And finally... spring! (And a plea for the bees)

A few days ago I complained about spring being late this year, so I thought I'd follow up with an update. :-)

Yup. I think it's here now. :-)

Sadly, I didn't see as many bees as I'd wished I did, and I fear it may not be a coincidence. Last year, my friend and colleague Bette Korber wrote a beautiful post on her blog and how we should all do our part to preserve these precious tireless workers:

"Bees are in trouble, and wild bees are disappearing. It's possibly caused by a lethal combination of virus and fungus, thought better able to take hold when bees are stressed and weakened. And stress them we do, with our pesticides, agricultural monoculture, and habitat loss. We can help the bees in a simple joyful way by planting native wildflowers in our gardens, different kinds, in abundance. Pesticide-free bee habitat restoration, one yard at a time. Spring is coming – get busy."

North Korea and the USA can indeed unite: in the battle against TB.

Tuberculosis (TB) is an infectious disease caused by a bacterium. It spreads through cough or sneeze from subjects with an active infection. While in most cases the disease is asymptomatic, a minority of latent infections does become active (i.e. the subject develops symptoms), and when it does, if left untreated, the disease can be deadly.

According to the CDC one third of the world's population are infected with TB, and while in the US the incidence of the disease has been declining over time, it is still a huge problem in parts of the world like Asia and sub-saharan Africa. While normally the chance of a latent TB infection becoming active is one in ten, the chance is much higher for HIV-positive subjects because their immune system is already debilitated by the HIV virus. As the CDC reports:

"TB is a leading killer of people living with HIV (PLHIV)."

A regimen of 3-4 drugs has been available for years to keep latent infections from becoming active. Sadly, TB infections from multidrug resistant strains (MDR) have been steadily increasing, setting back the progress made in the past decades.

From the World Health Organization:

"Drug resistance arises due to improper use of antibiotics in chemotherapy of drug-susceptible TB patients. This improper use is a result of a number of actions including, administration of improper treatment regimens and failure to ensure that patients complete the whole course of treatment. Essentially, drug resistance arises in areas with weak TB control programmes. A patient who develops active disease with a drug-resistant TB strain can transmit this form of TB to other individuals."

One of the countries plagued by MDR TB strains is North Korea, where the incidence of TB has dramatically advanced over the past years, reaching one of the highest incidences outside sub-saharan Africa.

In this week's issue, Science Magazine describes a joint effort between two countries that, according to the recent news, you'd least expect to pair up: North Korea and the United States. In collaboration with Stanford University, the Korean ministry of Public Health opened in 2010 a National Tuberculosis Reference Laboratory (NTRL).

"NTRL researchers can now diagnose TB cases that are resistant to first-line drug combinations, making it possible to spot patients who need more aggressive therapy. And the lab will soon add capacity to screen for extensively drug-resistant TB, known as XDR—the worst strains, some of which are close to impossible to treat."

The Science report covers stories of hope in the midst of desperation. It points to pressing issues the North Korean government has to address within its borders, and focusing on them would seem a more reasonable and logical strategy than polishing nuclear arsenals. Let's hope that the roots of this collaboration grow deeper than any political discrepancies. Let's hope that the battle against a common enemy (TB) will put an end to the empty, unfounded threats and pave the way to a broader, more civilized way of communication between countries.

Stone, R. (2013). Public Enemy Number One Science, 340 (6131), 422-425 DOI: 10.1126/science.340.6131.422

Can we functionally cure HIV?

Last March, Dr. Deborah Persaud, from the John's Hopkins Children Center, presented a stunning finding at the conference CROI, receiving great resonance across several newscasts: Persaud reported the first case of infant functionally cured of HIV. You can watch Persaud's presentation by downloading the podcast here, it's the seventh talk of the session "Is there hope for HIV eradication?"

Up until this finding, the only living person cured from HIV was the Berlin Patient, who was cured after receiving gene therapy for his underlying leukemia condition. Despite this one successful case, gene therapy is not a feasible way to cure HIV.

What does it mean to be functionally cured?

Once in the host, the HIV virus establishes reservoirs of latent virus: these are viral particles that stay dormant in cells and tissues and have the ability to quickly rebound in the event that therapy is discontinued. That's why it's so important for an HIV infected person to never discontinue the drug regimen, as the rebound virus may be drug resistant. HIV is so efficient at escaping the immune system and therapy that standard practice these days is a lifetime of not just one, but a cocktail of 3-4 antiretroviral drugs.

To be functionally cured means that drugs are no longer needed to keep the viral load (amount of virus in the blood) in check (close or below detection), something that until now had only been achieved by an extremely low number of HIV-positive individuals (less than 1% of infected adults), the so-called "elite controllers." In all other subjects, the reservoirs are never completely weakened and they enable the virus to bounce back once therapy is interrupted.

So, what was different with this child?

The mother went into labor without prenatal care. An HIV test was done during labor and normally, when the test is positive, antiretroviral drugs are administered. This is highly effective in preventing mother-to-infant infections as the only moment when the infant is exposed to the mother's blood is at birth. The antiretroviral drugs keep the viral load so low that the risk of infection becomes very small (around 2%). Unfortunately, in this particular case, the birth was so precipitous that there was no time to administer such drugs. The newborn baby was immediately tested for HIV.

This is my understanding of what was unique about this case: normally a first test is done and, if positive, a second follow-up test is performed and prophylaxis is started once the infection is confirmed. In this case, though, two independent tests were done at the same time and, since both confirmed the HIV infection, prophylactic treatment was started very early, when the baby was 31 hours of age. Also, unique to this case was the fact that a regimen of three drugs, of which one at the therapeutic level instead of the standard prophylactic dosage, was administered during the first week of life. After that, the baby was switched to a standard treatment of antiretroviral drugs (again, my understanding from the CROI talk).

