Best of PubMed #9

And yet another entry in the series… Hundreds of more gems from research in the waiting list! Stand by for new posts in the series at least twice a week. As usual, to follow up on these suspenseful bits of research, visit the PubMed website and paste the PMID number into the search box.

Cookie monster is autistic.
Cruz VK, Andron L, Sammons C.
Child Today. 1984 Mar-Apr;13(2):18-20.
PMID: 6723411

Let me whisper in your ear.
Hume A.
Nurs Times. 1988 Apr 20-26;84(16):39-41.
PMID: 3285329

Have we created the monster under the bed?
Hill MJ.
Dermatol Nurs. 2003 Jun;15(3):213.
PMID: 12875009

Gadgets are garbage.
Pogue D.
Sci Am. 2011 May;304(5):36.
PMID: 21595401

A 4-year-old with a “pirate face”.
Fossati-Bellani MR, Steele RW.
Clin Pediatr (Phila). 2011 Jun;50(6):567-9.
PMID: 21138849

Pirate teeth.
Curtis EK.
J Mass Dent Soc. 2007 Winter;55(4):56.
PMID: 17338466

Would you like a bite of my peanut butter sandwich?
Hofmann RJ.
J Learn Disabil. 1983 Mar;16(3):174-7.
PMID: 6864106

“Will there be peanut butter and jelly in heaven”?
Bennink RJ.
J Pastoral Care Counsel. 2006 Fall;60(3):299-303.
PMID: 17059120

Whiskey barrel explosions–a newly discovered danger.
Becker DW Jr.
JAMA. 1980 Jan 25;243(4):330.
PMID: 7351738

“Pour Me a Gin and Tonic, Honey; It’s After 5 in Paris.”
Wolff CG.
Prim Care Companion J Clin Psychiatry. 2001 Feb;3(1):28-29.
PMID: 15014626

The uses of hopelessness.
Bennett MI, Bennett MB.
Am J Psychiatry. 1984 Apr;141(4):559-62.
PMID: 6703135

Best of PubMed #8

Some of my all-time favorites today! The list never ends.

 

Impact of Yankee Stadium Bat Day on blunt trauma in northern New York City.

Bernstein SL, Rennie WP, Alagappan K.

Ann Emerg Med. 1994 Mar;23(3):555-9.

PMID: 8135433 [PubMed – indexed for MEDLINE]

 

Severe burns from inflammable cowboy pants.

BURNETT WE, CASWELL HT.

J Am Med Assoc. 1946 Apr 6;130:935. No abstract available.

PMID: 21019100 [PubMed – OLDMEDLINE]

 

[Coffee must be hot as hell, black as the devil, pure as an angel and sweet as love].

Bödding M.

Dtsch Med Wochenschr. 2006 Dec 22;131(51-52):2889-94. German. No abstract available.

PMID: 17163364 [PubMed – indexed for MEDLINE]

 

Would Tarzan believe in God? Conditions for the emergence of religious belief.

Banerjee K, Bloom P.

Trends Cogn Sci. 2013 Jan;17(1):7-8. doi: 10.1016/j.tics.2012.11.005. Epub 2012 Dec 11.

PMID: 23238119 [PubMed – indexed for MEDLINE]

 

Induction of an illusory shadow person.

Arzy S, Seeck M, Ortigue S, Spinelli L, Blanke O.

Nature. 2006 Sep 21;443(7109):287.

PMID: 16988702 [PubMed – indexed for MEDLINE]

 

On being treated as an ignorant hillbilly when escorting a patient to a London hospital.

Chellel A.

Nurs Stand. 1991 Dec 18-1992 Jan 7;6(13-14):42. No abstract available.

PMID: 1760310 [PubMed – indexed for MEDLINE]

 

How many angels could dance on the head of a pin?

Ehrlich GE.

J Rheumatol. 2002 Oct;29(10):2240; author reply 2240-1. No abstract available.

PMID: 12375343 [PubMed – indexed for MEDLINE]

 

Not my circus, not my monkeys.

Mulaik MW.

Radiol Manage. 2013 May-Jun;35(3):30-1. No abstract available.

PMID: 23785951 [PubMed – indexed for MEDLINE]

 

Long-term trends in human eye blink rate.

Monster AW, Chan HC, O’Connor D.

