesity, diabetes, cancer, etc. The HGP showed us that not all diseases are caused by single mutations and that genetic diversity does not explain the differences in health outcomes. The environment plays a big part.


Epigenome  is the software that controls gene expression to make the different cells that make up the human body.

Gene-environment interactions begin to answer why genetics alone cannot explain  varying health outcomes by considering that the environment may have varying effects on our genetic data. However, there is another dimension to our genetic background that could better answer why genes often can’t be mapped directly to a disease. Imagine that our genome is our computer hardware, with all the information necessary to create the cells we are composed of. However, something needs to configure the genome to differentially express genes so as to make skin and heart cells from the same DNA. Skin and heart cells have the same information (DNA) in their nucleus but only express what’s necessary to function as a skin or heart cell. In other words, software is needed for the hardware. For us, that software is the epigenome. The epigenome consists of a collection of chemical compounds, or marks, that tell the genome what to do; how to make skin and heart cells from the same information. The epigenome, unlike the genome, is flexible. It can change at key points in development and even during the course of one’s lifetime. This flexibility makes the epigenome susceptible to environmental factors and could explain: (1) Why our genome alone cannot explain the incidences of diseases such as obesity, (2) the health disparities within these complex diseases, and (3) the transgenerational inheritance of complex diseases like metabolic syndrome, defined as a cluster of conditions such as high blood pressure and high blood sugar that increase your risk for heart disease and diabetes.

Now of course, the more we find out the more questions are left unanswered. As stated before, the epigenome can change due to lifestyle and environmental factors which can prompt chemical responses. However, the mechanisms by which things like diet and smoking induce these chemical responses is unclear. But researchers have started to fill in the gap. For example, certain types of fats, like polyunsaturated fatty acids (corn oil is high in these), can generate highly reactive molecules and oxidative stress, which can cause epigenetic alterations. Tobacco smoke contains a mixture of chemicals that have been independently investigated with mixed results on the epigenetic effects. Psychological stress, more specifically child abuse, has been seen to cause increased methylation (a sort of mark on the genome) of a receptor for hormones responsible for metabolism (glucocorticoid receptor) in suicide victims. This has also been seen in mouse models where higher maternal care of pups decreased methylation of the glucocorticoid receptor. Increased methylation usually decreases the expression of the glucocorticoid receptor, and decreased methylation would increase the glucocorticoid receptor’s expression.

The HGP was an amazing endeavor of science and has given us amazing insight into the structure, organization, and function of the complete set of human genes. It has also helped point us in a new direction to better understand chronic diseases and seek to find the solutions to address the burden of disease.

Peer edited by Mejs Hasan and Emma Hinkle.

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Cloned Monkeys: Another Human Creation

http://english.cas.cn/head/201801/t20180123_189488.shtml Image credited to Qiang Sun and Mu-ming Poo, Institute of Neuroscience of the Chinese Academy of Sciences

First cloned none-human primates: Zhong Zhong and Hua Hua (Image credited to Qiang Sun and Mu-ming Poo, Institute of Neuroscience of the Chinese Academy of Sciences)

Cloned primates are here! Over three decades have passed since the birth of Dolly, the sheep, scientists have now tackled cloning mammals that are even closer to us on the evolutionary tree: macaque monkeys. What does this mean for a society that witnesses dramatic changes day by day: computers are outperforming doctors in calling out heart abnormalities in patients; 3D-printed organs are bringing us one step closer to tissue restoration; genome sequencing has become an online product easily available for anyone curious about their ancestry, bodybuilding, or just simply wine tastes. Breakthroughs in science and technologies are so prevalent in our life that by now, we probably shouldn’t be surprised by any new discovery. Yet when the two cute, little, cloned monkeys were born, the whole world was, once again, shaken.

Published in Cell on January 24th, 2018, a study from a group of scientists in China reported their methods in generating two non-human primates that are genetically identical. To clone the two identical macaque monkeys, the scientists applied Somatic Cell Nuclear Transfer, the same method that generated Dolly in 1996. The key idea behind cloning is that a new organism, be it sheep or monkey, is generated without sexual reproduction. Asexual reproduction is not as uncommon as one would think, plenty of plants do so. For example, Bryophyllum shed plantlets from the edge of the leaves to produce new plants. Some insects, such as ants and bees, also exploit asexual reproduction to clone a huge working class army. Since asexual reproduction is essentially an organism duplicating itself, the offsprings are all genetically identical. Evolution, however, doesn’t favor asexual reproduction as identical offsprings don’t prevail in a fast changing environment. On the other hand, sexual reproduction combines different sperms and eggs to create diverse offsprings, of which some may survive. To combat challenges from the mother nature, higher organisms, such as mammals, almost exclusively reproduce sexually. This is why a cloned monkey, an anti-evolution human creation, is mind blowing.


The succulent, genus Kalanchoe, uses asexual reproduction to produce plantlets.

To clone mammals, scientists came up with the idea of transferring the nucleus of a somatic cell to an enucleated egg (an egg that lacks nucleus). Unlike  germ cells (sperm and eggs), somatic cells refer to any cells that don’t get passed onto the next generation. These cells have the full genome of an organism that is split equally in germ cells during sexual reproduction. Carrying half of the genome, sperm and egg need to fuse their genetic materials to make one viable embryo. Technically, the nucleus of a somatic cell holds all the genetic information an organism needs. Thus, by inserting the somatic cell nucleus into an egg, scientists could generate a functional embryo. But why not into a sperm? Evolution has trimmed mammalian sperm tremendously so that it can accomplish its only job better: swim faster to fertilize the egg. As a result, not much other than the sperm’s genetic information is incorporated into the fertilized egg and the embryo relies on the cellular machinery from the egg to finish development. Using this technology, the scientists generated over 300 “fertilized” embryos. Of these embryos, 260 were transferred to 63 surrogate mothers to finish developing. 28 surrogate mothers became pregnant, and from those pregnancies, only 2 healthy monkey babies were born. Although they were carried by different surrogate mothers, every single piece of their genetic code is the same as the the somatic nucleus provider, a real-life demonstration of primate-cloning. Followed by millions of people since their debut to the world, these two macaque superstars are the living samples of a revolutionary breakthrough in our science and technologies.


