This post on Microbe World entitled: “Software for Programming Microbes” did attract my attention, and I followed its source in the MIT Technology Review: An amazing article presenting a fascinating newly emerging technology of programming bacteria to do whatever we want them to do, produce drugs more efficiently, clean up oil spills, anything… useful! But the methodology was quite beyond my imagination.
I was extremely lucky to be able to interview Dr. Christopher Voigt, Associate Professor at the University of California, San Francisco, who is the project leader. Dr. Voigt has published over 34 articles indexed in Pubmed and you can find more about his projects on his lab website.
Now I will leave you with the interview! I thank Radwa for reviewing it.
Dr. Christopher Voigt
1. May you please simplify the term “genetic circuit” to the micro-readers? What drove you to use software to genetically modify bacteria?
A genetic circuit functions like an electronic circuit, but uses biochemical interactions to do the computation. I am a computer programmer at heart and find living cells to be the ultimate challenge.
2. We used to hear a lot about the use of genetically modified bacteria in cleaning up toxicants or oil spills, producing drugs and biofuel. How is “programming bacteria” different from the “regular” definition of genetic engineering, which might be based on inserting a gene, a regulatory gene, or an operon that encodes for a certain needed functionality?
Genetic programming controls the timing and conditions under which those processes occur. It doesn’t refer to the pathways by which molecules are made or degraded.
3. In MIT Technology Review, you mentioned that like for a computer, programming bacteria is about writing a program to be encoded on a piece of DNA to implement a function. How can bacterial cells understand the code? How can the software make them sense the outer media?
The DNA contains codes for when molecules like proteins and mRNA should start and stop being produced and under what conditions. A protein can change its state when it senses a condition and bind to DNA to cause genes to be turned on or off. This acts like a sensor.
4. Honestly, I can’t imagine writing a piece of code to link bacterium to one another, because node->pRight!=NULL ? I just can’t imagine it. Is there any risk of overloading natural functions by accident?
5. How can programing bacteria make use of quorum sensing?
Quorum signaling enables cells to be programmed to communicate with each other.
6. How can drug discovery and production benefit from programmable bacteria in the near future?
It makes it easier to access and control those pathways.
Tags: Christopher Voigt
, genetic circuit
, programmable bacteria
, quorum sensing
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For a long time, mental retardation was believed to be incurable, as it is usually caused by gene mutations that disrupt brain development right from the beginning and even before birth. But thanks to a lot of hard-working scientists, there are trials now to improve the quality of life of such patients, along with their caregivers. The work has been focused on a condition known as “Fragile X syndrome”. In this disease, a mutation takes place in a gene called FMR1 , which is responsible for the production of proteins, that regulate neural development, usually leading to mental retardation according to the extent of such mutations.
Fragile X syndrome's common physical symptoms : elongated face, large ears, etc
Another important contributor to the condition is the metabotropic glutamate receptor-5, abbreviated to mGluR5. It is responsible for controlling the process of protein synthesis at the neuronal synapses, becoming hyperactive in case of fragile X. Being an interesting therapeutic target, a major pharmaceutical company developed AFQ056, an mGluR5-receptor blocker, in the hope that it’ll restore normal transcription levels. The results of the initial double blind clinical trials, conducted on 30 patients, were evaluated through the notes taken by the caregivers about the behavioral improvements of the patient. This included less repetitive behavior, less hyperactivity, less tantrums and having better chances of establishing communication with the patients.
What seemed like a puzzle is that some caregivers reported no change at all after the patients took the drug. So after data analysis, the researchers found that the only patients affected by the treatment were the ones (7 patients out of 30) having a certain genetic marker: complete methylation of the FMR1 gene regulator sequence, and therefore, complete lack of FMR1 transcription. Another disappointment was that the drug didn’t improve cognition or memory, but this, they say, might be attributed to the short duration of the trial, lasting for only 4 weeks.
The next step is to repeat the trial, but this time on 160 selected patients, after testing them for the marker and the experiment will last for 3 months, hoping to obtain better results that are more significant to the patients of this illness.