Such regimen successfully brought the child's viral load down to undetectable, which is normal in these cases. Despite this, because of HIV's ability to establish reservoirs, antiretroviral therapy is never discontinued. Like I said before, it is a lifetime therapy. So called "drug holidays" result in more virulent and drug-resistant HIV quasispecies. However, this child was lost to follow-up at 18 months of age and was once again seen by the doctors at 25 months of age, when the caregiver reported discontinuing the therapy. Immediate testing was done to assess the child's viral loads. The child was tested not once, but many times. Genetic testing was also done to make sure it was the same child treated before. The doctors must have been in disbelief as for the first time they were seeing the incredible: after 5 months since discontinuing antiretroviral therapy, the viral load in this child was still undetectable.

What are the consequences? As Dr. Persaud repeated many times during her talk, this is a single case and a proof of concept. We need more cases to be able to generalize (as statistics teach us). However, it points to something that indeed needs to be explored: how early in the infection can we (and should we) intervene? In a 2012 paper [1], Persaud and colleagues studied the dynamics of the latent HIV reservoirs in 17 infants on very early antiretroviral drug therapy (median start age 8 weeks) and found that the size of the reservoirs at age 2 was associated to how early undetectable viral loads were achieved during therapy. The earlier viral load was suppressed through therapy, the smaller the HIV reservoir at age 2. Is there a point, very early into the infection, when the virus is vulnerable and all reservoirs can be not just reduced in size, but actually completely eradicated through potent and prompt intervention?

In rare cases, HIV-infected patients are able to spontaneously maintain their viral load at a very low level without the need of drugs, the so called "elite controllers." What if, when administered early enough, antiretroviral drugs could transfer this type of spontaneous protection to every HIV-infected person?

Shortly after the CROI conference, a French study published in PLoS Pathogens [2] reported 14 cases of what they call "post-treatment controllers," in other words, people whose viral loads remained very low after interrupting treatment. With the exception of mother-to-infant transmissions at birth, it's extremely hard to catch this virus early because people often don't realize they've been infected: symptoms, if any, appear 3-4 weeks later and are often mistaken for a common cold. Twelve of the 14 cases reported in [2] had symptoms that prompted early intervention and start of therapy during the primary infection.

"Post-treatment controllers (PTCs) had a more severe primary infection with higher viral loads and were frequently symptomatic, which may have prompted the early treatment in some cases [. . .] Therefore, our results strongly suggest that the infection control in the PTCs was not achieved spontaneously and was favored by the early onset of therapy. Because the interruption of long-term antiretroviral therapy initiated early during primary infection is not recommended, only a very small proportion (~2%) of the patients in the French Hospital Database on HIV Infection experienced such an interruption, which may explain the rarity of PTCs worldwide [2]."

[1] Persaud, D., Palumbo, P., Ziemniak, C., Hughes, M., Alvero, C., Luzuriaga, K., Yogev, R., Capparelli, E., & Chadwick, E. (2012). Dynamics of the resting CD4+ T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age AIDS, 26 (12), 1483-1490 DOI: 10.1097/QAD.0b013e3283553638

[2] Sáez-Cirión, A., Bacchus, C., Hocqueloux, L., Avettand-Fenoel, V., Girault, I., Lecuroux, C., Potard, V., Versmisse, P., Melard, A., Prazuck, T., Descours, B., Guergnon, J., Viard, J., Boufassa, F., Lambotte, O., Goujard, C., Meyer, L., Costagliola, D., Venet, A., Pancino, G., Autran, B., Rouzioux, C., & , . (2013). Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study PLoS Pathogens, 9 (3) DOI: 10.1371/journal.ppat.1003211

Waiting for spring...

No sign of spring here in Northern New Mexico, so I brought in some flowers from Southern California. I didn't have the macro with me, these are all shot at 200mm, two stops down to make the background dark.

Science is sexy. And to prove it, we show you 50 sexy scientists.

No, I'm not joking. It's real, check it out:

50 Sexy Scientists

So, what do you think? Would you be flattered to be on that list?

I find it a little disturbing. Giving the scientist's looks the same merits as his/her work is like comparing pears with oranges. Or, like comparing liters with watts. In fact, I think it promotes a disturbingly negative message, which is: do I need to be beautiful to have my work noticed?

What do you think? Am I over-reacting?

NOTE: Link found via A.V. Flox.

Antiviral drugs to fight the flu: yes or no?

Disclaimer: I'm not a medical doctor. I cannot recommend taking or not taking a certain drug. However, I am a human being, I've got kids who do get sick from time to time, and I work on viruses. So when I heard that people were battling the unusually nasty flu this year with antiviral drugs, well, I had to do a bit of research.

Antiviral drugs have become increasingly popular after the highly pathogenic avian flu strain emerged. The idea is that in order to be prepared for a possible pandemic, we need to stock up on drugs, enough to treat millions of people.

Let's start with a few facts about viral infections:

A virus is made of genetic material packaged in a tiny shell. Once inside a cell, the virus hijacks the cell's proteins to replicate and create thousands of copies of itself. The new virions bud out of the cell membrane and infect new cells.

However, the infected cell has one more weapon up its sleeve: it "grasps" the virions that are budding out and tries to hold them back. In more scientific terms: there's a molecule on the cell membrane (called sialic acid) that binds to a protein on the surface of the virus (called hemagglutinin). The new virions have to break this bond in order to leave the infected cell and spread the infection. How do they do that? They use an enzyme called neuraminidase: the enzyme, found on the surface of the virus, breaks the bond between hemagglutinin and siliac acid, setting the virions free to spread out and infect new cells.

