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Birth Control for the Modern Age

12/1/2015

By Mariel Sokolov
Featuring Dr. Kelle Harbert Moley and Antonina Frolova

More than 37 million women in the United States alone are currently using some sort of birth control. By far the most popular form of birth control is “the pill”, a combined hormonal contraceptive that is taken daily to prevent pregnancy. But the pill is a chore to administer. It must be taken at the same time every day or will lose its effectiveness rather quickly. Because of this issue, some women choose to use intrauterine devices (IUDs). IUDs require very little maintenance and time apart from their initial installation, but they share a key drawback with birth control pills : hormonal IUDs work by releasing a huge influx of levonorgestrel, a synthetic hormone, into a woman’s body in order to block sperm from entering the cervix. However, as with many hormone-based treatments, IUDs can result in severe side effects, like irregular menstrual cycles, mental health changes, and ovarian cysts.

In response, researchers at Washington University have developed a non-hormone based IUD. Here’s how it works: In order for a woman to become pregnant, an embryo needs to implant itself in the lining of her uterus. For implantation to take place, a series of changes in the lining of the uterus, known as decidualization, are triggered by the hormone progesterone. After decidualization, the lining of the uterus, or endometrium, is ready for the implantation of the embryo.

Dr. Kelle Harbert Moley and Antonina Frolova of Washington University’s Department of Obstetrics and Gynecology realized that any process that inhibits decidualization will prevent pregnancy because the embryo will simply not be able to implant into the uterus. During the course of their work, Moley and Frolova have shown that inhibitors of the pentose phosphate pathway (a common type of signalling pathway) can be used to stop decidualization and therefore can function as a non-hormonal contraceptive.

This development holds much promise in the real world. When tested in mice, the PPP inhibitor successfully prevented the embryo from attaching to the uterine wall. A second set of studies also showed that pentose phosphate pathway inhibitors delivered locally can also prevent ovulation, and upon removal of the inhibitor mice regain fertility with no effect on offspring. This means that perhaps a new type of PPP-based IUD or some internal implant may be able to effectively provide contraception without the side effects of a hormone-based system.

The contraceptive market is expected to reach a value of $19.6 billion dollars by 2020. There is only one other non-hormonal IUD currently on the market. Known as ParaGard, this competitor uses a T-shaped plastic frame with copper wire coiled around the stem and two copper sleeves along the arms that slowly release copper around the lining of the uterus. ParaGard produces an inflammatory reaction in the uterus that is toxic to sperm, which helps prevent fertilization.” First used in 1984, ParaGard unfortunately comes with a myriad of side effects due to its rather toxic mechanism of action. Anemia, backache, bleeding between periods, cramps, inflammation of the vagina (vaginitis), pain during sex, severe menstrual pain, heavy bleeding, and vaginal discharge can all occur. Needless to say, another option for birth control that would eliminate both hormonal side effects and the side effects of the non-hormonal alternative would take over the market and improve the lives of thousands of women worldwide.

Patent Information :
Patent No. : US 20130065853 A1

For more information about the researchers/inventors :
E-mail : moleyk@wudosis.wustl.edu

Lab Address :
WUSM Obstetrics and Gynecology
660 S. Euclid Avenue
St. Louis, MO 63110

Edited by Jeff Bai

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A New Predictive Test for Alzheimer’s Disease

12/1/2015

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By Maggie Weng
Featuring Dr. David M. Holtzman, Dr. Anne M. Fagan

Alzheimer’s disease is a degenerative neurological condition that currently affects 5.3 million Americans. Although it is most common in the elderly, it can occur at any stage of life. At the time of this writing there are only a few ways to obtain a reliable diagnosis — let alone determine if someone is at risk to develop the disease, although some genetic links have been determined. The cause of this devastating disease are currently unknown, as are any effective cures. As a result, accurate, predictive diagnostic tests for Alzheimer’s Disease could help eliminate the uncertainty and fear of whether or not a person might be predisposed to developing the disease, and allow the start of a regimen of effective preventative care if so.