Biotelem Patient Monit. 1978;5(4):206-22.

PMID: 754827 [PubMed – indexed for MEDLINE]

 

 

Aiming for immortality…

Death is a disease that Google can cure? Come on…

I’m all for Google’s recent decision to cure death; in fact, once they post the on-line registration form for the treatment, I plan to be first in line to sign up. Providing, of course, they can guarantee I won’t spend eternity suffering from Alzheimer’s disease, or have to undergo permanent chemotherapy. And hopefully a lab somewhere will be growing replacement parts from my stem cells. It will be hard to find an organ donor among immortals; they’ll painstakingly avoid accidents and anything else that risks their chance for eternal life.

I’d also like to know where they plan to store all of us immortals – hopefully it won’t be in a drawer, or one of those shoebox-like hotels you find in Japan. But let’s not overthink this, or get fussy about the details. By the time the cure for death is found, I’m sure the big brains at Google will have solved much simpler problems like time travel, or instantaneous teleportation to the stars, or downloading my consciousness onto the Internet.

To take a more sober look at all of this, Google is putting the cart way before the horse. To use a metaphor: if you think of death as hitting the ground after a long leap, most medical research aims to raise the height of the diving board and to ensure that you’re as happy as possible until the moment of collision. Google’s approach is more like saying, “Jump into this hole; we don’t know what’s down there but don’t worry, you’ll never hit the bottom.”

Unfortunately, the hole always has a bottom. Most people used die from diseases or infections caused by viruses or bacteria. Many still do, but the development of vaccines and antibiotics, pesticides, and the introduction of modern sanitation largely removed those obstacles. New drugs and organ transplantations had a huge impact as well, meaning that 20th-century medicine lengthened average life expectancy by a couple of decades. It made for a longer fall, but it exposed a deeper layer of things to crash onto: cancer, cardiovascular disease, and Alzheimer’s. These conditions weren’t as prevalent in earlier times because they typically strike in old age, and people didn’t live long enough to experience them.

The first step in achieving Google’s great dream will have to be to cure those diseases – which, incidentally, is already the aim of a vast amount of biomedical research. As far as I know, the company has no secret plan that will cause this work to jump ahead and achieve some dramatic spurt of progress. If they do, I’m eager to hear it. Of course the injection of a huge amount of money alone into biomedical research is a good thing; it could fund new labs, or help existing groups acquire equipment that they can’t currently afford. It may help keep talented young researchers in the field; frustrated by heavy competition for scarce positions, many end up leaving the lab. It might also shift priorities by putting even more effort into fields such as stem cell research, regenerative medicine, and the other siblings of the science of aging.

A jump in funding, the creation of a new institute, and other measures along these lines are always welcome, but they won’t cause a revolution in biomedicine. Scientists solve huge problems by breaking them down into tiny parts. Even when they have a definitive goal in mind, they can’t predict the outcome of experiments in advance. The best road to progress is to follow results wherever they lead, which is often someplace completely unexpected. It’s the reason that science funding agencies have discovered that investing in basic research is usually much more productive and profitable than supporting narrowly defined work in pursuit of a particular application.

Suppose all those who have been doing this work so long, and so well – now with support from Google – succeed in curing most cases of cancer, cardiovascular disease, and neurodegenerative conditions like Alzheimer’s. We can expect that happen – if not within my lifetime, then surely that of my children. But immortality will remain a distant dream. Just as major infectious diseases had to be cured before the demographics of disease shifted to these next barriers, once the current challenges have been faced, we’ll crash against the next thing. We do not know what health problems typically strike people who are 120 or 130 years old, but we’re about to find out. Likely candidates are prion diseases such as kuru or Creutzfeldt-Jakob Disease (CJD, a cousin of Mad Cow Disease). Very few people currently suffer from these conditions, probably because they follow a period of incubation that is longer than the normal lifespan. Most victims of kuru were cannibals who ate brain material from other people, where the incubation had already reached an advanced stage.

Currently there’s no cure for prion diseases, and we don’t know what other syndromes will strike people in their second century of life. Once we recognize them, which will take a while, we’ll surely develop treatments as well. Then we’ll be able to move on to the diseases that strike 200-year-olds, and so on. The only hope of immortality is to find cures as fast as as new diseases are discovered. Even then, each challenge will expose a new one. Eventually we may run up against some fundamental physical barrier – a sort of biomedical “speed of light” – which dictates that the human body, at some point, will degrade back to the molecules that compose it.

