Wednesday, October 22, 2014

gene therapy comeback

The idea of treating diseases by fixing faulty genes was big in the late 90s, but then suffered some serious setbacks. Thanks to new vectors and a broader spectrum of disease targets, the approach is now making a comeback and one treatment has already gained official approval in the EU.

Read all about it in my latest feature:

New hopes for gene therapy
Current Biology Volume 24, Issue 20, pR983–R986, 20 October 2014

FREE access to full text and PDF

The book of life - a printout of the human genome on display at the Wellcome Collection, London. Own photo. (I was considering to use this picture with the feature, but didn't have space for it in the end.)

Thursday, October 16, 2014

useful anarchy

Intrinsic disorder in proteins has fascinated me ever since 1997, when Kevin Plaxco asked me to co-author a News & Views piece (1) on what was then an emerging topic. By now it is an established scientific phenomenon feeding a whole research community, so I even had the opportunity to attend a conference about it a few years ago, and write a feature for Chemistry World among other articles.

We now know that intrinsically disordered proteins play an important role in nature. Quite a few of them work in molecular recognition and can achieve specific binding by “folding around” their target. Others are medically relevant. For instance, there are disordered domains (an oxymoron for the protein folding crowd to chuckle or argue about) in virus proteins and in transcription factors that are important targets for cancer drugs.

If nature can find use for disordered sequences, maybe scientists can also use them in molecular design? Kevin’s group at the University of California at Santa Barbara has now demonstrated an intriguing approach in which disordered sequences (of DNA, this time) can make a receptor more cooperative, meaning more likely to bind a second molecule once it has bound the first (2). The best known natural example of molecular cooperativity is the binding of oxygen to haemoglobin in our red blood cells – it can carry up to four molecules, and each position filled increases the affinity of the remaining ones. The attraction, for haemoglobin as for biotechnologists, is that cooperative binding has a much sharper transition, switching from all empty to all full in a narrower range of concentrations than a non-cooperative receptor would.

But how do you force a receptor to be cooperative if it isn’t naturally inclined to do this? What first author Anna Simon and colleagues in the Plaxco lab did was to cut the receptor (a DNA aptamer in this work, but it should in principle be possible with proteins as well) in two halves, then duplicate each half. If you think of a complete working receptor as a pair of robotic hands that can grab a ball, they glued two left hands together and two right hands, but a connected pair of left and right was needed to carry out the desired function. They then connected the ends of the left and right construct with a DNA sequence that prefers to be disordered.

Bringing one pair of robot hands together to grab one ball comes at a cost, as the disordered DNA linker loses entropy (i.e. opportunities to adopt many random conformations) when its two ends are brought closely together. Once the first ball is firmly grabbed, however, and this entropic fee has been paid, the second pair of hands is suitably arranged in close proximity and ready to grab the second ball without having to pay any entropic costs for that. Thus, as in haemoglobin, the second binding event is much more favourable than the first.

Image: Anna Simon / ref. (2)

Simon et al. tried this out with three different DNA receptors, from a primitive one binding mercury ions to a sophisticated aptamers for the molecules cocaine and doxorubicin, and found that all showed some cooperativity, and one receptor, the one for doxorubicine, gave results within the error margins of the values that theory predicts for perfect cooperativity.

Seeing this works with all three DNA receptors tested, it should also work with others and could also be transferred to proteins. In fact, a recent paper suggests that nature also uses this trick in proteins already (3). Then it could be expanded to more than two binding sites, and it would be good to have high-resolution structures of these constructs to analyse their function in detail. The application of disorder in molecular engineering may be a whole new research field that has just been born.


(1) K. W. Plaxco and M. Groß, Nature 1997, 386, 657.
(2) A. J. Simon et al, Proc. Natl. Acad. Sci. USA 2014, DOI: 10.1073/pnas.1410796111
(3) A. C. Ferreon et al., Nature 2013, 498, 390.

Tuesday, October 14, 2014

a schnapsidee

... is the kind of inspiration that you only have after a few glasses of schnaps, and which may turn out not quite so inspired once you've sobered up. The idea to produce alcoholic drinks in powder form sounds like it could qualify for this label in more than one respect, as I discussed in September's Ausgeforscht column. On a more sober note, the round-up of German pieces published in September/October also includes fake graphene, neonicotinoids, and shark antibodies. Something for every taste, really.

