Are Existing Policies Regulating Recombinant DNA Technology Adapted for Synthetic Biology?

 

By Florence Chaverneff, PhD

 

Background on Synthetic Biology

Synthetic biology is gaining increasing interest as one of the most promising new technologies of the 21st century. Its revolutionary nature, wide-ranging applications across several scientific disciplines, and the fact that it may help solve some of the world’s most pressing issues, all contribute to the justified enthusiasm for the field. As the boundaries, prospects and even nature of synthetic biology still need to be clearly outlined, the definition advanced by a high-level expert group of the European Commission, encompasses it well: “Synthetic Biology is the engineering of biology: the synthesis of complex, biologically based (or inspired) systems which display functions that do not exist in nature. This engineering perspective may be applied at all levels of the hierarchy of biological structures-from individual molecules to whole cells, tissues and organisms.”

 

In the same manner that recombinant DNA technology revolutionized biology in the 1970s, synthetic biology is breaking new grounds. However, because it requires a greater need for DNA synthesis than recombinant DNA technology, synthetic biology brings life sciences closer to engineering. It aims to make biology easy to engineer. And that is the revolutionary part. Its multi-disciplinary nature at the nexus of biology, engineering, genetics, computational biosciences and chemistry implies that synthetic biology be practiced in a global and networked fashion, posing it as the ultimate collaborative venue for scientific research.

 

Applications of Synthetic Biology

The array of what synthetic biology allows to design and produce, from biomolecules, to cells, pathways, and ultimately, to living organisms, in by itself gives an idea of the power of the technology. Synthetic biology, with its new category of tools that allow advanced DNA synthesis, conceptualization of biologically complex systems, and standardization for mass production is more approachable to a less skilled workforce in a more efficient and manageable manner than what is currently practiced in biotechnology companies.

 

Applications of synthetic biology are wide-ranging, from global health (e.g. vaccine and antibody production, regenerative medicine, development of therapies for cancer, approaches for cell therapy) to generation of biofuels, to food production. And as the field is growing, technologies are bound to evolve, giving rise to an even wider array of applications. One of the most notable and highly publicized successes of synthetic biology was published in Nature Biotechnology in 2003. The article describes a novel way of producing the anti-malarial drug artemisinin, using the bacteria E. coli as a host, in which enzyme and metabolic pathway for artemisinin production were expressed. Artemisinin synthesized in this manner can be produced at much higher yield and much lower cost than by plant extraction. These considerations are of great importance for an anti-malarial drug, destined to large populations in low income countries.  Another powerful example of the promises held by synthetic biology lies in a study published last year in Science, reporting the assembly of a synthetic yeast chromosome, heavily edited from its natural counterpart, yet functional when expressed in its organism.

 

Crafting Policies for Synthetic Biology

Despite being over a decade old, synthetic biology is still in its infancy, its full potential has yet to be realized, and a regulatory framework indispensable to any new technology that can be applied to life sciences, will have to match the field’s evolution. Some policies for synthetic biology may be adapted from existing ones that were designed to regulate recombinant DNA technology and genetic engineering. However, it is critical that new regulations, tailored to synthetic biology, which is tantamount to engineering artificial life, be established. Considerable changes in regulations should be avoided, as they might result in holding up development of the fast-evolving synthetic biology.

 

Perhaps one of the most important policy aspects to consider for synthetic biology is linked to its sheer nature. Synthetic biology permits manufacturing of whole living organisms, which, if released in the environment, could greatly affect it by interacting with ecosystems. It is therefore imperative that preventive measures be taken and that ethical oversight be installed to avoid misuse of the technology. Another policy aspect particular to synthetic biology is related to its multi-disciplinary nature: all its practitioners, not just biologists, should be educated in biosafety. Additionally, policies should allow for training of scientist, researchers and other professionals to meet the demands of the field. Several top institutions in the US have already launched graduate programs in synthetic biology, but more educational programs are required.