So as far as I can tell, Google has no fabulous secret plan, and promises nothing new – still, maybe there’s a virtue in putting the label of “immortality” on a new campaign in biomedicine. It seemed to work out pretty well for physics; calling the Higgs Boson the “God particle” was surely effective in collecting the billions of Euros needed to build the Large Hadron Collider. I merely hope that before people become immortals, we’ve ensured that they’ll have a world to live in. First it would be nice to get a handle on overpopulation, pollution, and political strife.

Google may be planning to tackle those annoying little problems as well. Or maybe they intend to export immortals to a better place, using the interstellar starship they’ve begun building in a basement somewhere. You’d think we’d go to Mars before the Andromeda galaxy, just like we’d improve current health and social problems across the globe – for the developing world as well as wealthy countries – before aiming for immortality. But those aims may be a bit too pedestrian for the Google business plan.

Best of PubMed #7

Another update featuring brilliant pieces of research from the PubMed website. Today’s entries: the science of donuts, the medical benefits of swearing, samurai, and more!

 

The universal efficacy of the generic glazed donut.

Granchi P.

Pharos Alpha Omega Alpha Honor Med Soc. 2006 Spring;69(2):20-3. Review. No abstract available.

PMID: 16752792 [PubMed – indexed for MEDLINE]

 

Doc, I’m in the donut hole.

Plotzker RM.

Del Med J. 2008 Apr;80(4):155-7. No abstract available.

PMID: 18512645 [PubMed – indexed for MEDLINE]

 

Is the donut in front of the car? An electrophysiological study examining spatial reference frame processing.

Taylor HA, Faust RR, Sitnikova T, Naylor SJ, Holcomb PJ.

Can J Exp Psychol. 2001 Jun;55(2):175-84.

PMID: 11433788 [PubMed – indexed for MEDLINE]

 

The ethics of eating a drug-company donut.

Broznitsky K.

CMAJ. 1996 Mar 15;154(6):899-900.

PMID: 8634969 [PubMed – indexed for MEDLINE]

 

Death by cursing–a problem for forensic psychiatry.

Watson AA.

Med Sci Law. 1973 Jul;13(3):192-4. No abstract available.

PMID: 4729108 [PubMed – indexed for MEDLINE]

 

Swearing as a non-prescription drug.

Derraik JG.

N Z Med J. 2009 Oct 30;122(1305):104-5. No abstract available.

PMID: 19966886 [PubMed – indexed for MEDLINE]

 

Why swearing is good for you.

Sharples T.

Time. 2009 Aug 10;174(5):57. No abstract available.

PMID: 19728429 [PubMed – indexed for MEDLINE]

 

Personal predictors of spectator aggression at little league baseball games.

Hennessy DA, Schwartz S.

Violence Vict. 2007;22(2):205-15.

PMID: 17479556 [PubMed – indexed for MEDLINE]

 

Swearing–another means of assessing ease of intubation!

Bryden D, Wrench I.

Anaesthesia. 2002 Jun;57(6):624-5. No abstract available.

PMID: 12071177 [PubMed – indexed for MEDLINE]

 

The psychology of swearing among sportsman.

Narancic VG.

J Sports Med Phys Fitness. 1972 Sep;12(3):207-10. No abstract available.

PMID: 4669064 [PubMed – indexed for MEDLINE]

 

Chess psychology and the dentist.

Lewis RA.

TIC. 1982 Oct;41(10):6, 14. No abstract available.

PMID: 6959375 [PubMed – indexed for MEDLINE]

 

Water-hoarding in rats.

BINDRA D.

J Comp Physiol Psychol. 1947 Jun;40(3):149-56. No abstract available.

PMID: 20241992 [PubMed – indexed for MEDLINE]

 

Road rage behaviour and experiences of rickshaw drivers in Rawalpindi, Pakistan.

Shaikh MA, Shaikh IA, Siddiqui Z.

East Mediterr Health J. 2011 Aug;17(8):719-21.

PMID: 21977577 [PubMed – indexed for MEDLINE]

 

Blood vitamin C levels of motorized tricycle drivers in Parañaque, Philippines.