Neuraminidase inhibitors are antiviral drugs that, as the name suggests, block the neuraminadase enzyme. As a consequence, the virions remain stuck to the cell membrane and thus cannot spread the infection. Supposedly, this leads to a speedier recovery. I'm saying "supposedly" because there is an ongoing debate on whether this is true or not. Here's what I found in the literature.

Jefferson et al., 2009 [1]:

"Neuraminidase inhibitors have modest effectiveness against the symptoms of influenza in otherwise healthy adults. The drugs are effective postexposure against laboratory confirmed influenza, but this is a small component of influenza-like illness, so for this outcome neuraminidase inhibitors are not effective. Neuraminidase inhibitors might be regarded as optional for reducing the symptoms of seasonal influenza. Paucity of good data has undermined previous findings for oseltamivir's prevention of complications from influenza. Independent randomised trials to resolve these uncertainties are needed."

Wang et al., 2012 [2]:

"Oseltamivir and zanamivir appear to have modest benefit in reducing duration of illness in children with influenza. However, our analysis was limited by small sample sizes and an inability to pool data from different studies. In addition, the inclusion of data from published trials only may have resulted in significant publication bias. [...] The clinical efficacy of neuraminidase inhibitors in 'at risk' children is still uncertain. Larger high-quality trials are needed with sufficient power to determine the efficacy of neuraminidase inhibitors in preventing serious complications of influenza (such as pneumonia or hospital admission), particularly in 'at risk' groups."

Jefferson et al. 2012 [3]:

"We found a high risk of publication and reporting biases in the trial programme of oseltamivir. Sub-population analyses of the influenza infected population in the oseltamivir trial programme are not possible because the two arms are non-comparable due to oseltamivir's apparent interference with antibody production. The evidence supports a direct oseltamivir mechanism of action on symptoms but we are unable to draw conclusions about its effect on complications or transmission. We expect full clinical study reports containing study protocol, reporting analysis plan, statistical analysis plan and individual patient data to clarify outstanding issues. These full clinical study reports are at present unavailable to us."

The company that manufactures the brand name drug for oseltamivir responded here, however, according to BMJ, there hasn't been any release of data yet (source).

I have two more cautionary comments.

First: viruses mutate very rapidly and as such, they rapidly find escapes to drugs. An overuse of antiviral drugs may end up selecting drug resistant strains (for example, a flu strain that carries a neuraminadase enzyme that the inhibitor drugs cannot block). I'm not saying that antiviral drugs should not be used. Some life-threatening situations require the use of such drugs (for example, in the case of patients with immunodepression). Other non life-threatening situations don't (plain and simple).

Second: the US Food and Drug Administration recommends the use of antiviral drugs and in fact, last December they expanded the recommendation to children under one year of age (source). However, if you keep browsing the FDA website you find this very interesting Q&A page, where they report some supposed (though worrisome) adverse side effects:

"In the safety review mandated by the BPCA, a number of adverse event reports were identified associated with the use of Tamiflu in children 16 years of age or younger. These adverse event reports were primarily related to unusual neurologic or psychiatric events such as delirium, hallucinations, confusion, abnormal behavior, convulsions, and encephalitis. These events were reported almost entirely in children from Japan who received Tamiflu according to Japanese treatment guidelines (very similar but not identical to U.S. treatment guidelines). The review identified a total of 12 deaths in pediatric patients since Tamiflu's approval. All of the pediatric deaths were reported in Japanese children. In many of these cases, a relationship to Tamiflu was difficult to assess because of the use of other medications, presence of other medical conditions, and/or lack of adequate detail in the reports."

There is no direct evidence that the deaths were linked to the use of the drug. In fact, often it's high risk children that need to take the drug, which means they are likely to have other conditions and take additional medications. If we can't be certain of what one drug alone can do, imagine multiple ones combined. You can read more about the Japan reports here. I also found a reference [4].

Bottom line: drugs are wonderful things. They save lives. Drugs can also mess up with our body chemistry in ways that we don't always understand. The key point is to read, be informed, and use sparingly (as needed, not just as recommended).

NOTE: I strive to make these commentaries as objective as possible. If you feel I've missed some part of the story or you have more references to add to make a rounder point, please let me know in the comments. 

[1] Jefferson, T., Jones, M., Doshi, P., & Del Mar, C. (2009). Neuraminidase inhibitors for preventing and treating influenza in healthy adults: systematic review and meta-analysis BMJ, 339 (dec07 2) DOI: 10.1136/bmj.b5106

[2] Kay Wang, Matthew Shun-Shin, Peter Gill, Rafael Perera, Anthony Harnden (2012). Neuraminidase inhibitors for preventing and treating influenza in children (published trials only) The Cochrane Library DOI: 10.1002/14651858.CD002744.pub4

[3] Tom Jefferson, Mark A Jones, Peter Doshi, Chris B Del Mar, Carl J Heneghan, Rokuro Hama, Matthew J Thompson (2012). Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children The Cochrane Library DOI: 10.1002/14651858.CD008965.pub3

[4] Urushihara, H., Doi, Y., Arai, M., Matsunaga, T., Fujii, Y., Iino, N., Kawamura, T., & Kawakami, K. (2011). Oseltamivir Prescription and Regulatory Actions Vis-à-Vis Abnormal Behavior Risk in Japan: Drug Utilization Study Using a Nationwide Pharmacy Database PLoS ONE, 6 (12) DOI: 10.1371/journal.pone.0028483

San Francisco Bay Bridge

I recently got back from a 5-day trip to the Bay Area, where, over the week-end, I was privileged to go shooting with a group of local photographers. Since I don't have much water here in NM, the thing I enjoyed the most was doing long exposures by the water.