 

Synthetic biology research and frameworks for funding are also vital to support evolution of the field by strengthening research and development capabilities, and supporting innovation. Synthetic biology should be practiced in academic institutions and private ventures alike.  In both instances, policies should be adapted so that results from research meet demands of modern economy, by taking measures to industrialize innovation in commercially successful ways through facilitation of technology transfer and intellectual property management.

 

Finally, because synthetic biology is heavily reliant on openness and sharing and holds great potential for becoming the poster child of international scientific cooperation, national policies formulated in the US and elsewhere could serve as template for transnational policies.

 

You Can Help Cure Ebola!

 

By  Jesica Levingston Mac leod, PhD

Since the start of the outbreak last March, Ebola virus has already taken more than 8.000 lives and infected more than 21.200 people, according to the  Center for Disease Control (CDC). The panic raised from this situation rushed the testing of therapies to stop the outbreak and the research on the Ebola virus has seen a rebirth. Some research groups that have been working in this field for a long time can now openly ask for help. One of these groups is the one lead by Dr. Erica Ollman Shaphire at The Scripps Research Institute, California. In 2013 they published in Cell an analysis of the different conformations of Ebola VP40 (Viral Protein 40) aka the shape-shifting “transformer” protein. They reported 3 different conformations of this protein, and how this variety allows it to achieve multiple functions in the viral replication circle. This Ebola virus protein along with the glycoprotein would be used as target for anti viral research. In order to find new anti-virals, their approach is an in-silico scrutiny of thousands of compounds, using viral protein crystal structures in the in silico docking to find leads that may be tested in the lab as inhibitors. IBM is already helping them in this project, generating the World Community Grid to find drugs through the Outsmart Ebola Together project.  Here is where you can start helping, as this project involves a huge amount of data and computing time, they need volunteers that can donate their devices spare computing time (android, computer, kindle fire, etc) to generate a faster virtual supercomputer than can accelerate the discover of new potential drugs. This approach has been shown to be successful for other diseases like HIV and malaria, so you are welcome to join the fight against Ebola virus: https://secure.worldcommunitygrid.org/research/oet1/overview.do.

If you do not have any of these devices (I hope you are enjoying the public library free computers), you can still help Dr. Shapire quest to discover new therapies against Ebola. Her group is now “working to support the salary of a computer scientist to help process the data we are generating with the world community grid” as she describes it. To help identify the most promising drug leads for further testing you can donate money on: www.crowdrise.com/cureebola.

Other groups that were mostly working on other viruses, like Flu, also joined the race to discover efficient therapies. For example, last month, the Emerging Microbes and Infections journal of the Nature Publishing Group published the identification of 53 drugs that are potential inhibitors of the Ebola virus. One of the authors of this paper is Dr. Carles Martínez-Romero, from Dr. Adolfo García-Sastre’s lab in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai. In the study, Dr. Martínez-Romero and collaborators described how they narrowed the search from 2.816 FDA approved compounds to 53 potential antiviral drugs. This high-throughput screening was possible thanks to the use of the Ebola viral-like particle (VLP) entry assay. This allows studying Ebola viral entry without using the ”real”, full replicative virus. These 53 compounds blocked the entry of Ebola VLPs into the cell. Understanding how these market-ready compounds can inhibit Ebola entry and its infectious cycle will pave the way for a new generation of treatments against Ebola virus-associated disease.

Dr. Martínez-Romero had an early interest in science; “Since I was a child, I showed great interest in biological sciences and a great desire to question and discover. This led me to pursue my studies in Biotechnology in order to become a successful researcher.”Viruses are very interesting to me because, although they are not strictly living organisms, they are as old as life itself. Even though they are the origin of many illnesses in mammals and other organisms alike, we are tightly interconnected with viruses and they will continue shaping our evolution throughout the years to come.