Sia Su GL, Kayali S.

Ind Health. 2008 Aug;46(4):389-92.

PMID: 18716387 [PubMed – indexed for MEDLINE] Free Article

Related citations

 

On speaking to oneself.

Grumet GW.

Psychiatry. 1985 May;48(2):180-95.

PMID: 3991823 [PubMed – indexed for MEDLINE]

Psychiatry. 1985 May;48(2):180-95.

 

The energy requirement of selected tap dance routines.

Noble RM, Howley ET.

Res Q. 1979 Oct;50(3):438-42. No abstract available.

PMID: 545531 [PubMed – indexed for MEDLINE]

 

Smelly feet are not always a bad thing: the relationship between cyprid footprint protein and the barnacle settlement pheromone.

Dreanno C, Kirby RR, Clare AS.

Biol Lett. 2006 Sep 22;2(3):423-5.

PMID: 17148421 [PubMed – indexed for MEDLINE]

 

Comment: samurai attack.

Potterton M.

Afr J Psychiatry (Johannesbg). 2008 Nov;11(4):243-5. No abstract available.

PMID: 19588046 [PubMed] Free Article

 

The way of the samurai snail.

Koene JM, Chiba S.

Am Nat. 2006 Oct;168(4):553-5. Epub 2006 Sep 6. No abstract available.

PMID: 17004226 [PubMed – indexed for MEDLINE]

 

Homicide attempt with a Japanese samurai sword.

Raul JS, Berthelon L, Geraut A, Tracqui A, Ludes B.

J Forensic Sci. 2003 Jul;48(4):839-41.

PMID: 12877304 [PubMed – indexed for MEDLINE]

 

Capturing a ring of samurai.

McNally F.

Nat Cell Biol. 2000 Jan;2(1):E4-7. No abstract available.

PMID: 10620811 [PubMed – indexed for MEDLINE]

 

[The berserks–what was wrong with them?].

Høyersten JG.

Tidsskr Nor Laegeforen. 2004 Dec 16;124(24):3247-50. Norwegian.

PMID: 15608781 [PubMed – indexed for MEDLINE]

 

Is anybody out there?

Horseman RE.

J Calif Dent Assoc. 2013 Jun;41(6):458,457. No abstract available.

PMID: 23875436 [PubMed – indexed for MEDLINE]

 

Unmanned aerial survey of elephants.

Vermeulen C, Lejeune P, Lisein J, Sawadogo P, Bouché P.

PLoS One. 2013;8(2):e54700. doi: 10.1371/journal.pone.0054700. Epub 2013 Feb 6.

PMID: 23405088 [PubMed – in process]

 

Best of PubMed #6

Today’s entry gathers articles on the science of bathtubs and Barbie dolls, voodoo, Frankenstein and a hot potato, etc. If you want to see an entire article, go to the PubMed website, enter the “PMID” number in the search box, and hold on to your seat.

Ejection of a rear facing, golf cart passenger.

Schau K, Masory O.

Accid Anal Prev. 2013 Oct;59:574-9. doi: 10.1016/j.aap.2013.07.025. Epub 2013 Aug 6.

PMID: 23958856 [PubMed – in process]

[When poisonous darts get connected with arguments].

Scholz T.

Krankenpfl Soins Infirm. 2007;100(7):18-20. German. No abstract available.

PMID: 17760373 [PubMed – indexed for MEDLINE]

Hermaphroditism: What’s not to like?

Edlund L, Korn E.

J Theor Biol. 2007 Apr 7;245(3):520-7. Epub 2006 Nov 9.

PMID: 17184795 [PubMed – indexed for MEDLINE]

Three-Card Monte and pigs wearing earrings.

Hage SJ.

Radiol Manage. 2000 Jan-Feb;22(1):16-7. No abstract available.

PMID: 10787758 [PubMed – indexed for MEDLINE]

Swearing as a response to pain-effect of daily swearing frequency.

Stephens R, Umland C.

J Pain. 2011 Dec;12(12):1274-81. doi: 10.1016/j.jpain.2011.09.004. Epub 2011 Nov 11.

PMID: 22078790 [PubMed – indexed for MEDLINE]

Lifting spirits with bedpan shuffleboard.

Putre L.