Sources: Wikipedia and Science News
, fragile X syndrome
, mental retardation
, metabotropic Glutamate receptor 5 blockers
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Which hair colour a person possesses depends mainly on the proportional amount of two melanin pigments, mainly the black-brown pigment, known as eumelanin, and the blond-red pigment, known as pheomelanin. The assortment of hair colours present is a consequence of the numerous combination proportions of each pigment.
For quite some time now (since 1997), the gene responsible for the classic red-hair phenotype has been discovered. At that time, the research team was concerned with the MC1R gene on chromosome 16. Its role was the production of MC1R receptor, which assists in the conversion of pheomelanin to eumelanin. Individuals with two copies of the recessive gene, causing a mutation in the MC1R, are most likely to turn out red-headed due to the build-up of pheomelanin. However, since the other hair colours are controlled by a variety of genes, it was, until recently, a tough task to predict a person’s hair colour from strands of his/her DNA.
Now, researchers at the Erasmus University Rotterdam have released an article identifying 13 DNA markers, located on 11 genes, which can guide us to the prediction, with a fairly high accuracy, of an individual’s hair colour. “For our study, the authors utilized the DNA and the accompanying information regarding hair colour from hundreds of Europeans and analysed various genes, that were previously known to be involved with this trait”, pointed out Professor Manfred Kayser, who lead this study. The accuracy percentage is as high as 90% when it comes to black and red hair, but dropping down to 80% or more with blond or brown hair.
The further potential implications of the study will soon be applied to forensic investigations. Along with their previously published work regarding eye colour and height from the DNA, these researchers aim at forming a descriptive profile of previously unidentified individuals, whether victims or offenders.
, forensic medicine
, hair colour
, red hair
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Man or Machine? Bioinformaticians at McGill university are betting on man. They want to put, what was previously wasted, time on the internet into use. Thus, Phylo was created. That is the name of an online interactive game, aiming to solve the problem of multiple sequence alignments, one that has been agonizing researchers for some time now. The human mind is evolved in a way, that even computers supposedly can’t beat. We are capable of recognizing certain patterns and forming interrelations between them, a skill which numerous lines of codes can not easily accomplish.
So what to do? Once you open the link, go ahead and sign up, although it is possible to play as a guest. But hey, if I am taking time off to contribute to science, I want to be able to brag about it later on. 🙂 The creators of the game have formed a very comprehensive tutorial, explaining how the game works. They use down-to-earth terms and comparisons to simplify matters, so people from all walks of life can jump in as well.
The coloured blocks: Those symbolize the nucleotides. Correspondingly, there are four of them: Orange, Green, Blue, Purple. I wasn’t able to find exactly which colour codes for which nucleotide, something which particularly intrigued me, since purple blocks were scanty in my alignment.
Aim of the game: Our job is to align these blocks, as best as possible, so that the blocks’ colour in the first line are matching those in the second line. Matching blocks gives you a score of 1 point and mismatched ones deduct 1 point. This should be preferably done WITHOUT having to create gaps. They point out that gaps represent the mutations, which the sequences have incurred during evolution. In the easier stages, the sequences are provided on two lines, representing two different species. As it gets more difficult, more lines are provided and related together through a mini-phylogenetic tree, to allow you to pinpoint your priorities. Once you have reached the same score a computer had previously provided “par”, a star will blink to indicate that you are ready to move on, as the alignments are stored in a database for future use.
My experience: I stumbled upon a feature, where you can choose the type of sequences you want to work with. They are arranged according to disease, level ID, or simply random. I chose the blood and immune system disorders and was granted sequences, related to essential thrombocytopenia.
Statistics: At the end, I was provided with the following astonishing numbers. So far, 5344 users have submitted 70196 alignments for 2137 different levels. Personally, I think this number is quite surprising, since that many people are joining in since only November 29th, the date of the official launch.
Interested in more: In the “about” page, the following sentence is provided: “For more information about any one of these topics, click here“.