I also asked him about advice to his fellow researchers, and he answered: “There is a famous quote of Dr. Albert Einstein: “If we knew what we were doing, it wouldn’t be called Research”. As postdocs and researchers in general, we are constantly pursuing new hypotheses. It is a very arduous path with its ups and downs but full of rewards and new challenges ahead.” About the future of the antiviral research, he keeps a positive view: “Several antiviral therapies are being developed to combat the current Ebola outbreak, such as antibody cocktails (Zmapp), antiviral drugs, and specific Ebola vaccines. Together with re-purposing screens like the one we published, a combination of therapeutic drugs can be used to obtain better antiviral strategies against the Ebola virus.”

Teixobactin: Are We Jumping the Gun on a New Magic Bullet?

 

By Elizabeth Ohneck, PhD

The introduction of penicillin to the clinic in the 1940s ushered in an era of hope in our battle against bacterial disease. Penicillin, produced by a lowly mold, Penicillium notatum, was accidentally stumbled upon by Dr. Alexander Fleming in 1928, when he noticed areas of inhibited bacterial growth around the mold, which had contaminated a petri dish of Staphylococcus aureus. A team of researchers led by Dr. Howard Florey later purified the penicillin compound and developed a method for large-scale production. By 1944, penicillin was being mass-produced and commercial production methods refined. It was a powerful tool during WWII, drastically reducing deaths from infected wounds and surgical procedures. Finally made broadly available to the public in 1945, penicillin was heralded as a “magic bullet,” capable of curing a wide variety of bacterial diseases. For an excellent history of the discovery and development of penicillin, I recommend the book The Mold in Dr. Florey’s Coat: The Story of the Penicillin Miracle, by Eric Lax.

 

Just 4 years later, strains of bacteria resistant to penicillin began to appear, spurring a search for alternatives. Following the penicillin model, researchers turned to other microorganisms for potential antibiotic substances. Soil bacteria provided a rich reservoir for such compounds, leading to the discovery of antibiotics such as streptomycin, erythromycin, and cephalosporins. But carelessness, complacency, and overuse of antibiotics allowed the pathogens to fight back, developing ways to resist these new drugs and landing us in our current predicament, facing dangerous strains of bacteria resistant to almost all available antibiotics, such as MRSA (methicillin-resistant S. aureus), MDR-TB (multi-drug-resistant Mycobacterium tuberculosis), and Neisseria gonorrhoeae. Only a small percentage of soil bacteria – approximately 1% – are able to grow under normal laboratory conditions, and with this reservoir seemingly exhausted, biochemical laboratory synthesis efforts failing, and no new antibiotics in the pipeline, the need for new antibiotic candidates is obvious.

 

One team of researchers decided to go back to the soil. In an exciting paper published in Nature this month, Ling et al. describe the development of a novel method for growing previously uncultivable soil bacteria, leading to the discovery of a new antibiotic they have called teixobactin. To grow the finicky soil bacteria, a sample of soil was diluted and distributed into a multichannel device called an iChip so that each channel contained only one bacterium. The channels were covered with semipermeable membranes to keep the bacteria in but allow exchange of nutrients and growth factors between the channel and the environment. The iChip was then returned to the original soil from which the sample was taken, creating growth conditions highly similar to the bacteria’s native environment. This method increased the number of soil bacteria that could be cultured from 1% to nearly 50%. Even better, once a colony is established in the iChip, many of the bacteria can then be grown in a laboratory setting.

 

The researchers screened extracts from 10,000 isolates obtained by this method for antimicrobial activity against S. aureus and identified a new protein compound produced by the Gram-negative organism Eleftheria terrae, which they named teixobactin. Teixobactin showed potent activity against M. tuberculosis and Gram-positive pathogens such as Clostridium difficile (which causes intestinal infection sometimes referred to as “C. dif”), Bacillus antrhacis (which produces the causative agent of anthrax), and S. aureus, including drug-resistant strains. Unfortunately, it was not effective against Gram-negative bacteria. Teixobactin showed no toxicity against mammalian cells in culture, and effectively cleared S. aureus and Streptococcus pneumoniae infections in mice.

