I feel that single-target drugs are getting harder to make.
I remember years back, when there were three AIDS drugs going through clinical trials. We were all shocked when all of them failed. But some smart soul realized that when combined, the three were a miracle cocktail. Indeed, fast forward to the present and this cocktail has basically turned AIDS from a death-sentence to a background disease (of course, I simplify – the point is the success of the cocktail, combination therapy).
Combination therapy in this sense, should not be confused with drugs that are not complementary. For example, MMR and DPT vaccines are mixes of individual independent vaccines.
I claim that we need to explore how combinations of drugs, say antibiotics or antivirals, can work better than the constituent drugs alone.
Alas, as far as I can tell, this will complicate clinical trials, trying to deconvolute the contribution of each individual component. But I am hopeful that tools that can munge and analyze large data sets might able to do this deconvolution.
What do you think?
Link 1: PLOS ONE: A Longitudinal Trial Comparing Chloroquine as Monotherapy or in Combination with Artesunate, Azithromycin or Atovaquone-Proguanil to Treat Malaria.
Link 2: Access : New TB drug cocktail : Nature Reviews Microbiology
The development of novel combination therapies is one of several strategies that are currently being pursued to combat tuberculosis TB. Recently, researchers at the XIX International AIDS Conference presented the results of a groundbreaking clinical trial which showed that a combination of three drugs can kill more than 99% of Mycobacterium tuberculosis in infected patients.
Image from Wm Jas
Last Christmas-time, I was driving to go get my parents (they live a few states away) and was listening to a Science Friday about Mars. The guest was an advocate for human travel to Mars and mentioned how much it would cost to get there. I don’t know if Ira or the guest mentioned it, but I realized that the cost of the trip, spread over a 5 year program, was on the same order as a blockbuster Hollywood movie.
I immediately dictated an outline story for my entry into NaNoWriMo 2012 (I had recently completed NaNoWriMo 2011). The story would be about a Hollywood producer making a multi-year, multi-movie, reality-TV, and ancillary products production that would follow selection, training, and trip of a crew, the construction of the spacecraft, and other exciting thrills of a novel. [Though, like my other two novels and anthology of short stories, it probably won't be published beyond a personal copy from Lulu.com.]
Over the intervening months, the outline had become heftier and heftier, so I decided to forgo NaNoWriMo and, last Wednesday, I put down the opening scene. [Usually, my stories bounce around my head for a while, different key scenes developing and begging for attention, until the opening scene gels and demands to be written. It all then flows from that opening.]
Today, I wanted to look up again the current estimates of a manned trip to Mars. An, lo!, I found an organization that indeed is thinking of a commercially-funded Mars mission with funding from a reality-TV show (records indicate the announcement was 01 June 2012).
Human settlement of Mars in 2023
Mars One will take humanity to Mars in 2023, to establish the foundation of a permanent settlement from which we will prosper, learn, and grow. Before the first crew lands, Mars One will have established a habitable, sustainable settlement designed to receive new astronauts every two years. To accomplish this, Mars One has developed a precise, realistic plan based entirely upon existing technologies. It is both economically and logistically feasible, in motion through the aggregation of existing suppliers and experts in space exploration.We invite you to participate in this journey, by sharing our vision with your friends, by supporting our effort, and perhaps, by becoming the next Mars astronaut yourself.
via Home – Mars One.
Ideas are not unique
I’m not saying the brilliance here is on par with Leibnitz and Newton inventing calculus at the same time, but it’s one more of my examples that if you have an idea, it’s highly likely someone else does too. The key thing, of course, is all in the execution. Indeed, I’ve had many great ideas that I’ve seen come into being a few years later. By someone else. By someone more driven and talented.
OK, I never intended to actually drive a Mars program, but, to write the fiction, I’ve done a lot of thinking about it. And, of course, the way I see my story unfolding has the liberty of fiction, for me to craft the storyline in a way that reality doesn’t necessarily allow.