Despite the extremely low success rate, this technology erects another monument in the history of mankind’s creations. Carrying identical genetic information, cloned monkeys like these two can be a very powerful tool in biomedical research and diseases studies. Co-author Mu-ming Poo, director of the Chinese Academy of Sciences’ Institute of Neuroscience in Shanghai, said that these monkeys could be used to study complicated genetic diseases where environmental factors also play a significant role, such as Alzheimer’s and Parkinson’s diseases. While there are ethical concerns on this technology and its easy application to human cloning, it is worth noting that almost all human creations (explosives, GMO food, the internet, etc.) are double-sided swords. It is up to the hand that wields this sword to decide whether to do good or bad. It is wise to be cautious with the development of new technologies, but it’s also important not to constrain our creativity. After all, it is our creative minds that drive us toward creating a better life for everyone.

Peer edited by Cherise Glodowski.

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Cambridge Researchers use Mouse Embryonic Stem Cells to Grow Artificial Mouse “Embryos”

Let’s start at the very beginning. When a mammalian egg is successfully fertilized by a single sperm, the result is a single cell called a zygote. A zygote has the potential to grow into a full-bodied organism. It is mind-boggling that this single cell, containing the genetic material from both parents, can divide itself to make two cells, then four cells, then eight cells, and so on, until it becomes a tiny ball of 300-400 stem cells.


Early Development and Stem Cell Diagram, modified by author to include ESC and TSC labels.

At these early stages, these stem cells are totipotent, meaning that they have the potential to become either embryonic stem cells (ESCs), which will eventually become the fetus itself, or extraembryonic trophoblast cells (TSCs), which go on to help form the placenta. That ball of ESCs and TSCs develops into a blastocyst with a tight ball of ESCs on the inside, and a layer of TSCs on the outside (See Figure 1).

You might imagine the blastocyst as a pomegranate, with the seeds representing the ESCs and the outer skin representing the TSCs. The ESCs have the potential to transform, or differentiate, into any type of cell in the entire body, including heart cells, brain cells, skin cells, etc., which will ultimately become a complete organism. The outer layer TSCs have the ability to differentiate into another type of cell that will ultimately attach itself to the wall of the uterus of the mother to become the placenta, which will provide the embryo with proper nutrients for growth. 

Scientists in the field of developmental biology are absolutely bonkers over this early stage of embryogenesis, or the process of embryo formation and development. How do the cells know to become ESCs or TSCs? What tells the ESCs to then differentiate into heart cells, or brain cells, or skin cells? What signals provide a blueprint for the embryos to continue growing into fully-fledged organisms? The questions are endless.

The challenge with studying embryogenesis is that it is incredibly difficult to find ways to visualize and research the development of mammalian embryos, as they generally do all of their growing, dividing, and differentiating inside the uterus of the mother. In recent years, there have been multiple attempts to grow artificial embryos in a dish from a single cell in order to study the early stages of development. However, previous attempts at growing artificial embryos from stem cells face the challenge that embryonic cells are exquisitely sensitive and require the right environment to properly coordinate with each other to form a functional embryo.

Enter stage right, several teams of researchers at the University of Cambridge are successfully conducting groundbreaking research on how to grow artificial mouse embryos, often called embryoids, in a dish.

In a paper published in Development last month, David Turner and colleagues in the Martinez-Arias laboratory report a unique step-by-step protocol developed in their lab that uses 300 mouse ESCs to form tiny balls that mimic early development.


Mouse embryonic stem cell aggregates with polarized gene expression in a dish (4 days in culture). Image courtesy of authors.   doi.org/10.11.01/051722.

These tiny balls of mouse ESCs are collectively termed “Gastruloids” and are able to self-organize and establish a coordinate system that allows the cells to go from a ball-shape to an early-embryo shape with a head-to-tail axis. The formation of an axis is a crucial step in the earliest stages of embryo development, and it is exciting that this new model system may allow scientists to better study the genes that are turned on and off in these early stages.

In a paper published in Science this past April, Sarah Harrison and her team in the Zernicka-Goetz laboratory (also at Cambridge) report another technique in which mouse ESCs and TSCs are grown together in a 3D scaffold instead of simply in a liquid media. The 3D scaffold appears to give the cells a support system that mimics that environment in the uterus and allows the cells to assemble properly and form a blastocyst-like structure. Using this artificial mouse embryo, the researchers are attempting to simulate the growth of a blastocyst and use genetic markers to confirm that the artificial embryo is expressing the same genes as a real embryo at any given stage.

The researchers found that when the two types of stem cells, ESCs and TSCs, were put together in the scaffold, the cells appear to communicate with each other and go through choreographed movement and growth that mimics the developmental stages of a normal developing embryo. This is enormously exciting, as models like this artificial embryo and the Gastruloid have the potential to be used as simplified models to study the earliest stages of embryo development, including how ESCs self-organize, how the ESCs and TSCs communicate with each other to pattern embryonic tissues, and when different genetic markers of development are expressed.