 

Through several biochemical investigations, the researchers determined that teixobactin inhibits production of the bacterial cell wall by binding to highly conserved cell wall building blocks. Without a cell wall, bacterial cells lyse, spilling their essential contents into the environment. Other antibiotics, including penicillin, that inhibit the cell wall target its protein components. One mechanism of antibiotic resistance, known as target modification, results when these protein components, encoded in the bacterial DNA, acquire changes from random DNA mutations that alter the antibiotic target site, preventing antibiotic recognition and action. But teixobactin recognizes a lipid (fat) molecule, suggesting it could be less likely that resistance will develop in this manner. Excitingly, growth of S. aureus and M. tuberculosis on low doses of the drug and passage of S. aureus in the presence of subinhibitory concentrations for 27 days did not result in resistant isolates. In contrast, resistance to the antibiotic ofloxacin began emerging after only 3 days of serial passaging. (Research note: Oflaxacin targets DNA gyrase, an important enzyme in DNA replication and transcription. It would have been nice to see the serial passaging experiment done with penicillin and vancomycin, the antibiotic the researchers compare teixobactin to throughout the paper, as this would have provided control data related to other cell wall targeting antibiotics.) The potent effectiveness, lack of observed toxicity, and failure of immediate resistance development make teixobactin a good candidate for a new antibiotic.

 

These findings have been well celebrated in the media, with the suggestion that teixobactin might be a new “magic bullet”, its “resistance to resistance” finally giving us the upper hand in the battle against antibiotic resistance. It is important to keep in mind, however, that this drug is not effective against Gram-negative bacteria, which have a second membrane that protects the cell wall components which teixobactin targets. Thus, multi-drug resistant strains of pathogens such as E. coli, Pseudomonas aeruginosa, and N. gonorrhoeae are left to wreak havoc in the clinic. More importantly, claims of teixobactin’s “resistance to resistance” are a bit premature. Target modification is only one mechanism by which bacteria can gain antibiotic resistance. Other mechanisms include the acquisition of an enzyme that destroys or modifies the antibiotic, alteration of cell metabolism to avoid use of the product or pathway that the antibiotic targets, changes in cell wall composition or structure that keep the drug out of the cell, or use of an efflux pump, a cellular machine that can recognize and pump out antimicrobial compounds. While some of these mechanisms are more complex and may require exchange of DNA with other bacteria to acquire, all are possible. Development of resistance by serial passaging of a single strain in the lab is much different than within a human patient, where interactions with other pathogens and the normal flora (the bacteria normally found on and in the human body) are plentiful, and the presence of other antimicrobial compounds and alternative nutrient sources create a complex environment that could have significant effects on the development of resistance. There is evidence that genes for antibiotic resistance can be transferred among bacterial species, including those of our normal flora, in vivo.

 

The authors do acknowledge that resistance may develop, but assert that it would likely take several decades, citing the 30 years it took for development of resistance to vancomycin, which works by a mechanism similar to teixobactin, as an example. The comparison of the development of vancomycin resistance to that of other antibiotics, however, isn’t entirely fair. When vancomycin was first introduced, its relatively high toxicity and low efficacy kept it as an antibiotic reserved only for patients with allergies to β-lactams (such as penicillin) or resistant infections. In the early 1980s, as resistance to other antibiotics became more prevalent, vancomycin use spiked, and was followed by the development of resistant strains by 1986. Thus, the case of vancomycin resistance should actually serve as a warning: should teixobactin prove a viable antibiotic, careless overuse will quickly relegate it to the ever-growing pile of ineffective antibiotics.

 

Still, the significance of these findings should not be overlooked or understated. Ling et al. have provided us with the first truly promising antibiotic candidate in many years. Perhaps more importantly, they have developed a method for growing bacteria previously uncultivable in the lab, not only expanding the pool of available antibiotic candidates, but also creating a tool that could prove revolutionary in microbiology, ecology, and environmental research. We should be hopeful that teixobactin is safe and effective in human trials, and that either it can be modified to be effective against Gram-negative pathogens or that the iChip method reveals another compound as potent as teixobactin for their treatment. But we must also be responsible and cautious, so as not to squander these precious new drugs and hasten an era of untreatable bacterial diseases.