I wish the MarsOne folks the best of luck. I do think I’ll continue with the storyline, though the thrill of mixing reality-TV funding with a Mars mission has lost its shine a bit. Nonetheless, the story is calling me to write it, and there are lots of twists and turns that I know will not be part of the MarsOne story, so it’ll still be a fun story to tell.
Now is the time
What is true, though, is that I need to get this damned story off my chest, fast, now the MarsOne is making their mark. [And thank you, MarsOne, for some additional ideas for me to consider in my story.]
As for you, if you have an idea you believe in, do it NOW, post haste, toot sweet. Because there is someone out there with the same goddamn idea, and if you do nothing, they will get all the credit. Even if you planned it all out 6 months or 6 years before them.
Do you have a similar story of a well thought out plan that someone else executes on?
Of course, as is usual with me on the weekend, I started reading all my open tabs in my browser. And the first one I read was a paper where they crossed two pure strains of mice and correlated microbiome and genome.
Link: PLoS ONE: Murine Gut Microbiota Is Defined by Host Genetics and Modulates Variation of Metabolic Traits
“In this study, the BXD population [CS: the first generation hybrid mice] was used to detect and quantify genetic factors that may have a significant influence on the variation of gut microbiota. We have demonstrated that host-genetics is complex and involves many loci [CS: locations on the chromosomes]. These differences in microbial composition could impact susceptibility to obesity and other metabolic traits. Functional analysis of gut microbiota and characterization of the relationships with host-genotype [CS: genotype is the sum total of genes] has important implications to human health and agriculture. The gut microbial composition can be temporarily altered through dietary interventions tailored to host genotype, ultimately mitigating the effects of unfavorable alleles [CS: alleles are variations of a single gene across organisms] and inducing profiles that promote human health. Genetic variants that influence gut microbiota may also be used in selection programs of livestock to improve feed efficiency, disease resistance, and to reduce dissemination of pathogens associated with zoonotic diseases such as E.coli O157:H7 or Salmonella.”
Heavy stuff. We all knew this, but needed the simple scientific example of it. And this is foundational for this science moving forward.
So what did they do here? Lab mice are usually pure strains where each individual’s genome is identical. When you cross two strains though, the first generation of progeny are all mixed up in their genetic make up. So in this case, the scientists were able to see a whole range of variability in the genome and correlate that to the prevalence of different microbes in the gut. The idea is that regions in the genome would be associated with certain types of bacteria being maintained or lost.
Sure enough, they honed in on a region and “uncovered several candidate genes that have the potential to alter gut immunological profiles and subsequently impact gut microbial composition”. The region was rich in immune system genes. Also, these immune system genes were related to things like obesity as well, suggesting a connection with metabolism of food. Note: it’s not necessarily that there’s some auto-immune issue attacking the animal’s tissue, but could likely be that the immune system isn’t supporting the right bugs.
For those of you who know transfaunation as an option for helping resolve IBD: This might suggest that even if you do repopulate the flora of the gut, the host might not be able to maintain the flora, not just due to diet, but primarily due to immune profile.
Cool, isn’t it?
One comment that struck me, which points to the variability in frequency and intensity of IBD: “variation in gut microbiota and complex relationships with host genetics can represent unaccounted sources of differences for physiological phenotypes including susceptibility to obesity.”
But that makes sense.
What does this have to do with Eastern European Jews?
I happened to have an animated discussion last night with my wife and another couple, who are close friends (yes, we spent a lot of time talking about “poop” at a restaurant; yes, we’re total nerds). As we were leaving the restaurant, my wife reminded me that Eastern European Jews are know to have a higher rate of inflammatory bowel diseases.
That got me thinking.
And this is pure speculation: Eastern Jews are also known to have diseases that are related to genes in brain development. Folks have suggested that the living and working restrictions of Eastern Jews selected for variants of genes tied to things like increased intelligence (for much of their time in Europe, Jews were restricted to certain more white-collar, brain-centric professions). But as a consequence, while having one of these gene variants was helpful to brain development, having two copies led to severe mental development diseases.