I wanted to show you some examples of shots I took of the Bay Bridge. I do some editing, mainly I add contrast, lower highlights and tweak exposure as needed, but what makes these shots so different is the timing. As the light changes, so do the colors. I did use a graduated neutral density filter, which does not change the colors. All it does is darken the upper portion of the frame so that you can achieve a more uniform exposure (otherwise the sky would be too bright).

For me, the lesson learned here is that the best time to shoot is blue hour, right after sunset. And you have to be quick because the colors change by the minute. I've noted the time each shot was taken below. Which one do you like best?

Right after sunset, 5:32 pm:

5:33 pm:

5:39 pm:

5:47 pm:

5:54 pm:

Different day, much later: 6:44 pm. As you can see, the pastel colors are pretty much gone and all is left is yellow and blue-purple. I tried to fiddle with white balance, but got stuck with pretty much those colors. No filters here as it was already quite dark.

Much later at night, 12:56 am (in this one I switched to tungsten to drop the color temperature):

1 am (standard white balance, this time, but I tweaked temperature and tint):

I'm self-taught, so I'm learning all this stuff by myself (well, not quite, I'm learning from other photographers!). I welcome critique/tips/advice for next time. Thanks!

The Pedernal

It's freezing here in Northern New Mexico. Abiquiu Lake looks like this these days:

The thermometer hit 19F when I shot these (-7C). The peak to the left in the first picture is the Cerro Pedernal, Georgia O'Keeffe's favorite mountain. She once said that if she painted the Pedernal often enough, God would give it to her. So it now belongs to her. :-)

The life of a soap bubble, the movie

I coerced, er, I mean persuaded my 10-yr.-old to do a science project this year, and guess what I proposed he'd do? Soap bubbles, of course, so Mom could have a little fun taking colorful pictures.

I took several consecutive frames, until I realized that the best way to describe the beauty of these objects is through a movie. So here it is, I hope you like it. I thought it was fascinating!

More snowflakes!

Remember my first attempt at snowflakes?

Well, you know I wasn't going to leave it at that, right?

Here's more. :-)

They're still far from perfect, and heavily cropped. I'm told the way to go would be to stack several photos together in order to get a full snowflake in focus, but I've been lazy about it.

I hope everyone's having a lovely winter. Highs are still in the lower thirties around here.

Happy New Year

HAPPY NEW YEAR, FOLKS!

Thank you for reading, interacting, following, commenting.

The above is my favorite shot of 2012. It's my toast for a 2013 filled with scientific discoveries and great photography. :-)

Wishing you all a joyful, peaceful and healthy New Year.

elena

Whole genome harvesting

You think the human genome, with its three billion base pairs and 23 chromosome pairs, is too complex to unravel? Turns out, the wheat genome is six times as big and it's hexaploid, in other words, instead of chromosome pairs it's organized in chromosome sextets!

I've recently discussed genetically modified organisms, crops in particular, and while I still can't provide a definite answer on whether they are absolutely good or absolutely bad, one thing struck me as relevant as I was researching the topic: between climate changes and an exponentially growing population, we are making drastic changes to our planet and resources. While Mother Nature is usually able to buffer changes and constantly adapt to new environments, the changes human kind is bringing upon the planet are happening at such a fast rate that natural adaptation is unable to keep up.

I think at some point we will have to face a hard choice: either starve or give in to GMOs, where by GMOs I mean crops that are bioengineered to yield more in harsher conditions. Again, I'm not saying we should all embrace GMOs as they are healthy and good for us. I really don't know. What I'm saying is that we may not have a choice: in 2009 the FAO estimated that in order to meet the ever-growing demand, wheat production has to increase by 60% by 2050. In the 20th century, the Green Revolution met the increase in demand with the technology known at the time. Today, given the FAO estimate, we may face the need of a second Green Revolution.

With this in mind, you understand the importance of sequencing the wheat genome, a task that is complicated by the complexity of the genome itself. Its three sets of chromosome pairs originated first from the hybridization of two diploid wild grasses, which originated tetraploid wheats (two sets of chromosome pairs) like durum wheat. After thousand years of domestications, these underwent a further hybridization, yielding the hexaploid wheats commonly used today to make bread. Domestication led to a bottleneck in genome variety, nonetheless, the wheat genome has a high percentage of repeats (roughly 80%, mostly retroelements) that yield great variation in length and gene order, making it difficult to sequence.

Despite these obstacles, two papers [1,2] in the latest issue of Nature report using both whole-genome 454 sequencing and shotgun sequencing to assemble the genome of bread wheat and barley. Both sequencing methods have the shortcoming of being applicable to very short regions, and therefore additional work is required to reassemble the full genome out of the various short sequences.

Interestingly, the wheat genome appears to implement a lot of the variation mechanisms I've been extensively discussing here on the blog:

"Several classes of plant DNA transposons and retroelements create and amplify gene fragments, disrupt genes and create pseudogenes, which can influence gene expression through epigenetic mechanisms [1]."

Similarly, in barley:

"Abundant alternative splicing, premature termination codons and novel transcriptionally active regions suggest that post-transcriptional processing forms an important regulatory layer. Survey sequences from diverse accessions reveal a landscape of extensive single-nucleotide variation [2]."

Brenchley et al. [1] conclude:

"Major efforts are underway to improve wheat productivity by increasing genetic diversity in breeding materials and through genetic analysis of traits43. The genomic resources that we have developed promise to accelerate progress by facilitating the identification of useful variation in genes of wheat landraces and progenitor species, and by providing genomic landmarks to guide progeny selection. Analysis of complex polygenic traits such as yield and nutrient use efficiency will also be accelerated, contributing to sustainable increases in wheat crop production [1]."