 

The Epigenetics of Metabolic Reprogramming

 

By John McLaughlin

One of the greatest health issues facing the US is adult and childhood obesity, which exerts a huge human and economic cost on the healthcare system; therefore, its underlying causes are of enormous interest. While environmental factors such as diet and exercise are obviously major contributors, what roles do genetic variation or epigenetic effects play in predisposing individuals to obesity or affecting metabolism in general? Addressing these questions in simple, genetically tractable model systems is a time-tested method for pursuing the answers.

 

In recent studies on gene expression, especially related to disease, there has been growing interest in the role that epigenetic regulation plays in development and metabolism. On the web page of its “Roadmap Epigenomics Project,” the NIH defines “epigenetics” as referring to “…both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term alterations in the transcriptional potential of a cell that are not necessarily heritable.” Although the precise working definition of “epigenetic” is still contested, its usage by biologists generally includes phenomena such as DNA methylation and chemical modification of histones, which can cause changes in the transcriptional capacity of chromatin without altering DNA sequence.

 

In a recent Cell article, Öst and colleagues describe a phenomenon in Drosophila melanogaster which they term “intergenerational metabolic reprogramming” (IGMR). The study is intriguing because it adds to a growing body of work demonstrating intergenerational metabolic effects in a variety of organisms, including rats, flies and worms. An intergenerational effect, as described in this work, results when an environmental stimulus is applied to an organism and elicits a defined response in its offspring, which were not exposed to the original stimulus. Specifically, this study examined intergenerational effects on metabolism that are transmitted paternally; therefore, the mediators of the effect are presumably in the sperm cells at the time of egg fertilization.

 

Their IGMR experimental paradigm is straightforward: male flies are fed diets of varying sugar levels, mated to normally fed females, and their offspring characterized with regards to different metabolic features. The experiments were controlled to ensure that rearing conditions, such as diet and fly density, were identical among all groups of offspring. Interestingly, the progeny of both high-sugar and low-sugar fed fathers exhibited a similar phenotype: increased triglycerides, lipid droplet size, and food intake compared to offspring whose fathers had moderate sugar diets. In addition, this IGMR response was highly specific in causing metabolic phenotypes, as no general developmental effects were observed such as altered wing size, offspring number, or timing of adult eclosure. In other words, the male fly’s diet had a specific and significant impact on its offsprings’ metabolism.

 

An obvious question followed these results: what were the changes in gene regulation mediating this phenotypic response? The IGMR effect correlated with increased gene expression from X chromosome heterochromatin, suggesting an epigenetic process such as chromatin remodeling was at work. This idea was reinforced by an observed decrease in H3K9me3 staining, a histone mark typical of heterochromatin, in the fat bodies of IGMR flies. Although the authors didn’t identify the precise molecular mechanisms of paternal-diet-induced epigenetic reprogramming, they did several analyses comparing gene expression levels of flies fathered by control and IGMR males. RNA sequencing and computational analysis showed that several hundred genes, whose upregulation was correlated with the paternal high-sugar IGMR phenotype, are involved in known metabolic pathways in flies and other organisms.

 

So, what purpose might this type of intergenerational regulation serve? One possibility is that it increases the adaptiveness of offspring to local environments. Parents can “signal” to their offspring, through epigenetic mechanisms, the nutritional state of their surroundings, and thus the next generation of flies will be more metabolically primed to deal with the new environment. Of course, this one study should not be extrapolated to draw unwarranted conclusions about metabolic reprogramming in humans or other animals; much more work remains to be done on the subject. However, it is still exciting to ponder the myriad processes, both known and unknown, that work in the complexities of development. As our understanding of all the facets of gene regulation continues to progress, there will most likely be more amazing surprises to come.