This kind of test is exactly what researchers Dr. David M. Holtzman and Dr. Anne M. Fagan of the Washington University School of Medicine have developed. Their diagnostic test relies on genetics, a major risk factor for Alzheimer’s disease. A gene is a segment of code, written using 4 letters, that encodes for a certain characteristic or quality (like hair color). People generally have two copies of a gene; a single gene may have many varieties (alleles) which can affect a person’s outward appearance (phenotype), in many different ways. For instance, someone with two copies of a certain allele in a gene responsible for freckling will have freckles, whereas someone with just one or no copies may have light freckles or no freckling at all.

According to existing research compiled by Drs. Holtzman and Fagan, allele E4 of a gene known as apolipoprotein E (ApoE) is a known risk factor for Alzheimer’s disease. ApoE usually plays a key role in the central nervous system as a major lipid component of cerebrospinal fluid, but it interacts with and could be key in the creation of amyloid-beta, a misformed protein that forms the plaques responsible for Alzheimer’s disease.

The researchers used the E4 allele as a way of separating their subjects into two groups: those with one or both copies (some risk of developing Alzheimer’s disease) and those with no copies (no risk of developing AD). However, genetic testing is quite complicated and expensive — so although testing for the E4 allele is a sound way of identifying Alzheimers’ risk, it is not currently viable for use as a widely employed diagnostic test.

To remedy these concerns, Holtzman and Fagan turned to the relative concentrations of two lipoproteins (fat-bound proteins) in the CSF, namely Aβ40 and Aβ42. In those with one or more E4 allele, the relative concentration of Aβ40 was significantly higher than Aβ42. However, the test subjects were all cognitively normal at the time, so it is not entirely clear if their result has significance - only time will tell. The relationship between Aβ and the E4 allele constitutes what’s known as a biomarker — a biological sign or tag that can be used to signal the presence of a certain ailment, gene, protein, and more. By testing for the ratio of Aβ40/Aβ42, a researcher or doctor can determine whether a person has one or more E4 alleles and is therefore at a higher risk for developing Alzheimer’s disease, without the expensive and prohibitive testing previously required to come to the same determination.

Holtzman and Fagan’s research also raises many questions for further investigation and provides new inroads into finding risk factors for Alzheimer’s disease. The detection of these biomarkers raises the question of how they may be related to actual Alzheimer’s disease development and clinical onset. The Holtzman and Fagan labs continue to study the role of ApoE in Alzheimer’s development and search for other biomarkers of proteins and genes that may be involved. Higher than usual deposition of Aβ42 in the brain is possibly predictive of eventual clinical onset of Alzheimer’s, for instance, and thus warrants further investigation.

The relative simplicity of this test makes it a promising candidate for widespread implementation should it prove to be predictive. This test relies on already existing technology and methods available to hospitals: samples are extracted using a lumbar puncture, a procedure in which hospital staff have extensive training in, and can be analyzed using a simple kit devised by Holtzman and Fagan. In some part, this is an economic relief on the healthcare system: although age-related dementia research has been receiving more and more attention and funding in recent times, Alzheimer’s disease remains one of the most expensive (in terms of total expenses and lost productivity) illnesses affecting the industrialized world today. The importance of a reliable and cheap test for this disease cannot be understated, and research right here at Washington University can prove to be the key to such a test.

Patent Information :
Patent No. : US 20130065853 A1

For more information, please contact the Office of Technology Management :
OTM@dom.wustl.edu

Edited by Jeff Bai

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Shining Light on Cellular Function

11/30/2015

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By Colton Hemphill
Featuring Dr. Gautam

In recent times, we have expanded our understanding greatly about the processes that underlie the function of cells within our bodies. New developments have allowed us to explore cellular mechanisms and processes in previously unthinkable ways. Promising research from Dr. Narasimhan Gautam in the Division of Biology and Biomedical Sciences brings us closer to being able to actively manipulate and control the functions of many cells. This ability to manipulate cellular function – ranging from simple movement to the secretion of chemicals – has incredible implications for treatment of a large number of conditions and can be a keystone technology in targeted therapies for cancer.

The coordinated functions of a complex biological organism would be impossible to achieve without a complex network of receptors and cell signalling. For example, the epinephrine receptor binds to epinephrine, a chemical associated with the “fight-or-flight” response, After a multi-step biochemical pathway, large amounts of glucose is released, providing the organism the fuel it needs in this “fight-or-flight” response.