, contributions to science
, essential thrombocytopenia
, online games
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Viruses are defined as “ small highly specialized infectious agent”. This definition has been common for the last decades or century to define nature’s microorganisms, which tend to infect most living organisms from humans down to bacteria. Now, it seems that the definition would be widened to include even these little malicious computer codes –that they used to call worms– but now the word virus would seem more appropriate.
In July 2010, a malicious code was discovered and assigned the name “Stuxnet” the powerful virus, and –unlike the previous ones– this one simulates the biological virus in the way it acts. Speaking biologically, a common flu virus would enter the human body through the respiratory tract, bind to special receptors and infect the entire respiratory tract causing the common flu symptoms, this could have been applied to older computer viruses. The new Stuxnet virus, however, would resemble a more specialized biological viruses as hepatitis viruses or HIV; the Stuxnet virus gains entrance to the computer via “Universal Serial Bus“ –commonly known as “USB port”– and then spreads like wild fire in the entire network its device is connected to.
Up to this part, Stuxnet would be a common garden-variety computer virus, but this is not enough for Stuxnet. Just like HIV searches for CD4 cells and hepatitis virus searches for hepatic cells, the malicious code Stuxnet searchs the infected computer for its target, which is a special control program called “Supervisory Control and Data Acquisition (SCADA) developed by Siemens Co. for operation of industrial systems, and used to control manufacturing processes from centralized locations, for example it can be used to alter the motor work rate of a machine on a factory floor, or the pressure in a pipeline, so typical environments could be oil pipelines and power plants.
This highly specialized virus is also unique in its mode of action; the sophisticated virus uses a four “zero-day” vulnerabilities –zero-day vulnerability or zero-day attack is a security hole or breach in a program which the developer is unaware of. Using four of these zero-day vulnerabilities is quite weird because these zero-days are of great value ( for hacker and malware makers )and using 4 of them in a single code is quite odd. Again the code still surprises us with its resemblance to biological viruses, for examples, like flu virus that has the ability to mutate and change forms via multiple ways, and like any bacterium that acquires resistance through plasmids or other pathways, Stuxnet can upgrade itself via peer-to-peer architecture (p2p, a distributed application architecture that partitions tasks or workloads between peers) allowing it to be updated after the initial command and control server (the initial computer) is disabled.
Symantec Corp., one of the world computer security leaders, estimates that 45.000 computers have been infected, and like biological threats and biological warfare viruses, Symantec also estimates nearly 30.000 of these infected computers in Iran only, and earlier today (27 September 2010) undisclosed Iranian sources said the nuclear plant have indeed been hit by Stuxnet with no damage to the plant.
I guess Arnold Schwarzenegger (The terminator) wasn’t lying after all when he said “I’ll be back!! “
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Forget about the old Petri dishes and culture media! A brilliant new method for the growing of microorganisms in order to study their behavior, especially in a large community, again tracking the phenomenon of quorum sensing , has been developed and put to use.
The new invention, by Connell et al., resembles a trapping sack for microorganisms, made of bovine serum albumin covalently cross-linked by laser lithography to form a three dimensional structure. These harboring chambers are very small, with a 2 to 6 picoliter capacity, and are permeable, and thus allowing an infinite influx of nutrients and other essential small molecules for the bacteria growing inside.
Scientists have already compared the growth rates of Pseudomonas cells in “the trap sacks” to those in conventional culture media and mouse lungs and the results were promising! The new technique allows them to study patterns of antibiotic resistance, infection and biofilm formation more clearly and in earlier phases of bacterial growth…
Source: Science magazine, Vol. 330 issue 6004.