So might IBD be a similar thing where the mixed set of genes conferred some sort of microbial or dietary advantage? And then, having the full set of IBD genes causes the full disease? For example, crowded into cities, might have Easter European Jews been more exposed to city and crowding diseases, such as cholera, typhus, or tuberculosis? What is the prevalence of these diseases in Eastern Jews? What is the lung or gut microbial resistance profile in Eastern Jews and Eastern Jews with IBD?
In short, is there a connection between gut issues (or more likely, gut microbe populations) and the evolutionary history of Eastern Jews (city living, profession and dietary restrictions, and so forth). Might the genes involved in IBD, like the the brain development genes, actually present some adaptive benefit at some level?
Kinda makes one think, doesn’t it?
Image from a mouth-watering post on knishes in NYC
“That is my thesis; that’s why I think this matters. When I left the room at the SXSW “New Aesthetic” panel, this is what concerned me most. I left with the conviction that something profound had been touched. Touched, although not yet grasped.
I’d suggest getting right after it.”
I missed the session at SXSW (can’t get to all of them, you know). But I’ve been reading bits here and there of how it influenced folks’ thinking [Here's one by @thisischristina that mixes New Aesthetic with gene network refactoring, synthetic biology, Synthetic Aesthetics. "Pixelating the Genome"]
In the article quoted above, Bruce Stirling, gives an overview of the field, ties it to other areas of aesthetics and technology and philosophy, and then nudges New Aesthetics on its way with paternal pat on the tusch, a request, and a “get to it.”
via An Essay on the New Aesthetic | Beyond The Beyond | Wired.com.
Thomas Friedman recently wrote about a discussion he had with Frank Fukyama on the two-volume opus Fukyama is working on “The Origins of Political Order.”
Of course, I hardly ever get political here, but this article resonated with me.
“Indeed, America today increasingly looks like the society that the political scientist Mancur Olson wrote about in his 1982 classic “The Rise and Decline of Nations.” He warned that when a country amasses too many highly focused special-interest lobbies — which have an inherent advantage over the broad majority, which is fixated on the well-being of the country as a whole — they can, like a multilimbed octopus, choke the life out of a political system, unless the majority truly mobilizes against them.”
I think it’s amazing how well our nation has stood the test of time, seeing it was basically invented by a bunch of rich white men over 200 years ago. But two things always pop back up in my head – perhaps the concept of nation is out-moded and democracy doesn’t seem to have the ability to reinvent itself as radically as it was created.
In one of my novels, I have a character, who is in politics and policy, examine the whole idea and genesis of “nation”. She then discusses democracy and says:
“And the irony is that these are democracies, meaning that they are supposed to listen to the public and follow the will of the public. Yet in reality, the system is so complex that it can’t bootstrap a new system, molt into something different.
“Have you ever seen a democracy revamp itself? No, it can’t generate the necessary discontinuity of the same order that was needed to bring itself into existence.”
Part of me thinks we’re screwed if we can’t get ourselves out of this mess and that this is the worst the US government has been ever. But then the other part of me tries to think back to previous governments, congresses, and presidents and wonder if the immediacy of the stupidity and inanity of Washington DC has always been the same. Only nostalgia makes us forget.
Friedman’s article starts asking if we America needs an Arab Spring. And Fukuyama has some strong suggestions for change. Friedman concludes:
“I know what you’re thinking: “That will never happen.” And do you know what I’m thinking? “Then we will never be a great country again, no matter who is elected.” We can’t be great as long as we remain a vetocracy rather than a democracy. Our deformed political system — with a Congress that’s become a forum for legalized bribery — is now truly holding us back.”
I guess I’ve always been the inactive cynic. And, perhaps, I represent a large majority of the bourgeoisie of America. What’s it going to take to get me moving, if already I know the problem and just sit on my ass, like most of us.
Gah. Perhaps I should stick to science.