It is important to note that this artificial embryo is missing a third tissue type, called the endoderm, that would eventually form the yolk sac, which is important for providing blood supply to the fetus. Therefore, the artificial embryo does not have the potential to develop into a fetus if it is allowed to continue growing in the dish. The fact that these artificial embryos cannot develop into fully-fledged organisms relieves some of the controversial ethical issues of growing organisms in a dish, and will allow researchers to study critical stages of development in an artificial system.   

These techniques and discoveries developed by these teams of researchers have the potential to be applied to studies of early human development. These models may prove especially useful in studying how the maternal environment around the embryo may contribute to fetal health, birth defects, or loss of pregnancy. In the future, artificial embryos, coupled with the not-so-futuristic gene editing techniques that are currently in development to fix disease genes, may prove key in the quest to ensure healthy offspring. 

Peer Edited by Nicole Smiddy and Megan Justice.

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Get Alternative with Epigenetics

Our bodies are marvels of precise control, synchronization and design. Every one of our cells has the same genetic sequence, but we have many different types of cells – heart, muscle, lung, skin. Amazingly, our body has a mechanism to determine which cell is which even though they all share the same code. The field of epigenetics dives into this phenomenon. Epigenetics is a study of changes to DNA that does not change the actual sequence but modify it by repressing or activating certain parts of DNA. In short, epigenetics can reversibly turn genes on and off without changing the DNA sequence.

The genes in our body are like words that have to be spelled a certain way in order for them to work properly. All genes are made up of “base” molecules, which are assigned a specific letter (A, C, G, or T). These bases combine to form 3-letter “words,” or amino acids.  Amino acids serve as the “words” that form the “sentences” or proteins in our body that govern all the biological processes necessary for life. However, none of these biological phenomena could be produced if there are misspellings in the genetic code. Mutations are a misspelling of the original genetic code through deleting, duplicating, substituting or inverting parts of a gene. Mutations are permanent changes to the DNA code which can be passed on from generation to generation. This is the cause of many heritable diseases.

For a long time, genetic changes were thought to be permanent, but reversible epigenetic changes were uncovered around 1950 and have led to an explosion of knowledge in understanding the human body. Conrad Waddington was the first scientist to propose the concept of epigenetics. He studied embryonic development and saw how an embryo gave rise to all the different types of cells, even though every cell had the same genetic sequence. He visualized this model with “Waddington’s landscape,” which used the analogy of a marble rolling down a hill into different troughs to represent the developing cell becoming a muscle cell, heart cell or any other cell.


The marble example that Waddington used to describe an embryonic stem cell becoming other cells.

Alternative splicing is one epigenetic mechanism that allows for cells to be able to choose multiple fates. This can happen all over the body, such as in the brain, heart, and muscle. Our body has many genes, but we only use 2% of those genes to code for proteins, the other 98% are genes that help regulate the protein-coding genes. Alternative splicing is one way that we fully utilize the 2% of our genes that code for protein and accounts for our complexity. Splicing allows for the “word” of one gene to be broken up into many different ways to make many other genes. The word “lifetime” can be broken up into ‘life’ and ‘time,’ but can also be rearranged to make the words ‘fit,’ ‘lie,’ and ‘tile.’ The parts of protein-coding genes can be also be broken down and mixed and matched to produce different proteins. The sites for splicing are determined by the tightness of DNA, the accessibility to DNA, and other epigenetic factors that are still being actively researched.

Emma Hinkle

An example of how alternative splicing can produce different protein products.

Dr. Jimena Guidice at the University of North Carolina at Chapel Hill is actively investigating the epigenetics of alternative splicing in the heart to try to determine why certain heart diseases cause the heart to revert back to fetal alternative splicing as opposed to adult alternative splicing. A few weeks postnatal, the muscle cells needed to contract the heart are not yet mature and have a different alternative splicing pattern to facilitate growth into adult muscle cells. Eventually, the muscle cells are spliced with a different alternative splicing pattern which is a mark of adult muscle cells since these cells are large and can pump blood to the heart more efficiently.

If you’re interested in reading more about epigenetics and its history, I highly recommend Nessa Carey’s Epigenetics Revolution and Siddhartha Mukherjee’s The Gene.  

Peer edited by Deirdre Sackett.       

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One in a Million: The Importance of Cellular Heterogeneity and the Power of Single Cell Sequencing

One of the most overwhelming aspects of modern-day biomedical research is the overarching heterogeneity that consumes all realms of biology. Ranging from cell to cell to human to human, we have become increasingly aware of the important differences that drive divergent responses to therapeutics and biological stimuli.  The complexity of cancer is one such example.   

A landmark paper published by Gerlinger et al. in The New England Journal of Medicine demonstrated that analyzing multiple biopsies from a single patient’s tumor gives a much different picture of what the biology driving that tumor is, compared to examining a single biopsy alone. In addition, many studies characterizing the cellular heterogeneity of cancer have revealed that a tumor is much more than a mass of identical cells all growing out of control. Rather, a tumor is comprised of cancer cells at different stages of the cell cycle, engaged in different cell signaling pathways, as well as other cell types including immune cells and endothelial cells (the cells lining blood and lymphatic vessels).  


Figure 1: A schematic showing the multiple biopsy sites in a single patient tumor. The study found that the number of private mutations (i.e., a mutation found only at a single biopsy site and not at any of the other sites) are immense, suggesting that looking at a single biopsy alone greatly undermines the mutational diversity of a given patient’s tumor.