Pulverisierte Schnapsidee
Nachrichten aus der Chemie 62, No. 9, 951

Variationen zum Thema Graphen
Chemie in unserer Zeit Volume 48, Issue 5, page 329, DOI: 10.1002/ciuz.201490059
Abstract and limited access to full text
related content in English

Sorgenkind systemischer Pflanzenschutz
Nachrichten aus der Chemie 62, No. 10, 991
related content in English

Haie geben Einblick in die Evolution des Immunsystems
Spektrum der Wissenschaft No. 10, 12
Summary and limited access to full text
related content in English

own photo

Monday, October 13, 2014

Klundt Clan

Migration in my family tree normally works like this – direct ancestors coming in (eg from Wallonia), and aunts/uncles going out (eg to Brazil). There is one married couple of direct ancestors, however, who emigrated to Russia and stayed there for the rest of their lives (to make matters worse, many of their great-grandchildren later emigrated to the US). Fortunately, their firstborn son and his family stayed in Germany, otherwise I wouldn’t be here now and you might be staring at an empty screen. So here comes a story of fearless migrants and wine makers:

Johannes Klundt was born November 2nd 1759 in Wollmesheim, a village near Landau in the Southern Palatinate, a traditional wine growing region, the second of five children of Konrad Klundt and Maria Johanna Bodang (this name appears to be a palatinate distortion of the French name Bonnedame). His parents had a very small vineyard there (just half a hectare), and some 3.5 ha other agricultural land. Splitting this between him and his older brother would have left too little for either party to survive.

Johannes married Eva Hust (1762-1837) in 1781 – she may also have a migration background, as the name Hust is almost non-existent in Germany, but there are lots of them in France and Belgium. They had five sons and a daughter, born between 1782 and 1805.

Moving out

At the beginning of the 19th century, the Russian Tsars actively encouraged settlers from southwest Germany to move to the Odessa area at north coast of the Black Sea, which was then a new addition to the Russian empire and is today part of Ukraine. A village called Rohrbach (today: Новосвітлівка - Novosvitlivka), some 120 km north-northeast of Odessa, was built in 1805 and the first German settlers arrived there in 1806. My ancestors Johannes Klundt and Eva Hust got there in 1809, after a journey of 80 days, most of which was done by ship (specifically, in improvised wooden boxes that were used one-way only) down the Danube.


So who came along and who stayed behind? When Johannes Klundt left, his parents were no longer alive. We know that of his five sons, the first one, Johann Jacob (1782-1853; my four-times-great-grandfather), stayed behind. He had already set up his own family in nearby Godramstein, with his wife Katharina Barbara Müller (1781-1813) from that village and his son Georg Nicolas (1805-1851) who was to become a farmer and wine maker.

The second, Wilhelm (* 1785) was still unmarried and came along. Their only daughter Eva Catharina (* 1792) and two younger sons, Heinrich (1797-1851) and Johann Michael (1801-1876) were still children when the Klundts emigrated, so they came along by default and lived their lives in the German colony near the Black Sea. We don’t know what happened to the other son.

Johannes’s older brother Johann Jacob (1756-XXX) presumably inherited the modest house and land of Konrad Klundt and worked as a cooper and farmer. (There are two family vineyards called Klundt in neighbouring Mörzheim today (led by Sven Klundt and Walter Klundt), but we’re not sure exactly how they are related to this family.)

Intriguingly, one of the many Klundt descendants in Rohrbach, Heinrich’s granddaughter Katherina Klundt (1857-1949) later married a man called Johann Hust, who was also born in Rohrbach, which makes me think that a brother or cousin of our Eva Hust may have emigrated together with the Klundt family. We don't really know much about Eva Hust's family at all, except the names of her parents, so we don't know whom she left behind or may have taken along for the ride.

The four children who came along to Rohrbach between them provided Johannes and Eva with 26 grandchildren, who all (except one) appear to have stayed in the Odessa area all their lives. (Intriguingly the three sons contributed 13 grandsons carrying the name onwards). When Johannes died in 1833, and Eva in 1837, they left behind a healthy and thriving clan that seemed to have established itself in its now environment.