Hosp Health Netw. 2013 Jan;87(1):63. No abstract available.

PMID: 23413624 [PubMed – indexed for MEDLINE]

Be an Internet millionaire and we may like you.

Barry D.

Mich Health Hosp. 2000 Jul-Aug;36(4):54-5. No abstract available.

PMID: 11010411 [PubMed – indexed for MEDLINE]

How to die like a millionaire.

KINGSTON CT Jr.

Conn State Med J. 1954 May;18(5):452-5. No abstract available.

PMID: 13150755 [PubMed – indexed for MEDLINE]

Tapdancing to health.

Laurent C.

Nurs Times. 1993 May 5-11;89(18):18. No abstract available.

PMID: 8516118 [PubMed – indexed for MEDLINE]

Slash fiction and human mating psychology.

Salmon C, Symons D.

J Sex Res. 2004 Feb;41(1):94-100. Review.

PMID: 15216428 [PubMed – indexed for MEDLINE]

Slip an extra locust on the barbie?

Delamothe T.

BMJ. 2013 May 20;346:f3293. doi: 10.1136/bmj.f3293. No abstract available.

PMID: 23690504 [PubMed – indexed for MEDLINE]

Math is hard, Barbie said.

Begley S.

Newsweek. 2008 Oct 27;152(17):57. No abstract available.

PMID: 18972952 [PubMed – indexed for MEDLINE]

‘Under-12s have sex one night and play with barbie dolls the next’.

Harrison S.

Nurs Stand. 2005 Jun 8-14;19(39):14-6. No abstract available.

PMID: 15974540 [PubMed – indexed for MEDLINE]

Barbie Doll” prosthesis.

Zenni EJ Jr.

Orthop Rev. 1987 Feb;16(2):126. No abstract available.

PMID: 3453963 [PubMed – indexed for MEDLINE]

Is that a bathtub in your kitchen?

Peelen MV, Kastner S.

Nat Neurosci. 2011 Sep 27;14(10):1224-6. doi: 10.1038/nn.2936. No abstract available.

PMID: 21952264 [PubMed – indexed for MEDLINE]

 

Anatomy of a bathtub vortex.

Andersen A, Bohr T, Stenum B, Rasmussen JJ, Lautrup B.

Phys Rev Lett. 2003 Sep 5;91(10):104502. Epub 2003 Sep 5.

PMID: 14525483 [PubMed]

An unresponsive biochemistry professor in the bathtub.

Mutlu GM, Leikin JB, Oh K, Factor P.

Chest. 2002 Sep;122(3):1073-6. No abstract available.

PMID: 12226056 [PubMed – indexed for MEDLINE]

[Are bathtub lifters out?].

Wanke KR.

Pflege Z. 1996 Sep;49(9):607. German. No abstract available.

PMID: 8948977 [PubMed – indexed for MEDLINE]

[The wandering path of the bathtub].

Fabian E.

Arch Phys Ther (Leipz). 1969 Mar-Apr;21(2):89-106. German. No abstract available.

PMID: 4922165 [PubMed – indexed for MEDLINE]

Voodoo dentistry.

Devonald BT.

Br Dent J. 2011 Feb 26;210(4):151. doi: 10.1038/sj.bdj.2011.103. No abstract available.

PMID: 21350514 [PubMed – indexed for MEDLINE]

Evolution of protein technologies from voodoo to science.

Huisman G, Sligar SG.

Curr Opin Biotechnol. 2003 Aug;14(4):357-9. No abstract available.

PMID: 12943842 [PubMed – indexed for MEDLINE]

Voodoo Barbie and the dental office.

Neiburger EJ.

N Y State Dent J. 2001 Jun-Jul;67(6):26-7. No abstract available.

PMID: 11501242 [PubMed – indexed for MEDLINE]

The nurse of the 1990s: not too bright, believes in voodoo, often kills patients.

Rait C.

Neonatal Netw. 1996 Aug;15(5):7-8. No abstract available.

PMID: 8868692 [PubMed – indexed for MEDLINE]

Voodoo regulation.

Findlay S.

Bus Health. 1995 May;13(5):63. No abstract available.

PMID: 10164498 [PubMed – indexed for MEDLINE]

The ethnobiology of the Haitian zombi.

Davis EW.

