On BioScience and Life and Such

Archive for September, 2008|Monthly archive page


Thank you Genomic Experts

In Uncategorized on September 30, 2008 at 11:08 am


post to news.thinkgene.com

From: Me

To: HelixGene Genomic Experts

Thank you for adding me to your google group. I am excited to see what topics will emerge on HelixGene Genomic Experts and how the discussions will turn out.

I would love to see any project aiming to build a bridge between popular press and scientists, gain  momentum. As I mentioned on the comments to the Gene Sherpa blogpost, I have been wanting to do something similar for some time (SciPhu.com is supposed to be the starting point), but you are in a much better position than me to achieve this. To further the cause,  I’d like to share my thoughts on “peer reviewing” popular press scientific information by giving you a short summary of The SciPhu project proposal / business plan:

SciPhu.com shall be a website that brings experts and journalists (or the general public) together to produce accurate scientific information. Experts will be “peer-reviewing” what journalists have written or what a company wants to use as PR-material, and a label would go on the particular text to confirm scientific accuracy. Experts need to be approved, but can be recruited from any part of the world, in any scientific field and, in theory, on most academic levels (skillful grad-students and post-docs could easily participate). Experts could be graded upon the quality of their peer reviews, and such grading could be used as screen to get into doing peer-reviewing for paying customers like news-agencies and company PR-departments (the money incentive to get academics to participate). The website thus, would serve as a 24/7 resource for anyone wanting to do quality assurance on scientific information, some would pay for this service (news agencies, PR-companies/departments) and others would get it for free (institutions, government officials, general public)…

One of the HelixGene Genomic Experts approaches is to grade texts after publication. The other approach like mentioned in your about section, is to act as a liaison between journalists and scientist and this is what I strongly believe needs to be focused on. To that end, I have been looking at HARO (HelpAReporterOut) which is an e-mail group where journalists asks for expert opinions prior to writing their story. Incorporating such services I think could have great benefits (altough the current HARO is focused on life-style/travel and other trivialities of life, rather than hardcore science).

I have more details worked out in my mind and plenty more (premature) ideas, but neither the programming/web skills nor the time to go through with this alone. I’ll just repeat my willingness to contribute and collaborate. I am very happy to see that my thoughts are shared by others.

The goal is accurate information. Information is fundamental in shaping the developments that  constitutes our future. This is the time to put some quality control on that information. HelixGene is a call out to all scientists: Participate_in_this_mission.

Regards

Nils Reinton, PhD

Publishing revolutionary

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Hey junk people, I accept your challenge (part II)

In Uncategorized on September 25, 2008 at 2:19 pm

A follow up from this post and an ongoing discussion with Professor Larry Moran over at Sandwalk.

Let me start by saying that even though this has been a lengthy discussion, I do not think we’re disagreeing that much, – on the basic facts that is. And the comments following my first post, his second post, my third, his fourth and this (the fifth) post on the topic hopefully will illuminate this fact.

Secondly I will introduce this post as I did the last, with my c-gamma gene (PRKACG). This gene serves as an example of how introns, retroposons and even alu-elements can contain indicators of function.

The c-gamma gene is transcribed in a species specific manner, (primates only), it’s expression is also tissue specific (testis only). The gene is contained within an intron of another gene, it’s 3′ sequence constitutes an exon of this other gene and lastly, putative regulatory elements where found in and around alu-elements in it’s upstream 5′-region.

Now, you can argue that these are all coincidences, … and refuse to speculate on any function. You may even be right in doing so, which I elaborated upon in my previous post. But, this gene is one of the reasons I refuse to put the label “junk” on everything that has not been ascribed a function. In my opinion, the species and tissue specific transcription, the conserved reading frame and the peculiar positioning of this gene, are all indications that this sequence may hide a function. There are other examples too, especially when it comes to transcription of alleged “junk” which in my mind is enough to warrant further investigation and scientific speculation.

There is, as has become very evident from this discussion, evidence pointing towards much of the genome being “junk”, but there are certainly scientifically viable indications to the contrary too.  Listening to the counter-arguments and following links in this two-post series will tell you this.

Then… moving on to answers to Professor Moran’s last 4 points:

…

5. Why is the Fugu genome so much smaller than that of other fish?

and

6. When two similar species differ in genome size by a factor of two—probably due to an ancient polyploidization—is the majority of DNA in both species functional?

His argument is that since the genome size differs between species, much of it must be junk. But, you could easily use the same argument towards a function, by saying that the difference in genome size is a defining (functional) difference between species. We just do not know do we ! And, why does the difference in size not give you reason to speculate on function at least in parts of these regions ? Others have however, speculated far better than me on this topic, and a thorough introduction to such research can be found at junkdna.com and following this link to “The Principle of Recursive Genome Function“.