New technologies are emerging to enable us to better dissect the heterogeneity of disease and biology.  One such technique is single cell sequencing. Sequencing is a technique with which we are able to get a readout of the entire genetic composition of a cell. In its most basic form, sequencing can be performed to get a readout of DNA or RNA, which are two types of molecules  involved in different levels of genetic regulation.  Sequencing has traditionally been performed on bulk samples comprised of hundreds to millions of cells in aggregate. While we have made remarkable advances in our understanding of biology using bulk sequencing, the emergence of single cell sequencing has now allowed us to begin to  probe the genetic profile of a single cell at varying levels of complexity. The technology often takes advantage of molecular indexing, which is a technique whereby individual mRNA or DNA molecules are labeled with a molecular tag that is associated with a single cell, and then the cells are all pooled together into one tube and sequenced. During the post-sequencing analysis, the molecular tags are re-associated with each single cell, and then the profiles of each of the single cells are compared to one another.

This novel technique has allowed us to begin investigating and understanding biology with a higher degree of resolution than we ever could have imagined before, and will undoubtedly lead to the discovery of many new exciting realms of biological regulation. For example, the biomedical company Becton and Dickson have performed a research study analyzing single cells from tumors of mouse models of cancer. They found that within each tumor sample, there were distinct populations of cells with unique gene expression profiles, and these profiles were associated with vastly different biological functions. Understanding how these different populations work together as a community to promote tumor growth may help us better understand how to develop new treatments for cancer.

However, like all cutting-edge technologies, there are still limitations that need to be overcome. One concern is inefficient collection of sample, because the amount of genetic material in a single cell is much smaller than the amount of material from a large group of cells. An additional confounding variable is uncertainty of whether a low yield of genetic information from a single cell is the result of technical error, inefficiency of small sample collection, or simply the lack of expression of a gene in that particular cell. Discerning the difference between a true, biological negative result and simply a technical deficiency are often difficult to parse out.

Especially in fields such as cancer biology, we have increasingly begun to realize that heterogeneity has largely been an obstacle in our ability to develop effective therapies and to truly understand the mechanisms of regulation of biological processes. Advances in single cell sequencing research have allowed us to further realize that there is not one function or process driving disease progression, but rather a network of cells with distinct roles. Uncoupling the forces dictating the progression of this heterogeneity is what will help us to make the next great advances in therapeutic development in cancer and many other diseases.

Peer edited by Chiungwei Huang and Richard Hodge.

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H What N What? A Designer Protein Hits the Science Runway

Image ID: 10073 https://phil.cdc.gov/phil/details.asp

TEM Image of Influenza Virion. Content Providers: CDC/ Erskine. L. Palmer, Ph.D.; M. L. Martin, 1981.  Photo Credit: Frederick Murphy

Influenza is a virus that straddles two worlds: that of the past and that of the future. Responsible for more deaths than HIV/AIDS in the past century, the flu is one of the world’s’ most dangerous infectious diseases though it may not seem so, especially in the United States. However, the flu is responsible for millions of cases of severe illness and approximately 250,000 to 500,000 deaths worldwide each year.

Influenza Pandemics
Influenza A and B circulate each flu season, but it is the emergence of new influenza A strains that have been responsible for worldwide epidemics, or pandemics, in the past such as the 1918 ‘Spanish Flu’ pandemic and the 2009 H1N1 pandemic. There are 2 ways a new influenza virus can emerge. Every time the virus replicates, small genetic changes occur that result in non-identical but similar flu viruses: this is called “antigenic drift”. If you get infected with a certain flu virus, or get a vaccine targeting a certain flu virus, your body develops antibodies to that virus. With accumulating changes, these antibodies won’t work against the new changed virus, and the person can be infected again. The other source of change is “antigenic shift”, which results in a virus with a different type of hemagglutinin and/or neuraminidase, such as H3N2 to H1N1. The 2009 H1N1 virus is cited by some as a result of antigenic shift, because the virus was so different than previous H1N1 subtypes; however, as there was no change in the actual hemagglutinin or neuraminidase proteins, it was technically a case of antigenic drift.

Image ID: 13469 https://phil.cdc.gov/Phil/details.asp

This diagram depicts how the human cases of swine-origin H3N2 Influenza virus resulted from the reassortment of two different Influenza viruses. The diagram shows three Influenza viruses placed side by side, with eight color-coded RNA segments inside of each virus. The virus from the 2009 pandemic (right) has HA/NA proteins and RNA from Eurasian and North American swine instead of from humans like in previous years (left two viruses).
Content Provider: CDC/Douglas Jordan, M.A. 2011.


Challenges in Studying the Flu
Scientists and policymakers face many challenges when studying the influenza virus. For instance, the virus can be transmitted among people not showing symptoms and cough, sneeze, or handshake can spread infectious droplets from someone who doesn’t know they’re sick. Scientific study is further complicated by the virus itself: there are 3 antigenic types of influenza virus that infect humans, (A, B, C), with various subtypes and strains. Each year, government agencies work with scientists to decide which strains to target in that year’s vaccine manufacturing. The lag time between production in the spring and the flu season in the winter provides time for unexpected types to emerge.

Image ID: 17345 https://phil.cdc.gov/Phil/details.asp

This is a 3D illustration of a generic Influenza virion’s fine structure. The panel on the right identifies the virion’s surface protein constituents. Content Provider: CDC/ Douglas Jordan, Dr. Ruben Donis, Dr. James Stevens, Dr. Jerry Tokars, Influenza Division. 2014. Illustrator: Dan Higgins.

The H#N# nomenclature for influenza A subtypes refers to the hemagglutinin (H) and neuraminidase (N) proteins that sit on the surface of the virus. There are 18 types of hemagglutinin and 11 types of neuraminidase. Hemagglutinin aids the virus in fusing with host cells and emptying the virus’ contents inside. Neuraminidase is an enzyme embedded in the virus membrane that facilitates newly synthesized viruses to be released from the host cells to spread the infection from one cell to another.