Image source: Microbiology Bytes
Tags: antibiotic resistance
, culture media
, microbial trapping
, pseudomonas biofilms
, quorum sensing
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So, we thought the worse was over; we thought we are done fighting the bad guys, HIV, SARS and H1N1A, but now it seems that a new menace is eminent. Our chaotic and rather foolish use of antibiotics have created this unknown danger that could add a new chapter to the history of medicine and fighting infectious diseases. This danger is called New Delhi metallo Beta-Lactamase -1, AKA NDM-1
Meet the Bug
In December 2009, a super villain appeared on the scene; he’s violent, resistant and determined to do as much damage as he could. Our super villain is the NDM-1 (New Delhi metallo beta lactamase – 1), a newly emerging beta-lactam resistance enzyme including carbapenems, which are one of few alternatives used for antibiotic-resistant bacterial infections. The NDM-1 gene is classified as a Carbapenemases . The enzyme is named after the city in which it first appeared, New Delhi, the Indian capital. In December 2009, a Swedish patient in India acquired an antibiotic resistant infection. Being unsuccessfully treated in India, the patient was further transferred to Sweden. The carbapenem-resistant Klebsiella pneumoniae was identified carrying the novel NDM-1 gene. A later study in India found that carbapenem-resistant strains from patients in India carried the NDM-1.
In May 2010, an E. coli expressing the NDM-1 gene was isolated from a patient in the UK, the patient was of Indian origin and had visited India 18 months ago where he had been undergoing dialysis. According to CDC Morbidity and Mortality Weekly Report (MMWR) , as of June 2010, three Enterobacteriaceae isolates carrying the NDM-1 gene were discovered in the U.S., which were E. coli, Klebsiella pneumoniae, and Enterobacter cloacae, NDM-1 provided the three isolates with resistance to all antibiotics except for Aztreonam. Fortunately to the bacteria but unfortunately to our patient, the isolates conferred resistance even to Aztreonam by different mechanism other than the NDM-1, and the MMWR established that all the three U.S. isolates were related to patients who had medical care in India.
Furthermore, a team in India in July 2010, reported cases of Acinetobacter baumannii carrying the NDM-1 in India. A recent study by a multinational team published in “The Lancet Infectious Diseases, September 2010” reported that the isolation of 44 isolates with NDM-1 in Chennai, 26 in Haryana, 37 in the UK, and 73 in other sites in India and Pakistan. NDM-1 was mostly found among E. coli (36) and Klebsiella pneumoniae (111), which were highly resistant to all antibiotics. Luckily, all the studies have confirmed that all NDM-1 isolates were susceptible to the antibiotics tigecycline (the FDA-approved glycylcycline antibiotic developed by Francis Tally and marketed by Wyeth under the brand name Tygacil®), and colistin (polymyxin E antibiotic, which causes nephrotoxicity and neurotoxicity at high dose IV). Some unconfirmed reports indicate the NDM-1 appearing in Canada and Japan earlier this month (Sep 2010).
In June 2010, patient zero –the first reported death– was a Belgian man who had a car accident in Pakistan, first being treated in a hospital in Pakistan and he became infected with the Bug carrying the NDM-1. He was further transferred to Belgium where he was hospitalized with major leg injury, and despite being administered colistin, the patient died!
We now face a new challenge. Could this superbug mean the end of the beta-lactam antibiotics era?!
Tags: bacterial resistance
, escherichia coli
, klebsiella pneumoniae
, resistant strains
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The pursuit of renewable sources of energy just hit a crucial breakthrough. Since the stores of fossil fuel are diminishing as we speak, researchers are trying to exploit the machinery of microorganisms for the production of diverse chemical compounds, which can be consumed by themselves or later channeled into some form of combustible fuel. One major group of those compounds are alkanes, those saturated organic compounds abundantly found in gasolline.
The study started off when ten out of the eleven strains of Cyanobacteria, that were photoautotrophically cultured, produced forms of alkanes, mostly those with 15 & 17 carbons atoms “termed penatdecane and heptadecane respectively”. Logically, that indicates that the ‘alkane-producing gene’ is shared in all ten of them, yet absent in that unlucky 11th strain. So the search was launched.
Trying to pinpoint the gene responsible for the production of alkanes through using a method referred to as subtractive genome analysis, the study authors compared ten genomes of the alkane-producing strains to figure out which genes they have in common. Next, any of those shared genes was immediately eliminated if it had additionally showed up in the genome of the NON-alkane producing strain. Eventually, the researchers were left with 17 genes found in common and the function of 10 of them had already been previously assigned. Through careful scrutiny of the families to which proteins of those remaining 7 genes probably belong to, two of them particularly stood out, being likely participants in the pathway of the alkane synthesis.