And now back to our regularly scheduled program…
via Down With Everything – NYTimes.com.
Note: The article got hundreds comments and I saw good ones. Sigh. If only we had better tools to follow the comments as well. Of course, I’ve ranted about this before (here in 2009 and here in 2008).
“Researchers have documented repeated evolution in other organisms, but the sticklebacks are unique because the freshwater transition has occurred so many times. “Sticklebacks have been a phenomenal system for understanding rapid evolution,” says evolutionary biologist Erica Bree Rosenblum of the University of California, Berkeley, who wasn’t involved in the study. “This paper shows that repeated evolution can occur by ‘reusing’ the same genetic mechanisms over and over again.”"
This quote is from a review in Science of a Nature paper where stickleback fish genomes were sequenced and compared. The catch is, the stickleback fish used to be a sea fish until glaciers melted 10,000 years ago and left many stranded in freshwater lakes and streams.
What then happened is that the freshwater sticklebacks all had to evolve to survive in the freshwater.
What is interesting, is that it’s clear that all of these fish evolved the same adaptations. And now there is genetic evidence that most of these independent changes were in the same places of the genome in each of these freshwater fish.
While this has been seen in other organisms, the stickleback provide an experiment where this has happened multiple times, showing “repeated evolution can occur by ‘reusing’ the same genetic mechanisms over and over again.”
I am not surprised.
I picked up a term from futurist Paul Saffo, “adjacent possible” (I use it a lot to point out interesting things in evolution). Applied to evolution, it means an organism can really only sample the possible mutation paths that are adjacent to its current make-up. An organism cannot evolve from bacteria to bird in one move, much like “you can’t get there from here” in one move. In both cases, each step must be an adjacent possible step.
In this case, all the sticklebacks had similar adjacent possible ways to adjust to freshwater living. So they were constrained by their genome. But also, the environment exerted similar pressures, so the adjacent possible were further constrained.
The sticklebacks all had to make the same choices, with the same starting material, to adapt to the same environment.
What do you think?
I think this is cool.
Read the review How Evolution Copies Itself – ScienceNOW.
“The main difference from eukaryotes is that prokaryotic reproduction is independent of DNA acquisition and recombination. Instead, DNA is obtained from fragmented chromosomes obtained via parasexual means (that is, without reproduction). These mechanisms of DNA exchange are not restricted to gene exchange within species, and therefore traits can and do come from highly divergent organisms. For example, imagine that acacia trees could exchange DNA with lions and that the resulting new tree developed “limbs” that allowed them to attack grazing giraffes. This is in a sense what prokaryotes do all the time.”
I am fascinated by horizontal gene transfer, whereby microbes from different species share genetic information. Species, as we all learn, are defined by not being able to exchange genetic information and produce fertile offspring.
Of course, microbes flaunt this rule.
The prevalence of gene transfer, where bacteria of different species exchange genetic information, blurs the boundaries between “species”. I remember listening to Penny Chisholm talk to Ira Flatow about Parachlorococcus and redefining what we call a species of microbes, which she called “genomic variants.”
The quote above is from a review of an article in Science that examines speciation in marine bacteria. It discusses how the investigators found prevalent horizontal gene transfer. But the cool thing, as I understand it, was that many of the same genes were being captured by bacteria in the same ecological niche.
In short, the environment is selecting for horizontally transferred genes to be conserved. These genes are not transmitted through organisms in the same species, but all of the bacteria are being selected to keep these transferred genes. In short, many of the genes from a population do not have a common ancestor (as in, cells dividing and propagating genes that way).
Even cooler, an analogue has been seen in prokaryotes, in a sense. Darwin’s finches all share genetic information through the usual repeated back-crossing between species, but ” the characters defining their ecological niche appear to be maintained through selection.”
So I guess we are talking about genomic variants, but not necessarily variants with the same ancestor – the ecological niche selects for that genomic variant, which has a collection of genes from the mother cell (ancestor) and from other cells (horizontal gene transfer)
That’s so cool.
via How Bacterial Lineages Emerge.