7. In the human lineage there are over one million Alu sequences. They all look like degenerate versions of 7SL RNA. Are all of these sequences functional? If so, what function could they be doing? And why do the human Alus look so different from the mouse ones?

I am not saying all Alu-elements are functional. On the “what is junk” scale, one extreme is that everything that hasn’t been ascribed a function is junk (Larry Moran’s position !?) and on the other end is “nothing is junk”. My position is somewhere in the middle: Some of the DNA in our genome is possibly junk. A number of individual Alu-elements will undoubtedly end up in the “junk”-category when more is known about our genome. That said, it has been shown that Alu-elements can constitute (parts of) regulatory and functional elements. It’s rather hard to tell which ones are functional by just looking at them. I therefore refuse to call them “junk” by default, – I strongly feel that the “junk”-label is a dismissal of any possible function(s) and should be used with caution if at all, – even for Alu-elements.

8. Most intron sequences do not seem to have a function. Why does the size of introns in the same gene vary so much in related species and why isn’t the sequence conserved in most cases?

This argument is similar to the genome size argument above, and the answers for bullet 5 and 6 are equally valid here. Thus, there may be many reasons for a variation in intron size and this variation is not a very good argument to support the “junk” hypothesis. Also, the intron can contain regulatory elements and the c-gamma example above goes to show that introns can even contain functional (as in transcribed) genetic elements.

…..

My final note is this: A lot of this alleged “junk”-DNA is being transcribed into RNA. If it was just “junk” then why has selection preserved the transcription from these regions when transcription is an energy consuming process ? I think the position of “junk”-DNA may have some persuasive arguments, but it’s exceedingly harder to argue that the transcripts from these regions are also “junk”.

No matter what constitutes junk, and how much of it there is, this discussion has been extremely rewarding for me personally. I need to admit that the “junk”-position is more understandable to me now. I even find myself agreeing with many of the arguments, like the importance of drift over selection.

Conversely, even though I think he will never admit to it, Professor Moran indicates in one of his questions during the discussion, that he too is not completely locked into the “everything is junk” position:

How many of those transcripts are functional, according to your speculation, and what the heck are they doing?

Which I think is a perfect ending quote because it goes to show that we are all wondering about this……and that our disagreement is not as fundamental as some have suggested.

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Hey junk people, I accept your challenge (part I)

In Uncategorized on September 23, 2008 at 1:42 pm

Some say that almost a half of the human DNA is “junk”, I say that the evidence indicating otherwise is strong enough to allow for speculation on (and research into) possible functions. In a recent discussion with Professor Larry Moran over at Sandwalk, on this topic, I received this challenge:

If you enjoy speculation so much then speculate on this [list of 8 questions]…

And I’ll answer each question as thoroughly as I can (please, find the first 4 below) but first, as an introduction, I would like to explain one of the reasons I take interest in the subject of “junk”-DNA. Bear with me, it’s an interesting story….

Back when I did my PhD, most of us PhD-students would get at least two projects to work on. One would be a “safe” project that would be reasonably easy to publish and the other one would be a high risk project where the outcome was more uncertain, but could potentially be published in ha higher impact journal (this is an approach I think all labs should follow !!). My “safe” project was to clone and characterize a gene for an isoform (of cAMP-dependent protein kinase) where the mRNA (cDNA) was already published (yes,believe it or not, this was actually publishable back in the days 10 years ago).  So, I cloned and I started sequencing looking out for exon/intron boundaries and intron sequences as was standard procedure. Problem was that I didn’t find any intron sequences. The genomic sequence was identical to the mRNA (cDNA) sequence.  At the ends where the cDNA and genomic sequences stopped being homologous, I found  direct repeats. These are the hallmarks of a retroposon. A retroposon is an mRNA that has been reverse transcribed and inserted into the genome. To add to this peculiar finding, my gene, the PKA C-gamma gene, it turned out, was a retroposon inserted into the intron of another gene (see illustration).

From my C-gamma paper: “genomic mapping of the STM7 gene demonstrated that the C-gamma open reading frame was situated within the intron separating exon 16 and 17 in the STM7 gene. In addition, part of the 3’-untranslated region of C-gamma (nucleotide 1478 to 1538 in fig. 2) constitutes an alternately spliced exon (exon 17) in the STM7 gene. The two genes are transcribed in opposite directions in the human genome, ……”

The common perception is that a retroposon is not functional. But, the circumstances in this case, I believe points towards some kind of function. C-gamma translates into mRNA in vivo (as is the case with a handful of other retroposon’s), and since it has an intact reading frame this mRNA can be translated into protein in vitro and in cell lysates. So is this protein detected in vivo ? ….and what if anything, does the protein do………?