 

 

 

The Hunt for the Holy Grail: A Potential Vaccine against MRSA

 

By Elizabeth Ohneck, PhD

Vaccines represent the “holy grail” in prevention and treatment of infectious diseases. Effective vaccines have allowed the eradication of small pox and contributed to drastic declines in cases of diseases such as polio, measles, and pertussis (whooping cough). As bacterial pathogens become more resistant to a broader spectrum of antibiotics, the desire to develop vaccines against these offenders to prevent disease altogether heightens.

 

Staphylococcus aureus is a common cause of skin and skin structure infections (SSSIs), as well as post-surgical and wound infections. SSSIs, which frequently present as abscesses in the upper layers of skin tissue, can serve as sources of more serious infections with high mortality rates, such as pneumonia, endocarditis, and bloodstream infections, when the bacteria break through the upper layer of tissue and invade other sites of the body. With the high prevalence of methicillin-resistant S. aureus (MRSA) depleting our antibiotic arsenal, S. aureus infections have become difficult to treat, spurring intense investigation into vaccine development.

 

A group from UCLA recently developed a potential vaccine, NDV-3. This vaccine is actually based on a protein from the fungal pathogen Candida albicans, which causes diseases such as thrush and yeast infections. The C. albicans protein is similar in structure to S. aureus adhesins, proteins on the bacterial surface that allow the bacterial cell to stick to host cells. In preliminary studies, the NDV-3 vaccine was shown to be protective against both C. albicans and S. aureus. In a recent paper in PNAS, Yeaman et al. examine in detail the efficacy of this vaccine in MRSA SSSI and invasive infection.

 

To determine the efficacy of the NDV-3 vaccine in prevention of S. aureus SSSIs, the researchers vaccinated mice with NDV-3, and administered a “booster shot” 21 days later. Two weeks after the booster, the mice were infected with S. aureus by subcutaneous injection, or injection just under the skin, to induce abscess formation. Abscess progression and disease outcomes were then monitored for 2 weeks.

 

Abscess formation was slower and the final size and volume of abscesses were smaller in vaccinated mice compared to control mice. In addition, mice vaccinated with NDV-3 were able to clear S. aureus abscesses by 14 days after infection, whereas abscesses in control mice were not resolved. Using a S. aureus strain expressing luciferase, a protein that emits light, the researchers were able to watch proliferation of the bacteria within the abscesses by measuring the strength of the luciferase signal. Vaccination with NDV-3 resulted in a significantly weaker luciferase signal than in unvaccinated mice, indicating NDV-3 vaccination prevents growth of the bacterial population. This finding was supported by a decrease in the number of CFUs (colony-forming units), an estimate of the number of viable bacteria, isolated from abscesses of vaccinated versus unvaccinated mice. Importantly, the researchers conducted these experiments with 3 distinct MRSA strains and observed similar results for each. Together, these findings demonstrate that while the NDV-3 vaccine does not completely prevent SSSIs under these conditions, vaccination can significantly reduce severity.

 

As skin infections can often serve as a source for more serious disseminated infections, the researchers also examined the effect of NDV-3 on the spread of S. aureus from the original site of infection. While control mice developed small abscesses in deeper tissue layers, vaccinated mice showed little to no invasion of infection. Additionally, significantly fewer bacteria were found in the kidneys of vaccinated mice compared to control mice, indicating NDV-3 can prevent the spread of S. aureus from skin infection to more invasive sites.

 

To examine how NDV-3 was stimulating a protective effect against MRSA, the researchers measured the amount of molecules and cells important for immune response to MRSA in vaccinated and unvaccinated mice. Abscesses of vaccinated mice showed a higher density of CD3+ T-cells and neutrophils, as well increased amounts of the cytokines, or immune cell signaling molecules, IL-17A and IL-22. Vaccinated mice also showed higher amounts of antibodies against NDV-3, as well as increased production of antimicrobial peptides, small proteins with antibiotic activity produced by host cells. Thus, the NDV-3 vaccine helps encourage a strong immune response against MRSA.