[1] Brenchley, R., Spannagl, M., Pfeifer, M., Barker, G., D’Amore, R., Allen, A., McKenzie, N., Kramer, M., Kerhornou, A., Bolser, D., Kay, S., Waite, D., Trick, M., Bancroft, I., Gu, Y., Huo, N., Luo, M., Sehgal, S., et al. (2012). Analysis of the bread wheat genome using whole-genome shotgun sequencing Nature, 491 (7426), 705-710 DOI: 10.1038/nature11650

[2] Mayer, K., Waugh, R., Langridge, P., Close, T., Wise, R., Graner, A., Matsumoto, T., Sato, K., Schulman, A., et al. (2012). A physical, genetic and functional sequence assembly of the barley genome Nature DOI: 10.1038/nature11543

The simulated brain

His name is Spaun, which stands for Semantic Pointer Architecture Unified Network, and he's a brain -- a simulated, brain. His 2.5 million neurons, organized in subsystems that simulate different brain areas, allow Spaun to perform tasks such as image recognition and recalling sequences, and respond through a motor arm. For example, Spaun can recognize numbers on a screen and write them on a piece of paper.

Spaun is the brain child (pun intended!) of authors Eliasmith et al. [1]. It models three specific brain areas: the prefrontal cortex for memory, the basal ganglia to select actions, and the thalamus. Spaun's functional architecture consists of a working memory that, given a visual input, compresses the information and translates the input into firing patterns. The next step is the action selection step, which results in a motor output through the robotic arm. Spaun's memory doesn't just store information, but it also correlates new information with the old one. A nice feature of the model is that different neuron parameters can be chosen from random distributions in order to simulate different population behaviors. This simulates the human brain so well that Spaun expresses a common human behavior: the tendency to remember best the first and last items in a list.

On the other hand, Spaun exhibits noteworthy deviations from human brains: while it can get better and better at a particular task, it cannot learn a completely new task. Another shortcoming is that Spaun's attention and eye position are fixed, so that, contrary to a real human brain, it cannot control the input.

As the authors explain:

"Anatomically, many areas of the brain are missing from the model. Those that are included have too few neurons and perform only a subset of functions found in their respective areas. Physiologically, the variability of spiking in the model is not always reflective of the variability observed in real brains. However, we believe that, as available computa- tional power increases, many of these limitations can be overcome via the same methods as those used to construct Spaun."

[1] Eliasmith, C., Stewart, T., Choo, X., Bekolay, T., DeWolf, T., Tang, Y., & Rasmussen, D. (2012). A Large-Scale Model of the Functioning Brain Science, 338 (6111), 1202-1205 DOI: 10.1126/science.1225266

Make a donation to NOAH, get a free 8x12 print

As many of you know, my research is on HIV, with a focus on HIV vaccine design. I work in Bette Korber's group, and through Bette, I came to learn about NOAH, an organization she co-founded.

Taking care of AIDS orphans has been one of the most prominent issues in Sub-Saharan Africa, where two-thirds of the people affected by HIV/AIDS live. Mother-to-infant transmissions are highly preventable yet, sadly, the drugs are expensive and not always available in Africa. A staggering 2.5 million African children have been orphaned by AIDS, and many of them are born HIV-positive. There are villages where a whole generation has disappeared because of AIDS.

NOAH takes care of these children without taking them away from their homes. NOAH is not an orphanage. The organization provides schooling, day care and food for the kids, while the kids continue to live in their village with older relatives. $80 covers one child for one year.

For the whole month of December, if you make a donation of $30 or more, I will send you an 8x12 print of one of my pictures. Follow this link to donate, forward the email receipt to eegiorgi (at) gmail.com, include your shipping address, and pick the picture of your choice from my G+ album (click on "Photo details" to see the file name).

Donations are tax-deductible.

THANK YOU!

Proteins as gene carriers

By now you probably know everything about pluripotent stem cells, right? They are the hot topic in genetics right now, to the point that the fear of being scooped has pushed some people to lie about their results. Pluripotent stem cells are cells that have the ability to divide into a specialized cell and another undifferentiated cell. This of course is greatly useful in repairing damaged organs and/or regenerating tissue, and has great potential in medicine.

Lately there has been a lot of buzz on the notion that pluripotency could be re-induced in already differentiated cells. Studies have shown that four reprogramming factors can indeed reprogram fibroblast cells into pluripotent stem cells when over-expressed.

But how to over-express these factors?

The typical route is to transfect the genes into the cells by means of a viral vector. Basically, the genes are delivered into the cell using a retrovirus. Though effective, this poses the question of side effects: whenever you introduce foreign DNA into a cell you have the potential to silence secondary genes or disrupt the usual gene regulation. Unanticipated epigenetic changes in the cell can occur. A recent study [1] shows a safer alternative: cell-permeant proteins, or CPPs. These are small proteins that can cross the cell membrane and carry peptides inside the cell in a process called "protein transduction," thus offering a valid alternative to viral vectors.

By comparing the two methods (CPPs and viral delivery) on human fibroblast cells, Lee et al. noticed that gene expression was achieved much faster when using the viral vector. Puzzled by this difference, they wondered what was so special about the viral route that made the gene delivery so much more efficient. There had to be something in the viral vector that aided the delivery of the genes. Lee et al. hypothesized that this could be linked to the fact that the viral vector somehow activated an inflammatory pathway in the cells which in turn aided the delivery of the genes. So the next question was: can we enrich the CPPs so they too activate the inflammatory pathway?

Indeed they could! They used TLR3 agonists, molecules that activate the TLR3, or Toll-like receptor 3, a receptor that recognizes double-stranded RNA generated by retroviruses and thus activates inflammatory pathways. Once combined with the TLR3 antagonists, over-expression of the reprogramming factors was achieved faster through CPPs than it was with the viral vectors, validating the hypothesis that the gene delivery has to be achieved via the activation of the immune pathway. In fact, the contrary was also true: when TLR3 was knocked down (biology jargon to say that the gene was silenced), the viral vector was also inefficient in delivering the genes.