And as always, there is no better way to test the hypothesis than to consult a microbiologist’s favorite lab microbe. To our pleasant surprise, extracts from the colonies of Escherichia coli engineered to express both genes did in fact contain alkanes. So, although we are still not fully aboard the track heading the way towards large scale production of alkanes using such microbes, this is definitely a gigantic leap in the right direction!
, escherichia coli
, subtractive genome analysis
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When you have to make a tough decision, a difficult choice, one that will affect your life and the lives of those around you, you always have to involve them in the process, and you will find that the wisest thing to do is to unite and make the decision collectively…
Starting from us, humans, and reaching bacteria, collective decision making can be a matter of life and death, yet many factors can influence the way we think and switch our behavior from one way to another. In quorum sensing, bacteria behave in a completely different way upon reaching a certain population density, from the way each one would behave individually.
This is all obvious, but I was lately wondering, do viruses exhibit any form of such “attitude”?? What is the equivalent to quorum sensing in the world of viruses?
The work in this field was all focused on bacterial viruses or bacteriophages, and especially on the temperate lambda virus (a phage that infects E. coli).Temperate means that upon infecting a bacterial cell, the virus will be allowed to choose between two scenarios:
Either: the lytic pathway, in which the virus will use the bacterial resources to replicate itself several times, then bursting out of the cell, killing it and releasing the viral progeny.
Or: the latency or lysogenic pathway, in which the virus integrates its genetic material into that of the host, undergoing minimal transcription and translation, and just replicating and vertically transferring it as the cell divides.
So what really helps or even forces the virus into a certain direction? For a long time, it was thought that the choice is completely random, and greatly affected by environmental conditions. But Joshua Weitz (assistant professor in the school of biology, Georgia Tech) and his team were not satisfied by this answer. They wanted to justify the experimental observation that when one virus infects the cell, the result would be lysis and cell death, whereas if two or more co-infect the host, the result would be latency.
Their mathematical model, based on the gene regulatory dynamics of the λ phage, shows us that the true answer lies in the levels of “gene expression”. Apparently, the process turned out to be controlled by three key genes: cro, cI, and cII. These genes are bound together by a decision loop (a feedback system) that is nonlinear and thus is tremendously affected by minimal changes in the levels of their expression into proteins, which depends on the total number of viral genomes in the host.
The negative feedback system was linked to the “cro” gene, and was triggered by the overall lower rate of mRNA transcription present at this stage, and thus its protein products inhibited the genes responsible for the production of the lysogenic proteins, and so lysis takes place.
In case of co-infection by two or more viruses, as the overall level of viral mRNA transcription is higher (although the increase could be so small!)& the products activate the “c I” gene transcription, translated into lysogenic proteins that activate & accelerate the positive feedback system, leading to even higher levels of production of the lysogenic proteins, and the cell is kept alive and kicking for a certain time period.
The “c II” gene represents a “gate” to the activation of the lysogenic cascade, activated prior to the c I gene. This is a figure I designed to simplify the idea.
Although it is far from settled, but proposing the ability of viruses to make collective decisions based on the number of viral genomes in the surrounding environment can be a very important “life” history trait. Having this trait may be critical to the evolution and survival of certain types of viruses and can explain a lot about that. But what I thought to be most interesting is this: knowing about these mechanisms can allow us to manipulate them in the future! We might be able to slow down the aggressiveness of some viral infections by driving them to latency. Even if is not a radical cure, it can greatly improve the life quality of lots of patients. Maybe in the future we would be able to find other viral functions that are driven by the same mechanisms like host resource usage or cellular penetration, and so defeating viruses in some new unconventional ways…..so let us hope and work!