Targeted Therapy
In studying ways to prevent and battle influenza, research scientists have focused their efforts on blocking the actions of neuraminidase and hemagglutinin. Antiviral drugs, such as oseltamivir (Tamiflu®) and zanamivir (Relenza®), bind neuraminidase, both interact with neuraminidase at sites crucial for its activity. The drugs act to render the virus incapable of self-propagating. A computational biologist at the University of Washington in Seattle, David Baker and his team know the hemagglutinin protein well. In 2011, they utilized nature’s design by studying antibodies that bind hemagglutinin in order to design a protein that targets the glycoprotein’s stem in H1 subtype flu viruses and prevent the virion from infecting the host cell. However, antiviral resistance contributed to by antigenic drift, is a serious issue. Researchers much constantly develop new drugs to keep up with changes in the virus.

David Baker and his team now focus their research on the hemagglutinin protein. Utilizing a computational biology approach, they designed a protein that fits snugly into hemagglutinin’s binding sites. They tested their designer protein on 10 mice and found that in mice exposed to the H3N2 influenza virus, their protein worked both as a preventative measure and as a treatment.  Though there is a long road to human testing, this binding protein shows promise for bedside influenza diagnosis as well as a model for possible treatments.

Want to know more? 

Image ID: 8675 https://phil.cdc.gov/phil/details.asp

This photograph depicts a microbiologist in what had been the Influenza Branch at the Centers for Disease Control and Prevention (CDC) while she was conducting an experiment.  Content Provider: CDC/Taronna Maines. 2006. Photo Credit: Greg Knobloch.

Learn how scientists monitor circulating influenza types and create new vaccines each year.

See flu activity and surveillance efforts with the CDC’s FluView and vaccination trends for the United States using the FluVaxView.


Peer edited by Richard Hodge and Tyler Farnsworth.

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Science and Ethics

So let’s say, hypothetically, that your lab receives blood samples from a group of individuals to study genetic links with diabetes.  However, these samples would also provide important insights into other diseases.  But the researchers did not get consent from the blood samples donors for the extra research.  For researchers at Arizona State University (ASU) and the University of Arizona (U of A), this was not a hypothetical situation.  


DNA from blood samples provide the information needed to potentially cure many diseases that plague us today.  But if the proper procedure is not followed, these scientific breakthroughs may never leave the courtroom.

They collected 400 blood samples from the Havasupai Tribe around 1990 to understand if there was any connection between genes and diabetes, at the tribe’s request. This particular tribe is from an isolated area of the Grand Canyon, with a restricted gene pool contributing to genetic diseases.  This Native American tribe has a high-incidence with diabetes.  The researchers did investigate this problem with diabetes, but they also wrote a grant proposal for researching schizophrenia in the Havasupai Tribe, which the tribe was not aware of nor gave consent for.

The main issues raised in this case are:

  • What is informed consent?  In this case, the consent form stated that the samples were to be used for studies on behavioral and medical diseases. But, meetings between the researchers and tribe members indicated that only diabetes was to be studied.  Using broad or vague language in consent forms can lead to miscommunication between scientists and subjects.
  • What information in the medical records can be accessed and by who?  Some researchers gained access to medical records without permission. Files should be kept in a secured place where only the authorized users have access.
  • Who has control of the samples?  This is a question that needs to be discussed with the subjects before samples are collected.  Researchers might want to contact their university’s research center for more information on sample ownership.


As scientists, we have a set of standards, or ethics, that help members coordinate their actions and establish trust with the public. Below are four ethical norms (or goals) that affect graduate students:


Scientists build and maintain credibility with the public by conducting research responsibly and with integrity.

  1. Promote the goals of scientific discovery, such as furthering knowledge and truth.
  2. Advocate collaboration between scientists; diversity and collaboration create new and novel discoveries that we can all benefit from.
  3. Promote accountability to the Public; it’s essential that the Public can trust the scientists to do their best work and avoid misconduct, conflicts of interest, and ensure that human/animal subjects are properly handled.
  4. Build Public support, without federal funding many of us graduate students would not be able to do our research.

For the misuse of their DNA samples, the  Havasupai Tribe filed a lawsuit against Arizona Board of Regents and ASU researchers in 2004, which eventually led to a settlement in 2010.  The tribe received $700,000 and their blood samples were returned.  The situation with ASU and U of A researchers has left an air of mistrust in Native American communities.  As scientists, it’s our responsibility to build trust with the public and maintain open and honest communication.  


Peer Edited by Bailey DeBarmore

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Fossils That Slumber in the Mountains and the Mud

Over 200 million years ago, a reptile, 11 feet long and 1500 pounds, was prowling about, likely feeling very pleased with himself. Not only did he have four crunchy creatures starting to digest in his stomach, but he had bitten another weakling in the neck and then crushed it under his left knee. Just at this moment of triumph, the reptile got stuck in the mud of ancient Jordan Lake, and slowly drowned.

Around the same time, by the seaside of what would one day become Italy, the forerunners to today’s oyster were nestling on the sea floor.

41 years ago, in 1976, Dr. Joe Carter obtained his PhD from Yale University and then drove down with his wife to start a new job at Chapel Hill’s geology department. He came as a sleuth for fossils. Ancient oysters, clams, mollusks, bivalves – Dr. Carter wanted to learn as much about them as he could.

credit: Mejs Hasan

Dr. Carter and one of his fossil replicas

For most of us, shells are just the violet-tinted, half-moon shaped spectacles that nip our feet at the beach.

But for Dr. Carter, these bivalves – and especially their fossils resurrected millions of years after they lived – are clues into evolutionary history.