In a similar fashion to the system just described, other receptors (especially those in the eyes) respond to light instead of a chemical signal. This also results in a cellular response (e.g. the sensation of light in the eye). These receptors found in the photoreceptor cells of the retina, called opsins, can be used for the laboratory manipulation of cells that may not ordinarily have receptors that respond to light. By taking these opsins and placing them in other cells throughout the body, cells that usually only respond to very specific stimuli will now readily respond to light. Because the cell in which the opsins have been transplanted can now be controlled using light, scientists are able to activate it with precision by shining light on the receptor. Using specialized lasers that are able to focus light on extremely minute areas, this signal can be made to be even more specific than the signal that usually activates the cell. This allows researchers to probe into previously unexplorable processes by targeting one area of a cell but not others.

The implications of generalizing this cellular response to light to other cells are incredible. Immune cells that normally respond to the establishment of a chemical gradient may now be controlled by light, allowing researchers to use light to target these cells to places in the body that might ordinarily be ignored by the immune system, such as tumors.

As tumors are comprised of cells that have lost the ability to stop dividing but still retain cell surface markers identifying it as as non-foreign, the body’s immune system will often fail to identify them as something to take action against, despite the fact that the cell has a major problem. By shining light on immune cells embedded with the opsin receptor, physicians will theoretically be able to target immune cells to attack the tumor, in spite of the fact that the immune cell would not naturally do so on its own. In this way, addition of the opsin receptor to a cell serves as a form of “manual override”, allowing researchers to guide important cellular processes when the natural response is insufficient. Given how the greatest disadvantage of radiation therapy and chemotherapy is the massive collateral damage they inflict on a person’s health, targeted therapies like the one described above have massive advantages and have the potential to revolutionize cancer treatment.

Ultimately, this new method of controlling cells through use of a light-sensing receptor is a novel technology that will have significant effects on the treatment of disease as well as the future of biological research. By enabling precise control of cells, Dr. Gautam’s research will propel research forward and elucidate functions and pathways that were once hidden to us, potentially unlocking many new cures now and in the future.

For more information about Dr. Gautam :
E-mail : gautam@wustl.edu
Website : http://elysium.wustl.edu/gautam_lab/lab_overview/
Phone : (314)362-8568

Lab Address:
5548 Clinical Sciences Research Building
4939 Children’s Place
St. Louis, MO 63110

Edited by Jeff Bai, Luis Muniz

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How do Wikipedia Administrators Influence Public Opinion?

11/30/2015

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By Eesha Sabherwal
Featuring Prof. Sanmay Das

Wikipedia is a free-access, open source online encyclopedia founded in 2001. Since its initial inception, Wikipedia’s policy of generally allowing anyone to edit any article has allowed it to grow into one of the most popular websites today -- an enormous, freely-accessible, and multilingual repository of the world’s knowledge, with over 5 million articles on the English version alone. Search for a topic in a search engine today, and chances are you will be greeted with the corresponding Wikipedia article.

However, the open nature of Wikipedia does beg some important questions : how do we determine the objectivity and validity of the information on Wikipedia -- be it scientific, historical or related to current affairs? Many turn to Wikipedia as a quick reference for critical and quotidian facts, but how is it regulated? It is integral to the understanding and knowledge of our society that encyclopedic information shared be both valid and as impartial as possible. Such issues are addressed by Professor Sanmay Das of the Department of Computer Science & Engineering in his current research regarding collective information sources. His research has revealed many new insights into the various phenomena that arise in the editorial oversight of Wikipedia, run primarily by a very large, diverse, and decentralized body of volunteer ‘administrators’.

In the Wikipedia community, administrators hold the power to perform special actions, including the ability to block and unblock accounts from editing pages, the power to edit fully protected pages, and to delete and ‘un-delete’ pages. Administrators gain these responsibilities through an intricate community review process called a Request for Adminship (RfA), in which the individual has to be nominated by a ‘bureaucrat’ (a person responsible for vetting administrator candidates), present a personal statement, survive public discussion, and be voted on by a group of at least 100 people. Generally, most of those that receive above 75% of the votes pass, and most of those below 70% fail, but the decision of passing and failing is ultimately subject to the decision of the ‘bureaucrat’.