J Ethnopharmacol. 1983 Nov;9(1):85-104.

PMID: 6668953 [PubMed – indexed for MEDLINE]

Frankenstein and the hot potato.

Leeder S.

Aust N Z J Public Health. 1999 Jun;23(3):227-8. No abstract available.

PMID: 10388161 [PubMed – indexed for MEDLINE]

“From so simple a beginning endless forms”

Another post from an MDC highlight… See more stories at http://www.mdc-berlin.de. Click on one of the highlights in the center and follow the links to past archives.

Wei Chen’s group captures the first full view of one of nature’s most complex genes

 “One gene makes one enzyme,” declared George Beadle and Edward Tatum in 1941, in work that led to a 1958 Nobel prize in Physiology or Medicine. This established a research pathway that forms the heart of modern genetics, but their principle has been vastly refined. Studies of the genomes of humans and other organisms have revealed that the vast majority of genes have a boxcar-like structure built of protein-encoding regions called exons and noncoding information called introns. Exons can be mixed and matched into a variety of proteins, each with a unique chemical recipe, in a process called alternative splicing. This allows amazing diversity from a limited number of genes and underpins many biological processes. A gene called Dscam in the “simple” fruit fly Drosophila melanogaster is the current record-holder; it has 115 exons that can potentially be used to produce 38,016 distinct proteins. Each version may make an important contribution to the wiring of neurons in its brain, yet it has been extremely difficult to figure out which of all these possible candidates the fly actually produces, in which types of cells, and why the fly genome encodes such a seemingly unnecessary diversity. A new method by Wei Chen’s group reveals a way to answer these questions. The work is a collaboration with the lab of Dietmar Schmucker at the Vesalius Research Center in Leuven, Belgium, and appears in the June 21 issue of the EMBO Journal.

Dscam is an abbreviation for Down syndrome cell adhesion molecule. In 2007 scientists discovered that its potential diversity plays an important role in the wiring of the fly brain. Neighboring neurons in flies that produce identical forms repel each other, while those that become attached expressed different ones. In humans this process is largely governed by related cell-adhesion molecules of the so-called clustered protocadherin receptors.

Traditionally, it has been almost impossible to detect different forms of such complex molecules. Wei Sun and other members of Wei Chen’s group managed this with Dscam by developing a method called CAMSeq(for “Circularization-Assisted Multi-Segment Sequencing”).

“Cells transcribe Dscam into a huge RNA molecule that then undergoes a process called ‘alternative splicing,’” Wei Chen says. “A few regions remain in all versions of the protein, but the RNA also has four blocks containing multiple exons from which it chooses one version of each.”

It’s a bit like assembling your  wardrobe out of a catalogue that offers only one type of shoe, but 12 styles of socks, 48 types of trousers, 33 shirts, and two different hats. Altogether, those items could be combined in different ways to create 38,016 possible wardrobes. In the past, Wei Chen says, it was possible to look at just the “socks” exon and determine which form a molecule had, or the “shirts” exon. But you couldn’t step back and view the whole ensemble when comparing different versions of Dscam. It would be like knowing that 3,000 individual proteins had received the exon equivalent of a Hawaiian shirt, and 1,000 the blue shorts, but you couldn’t tell whether they were being worn together.

Part of the problem in studying Dscam diversity has been fundamental limitations on the high-throughput technologies such as microarrays or deep sequencing methods that prepare the RNA transcripts and then analyze their complete composition. Normally, “deep sequencing” methods can only approach molecules that have a maximum of 1,000 bases in length, and then “read” their composition by starting at either end and working inward. “This is only accurate to about 150 ‘letters’ of the code, meaning that you can analyze  about 300 nucleotides long from molecules shorter than 1,000 bases,” Wei Chen says. “But the variable region of Dscam is much longer, which means that the normal method won’t work. An alternative has been to look at the single exons present in an RNA separately, but again, this doesn’t give us a view of how they are combined.”

To solve these technical problems, Wei and his colleagues added a few new steps to the sequencing process. They began by using PCR to produce cDNA molecules that contained the “variable regions.” But about half of this section is occupied by a very long stretch right in the middle that doesn’t vary and thus wasn’t interesting to look at.

“We realized that we could eliminate this section by drawing the cDNA into a ring, which puts the variable sections much closer together,” Wei says. “That places them in a stretch that is about 1,000 bases long and can be approached by our methods.”