"TLR3 activation enables epigenetic alterations, including changes in methylation status of the Oct4 and Sox2 promoters as well as changes in the expression of epigenetic effectors, that promote an open chromatin configuration. The knowledge that the activation of innate immune response affects nuclear reprogramming permitted us to enhance the efficiency and yield of human induce pluripotent stem cells by using reprogramming factors in the form of CPPs."

Lee et al. conclude:

"Our observations highlight a previously unrecognized role for innate immunity activation in nuclear reprogramming. The viral vectors constructs used to induce pluripotency are more than mere vehicles for the reprogramming factors. Innate immune activation causes striking changes in epigenetic modifiers that favor an open chromatin configuration. These changes enable a fluidity of cell phenotype that contributes to successful nuclear reprogramming."

[1] Lee, J., Sayed, N., Hunter, A., Au, K., Wong, W., Mocarski, E., Pera, R., Yakubov, E., & Cooke, J. (2012). Activation of Innate Immunity Is Required for Efficient Nuclear Reprogramming Cell, 151 (3), 547-558 DOI: 10.1016/j.cell.2012.09.034

Is creativity an illness? But then... what is an illness?

Are you creative? Do you ever feel that when your creativity strikes you become absolutely compulsive about your "inspiration," and totally depressed when, for some reason, your inspiration wanes? It always strikes me to read about how some of the most beautiful works of art were created: their creators were obsessed, compulsive, borderline dysfunctional. Gabriel Garcia Marquez sold his car and had his family live on credit for eighteen months so he could write One hundred years of solitude. Brunelleschi's obsession was the dome of Santa Maria del Fiore, Antoni Gaudi's obsession was La Sagrada Familia. It seems to me that obsessions may ruin your life (or most likely the life of your closest ones) when you have them, but they may also lead to the most wonderful things.

So, is creativity a good thing or is it an illness?

My friend and collaborator Tanmoy Bhattacharya brought to my attention an interesting BBC post that discussed the issue. The article came up in a Facebook discussion because it raised the question: "How do you define illness? When, exactly, does a behavior trespass the normality threshold and becomes an illness?" I really liked Tanmoy's take on the issue, and I asked him permission to repost it here on the blog. It's the best thing I could get since he won't do a guest blog for me. :-)

I think he raises excellent points on the complexity of the brain, its stimuli as well as its constraints. I enjoyed reading it, I hope you will too. And if after reading this you have questions for Tanmoy, go ahead and post them in the comments and I will forward them to him.

TB: In a system as complex as the brain, which interacts with such diverse environments, it is difficult to define health and disease. There has been a long standing hypothesis that certain brain functions like deductive logic and creativity are kept in check evolutionarily because the same "structure" that can give rise to very highly creative adaptations in one environment would give rise to maladaptive behavior in a different environment. The interest in the research is, therefore, understanding the architectural limits on the brain, not to stigmatize writers or expect every bipolar to pen out a story about an old man and the sea.

EEG: That's a very interesting theory. All greatest masterpieces required such great energy and dedication from their creators that these individuals had to, at some level, become unsociable, as focused as they were on their creation. I can see how, at a species level, "being socially fit" puts a constraint on the amount of time and "obsession" the brain can dedicate to a certain task.

TB: I do not believe that we yet have a definition of illness which is "biologically" meaningful. Sure, there is a diagnostic manual that tells a doctor today when to diagnose a particular mental illness, but it is more an expression of "social" reality than a "biological" reality. So, for example, the discussion of whether homosexuality is a disease is not argued on any grounds about what it does or does not do to the person, but rather whether the majority of doctors consider it within the "normal" spectrum of behavior. No wonder its classification changed from a disease to a non-disease as the social acceptability of homosexuality grew: not because such acceptance lessened the mental load on the person with the trait (it is now not considered a disease even when the person with the trait lives in a non-accepting community), but because it became "socially" acceptable as a "normal" behavior. Currently, there is a similar debate about whether bereavement distress should be considered normal even when it leads to behavior sufficiently aberrant to otherwise merit a diagnosis of clinical depression. In other words, the question is not whether the person is depressed after a loss: the question is whether it is a disease (possibly temporary like say getting the 'flu is a disease) or whether it is not a disease because it is "normal". The classification is not done based on any kind of biological reality, except whether it is considered normal; which is determined by methods of social science, not biology.

Does this concept of normality depend on a biological reality? In other words, is there a way, other than surveying doctors (the social science method), to figure out whether some one is abnormal? Remember that we know pretty much that all of us are different in many ways, if you defined me abnormal simply because I am unique (which I certainly am), then everyone would be abnormal. One could always say that one should not look at the totality (which made everyone unique), but trait by trait, and ask whether I have traits that very few other people have? Defining abnormality this way would, of course, make Picasso abnormal; but during a mass hysteria, it would classify everyone as normal. We again see that this definition fails to capture the abnormality that is relevant to defining disease.

I claim that the only way people have found to capture the relevant abnormality is by taking the design stance: human brains (and bodies) are supposed to be "for" something. When the organ (or the totality) is carrying out this function, it is normal; when it fails to carry out this function, it is abnormal. Note that this does not solve the underlying problem: someone still has to define the function, but that turns out to be an easier problem.

We could define a disease objectively as a malfunction if we could define function objectively. And, here, biology can bring an insight: the function of brains (and bodies) is to survive and use the environment, physical, biological, and social, to further the fundamental goals of long term survival of the traits. This is usually called reproduction, but it is far more subtle: for example, one can help raise grandchildren and contribute to the long term survival; under appropriate conditions, one can help other helpful members of one's community to help survival of the helpfulness trait. The mathematics is not simple, but recent work has made much of this clearer, and it is far more than pure reproduction. The part relevant to this discussion is that for a social animal this survival depends a lot on social calculations as well as other considerations.