This I’ll answer after returning to speculations on Larry Moran’s list of questions:

…

1. Why do pseudogenes and most of the transposon-related sequences look so much like broken genes?

By a broken gene I guess he means a broken reading frame that seems not to code for a protein product. The genetic sequence may still constitute a regulatory element influencing other genes (as was the case with the finding that led to the original discussion, see here for reference). Also, any trancribed RNA from parts of this DNA may have function either as long RNA molecules, miRNA’s or siRNA’s.

2. Why is the DNA sequence in most of our DNA not conserved?

Shorter segments may be conserved interspersed with unconserved regions. Also there has to be a great deal of non-conserved sequence to allow for evolution. This DNA serves a buffering capacity in that it is a reservoir for evolution (that does not make it “junk” !!, see below). Another point on conservation comes from the fact that miRNA’s function on the basis of their structure rather than a conserved sequence (many different sequences can give rise to similar two/three dimensional RNA structures). Thus conserved DNA sequences may not give any information on the function of such sequences and new approaches are needed to study their function.

3. Why can we delete large segments of mammalian DNA with no observable effect?

If you were an alien scientist examining a modern car you would find essential stuff like wheels, steering and breaks. You would also observe parts that seemed not to have any apparent function like the seat-belts, car-radio, air-conditioning, anti-spin system, ashtray, maybe a fire extinguisher and so on. These parts have a distinct function only under certain conditions and unless you are observing the car the instant these items are used, you might, -if you are of the “junk”-people, think that these parts are “junk”. Your conclusion would be strengthened by the fact that you could remove most of these items and the car would still be performing it’s basic functions (start, forward, reverse, turn, stop). Same could be true for the possible functions of large parts of our DNA.

4. Why is there so much variations in repetitive DNA within a species? Some people have segments that are ten times longer than segments found in other people. Are all of the nucleotides in the longer segments functional?

Repeat variation like STR’s are common variations that sometimes leads to functional differences between people, thus they are not “junk”. Similarly, Copynumber variation is a relatively newly discovered phenomenon that may have profound effects. That there is copynumber variation also in DNA yet to be ascribed a function, comes as no surprise and is not an argument for “junk”.

…

Then again, professor Moran might be right, it may all be junk. This may also be true for my C-gamma gene. because, the protein has never been found in vivo and consequently no function is known to date. Many have tried to find the protein (and/or a function) and some have suffered under the lack of results.

And I should mention in all fairness, that for me personally, it was wise to stop working on this and move on to other research projects and ventures.

Thus, I do understand the position of the “junk” people……..but, and here’s where my disagreement with them starts…..

That we haven’t found a function so far, does not mean that there isn’t any. Reports on new functions of DNA sequences are frequent and one of them was the ….. “opposing thumb” regulatory element….

This belief that there’s hidden function to be found, treasures to unearth if you will, is the difference between those advocating these parts of DNA as “junk” and me. In my opinion, It’s not the details of what is junk and what isn’t, ..- and how much, that bothers me…..

It’s the attitude. To dismiss something as junk is contrary to my idea of science being driven out of curiosity and the need to explore. Curiosity may kill a cat every now and then, but I’ll take that risk and continue to praise the scientist who recognize possibilities in the junk rather than dismissing it.

Answers to the last 4 points made by professor Moran to follow….

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What you know is based on luck in this day and age

In Uncategorized on September 16, 2008 at 11:46 am

The other day I was listening to a talk on evidence-based medicine and how to navigate the literature without getting lost in too much information. The speaker went through some of the guidelines to effectively use scientific evidence in the clinical practice and medical research. These guidelines alone constitute information overload it seems, but if you want to try yourself, a starting point can be found at Cambridge university Library.

One of his conclusions that I found particularly interesting, was that to penetrate this massive amount of information, you need to use Sturgeon’s law. This law states that: to avoid information overload, you have to assume that

“Ninety percent of everything is crap”.

I immediately thought of friendfeed, not because there’s a lot of crap there, which there isn’t, not in my crowd anyway, ….not yet… But, because friendfeed is the current spearhead aggregator of information, – information from channels that were already overloaded, like twitter, the blogosphere and web-news.