Now the scientists could copy just the relevant stretch of Dscam using PCR. This allowed them to study combinations of the three most variable exons in RNAs, produced by cells in different tissues at various stages of development. They found 18,496 out of the 19,008 possible forms – another landmark in the paper.

“Previously scientists had no way to know all these possible combinations of exons were actually being used in the fly,” Wei Chen says. “They might just be ‘theoretical possibilities.’ For instance, the selection of a particular exon at one place might determine which one was being selected from another variable group, meaning that some combinations never appeared.”

But based on their results, Dscam doesn’t seem to be very particular about matching its “wardrobe”: the choice of one exon doesn’t seem to influence the selection at another.

“These measurements are permitting us to make a thorough evaluation of the total protein diversity in an organism, as well as different types that might be made by single cells,” Wei Chen says. “Those factors are essential in the way neurons weave together to make a functional brain architecture. Interestingly, the isoforms of Dscam were expressed at very different, fluctuating amounts. Some appeared at quantities tens of thousands of times higher than others, in a way significantly biased in specific cells and tissues and at various developmental stages. Until now this has been underappreciated, but such bias can dramatically reduce the ability of neurons to display unique surface receptor codes.”

One of the great puzzles related to Dscam has been the question of why flies would need to create a protein in so many different forms – producing each one costs energy and requires a great deal of cellular management. “What we see is that given the splicing biases and the random nature of the splicing process, this seemingly excessive diversity might nevertheless be essential so that neurons can clearly distinguish between ‘self’ and ‘non-self’ types.”

The method can also be applied, he says, to other cases of complex genes – including those of humans – that are spliced in many different ways to fulfill a wide variety of biological functions.

 

Note: The title of this story is a reference to Charles Darwin, taken from the last sentence of the 6th edition of the Origin of Species: “There is grandeur in this view of life, with its several powers, having been originally breathed by the Creator into a few forms or into one; and that, whilst this planet has gone circling on according to the fixed law of gravity, from so simple a beginning endless forms most beautiful and most wonderful have been, and are being evolved.” Darwin and his contemporaries knew almost nothing about cellular chemistry, but this basic idea applies equally well to alternative splicing.

 

 

chen2Wei Chen’s group found a unique solution to capturing a complete view of combinations of the variable regions of Dscam: They drew the molecule into a ring shape that clustered these regions together and allowed them to eliminate invariable sequences. Now the cDNA was short enough to be copied and sequenced using standard methods.

Highlight Reference:

Sun W, You X, Gogol-Döring A, He H, Kise Y, Sohn M, Chen T, Klebes A, Schmucker D, Chen W. Ultra-deep profiling of alternatively spliced Drosophila Dscam isoforms by circularization-assisted multi-segment sequencing. EMBO J. 2013 Jun 21.

Hearing a small and quiet chorus in a vast and raucous crowd

(Another new science article that I wrote for the homepage of my institute, the MDC. See the archive there for more stories from MDC research.)

The labs of Young-Ae Lee and Norbert Hübner help identify new genetic risk factors for atopic dermatitis

If you suffer from atopic dermatitis, you surely know it. Infants develop rashes and a susceptibility to allergies that usually persists their whole lives. For years researchers have known that most cases have a hereditary basis, and a few culprit sites have been identified in the human genome. But others have been very difficult to detect. The laboratories of Young-Ae Lee and Norbert Hübner at the MDC, collaborating with other groups from Germany, the U.S., Ireland, China, and Japan, have now identified four new sites associated with atopic dermatitis. Some of these loci are involved in other diseases as well. The work draws on recently developed methods of correlating genetic factors to disease risks and huge cohorts of patients, nonaffected family members, and controls from several countries. The study appears in the July edition ofNature Genetics.

Finding the genetic causes of diseases like atopic dermatitis, which may involve multiple, subtle defects in DNA and environmental factors, has been one of the greatest challenges in disease research. Whether someone is affected or not might depend on a combination of single “letters” in the 3 billion nucleotides that make up a person’s DNA, and even very close relatives exhibit many “spelling” differences. Adding more distant relatives and others introduce a great deal more “noise”, making it extremely difficult to detect a specific site related to a disease.