In 1980, Dr. Carter took a trip to the mountains of northeastern Italy. There, he found an 80-year-old man who had been collecting Triassic fossils for decades – bivalves that lived 200 to 250 million years ago. The prospect of so many fossils was like coming upon a casket of jewels for Dr. Carter. The Italian man gave him a generous sampling of his fossil collection, and Dr. Carter fell to examining them.

“Well, this looks like an oyster,” Dr. Carter speculated, as he dwelt upon one of his fossils. Or was it? Oyster fossils dated back in time for 200 million years, beyond which they disappeared into the guarded slumber of the unwritten past. Scientists had assumed this marked the juncture at which oysters evolved, and as they cast about for a suitable ancestor, they decided upon scallops: both oysters and scallops have similar, non-pearly shells.

But perhaps the little Italian oyster told a whole new story. To investigate, Dr. Carter participated in a blatant case of disturbing the peace of the deceased. He took his Italian bivalve, sharpened his knife, and embarked on a long-delayed autopsy.

He dissected the defenseless fossil into impossibly tiny 150 micrometer slices. He examined each slice carefully under a microscope, then enlarged them on plastic drafting paper. Then, he had a “eureka” moment.

Today’s oysters are almost all calcite and non-pearly. But Dr. Carter’s ancient Triassic oyster had only a hint of calcite and it consisted mostly of mother-of-pearl. Could the mother-of-pearl oyster indicate that oysters evolved from “pearl oysters”, rather than from scallops?

credit: Mejs Hasan

Momentos from a long career

It was time to see if DNA could confirm the hint provided by the fossil record, a task given to Dr. Carter’s student, Kateri Hoekstra. She performed one of the first DNA analyses of living bivalves ever to focus on their evolutionary relationships. Just as the fossil record predicted, the DNA confirmed that the oyster from the Italian mountains, dug up after its rest of 221 million years, was a closer relative of pearl oysters than scallops.

Dr. Carter sent a letter to many natural history museums in Italy, asking them to find more of the mother-of-pearl oyster. But no one ever did. Still, Dr. Carter had fine pictures and drawings of the single known fossil. People started citing the fossil as UNC-13497b.

Such a clunky name would never do for the only mother-of-pearl oyster in the world, even if it did honor our great university. Dr. Carter finally christened it Nacrolopha carolae: Nacrolopha after the nacre (mother-of-pearl) in the Lopha-like oyster, and carolae after his wife, Carol Elizabeth.

This is the sweet side of invertebrate paleontology: a fine day in the Italian mountains, mother-of-pearl oysters, and suffusing the faint echoes of history with the name of your loved one.

But not everyone wants to give fossils their due attention.

The fossil record isn’t always perfect. For example, jellyfish rarely even leave fossils. For snails, the fossil record is misleading due to convergent evolution. The same features evolved in so many different snails that it’s hard to put things in order. You see the same shapes come up again and again.

As a result, many biologists have decided to send the fossil record packing. Since it doesn’t enlighten relationships for all groups of species, the idea that it might provide clues for a few is uncharted territory.

On the other side of the line-up, you have a handful of scientists, Dr. Carter, his former students, and his research colleagues among them. They are trying to convince the biologists that for some groups of species – especially bivalves – the fossil record is actually crucial.

It’s an uphill battle because, as Dr. Carter explains, the biologists have all the money. They are awash with government funds through the “Tree of Life” project that puts primary emphasis on DNA linkages between species.

credits: Mejs Hasan

Dr. Carter working in his lab.

Dr. Carter recognizes that DNA is a necessary tool. After all, it was Kateri’s DNA analysis that confirmed the origination of Nacrolopha carolae and modern oysters from pearl oysters. But it’s not the whole story. For example, DNA tells us that our closest relatives are the chimps. But that does not mean we evolved from them, or them from us! Fossils are the missing key that can shed light on the extinct creatures who filled in the evolutionary gaps.

Dr. Carter, along with David Campbell, his former student, now a professor at Gardner-Webb University, published a paper where they described how DNA and the fossil record can be used in symphony. Unfortunately, as Dr. Carter explains, “lots of people thought it was baloney.”

That reception is not stopping Dr. Carter. He and David Campbell are trying to publish a series of papers with examples of how DNA can give faulty evidence that the fossil record can correct. As Dr. Carter says, it will be interesting to see what the opposition says at that point.

Opposition aside, there’s one set of fossils that dazzles everyone – those of dinosaurs. Dr. Carter’s one foray into reptilian fossils happened by accident. Two of his students were studying a Durham quarry in 1994, when they came across the ankle bones of “a weird new guy”. It was the same unfortunate creature that, having filled his stomach with four prey, sank into a mudhole of ancient Jordan Lake and drowned just at its very moment of triumph. Digging it up, Dr. Carter and his students found hundreds of bones. Once cleaned and reassembled, it turned out to be a reptile shaped very much like a dinosaur, but not quite.

Dinosaurs roamed about on tiptoe, but this reptile’s foot walked on both toes and heels, like humans do. It was the best-preserved skeleton of this group of reptiles ever found. Dr. Carter toured museums in Europe and the US to make sure the reptile had not been named before.

Just thereafter, Karin Peyer walked into Dr. Carter’s office. She had an undergraduate degree in paleontology, a husband starting graduate school at UNC, and time on her hands. She asked: do you need any help?

“Boy, did you come at the right time!” Dr. Carter greeted her. Karin worked with Dr. Carter and experts from the Smithsonian Institution to formally describe and name the find.

They called it Postosuchus alisonae – alisonae a tribute to a friend of Dr. Carter’s who was dying of cancer at that time.