Here’s a descriptive tweet (on friendfeed) from Berci Mesko some time ago:

“I’m absolutely not worried when I see I have 1500 feed items to read. Am I totally mad?”

A possible solution (using something similar to Sturgeons law) comes from the blog post Why I Stopped Reading Blogs (for a while):

1000+ items.  That’s what Google Reader told me I need to read to catch up with my RSS subscriptions.  It’s intimidating.  My RSS feeds were mocking me. I could see them with sneaky voices “hee hee, you’ll never read me, you don’t have the time. ha ha.”  The sad part is, they were right………..

….took a nice long look at the list and asked myself – does this matter to me?  Do I even know this person?  Will I be worse off without this content in my life?  No. No. No.

And doing something like this may help you avoid some dire consequences (from Slaw.ca):

They are numerous studies to suggest that information overload makes us dumber: Persons exposed to excessive amounts of information are less productive, prone to make bad decisions, and risk suffering serious stress-related diseases.

Me on the other hand, I never got to the point where I had 1000+ entries in my reader, I only have three or so blogs there. But, I also follow twitter and friendfeed. And then I’ve got a couple of (three ?, – maybe four ?) science news sites I go through on a semi-daily basis, and in addition I am following feed-networks like The DNA Network, and there’s mail correspondence and of course journals to skim through (and consequently, articles to examine) as well as a couple of books I’d like to read…..

What I do to keep from overloading is simply to click and read only when I have some time to spare. I also very rarely go beyond that first page of friendfeed and seldom look at historic postings on blogs or news sites. I just do not have the time. I have this life I need to live and it keeps getting in the way of the internet and reading in general.

This does however, mean that I am missing out on a hell of a lot and that the timing is essential to the information I get. Thus, although I have tried to optimize the information channels I take in, I am basing my information (knowledge ?) on luck of timing.

I will continue to do so I guess beacuse you just can’t have all the cakes and eat them too. Which basically is Sturgeon’s law, only reformulated, and a comfort to my ignorance.

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Junk, DNA, RNA, Brain, Biology and Possible Solutions

In Uncategorized on September 11, 2008 at 10:10 am

We and all other organisms are complicated biological structures made from very simple building blocks on an information template of DNA. Individual variations in DNA are rather easy to work out although you do need lots and lots of DNA sequencers, data-storage facilities and data comparison programs. Fact remains, – you basically only need time and money to do this.

We know that the DNA sequence itself is diverse enough to make every individual exclusive while retaining enough common features for speciation. So, DNA explains a lot, but the final functionality including the ability to adopt to changing environments, depends on the next levels of variation…

Take the Necker Cube below. As described by  Edge writer Nathan Myhrvold:

This is a perfectly good 2D picture, but we cannot help trying to force into being a 3D object. The 3D reconstruction problem is ill posed—there are two very different solutions, each of which is feasible. So, when you look at it you alternately see one then the other—you can feel it pop in, or pop out. Without a unique solution your brain flips between the possible solutions.

The analogy to biology is as follows:

Strictly speaking, the cube is two-dimensional. But, for all practical purposes it is a three-dimensional object. At the same time it’s three dimensional form shifts from one confirmation to the other.

The analogy to DNA is that while the written DNA-sequence is linear (two-dimensional) the resulting molecular three dimensional structure allows for transcription into RNA and interactions with proteins both at the DNA and RNA level. These interactions in turn can lead to effects that vary depending on the surrounding environment. The Necker cube is made out of 12 identical lines giving rise to two different three dimensional conformations. DNA is made out of four versions of millions of basepairs. Resulting in a vast number of possible final variations of effects.

Biology handles a chaotic and changing environment using simple building blocks to make flexible, hyper variable, intricate and complicated possible solutions. Knowing the DNA-sequence, the transcriptome and the proteome is basically just discovering the two first dimensions in a many-dimensional organism.

New ideas, approaches and tools are needed to explain how this seemingly chaotic system works. Dismissing reasons for the obvious complexity using terms like “junk-DNA” is not going to get us anywhere.

Instead, let’s start by acknowledging that we know very little. All we know is that function comes out of an apparent chaotic mixture of DNA protein and RNA. Let’s speculate that everything is there for a reason. Without reason you loose hope and visions and those are qualities that science is vitally dependent upon.

Illustration taken from http://wisebytes.net/illusions/


Quote of the month September 08

In Uncategorized on September 8, 2008 at 10:30 am

From: THE PRODUCTION LINE, Nature news feature

To: All those who advocate “junk” DNA/RNA in any shape or form

The doubters, [John Mattick] says, “keep regressing to the most orthodox explanation [that the long RNAs are junk]. But they can’t just sit on their intellectual backsides and tell us to prove it.”