In his research, Professor Das investigates the influence of conscious and unconscious biases of administrators and their ultimate impact on Wikipedia articles. Professor Das establishes multiple metrics used when gathering relevant data. First, a Controversy Score (C-Score) is established as a measure of the proportion of attention an editor focuses on topics that are contentious or controversial. Second, Das uses the C-Score to develop a Clustered Controversy Score (CC-Score), which is useful in finding individual editors who focus the majority of their time on articles related to a single, controversial topic. Lastly, information from the RfA phase is gathered, including (1) the general behavior of a candidate, (2) the voting history of the people involved in the RfA, and (3) the percentage of positive votes a candidate received during his/her RfA vote.

Das’ results reveal that there is sound evidence for the existence of article manipulation and an increased activity on controversial topics as an editor makes the transition to the role of administrator. While the so called ‘manipulation’ may be unintentional and solely sourced from the administrator’s intrinsic biases, it could also indicate malicious intent. As such, we must find a way to analyze more critically all potential administrators before promoting them.

If Wikipedia users believe an administrator is abusing his/her power, grievances may be reported directly to the administrator in question, to another administrator, or a ‘steward’ - an individual with complete access to the Wikipedia interface and all administrative powers. If problems persist, the abuse can also be reported to the Arbitration Committee, a panel which typically rules on disputes between editors. A ruling from the Arbitration Committee or an executive decision from a ‘steward’ can result in the removal of privileges from an administrator.

Das’ results also provide reason for optimism -- when experienced, benevolent, and engaged voters participate in the RfA process, they do a better job of filtering out those prone to manipulation. Thus, we can improve the quality of Wikipedia administrators by taking into account how influential different participating voters are during the RfA process. We can use that information to increase the standard of RfA voters in general, in turn decreasing the amount of bias and manipulation.

While the research Professor Das conducted gives much insight into how to improve Wikipedia’s administrator selection process, it also shines light on an important aspect of online interactions today. Individuals editing and administrating Wikipedia articles are not given a salary -- they have no monetary incentive to make their contributions and edits. Essentially, knowledge on Wikipedia is distributed in a non-market way. An interesting field to explore in the future is how similar online non-market interactions affect factors such as accuracy and objectivity in arenas other than Wikipedia. Additionally, in the absence of monetary incentives, what motivates individuals to contribute online? Is there an increase in personal bias because intrinsic motivation is necessary? Non-market systems are arising throughout the online realm, be it when individuals post solutions to homework problems, post information on recommendation sites such as Yelp, or, as was previously discussed, write Wikipedia articles. Only time will tell how such unprecedented interactions will affect society in the future, and if it will be a change for the better or worse.

For more information about Professor Das :
E-mail : sanmay@wustl.edu
Website : http://www.cse.wustl.edu/~sanmay/
Phone : (314)-935-7302

Lab Address:
510 Jolley Hall
Washington University in St. Louis
1 Brookings Dr
St. Louis, MO 63130

Edited by Jeff Bai

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Picking Apart Wildfires

11/30/2015

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By Drew Ells
Featuring Dr. Rajan Chakrabarty

Vehicular pollution is old news. Although our demand for combustion-powered transportation is continually increasing, scientists are now concentrating on a far larger contributor to global climate change – and it’s time you recognize it, too. Wildfires, from the dramatic walls of flame commonly seen in California to the slow smolder of Arctic peat fires, are now regarded as one of the most significant global contributors to carbon-based pollution.

However, comparatively little research has been done on these natural pollutants. Dr. Rajan Chakrabarty, a faculty member of Wash. U.’s Department of Energy, Environmental, and Chemical Engineering, conducts research to better understand the variety of pollutants produced by wildfires in the United States. He believes that the increasing frequency and range of devastating, habitat-destroying wildfires in recent years necessitates a more lucid understanding of their long-term impact on our ecology and biosphere.

When wildfires burn, they produce a multitude of tiny particles, or aerosols. You can easily see them manifest in the thick, black smoke of a fire. Scientists refer to these visible aerosols as “black carbon.” According to the Environmental Protection Agency (EPA), black carbon can absorb the most solar radiation by mass of any particulate matter. Releasing it into the atmosphere allows it to trap and hold heat, which is believed to contribute heavily to global warming. However, burning biomass also releases “white,” or “organic” carbon. In the past, many scientists have believed that white carbon has an opposite, cooling effect that can partially counteract black carbon emissions. Dr. Chakrabarty challenges this belief, hypothesizing that white carbon could just as easily disrupt the Earth’s delicate energy balance and, although not studied directly by his lab, may have deleterious consequences for our health and well-being as well.