It was December 2015. In Dr. Carter’s large dim lab, filmy sheets of plastic drafting paper were ruffling in a soft breeze from the open window looking out on a hillside over Columbia Street. Sickle-shaped knives were stacked here and there, beside replicas of treasure from King Tut’s tomb. In between sectioning and sketching an ancient bivalve called Modiolopsis, Dr. Carter was packing.

credits: Mejs Hasan

Dr. Carter at his retirement party

He was retiring after 39 years. In practice, that merely means that Dr. Carter can now avoid going to faculty meetings. Otherwise, he can still serve on graduate student committees; he is coordinating the revisions of bivalves in the Treatise of Invertebrate Paleontology. He still has fossils to section and examine, and biologists to convince of the worth of the fossil record.

The only difference is, when Dr. Carter began his professorial work, it was just him and his wife, a young daughter and a baby boy. Now his daughter is 45 years old and his son is 39, and they both have their own families that Dr. Carter will be spending a lot of time with. It’s amazing what changes four decades can bring. But perhaps it’s easier to be philosophical and surrender to what’s ahead when you hold in your hands an oyster that lived 221 million years ago.

Peer edited by Lindsay Walton and Alison Earley.

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Reverse Aging and Live Longer: No Creams, Just Genes.

https://pixabay.com/en/cream-jar-white-skin-care-1464295/Gray hair, wrinkles, balding, crow’s feet – some wear these hallmarks of aging as a proud badge of wisdom and a long adventurous life, while others spend the latter parts of their lives fighting the signs of aging. There are a plethora of creams, lotions, diets, and therapeutics promising to make you look younger. However, a recent study suggests that the key to reversing the signs of aging and to living longer lies not in creams or lotions, but in the expression of your genes.

A recent study by Dr. Alejandro Ocampo and colleagues reversed multiple hallmarks of aging or the time-related decline in bodily functions required for survival and reproduction, in mice by expressing excess levels of four genes in various tissues and organs. The products made by the four genes are collectively called Yamanaka factors, after Nobel Laureate Dr. Shinya Yamanaka. Before the work of Dr. Yamanaka, it was thought cell programming is a unidirectional process; that is, an unprogrammed stem cell can be programmed into a skin or muscle cell, but once cellular programming has taken place, the cell cannot be reverted back to a stem cell. Dr. Yamanaka disproved this theory when he showed that excess expression of all four Yamanaka factors, which are naturally found at some level in all human cells, could revert or reprogram mouse fibroblast cells back into unprogrammed stem cells. Other techniques could then be used to reprogram these stem cells into any one of multiple cell types.  

The ability to reprogram fibroblasts into stem cells opened many new avenues of research in the stem cell field. Perhaps, one of the most intriguing is the study of stem cells in the regeneration of human tissue. Following an injury, stem cells can program themselves to fill in for the injured cells, thus allowing the body to continually regenerate tissues and maintain optimum function. Because of their vital role in regeneration and tissue maintenance, we are born with large pools of unprogrammed stem cells in our bodies. However, as we age, this pool of unprogrammed stem cells decreases, and we are less able to regenerate injured tissues or organs. This leads to the classic signs of aging such as increased recovery times, susceptibility to illness, and metabolic issues. The premise of the studies by Ocampo and colleagues is that replenishing the pool of unprogrammed cells would increase regeneration in mice and reverse the aging process, while extending the organism’s lifespan.


To replenish the pool of stem cells, scientists developed prematurely aging mice that produce the four Yamanaka factors in multiple tissues and organs of the mouse body. Production of the factors was placed under control of the antibiotic doxycycline, so that the cells would only produce excess Yamanaka factors when the mice were fed doxycycline. This allowed the scientists to control production of the factors and turn them on and off, similarly to how a lightswitch controls the lights in your living room. After doxycycline treatment, collagen producing cells in connective tissues of the mice were found to have increased metabolic function. In other words, these cells were more efficient at using nutrients to make energy and other biological molecules necessary for proper cell function. Furthermore, these cells were better able to maintain their DNA, as they showed less DNA damage than cells not expressing the Yamanaka factors. Because DNA damage is a hallmark of aging, these results suggest the aging process was reversed in the isolated collagen cells.

In addition to short-term effects on DNA damage and metabolic functions, Ocampo and colleagues explored the long term effects of Yamanaka factors on aging. Because previous studies showed excess expression of Yamanaka factors in mice leads to cancer, the first step to examining long-term effects was to develop a protocol to avoid cancer development in the mice. After much optimization of their inducible system, Ocampo and colleagues showed lower, intermittent doses of doxycycline resulted in excess expression of Yamanaka factors without cancer development. Even with decreased production of the factors, mice still exhibited fewer signs of aging than mice without inducible expression of the factors. The most striking evidence of age reversal in the mice was an increase in lifespan. Mice producing the Yamanaka factors lived 33% longer than mice not producing Yamanaka factors. In addition to increased lifespan, mice expressing Yamanaka factors had healthier, thicker skin, a healthier spleen, and less thinning of the gastrointestinal tract, suggesting the mice experienced a reversal in the aging process within these tissues.

Although reductions in age-related tissue damage were remarkable, aging was not reversed in all tissues and organs. There was little, if any, improvement in the aging of the heart, liver or skeletal muscle. Despite the fact aging could not be stopped or reversed in every organ, the ability for Yamanaka factors to reverse the hallmark signs of aging greatly increases our understanding of the aging process. Because aging is a large risk factor for many diseases and illnesses, comprehending the aging process could improve treatment of diseases that primarily affect the older portion of the population. Furthermore, knowledge of the aging process could lead to new therapeutic drugs to combat aging for health and cosmetic reasons. It is unlikely that a magic pill to stay young forever will be on the market in the near future. However, the work of Ocampo and colleagues will surely help pave the way in our fight against age related diseases.