The village economy in general seemed to be doing well in those times, according to this report. Villagers grew large amounts of wheat, but also held sheep and produced some wine. The population of the village grew from 602 in 1816 to 1581 in 1859.

Moving on

From 1871 onwards (with a ten-year transition period), the colonists lost the privileges that they had enjoyed for two generations, and life on the Black Sea suddenly looked a lot less attractive. Apart from the loss of financial incentives, the young men were also facing the obligation of six years service in the Russian army. Thousands of German settlers emigrated again. The population of Rohrbach peaked in 1894, then dropped by a third, mainly as a consequence of migration to the US. Of the more than 60 great-grandchildren of our founding couple, at least 12 emigrated to the US, where they kept the reproduction rate up, so there must be hundreds of descendants of the Klundt families from Rohrbach in the US and also in some other parts of the world. They are listed here by a descendant of Heinrich and here by a descendant of Eva, but I haven't counted.

In 1884, Jacob Klundt (1855-1939), the eldest of Johannes's great-grandchildren, and his wife Maria Lutz (1854-1939) with their children (three were born in Russia, but not sure if all three survived) took the lead and emigrated to Mitchell County, South Dakota. Then they moved to the city of Alexander, South Dakota. Jacob’s mother, Juliana Kulatus (1835-1925), five brothers and one sister, Katherina (the one who married Johann Hust) joined them there in 1889. As the remaining three siblings and their father Heinrich Klundt had died before the emigration, this means the entire surviving clan moved to the US, where Juliana became a proud grandmother of 50. A bunch of Johann Michael’s grandchildren also emigrated to the US between 1893 and 1907, as did a few scattered individuals and families across the board. They had a lucky escape, because the 20th century held disaster in store for those settler families who stayed in Russia.

In 1889, the combined Klundt families moved to Dakem, North Dakota, on three covered wagons. During the years in South and North Dakota, Jacob Klundt and Maria Lutz had another eight children. They tried to establish a farming business there, but found the climate too different from what they were used to on the shores of the Black Sea.

Thus, in 1902, Jacob’s family (with ten children) migrated further west to Franklin County, Washington, where they bought land near the Snake River, north of the town of Walla Walla, from a Mr Page – after whom the location was named in 1903. Conrad’s family followed them, while Katherina and the other brothers stayed in North Dakota.

Until 1919, the Klundts ran a ferry across the river as well as their farm. Jacob’s son Charles Klundt became the first postmaster of Page when a post office was installed in 1903, later to be followed by two of his brothers.

The Klundts also set up a shop, a church, and fisheries. They also established a modest vineyard of two acres and actually produced wine. This makes me think that they probably handed down their wine-making traditions over the generations since they left the palatinate, and also grew vines in Rohrbach. For a more detailed account of their lives in the US, see the historical sketch provided on this page. The village of Page no longer exists, sadly, as it disappeared under water in 1961, when a dam was built on the Snake River. But there are a lot of vines growing on the slopes near the Snake river nowadays, and maybe the Klundts have something to do with that.

So the bottom line is I have every excuse to obsess about wine, it runs in or veins …

Note: Alternative spellings of the name in old records include Clund, Klund, Chlundt.

Monday, October 06, 2014

science in antarctica

I had a feature on the shrinking arctic sea ice a couple of years ago, so here comes the southern counterpart. Apart from the concerns over climate change and loss of continental ice, I'm also looking at the recent investigation of biotopes in the subglacial lakes and their importance for astrobiology.

Shrinking ice caps in the spotlight

Current Biology Volume 24, Issue 19, 6 October 2014, Pages R941–R944
DOI: 10.1016/j.cub.2014.09.040

abstract and limited access to full text and PDF file
(should become free access one year after publication)

A mosaic of satellite images of Antarctica taken by RADARSAT-2.

Credit: RADARSAT-2 Data and Products © MacDonald, Dettwiler and Associates Ltd. (2008) All Rights Reserved. RADARSAT is an official mark of the Canadian Space Agency. (PR)

Thursday, October 02, 2014

viral DNA

Many DNA viruses pack their DNA so tightly inside their capsids (protein shells) that the molecular chain can no longer move and remain frozen in a glassy state. But how does it get out of that freeze when the virus infects a cell? The answer is in my latest news story in Chemistry World:

Viruses melt ‘glassy’ DNA (free access)

source: found floating around on tumblr