To test his hypothesis, Chakrabarty has amassed selected samples of leaves, wood, and other organic matter found across the United States, with a special emphasis on samples found in the arid Southwest where such fires are most common. Examples include common trees such as hickory, oak, and spruce, as well as smaller plants like common reeds, ferns, and sawgrass. The biomass is then loaded into Chakrabarty’s novel combustion chamber. At 17 m3 (the volume of twenty built-in refrigerators), it’s a truly massive contraption. Inside, Chakrabarty can perform a controlled burning of the biomass while slowly drawing the released aerosols into second chamber meant to simulate the composition and characteristics of Earth’s atmosphere. As a result, the lab can learn about the properties of these pollutants as though they were flying freely in the air. Impressively, the design and engineering of the apparatus allows Chakrabarty to conduct observations for up to 7 or 10 days – the usual lifespan of atmospheric particles before their degradation. “The goal is to better understand the nature of these particles. With this technology, we can learn what pollutants are most important for mitigation efforts and where they come from,” said Chakrabarty.

Continuing his current aerosol studies, Chakrabarty has also developed a novel method for simulating and observing the wildfires we are growing increasingly accustomed to seeing. The end goal is the same – to make observations on the different particles emitted by large fires, but with a special emphasis on the unique characteristics of wildfires – those that differentiate them from a conventional conflagration. Without going into too much detail, the technology is called a “buoyancy opposed flame reactor” and makes use of a negative gravity flame. With this device, Chakrabarty can mimic a wildfire on a miniature scale in his lab – it’s a very useful tool to have as he continues his investigation.

For writing the research proposal outlining and detailing this research project, Dr. Chakrabarty was awarded an NSF CAREER Award earlier in the year that amounts to $691,180 over a five year period. According to the National Science Foundation, CAREER Awards are given “in support of junior faculty who exemplify the role of teacher-scholars through outstanding research, excellent education and the integration of education and research within the context of the mission of their organizations.” Dr. Chakrabarty is the 25th professor in the School of Engineering & Applied Science to be given this award.

The purpose of the award is not only to fund his continuing efforts in research, but also to assure that the next generation is thoroughly educated about its implications. Seeing how environmental research “is a direct application of all the chemistry, physics, and math kids learn in school,” Chakrabarty plans to accomplish this goal by educating teachers from school districts in St. Louis about the importance of pollution. Why not directly lecture the students, some might ask? “Because teachers are the best at transmitting this information to their students. They know how to make it relevant,” replied Chakrabarty.

In our interview, Chakrabarty promoted “relevancy” as the key to educating the public about climate change and pollution. Indeed, the topic at hand could hardly be any more important or relevant for modern civilization – we are already beginning to see various ‘symptoms’ indicating global climate change, and we clearly understand the dire consequences to all life on Earth should we allow this warming to occur indefinitely. It is time we start to understand the detailed root causes and elusive contributors to this phenomenon – only that way can we understand the most appropriate course of action to take as we continue our efforts as a species to build a sustainable world.

For more information about Dr. Chakrabarty :
E-mail : rajan.chakrabarty@seas.wustl.edu
Website : http://air.eece.wustl.edu/
Phone : (314)-935-6054

Lab Address:
Washington University in St. Louis
3049 Brauer Hall
1 Brookings Dr
St. Louis, MO 63130

Edited by Jeff Bai, Luis Muniz

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Party and Checkerboard: A New Model to Explain How Our Brain Sees

Birth Control for the Modern Age

A New Predictive Test for Alzheimer’s Disease

Shining Light on Cellular Function

How do Wikipedia Administrators Influence Public Opinion?

Picking Apart Wildfires

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Party and Checkerboard: A New Model to Explain How Our Brain Sees﻿

Birth Control for the Modern Age

A New Predictive Test for Alzheimer’s Disease

Shining Light on Cellular Function

How do Wikipedia Administrators Influence Public Opinion?

Picking Apart Wildfires

Editorial Board

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Party and Checkerboard: A New Model to Explain How Our Brain Sees