So, then, we can define function as being able to properly calculate and take appropriate action; but that depends on the environment one faces. The same trait of fast decisive action to take the life of an unexpected person is wonderful in times of violent combat but completely malfunctional in a peaceful society. Similarly, it is easy to show that a mental make up that helps everyone, whether or not they are helpful to others, is malfunctional in the sense that it does not help its own survival except in societies that pays a high moral premium on that. Now, since most traits will find themselves in various environments, the malfunctional has to be defined as an intermediate: it should not be "fatal" in any of the environments that an individual is likely to face. But, this depends on the environments one is "likely" to face.

Given this situation, therefore, most traits tune themselves to intermediate values, because extreme values are typically extremely ill suited in some environments one is likely to face. And, all this is further constrained by the possible organization of the brain: for example, it is completely possible that the brain is composed of two parts, one that can analyze and model its environment in terms of an "open-loop" system controlled by impersonal physical laws which constrain and guide change, and a social system that can alternately assign agency (or "will") to parts of the environment. If this simple separation of thought patterns is an useful approximation, the division of resources between the two will affect a lot of behavior: a lot of resources devoted to the physical system will make one unable to understand complicated social dynamics; whereas too high a reliance on the social system might make one unable to understand that physical phenomenon often do not have wills and desires. Both of these taken to an extreme are obviously malfunctional, and, therefore, diseased: one can think of autism or schizophrenia as examples illustrating such symptoms. But, where exactly one stops being analytical and starts being high-functional autistic will depend on what environment one is defining with respect to: when the norm is highly complex social environments, one will probably classify some highly analytic people as diseased because they cannot function in society (i.e., the "mad scientist" or "computer geeks" will get classified as "mad" or "autistic"), whereas when complex physical systems but with little social structure are the norm, some people who see willful patterns in the universe will find themselves considered ill (e.g., a "religious fanatic" will be considered "mad").

So, what have we done through all this argument? We started by arguing that DSM (diagnostic manual) definitions depend on a certain standard of normal and are not objective. Through the chain of arguments, I have tried to establish that the former (i.e. dependence on the standard of normal) is inherent part of the problem, and cannot be removed except in the trivial sense that some things have never been normal. I have also argued, however, that this dependence does not need to be subjective: what is important is not what the "doctors" have experienced as normal, but rather the environments that the *person* being diagnosed has experienced and is likely to experience.

The interesting question is that supposing we take a bunch of brains and tune up their creativity (by changing whatever neurotransmitter chemistry or electrochemical connections that we need to). Now, in some environments and depending on the rest of the circuits in the brain, this will work perfectly fine and be very useful in understanding and modeling otherwise-hard-to-model systems (somewhat similar to a physical effect called "annealing"). If the same tuning is done to a different brain which does not have the same set of controls, this tuning could lead to a bipolar disorder. Basically this hypothesis would say that creativity needs to be balanced by other control systems, so any means of independent inheritance will quite often lead to getting the creativity structures without the control structures, leading to madness. Under this hypothesis, creative people are not insane, but biology would dictate that they are at a higher risk of having insane relatives (children/siblings/etc.) than less creative people.

But, there is a different possibility as well: the "control" unit hypothesized in the previous post may not be inherited much, but developed based on experiences; or its need may be dependent on the environment. In this case, the only difference between creative people and people with some forms of insanity would be the environments they have faced or will face. Creative people can then look at bipolars and paraphrase Bradford "But for the grace of environment, there go I". We do not know if either of these hypotheses are correct, but I hope I have explained why I find it interesting to ask these questions, and why the data presented in the article is consequently interesting.

I haven't abandoned the blog!

Sorry for the absence, I've been, and still am, extremely busy. Unfortunately I have to slow down the frequency of posts. But I'm still here!

We've had our first snow and I found a new photographic challenge: snowflakes. They're harder than water refractions, with the added difficulty that after a few clicks my fingers are frozen.

For those of you who know how I spend my nights... yes, you've guessed it, my muse struck again.

I'll leave you with a question to muse: What do you think the future of the Internet will be, say twenty years from now?

Don't forget to vote today (US)

It is not titles that honour men, but men that honour titles.
Niccolò Machiavelli

Don't vote based on ideal principles. Be pragmatic. Vote for our children, vote for the best of the Country.

When you vote, remember the past and look up to the future.

Vote.

GMOs love me, GMOs love me not..

I've been asked to discuss genetically modified foods and I confess I've been procrastinating. Why? Because I don't have an answer on whether or not GMOs are good or bad, and I can't offer one. But, what I can do is offer a few thoughts. Food for thought is usually super-natural, organic, and pesticide-free, so here it goes. :-)

1. What are GMOs?
Technically, all domesticated plants and animals are "genetically modified" since, rather than letting the species evolve through natural selection, mankind has steadily selected offsprings according to some man-made criteria. However, today's technology allows us to artificially modify an organism's genome. The difference between the two is not just in time scale: when selecting crops, or, more in general, any organism, generation after generation based on phenotype, uncharacterized genes are introduced in the species. Genetically engineering, or bioengineering, however, introduces a few well-characterized genes (often from a different species) into the organism. In a way, this is no news: gene therapy creates genetically modified organisms. Humanized mice are created in labs to test drugs and other therapies. The question of whether or not GMOs are good arises in the food industry. Are they safe to eat?