Peer edited by Kaylee Helfrich and Katie Veleta.

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UNCseq: The Journey from Cancer Biopsy to Cable TV

This past October, CBS 60 Minutes aired a feature on Artificial Intelligence. They were taking a peek into the world of Watson, a computer system developed by I.B.M that can answer questions framed in natural languages. The same 60 Minutes episode also featured Dr. Norman Sharpless, Director of the UNC Lineberger Comprehensive Cancer Center, who provided an overview of how Watson’s artificial intelligence is being used at UNC to make treatment decisions for cancer patients.

Watson became an instant celebrity in 2011 when it was successful in beating human champions of the quiz show ‘Jeopardy!’. Since then the ‘robo-geek’ has come a long way, and its ability to analyze and interpret information has taken a big leap, so much so that it can now read and keep track of thousands of academic papers, medical records and clinical trial results, and then translate that information to make potential treatment suggestions to clinicians.

In 2015, I.B.M. began collaborating with pioneering cancer institutes across the nation, including UNC Lineberger, to hasten the process of analyzing the patient’s cancer on a molecular level. By exploiting Watson’s data analysis and data visualization capabilities, I.B.M and UNC seek to tailor suitable treatment options. With the special segment on 60 Minutes, UNC got a fair share of spotlight in primetime national television. But, is crazy to use a computing device to make critical treatment decisions in a disease like cancer? 


The progression of events from collection of patient tissue to recommendation of a treatment option

Every living organism, including humans, are composed of millions of cells, the basic fundamental units of life. Cells contain DNA, which encodes the necessary instructions required for a living organism to survive and grow. These instructions are found in segments called genes. During exposure to environmental factors like sunlight, smoking or  ageing, the DNA may become damaged. While the cells have their own tools to repair damaged DNA, sometimes the damage is too overwhelming and may escape the cell’s quality control mechanisms. The damaged DNA, also known as mutated DNA, may be passed onto subsequent generations of cells. The mutant DNA may now instruct the cells to grow uncontrollably, and as a result the cells can deviate from their normal functions. This is when a cell can turn cancerous. When a group of these cancerous cells clump together, they form a tumor. Historically, cancer treatment regimens have been directed toward where the tumor is located in the body, and while this has some positive therapeutic effects, it has not been very efficient.

Over the years, as genetic research progressed, scientists began to classify tumors on the basis of their genetic characteristics. They are now able to identify the genes and the corresponding mutations that drive tumor growth.  Drugs targeting these mutations have been designed, and some of them have demonstrated considerable improvement in patient survival. The question now is can cancer be effectively treated based on the broad pathology of the tumor in the body. An individualized approach based on the genetic makeup of the patient’s cancer is being considered as an alternative treatment.

If this sounds too abstract, let’s consider a clinical example. It is well established now that tumors in some breast cancer patients have high expression of estrogen receptors. This means that the cancer cells may receive signal from the hormone estrogen, which may facilitate tumor growth. A class of drugs called ‘aromatase inhibitors’ prevent the body from producing estrogen and may work well on this subset of patients. However, only about half of patients whose tumors tested positive for estrogen receptors responded to these class of drugs. With a genetic-based approach to cancer treatment, the genetic profile of the patients who respond to the therapy may be used to look for treatment patterns. Now, if these patterns are consistent with one another and they match the genetic map in a section of patients that respond positively to aromatase inhibitor therapy, then this may stand as an effective treatment strategy. Other estrogen receptor positive patients may be treated using a different strategy without wasting time on a therapy that may not work. This new era of treatment is referred to as the age of ‘precision medicine’.

At UNC, when a patient agrees to participate in the ongoing clinical trial UNCseq, a tissue sample is collected by biopsy or during surgery and is analyzed to determine the genetic makeup of the tumor.  A blood sample is also drawn to examine the genetic profile of the patient. The samples are then analyzed by rapid DNA sequencing methods. Then the building blocks of the cancerous and normal DNA are compared one block at a time to identify the mutations present in the tumor. Now, if a mutation affects a protein which helps a cell to survive and grow normally, it may be a cancer-driving mutation. However, there may be hundreds to tens of thousands of other ‘innocent’ mutations that do not affect  cancer growth. Rigorous analysis is required before key mutations can be determined.

A single patient’s genetic information may clog up gigabytes of storage space, and analyzing all of these data to search for patterns may require a fair amount of mathematical effort and computation time. All of this occurs in a situation where a patient awaits treatment, so every bit of time is precious. This is where a supercomputer like Watson comes in. Watson had been able to analyze the DNA profile of tumors very efficiently and proposed treatment regimens that matched the decision of the clinicians 99 out of 100 times. What is more interesting is that in about one third of the cases, it was able to identify new treatment strategies that the doctors had not previously considered. It is to be seen whether this approach helps improve overall standards of care in a large cohort of patients in the long haul.

Cancer therapy still has a long way to go. Just because we know about the aberrations in the cancer cell doesn’t mean we can develop a complete cure. Current chemotherapy drugs can effectively kill cancer cells, but they may pose significant toxicity to the patient as they also attack healthy cells. Targeted therapies against genetic mutations work very efficiently in a few cancers, but only for a short span of time. The cancer becomes resistant in days to months and returns aggressively. Immunotherapy approaches where the immune system is stimulated to fight cancer is the new hot-topic in clinical discussions. Unfortunately, only a small subset of patients respond to these therapies, and for unknown reasons. However, with precision medicine, we expect to provide the most appropriate care to each patient, resulting in considerable improvements to their survival and quality of life. We continue our fight against beating cancer, and as a Tar Heel, I am proud that UNC is leading the way.

Edited by Nicole Tackmann and Alison Earley.

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