Original paper: collective decision making in bacterial viruses
Biophysical journal 15 Sept 2008 (available online)
References (Citation by ResearchBlogging)
WEITZ, J., MILEYKO, Y., JOH, R., & VOIT, E. (2008). Collective Decision Making in Bacterial Viruses☆ Biophysical Journal, 95 (6), 2673-2680 DOI: 10.1529/biophysj.108.133694
Edited on Sep 24, 2010 (07:21 CLT)
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How about taking a “closer” look onto a microbe??? I’ll try to take you on a journey deep into the nature of the particles constituting it, deep to the extent of subatomic levels, in a trial to learn more about the beginning of life and matter…
Since being a nuclear physicist has always been a dream for me, but obviously didn’t come true, I have been very interested lately in the news about the re-operation of the Large Hadrons Collider (LHC) at CERN and the experiments being conducted there in their attempts to find out more about the composition of matter and the origins of our universe, and the effects these discoveries will have on all different fields of science.
My readings into this topic have brought me to know more about one of the fundamental building blocks of matter, the Quark. Being an elementary particle, quarks theoretically can’t be broken down into smaller units. Their existence was first proposed by physicists Murray Gell-Mann and George Zweig in 1964 as “the Quark model”. The model was introduced to give a better explanation and understanding of atomic Nucleii composition, but there was little evidence for their existence. This lasted till “deep inelastic scattering “experiments were conducted at SLAC National Accelerator Laboratory operated by Stanford University in 1968. since then, six types of quarks also known as “the six flavors” have been discovered, divided into three generations : 1st generation including ( up) and (down) quarks, 2nd including (charm) and (strange) quarks and the 3rd including (bottom) and ( top) quarks. The (top) quark, first observed at “Fermilab” in 1995, was the last to be discovered. There have been trials to prove the existence of a 4th generation of quarks, but till now, all have failed but in the future, and thanks to the current LHC experiments, who knows? After all, protons, neutrons and even atoms were once considered fundamental units of matter and that there was nothing more beyond them!!!
Higher generations of quarks are heavier and less stable, so they undergo certain type of particle decay into the more stable types, those are the up and down quarks, the most abundant in our Universe. The higher generation quarks can’t be produced except at extreme conditions of heat and pressure and with the help of high energy collision, a state believed to exist just after “The big bang” that created our universe.
Unfortunately quarks can’t exist solely in space. They form composites known as Hadrons, the most stable of which are protons and neutrons (so quarks are the building units of the building units of the nucleus of an atom!). This is because of two very important physical phenomenons known as “color charge” and “strong interaction”. These very strong bonds are mediated by energy carriers known as “gluons” (actually derived the word glue, as to stick!) and therefore quarks can’t be isolated singularly, making their observation not an easy task for physicists through the years. Simulating the cosmic conditions present just after the big bang, at which quarks were supposed to exist singularly in what is known as “the quark-gluon plasma” is one of the major aims of the CERN experiments through the LHC.
So you might ask yourself, if they can’t be observed by themselves and can’t exist singularly under normal conditions, how can they prove their existence in the first place? The answer simply is that proposing their presence justifies a lot of physical phenomenons and fits into certain physical models and gives the right answers to lots of experiments, so science has to admit that they are there!
Quarks have lots of interesting characteristics. For example, they have fraction charges ( like -1/3, and +2/3). Each quark has an antiquark having the same magnitude, mean half life but opposite charges (+1/3, -2/3).Hadrons, consisting of quarks, will always have integer charges (for example, a neutron has a charge of 0 consisting of 1 up quark (+2/3) and 2 down quarks( 2*-1/3) that is a sum of zero). They are the only elementary particles in the Standard Model of particle physics to experience all four fundamental interactions, also known as fundamental forces (electromagnetism, gravitation, strong interaction, and weak interaction) .
The quarks got their name when Gell-Mann named them after the sound made by ducks!!!! The “strange” quarks were termed so because they had exceptionally long half lives!!.As for the “charm” type, Glashow, who co proposed charm quark with Bjorken, is quoted as saying, “We called our construct the ‘charmed quark’, for we were fascinated and pleased by the symmetry it brought to the subnuclear world.”
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