2. The Cartagena Protocol on Biosafety
As California gets ready to cast its vote on Proposition 37 [1] (which would require foods to denote their GMO content on the labels), it is good to review what currently is in act to "protect" us from possible hazards. From Wikipedia:

"The Cartagena Protocol on Biosafety is an international agreement on biosafety, as a supplement to the Convention on Biological Diversity. The Biosafety Protocol seeks to protect biological diversity from the potential risks posed by genetically modified organisms resulting from modern biotechnology."

"The Biosafety Protocol makes clear that products from new technologies must be based on the precautionary principle and allow developing nations to balance public health against economic benefits. It will for example let countries ban imports of a genetically modified organism if they feel there is not enough scientific evidence that the product is safe and requires exporters to label shipments containing genetically altered commodities such as corn or cotton."

3. Why are foods genetically modified?
For a number of reasons, some good and some not so good. Some are just practical reasons in a world that, whether we like it or not, is getting more and more "globalized": the first bioengineered produce was a tomato designed to have a prolonged shelf life. Some crops are genetically modified to resist harsher herbicides and pesticides. Others, are genetically modified to desist bugs from eating them. For example, genes producing Bt toxins have been introduced in cotton and corn. These toxins kill caterpillars that would otherwise eat up the whole crop. Notably, the modification benefits not only the genetically modified crops, but, since it reduces the global population of harmful caterpillars, it also benefits the non-modified crops.

I expect foods that can resist herbicides to be soaked in chemicals. On the other hand, if a crop is genetically modified so its flowers/fruits/seeds no longer offer a viable environment to certain parasites, I expect those foods to be pesticide-free. Yes, I'll take a few modified genes over harmful chemicals. Bottom line: NOTING WHETHER OR NOT A CERTAIN FOOD CONTAINS GMOs DOES NOT HELP. What you should really demand in a label is WHY SUCH FOOD WAS MODIFIED AND WHAT WAS ACHIEVED THROUGH THE BIOENGINEERING. Notice that while the Food and Drug administration currently does not impose any GMO labeling, their guideline recommendations state that the GMO content be noted, as well as the reason why the food was modified, and what was achieved through the modification.

4. Genetic homogeneity is bad
Rice is one of the most consumed crops in the world. Again, from Wikipedia:

"As of 2009 world food consumption of rice was 531,639 thousands metric tons of paddy equivalent (354,603 of milled equivalent), while the far largest consumers were China consuming 156,312 thousands metric tons of paddy equivalent (29.4% of the world consumption) and India consuming 123,508 thousands metric tons of paddy equivalent (23.3% of the world consumption). Between 1961 and 2002, per capita consumption of rice increased by 40%."

Rice is also highly "domesticated", as it has been selected over thousands of years to fit human needs. Currently, there are 20 different kinds of rice, but, according to FAO, the Food and Agriculture Organization, "It is estimated that not even 15 percent of the potential diversity has been utilized." This is a THREAT to food security. If a pesticide-resistant parasite were to attack rice crops, it'd be lethal to the vast majority of rice varieties currently harvested. Heavy use of pesticides favors the selection of pesticide-resistant organisms, while domestication favors genetic homogeneity in crops. This is NOT a good combination. Another reason why, between GMOs and pesticides, I'd favor GMOs. And if GMO research can prevent a pesticide-resistant organism to wipe out 50% of the world-wide food, hey, who's to complain?

5. Knowledge is NOT power if that knowledge is poorly understood
We live in a strange era when technology leaps forward at a higher speed than our ability to comprehend its output, especially in the field of genetics. We have loads of data we don't quite know how to store, let alone analyze. It's getting cheaper and cheaper to have a full human genome typed and companies are advocating that we do it for every individual. But are we capable of understanding the data? Last week I posted a shocking story of a boy discriminated because he carries a recessive mutation for a disease he doesn't have and he's at no risk of contracting (that's what recessive means). The Internet is full of bogus info on genes, genetics, mutations, etc. There's more noise than ever, giving people the illusion that they know when in fact they don't. I fear that the same will happen for GMOs. Once those labels come out, will people be able to understand what they mean? If Prop 37 will only require a "content" statement without a "reason", for example, will the information be really useful or will it just generate a stigma?

You now see why I cannot tell you whether GMOs are good or bad. They can be both! (Aren't we all?)

Food always has a higher impact than other things, but if you think about it, there are so many things that we've introduced in our daily lives in the past few decades that we simply don't know whether or not they are good IN THE LONG RUN: wi-fi, for example. Cell phones. Chemicals in skin products, from sun protection to cosmetics. I'm afraid the next generation will be the test. So the real question is: do we want to experiment with our children as guinea pigs? Sadly, when you put it in these terms, it seems to me it's too late to go back. The experiment has already begun.

If these few thoughts weren't depressing enough, read Pamela Ronald's review, referenced below [2]. One of the great points Ronald makes is that we are changing our climate and environment much faster than ever before (thanks to climate change and an exponentially growing population). Natural selection can't keep up with the pace, hence

"an important goal for genetic improvement of agricultural crops is to adapt our existing food crops to increasing temperatures, decreased water availability in some places and flooding in others, rising salinity, and changing pathogen and insect threats."

The review is clearly biased in favor of GMOs and it lists several benefits from such procedures. While advocating for adequate testing on every newly modified organisms, it also reports that all genetically modified crops tested so far have been deemed safe and substantially no different than conventionally selected crops "in terms of unintended consequences to human health and the environment."

Bottom line: I can't tell you what to vote on Prop 37 and I can't tell you whether or not you should avoid GMOs. Just read as much as you can and be sure to form your own opinion.

REFERENCES:

[1] Baker, M. (2012). Companies set to fight food-label plan Nature, 488 (7412), 443-443 DOI: 10.1038/488443a

[2] Ronald, P. (2011). Plant Genetics, Sustainable Agriculture and Global Food Security Genetics, 188 (1), 11-20 DOI: 10.1534/genetics.111.128553