 

The NDV-3 vaccine was recently tested in a phase I clinical trial and found to be safe and immunogenic (i.e., stimulates an immune response) in healthy human volunteers. While the vaccine in it’s current form doesn’t prevent S. aureus infections altogether, it could help make infections easier to treat by slowing bacterial growth, preventing spread to other tissues, and boosting the host immune defenses. Further research on this vaccine may also lead to a form that is more protective and can better prevent infections.

 

Scientists Letters to Santa Revealed

 

By Elizabeth Ohneck, PhD and Padideh Kamali-Zare, PhD

For many children, Christmas morning was the culmination of months of eager anticipation, the reward for a year of good behavior, the moment the generosity (or perhaps judgment) of Santa Claus was finally revealed. There was undoubtedly gleeful satisfaction (Lady scientist Legos? YES!), and sighs of disappointment (When will Santa bring me a pony? I’ve been asking for 29 years!) In the afterglow of the holidays, these children (and, let’s face it, many adults) are carefully inventorying their holiday spoils against their submitted wish lists, and already composing their next letters to Santa.

Scientists also have wish lists they cultivate year-round, although the nature of the items differs greatly from that of hopeful children (except Lady Scientist Legos; those definitely belong on both lists). While the magic of Santa Claus has long since been lost to the logic of adulthood and science itself, as we easily overthink the constraints of physics and time that would make flying around the world in a sleigh pulled by reindeer delivering toys to every child in one night impossible, we might still find ourselves caught up in the holiday spirit, hoping for a Christmas miracle. So, for a moment, let’s suspend this practicality. Let’s pretend that there is a Santa Claus for science, a jolly, magical figure who flies around the world granting the wishes of labs one night a year. What, exactly, would scientists ask for? And would Science Santa Claus deliver?

Below, a few scientists offer the letters they submitted to Santa this year.

 

Dr. Claus,

As the holiday season approaches, it is time to submit our annual progress report to the Naughty or Nice committee for review. Herein, we provide evidence for the inclusion of our lab on the Nice List, and a list of proposed items that would add to the continued success of our group.

 

This year, we have worked collectively over 500 hours each week, including late nights, early mornings, weekends, and holidays. We have published or contributed to the publishing of 10 peer-reviewed papers. In addition, we have given several successful poster and oral presentations. One of our postdocs successfully obtained a faculty position. And we hosted one heck of a department mixer. Taken together, we believe these data qualify our lab for the Nice List. As such, we would like to request the following holiday gifts:

 

  1. A first author paper. Ok, 9 first author papers, if we’re being perfectly honest. But we’d be happy with 4. You can team us up for some co-first author publications.
  2. An automated plate spreader, an automated colony counter, a machine that automatically does all the washes for ELISAs in a 96-well plate… basically anything automated. It’s not that we’re lazy (well, maybe a little). We’re just trying to be more efficient with our time and energy. We could do bigger experiments and fit more experiments into a day. (On second thought, we might re-think this one. Hold off for a bit. We’ll get back to you.)
  3. Repeat pipetters. Or, at the very least, a fully functional, easy to use, consistently accurate P10 multichannel pipette. Such an item would greatly increase both the precision and accuracy of our results, slow the inevitable development of carpal tunnel syndrome, and probably prevent that one postdoc from having a nervous breakdown (you know which one we’re talking about).
  4. Stuff to work. Particularly cloning, transduction, qPCR, and getting repeatable results from that one stupid experiment.
  5. The PI would like a 24-hour lab.

We are aware that funding is tight, which may prevent the granting of more than one request per lab. Should this be the case, you may disregard the above list in exchange for only the following:

Please, for the love of science, do NOT allow #5 to happen. Ever.

Thank you for your time and consideration. We wish you safe travels this holiday season.

 

Best regards,

The Microbiology lab

 

 


 

Dear Santa,

I know you must be very busy this time of the year so I make it short. Below is the list of my requests to you that would appreciate a lot if you take a look:

 

  1. Please provide some different ways of funding for science so the PIs are not so much under pressure of getting data, publishing papers and applying for grants. There is something seriously wrong with such an ecosystem that makes everyone at any level unhappy. And beyond that, it makes the science world full of discoveries that are in response to “call for proposals” and not scientist’s inner motives to “discover the unknown”. This is not the way science should be. You agree?