– John Mattick (..a long-time advocate of non-coding RNA’s importance..), the director of the Centre for Molecular Biology and Biotechnology at the University of Queensland in Brisbane, Australia

I think the term “intellectual backsides” is particularly pertinent.

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Down Low Women, Milan Meeting Update II

In Uncategorized on September 5, 2008 at 2:12 pm


post to news.thinkgene.com

A follw up on this post.

Being a molecular biologist lab rat, I do not have much experience with clinical work. I have been perfectly happy to miss out on the ickier parts of human pathology, and this weeks meeting on sexually transmitted infections (STI’s) seem to have strengthened my conviction. Some of the images I have seen has made me think I will never have voluntary sex again, – man have they been gross…

However, well into the second day, I have been immunized and finally find myself able to take in some of what the speakers say. And just to modify the somewhat comic impression from the last post, I will present a couple of talks that touch upon serious issues. At the same time it’s all about sex which makes them interesting (even though I’ll never have it again).

A talk that should have been on the list in the last post was

The Prepuce: Fact and Fiction

Which concluded that the prepuce (aka foreskin) is considered beneficial by some and without importance by others. The speaker Derek Freedman (Ireland) posed the entertaining question: “Do we have sex with our penises or with our brains” when commenting on the possible loss of sensitivity when circumcised. Now, the serious part was when he asked another and much more important question:

“Why has it taken so long to discuss circumcision to prevent HIV-transmission, and why is it not implemented in prevention programmes when circumcision confers 60% protection rates…?”.

A thought provoking question I think, considering that such a (relatively) simple procedure could potentially save millions of lives.

Another talk that I learned a lot from, and that touched upon some very different, but equally important issues, was

Down Low Women – by J.Risser University of Texas

Did you know that in poor areas of Houston US there’s a 2,5 % incidence rate of HIV. Did you know that women in these areas expose themselves to extremely high risk because having multiple boyfriends provides them, not with necessities like food and clothes, but with cell phones or money for a professional hair-do.

I ask them to help me with my wants; my needs I can take care of myself.

They are consequently not prostitutes as such, but still behave like them to posess (in my opinion) meaningless status-items. In doing so they are putting themselves at very high risk of HIV and other STI’s, – since they’re not using condoms in fear of exposing the boyfriends to each other, and since they apparently need several boyfriends to satisfy these needs. Appaling facts, – absolutely appaling.  If I get the chance I am going to come back and blog more on Dr. Rissers research. Because, even though the facts are sad, the issues are fascinating.

No wonder sexually transmitted disease is hard to fight.

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Meeting update, talks in the category: “Did he really say that …?”

In Uncategorized on September 3, 2008 at 5:26 pm

I am in Milan, a very Italian city with extraordinary shopping opportunities and quite a few cultural highlights (the last supper painting, the “duomo” and La Scala can be mentioned). I am attending the annual International Union against Sexually Transmitted Infections (IUSTI) meeting. Browsing through the programme I see that I have a lot to look forward to and a lot to learn this week. But, also looks like there will be room for some fun….

Although STI’s are a serious matter, a few of the talks have titles that sounds entertaining, which of course, makes them a must-hear, – which I am sure is (mostly) intentional. Some examples:

Best ones first:

How to catch the casanovas

Entertainment education for sexual and reproductive health

That last one I hope is not porn.

In the category “lost ?”

CHLAMYDIA SCREENING IN THE UNITED STATES: WHERE ARE WE NOW?

In the US !!??

Next category: still lost, but spatially defined:

Syphilis and Genito-Ulcer Diseases: Where are we now?

Well we’re clearly not in the upper part of the body are we….

And finally in the category, not lost, but still:

Chlamydia Screening in Europe: do we Know where we are going ?

And in the category of titles that just sound strange:

A quantified green tea extract in the treatment of external ano-genital warts

Vulvodynia: a brief overview

Putting sex back into STI prevention

“A brave new world?” – Experiences of STI testing, prescribing and
dispensing via the Internet

If this last title holds any truth, I am simply horrified by the prospects of STI dispensing via the internet…..

And finally, for the fashionable (very Milan’ish !!)

Designer genitals/genital adornments

Joking aside, this looks like it is going to be a very informative meeting. And, behind most of these titles are, even if they sound strange, serious issues like dealing with the continuing spread of sexually transmitted infections and how to eradicate the bugs causing them. The implications are no laughing matter as all HIV-patients and infertile couples (Chlamydia, Trichomonas, Mycoplasma ?) will tell you.