A second hurdle has been the need to involve very large groups of patients, family members, and control individuals – preferably several such cohorts from different countries. That has to be done to distinguish sequences that cause a disease from those that originated in common ancestors, long ago, and have spread through any intermingling population. Young-Ae and her colleagues could draw on years of work by Germany and other countries to assemble cohorts of families affected by atopic dermatitis and a number of other diseases, and that work continues.

This type of research is considerably easier if a disease can be linked to changes in a single gene or DNA sequence; here, several sites in the genome are involved, and the environment seems to play a role as well. These factors combine to make the task incredibly complex. Imagine recording every conversation on Earth for a year, in hopes of finding a few people who are somehow similar, saying the same thing at the same time – without knowing in advance what topic or type of person you’re looking for. Multiply that problem by a factor of a few million and you get the idea. Even the best eavesdropping software would grind to a halt.

Over the past few years researchers have developed a methodological solution called genome-wide association studies (GWAS) that hammers at the problem statistically, using sophisticated analytical algorithms. The method is applied to the genome of every individual in the study. It establishes the statistical likelihood that certain regions of DNA are involved in a particular disease such as atopic dermatitis. Such studies give researchers “hot spots” for further investigation, in hopes of identifying exactly what sorts of genetic variants bring along increased risk, and why.

“If you compare the genetic code of different individuals, you’ll find differences such as single nucleotide polymorphisms, or SNPs, where the ‘spelling’ of a single nucleotide is swapped for another,” Young-Ae says. “Some of these SNPs confer a higher disease risk for individuals. In the current study we looked at every region of the genome that was somehow linked to processes of chronic inflammation, because past work has shown a link between these factors and atopic dermatitis.”

Young-Ae and her colleagues used a “DNA chip” that contained every SNP found so far in humans for these regions. Now they scanned the DNA of 2,425 German individuals with atopic dermatitis and 5,449 controls, looking for single letters of the code that conferred higher risk. This produced a list of “hits” that seemed to be significant; then the group expanded the study to 7,196 patients and 15,480 controls from Germany, Ireland, Japan and China, hoping to replicate the findings.

Young-Ae and her team confirmed earlier reports by other groups linking several SNPs to the disease; more importantly, they found four new ones. These sequences also corresponded to a person’s likelihood of having other chronic inflammatory conditions as well. Atopic dermatitis is associated with defects in the differentiation of skin cells called keratinocytes as well as problems with the immune system. Answering this question might show that multiple diseases could be traced back to a common biological mechanism.

For example, researchers have known that immune cells called T helper type 2 cells, which cluster at the skin during inflammations, are somehow involved. One of the genes confirmed in the study is the used to produce a protein called DcR3 that is found in abnormally high amounts during the inflammation associated with atopic dermatitis. New genes identified in the study include IL2-IL21, PRR5L, CLEC16A-DEXI, and ZNF652. CLEC16A, which is highly expressed in immune system cells such as B-lymphocytes, seems a particularly interesting candidate for further investigation, Young-Ae says.

Combining the new findings with those made previously now brings the total number of culprits to 11. “We estimate that this now accounts for about 14.4 percent of the hereditary factors involved in atopic dermatitis,” Young-Ae says. “Increasing that number will probably require expanding the study to new and larger cohorts, as well as developing new methods to find even more subtle associations between DNA, the disease, and environmental factors that might play a role.”

–       Russ Hodge

Highlight Reference:

Ellinghaus D, Baurecht H, Esparza-Gordillo J, Rodríguez E, Matanovic A, Marenholz I, Hübner N, Schaarschmidt H, Novak N, Michel S, Maintz L, Werfel T, Meyer-Hoffert U, Hotze M, Prokisch H, Heim K, Herder C, Hirota T, Tamari M, Kubo M, Takahashi A, Nakamura Y, Tsoi LC, Stuart P, Elder JT, Sun L, Zuo X, Yang S, Zhang X, Hoffmann P, Nöthen MM, Fölster-Holst R, Winkelmann J, Illig T, Boehm BO, Duerr RH, Büning C, Brand S, Glas J, McAleer MA, Fahy CM, Kabesch M, Brown S, McLean WH, Irvine AD, Schreiber S, Lee YA, Franke A, Weidinger S. High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat Genet. 2013 Jul;45(7):808-12