 

  1. Please send scientists, once in a while, messages that include an overview of their projects so they don’t get lost in details. Something like a map that shows the big picture! And please help them read the map if it’s not in a nerdy language.

    3. In the end scientists wanted to make a difference that’s why they chose science among all other much-better rewarding career paths. Please help them find their individual ways to do so. Still most scientists believe science as a life style, as a way of thinking and not a job! Don’t let them become disappointed… PLEASE!

 

Thank you very much and looking forward to seeing some magical action from you this year! Yes! You can! Do it!

 

-Padideh Kamali-Zare

 

Did you have a science holiday wish list? What did you ask Science Santa for? Did he (or she) deliver? You’ll be happy to know the Microbiology Lab made the Nice List and received TWO new, state-of-the-art P10 multichannel pipettes. They’re still waiting to see whether their experiments have started working. And seriously hoping the 24-hour lab request was overlooked.

How Our Environment Affects the Development of Autoimmune Diseases

 

By Asu Erden

In the past fifty years, there has been a significant increase in the incidence of autoimmune diseases, such as type 1 diabetes and lupus, in the West and in countries adopting western lifestyles. Given that half a century is too small a time scale for human evolution to occur, what exactly is contributing to this increase? Recent studies have been highlighting the role of environmental factors.

 

If the age-old debate regarding the relative importance of nature versus nurture taught us anything, it is that the more apt position lies somewhere in the middle. Both our genetic makeup and the environment in which we live affect our phenotype. However, the study of autoimmune diseases has often focused on the contribution of genetic factors. The etiology of these diseases relies on recognizing one’s own proteins – also called self-antigens – and on triggering an immune response against them. For such a response to occur, these antigens need to be presented to the immune system by genetically encoded molecules called human leukocyte antigen (HLA) molecules. They constitute the most highly associated factor with autoimmune diseases. It is therefore easy to overlook the role of the environment.

 

Two seminal studies have contributed to shifting this bias. The first by Mahdi and colleagues at the Karolinska Institute in Stockholm, Sweden, looks at the impact of smoking on the development of rheumatoid arthritis (RA). The other by Dr. David Hafler’s team at Yale University, in New Haven, Connecticut, dissects the role of our diet in the etiology of multiple sclerosis (MS).

 

In their study published in the scientific journal Nature Genetics, Mahdi’s group carried out a population study based on three RA cohorts from the UK and Sweden. Comparing RA patients and healthy individuals, they identified that smoking contributes to RA development by increasing an individual’s immune response to the self-antigen citrullinated α-enolase. Importantly, the association that they found between smoking and RA requires a susceptible genetic background (e.g. HLA-DRB1*0401, HLA-DRB1*0404). This means that smoking alone cannot cause RA in a person that does not have the “right” genes.

 

The increasingly high salt content of Western diets led Dr. Hafler’s group to investigate the effect of these recent dietary changes on autoimmunity. In their study published in the journal Nature, they observed that a high sodium chloride diet results in a high concentration of this mineral in organs. In turn, this results in an increased number of activated CD4+ T cells – a subset of immune cells that participate in the adaptive immune response – that become helper T 17 cells (Th17 cells). These Th17 cells are responsible for inflammatory conditions that promote MS as shown in mouse models of the disease. Thus high salt intake primes the immune system to respond to self-antigens in the context of MS.

 

Despite great advances in our understanding of the mechanisms through which environmental factors contribute to the development of autoimmune diseases, challenges remain. A given environmental factor does not affect the development of all autoimmune diseases in the same way. Smoking may increase the risk of RA onset in patients with genetic predispositions. However, nicotine is also known to alleviate symptoms of ulcerative colitis, a type of inflammatory bowel disease (IBD) closely related to the autoimmune condition Crohn’s disease. Overall, the fact remains that the incidence of autoimmune diseases has increased greatly in the last half century. And, to some extent, it seems that we are doing it to ourselves…