“In conclusion, a time window exists that enables the artificial colonization of GF mice by a single oral dose of caecal content, which may modify the future immune phenotype of the host. Moreover, delayed microbial colonization of the gut causes permanent changes in the immune system.”
Ok. So there’s mounting evidence that rapid colonization of the gut of neonates is important to immune development. Next step is to translate that into real medical therapies. There are immune and gut diseases that afflict newborns (also, in many cases, newborns are bombarded by antibiotics at this crucial time) – what have we learned to make them healthier and also ensure that their immune system develops properly?
via PLoS ONE: Patterns of Early Gut Colonization Shape Future Immune Responses of the Host.
“Finally, the text still requires context. As publishers spin up their digital and print-on-demand backlists, more and more is published with less and less context. These efforts amount to land-grabs and rights-squatting, without adding value. Works without TOCs, indexes, author bios, footnotes. Placing work in context is one of publishers’ primary tasks, stretching out to commissioning introductions, assembling background material, supporting biographies and critical studies. Design belongs here too: good book design, appropriate book design, as important now as it has ever been.
“Velocity, depth, breadth. These are the dimensions we can add to books, that are the gifts of a digital age, not gimmicks, glossy presentation and media-catching stunts.”
What I like about James Bridle is that he’s in love with books and is able to bridge the bits and atoms worlds, translating and informing in both directions.
One thing about me I don’t talk about much: I have an obsession with writing. And not the kind that you’ve read from me – websites, blogs, and the like. I’ve been actually writing stories, sketching narratives, jotting down snippets on and off for 30 years.
Of course, I’ve been writing online for almost 20 of those years. And, while James (in the article quoted above) does not think that is publishing, I do. Of a sort. On the level of bulletins and pamphlets of old.
At the same time, I absolutely agree with him that it’s not Publishing, capital P.
I am of the camp that thinks there’s a need for editors and publishers who, as James says above, provide context. Partly there’s the culling the chaff and bad writing, pointing out what’s valuable and well-written, no different than how we tend towards online publications that eloquently point us to what’s interesting and worth our attention.
But, James points out further that Publishers wrap text in a rich layer of context to enhance the text. So true. So necessary.
I have posted some of my short stories here (see Narratives tab above), but have never felt complete (I have two novels and a few dozen short stories). A large part of me wants to see the stories in print, in a physical book (meh, Kindle?), for folks to flip through, fondle, read without having to know me. Yeah, good old-fashioned traditional Publishing.
Services like LuLu emboldened me to head down the path of just publishing it myself, but I know in my bones that I want an experienced editor to read my book, make it better (this is what editors do), and give it to a Publisher who can give it a design, context, audience access, and have it rub elbows with other books. No I am not looking for fame or fortune, just that I publish a wholesome book that I will be proud of.
I’ve known this all these years, and every time I put my novel or short stories into a book format (and go through the contortions of endless editing, layouts, design decisions), I am reminded that the mechanics and business of Publishing is not going away any time soon. [UPDATE: No sooner had I posted this I saw a tweet that pointed to this article "Publishing is no longer a job or an industry — it’s a button" which takes another tack to say Publishing is dead and Publishing is necessary - well, parts are dead and other parts are necessary. Basically, the same thing James says and I comment on.]
It’s hard work.
And LuLu knows that – check out all the Publishing services they offer á la carte.
What do you think?
Read Jame’s whole article: The New Value of Text | booktwo.org.
Another hat-tip to James, I recently made a travel guide for my wife – travel guide, tips, language guide, photos, some fun things, and so forth. I cleaned up and formatted the text, added photos, laid it out, added a TOC (an index would have killed me), personalized it a bit. LuLu was just my printer. And it was great to not really have to worry about the copyrights. Only thing, it cost more to ship it than to print it (I shipped it fast – couldn’t wait to see it). Ugh. Atoms still have to be moved.
And, yes, she liked it.