The nobel prize for physiology and medicine 2015: William C. Campbell, Satoshi Ōmura, Youyou Tu

Drug, In General, Malaria,

This morning the Nobel prize in physiology and medicine 2015 was awarded to research on parasites and malaria.  Willaim C. Campbell and Satoshi Ōmura share one half for their work on parasites; Youyou Tu gets the other half for identifying new malaria drugs from Traditional Chinese Medicine. I have to eat my hat since I could never imagine something from Traditional Chinese Medicine could be really effective, much less be awarded the Nobel prize, but there it is and I might be more cautious in the time to be.

You have to read the paper of Youyou Tu (2004) where he summarizes his work since his graduation in 1969. It is chemical science starting with material out of the prescription book of Traditional Chinese Medicine. Qinghaosu was the first product they found and that is now chemically modified to give much more potent anti-Malaria drugs.

Congratulation to this achievements!

Fig.1:Artemisine - QINGHAOSU
Artemisine – QINGHAOSU

Genes for depression

Depression, Genetics

Major depression (MD) is an understated disease. It is present in any culture and worldwide. I saw with regard to this a research highlight in Genome Medicine by M.Rivera and P. McGuffin, who commented on the succes of a whole consortium whose members did a tremendous search for genes linked to Major Depression and found them.

I then went to the paper itself in Nature which is prepared and written by the Coverge Consortium from China, Oxford and VCU in Richmond, VA. Some 5300 people with the disease were sequenced and compared to some 5300 healthy controls. The researcher were pointed to two genes which were analyzed in detail and variants thereof proved to dispose for MD. These are SNPs close to the  Sirtuin 1 and the LHPP genes both on chromosome 10.

SIRT1 is a stress-response and chromatin-silencing factor. It is an NAD(+)-dependent histone deacetylase involved in various nuclear events such as transcription, DNA replication, and DNA repair (citation from OMIN 604479). LHPP is the phospholysine phosphohistidine inorganic pyrophosphate phosphatase. This gene has already been implicated in MD: http://www.nature.com/mp/journal/v14/n6/full/mp20088a.html.

This is an intriguing story for those involved in the science of MD, but also for the persons concerned. If there is a gene or some gene responsible, one is not to blame personally. This is a good finding.

 

RNA polymerase in action

Biochemistry, Cell physiology, transcription

To see an RNA polymerase II (Pol II) in action has been the dream of any molecular biologist. Imaging the possibilities to see and not to suspect transcription of DNA into RNA, to see what the interactions are and not to suppose. A team around Guillermo Calero in Pittsburgh, PA, and Craig D. Kaplan at Texas, A & M University, has achieved this molecular dream.

The paper in Molecular Cell by C.O. Barnes and M. Calero depicts the crystal structure of a RNA Pol II complex together with DNA and the newly transcribed RNA stabilized by transcription factor II F (TFIIF). The structure from Saccharomyces cerevisiae reveals  the unwinding of the the DNA duplex, the so-called nucleic acid scaffold (NAS) where the RNA is formed and the downstream duplex. The down stream duplex builds a 130 ° degree angle to the upstream duplex in the complex.  The pictures show for the first time the unwinding of DNA, the RNA synthesis, the re-winding, and the contributions of the different Pol II subunits.

Unfortunately the accession numbers for the structure are not yet availabe in the Protein Data Bank (5C4X/A/4/J, 5C3E). (They are now.)

This paper is a must for any one teaching molecular biology, for students in any case.

 

Puberty – new evidence for its regulation

Brain, Cell physiology, Endocrinology, GnRH

It has been a long standing mystery how the start of puberty is initiated. Fact is that menarche, the begin of active reproduction capacity is preceded by and a consequence of the adrenarche, the begin of androgen production in the adrenal gland. Puberty is characterized by the beginning of sporadic gonadotropin releasing hormone (GnRH) pulses which in time become regular and finally acquire their one-in-two hour rhythm at the end of puberty.

A report in the Journal of Molecular Endocrinology by Abreu and colleagues from Boston and Sao Paulo has uncovered  that the Makorin ring finger 3 (MKRN3) gene is mutated in cases of central precocious puberty (CPP) . CPP is diagnosed when the children enter into puberty much to early for their age. They analyzed the protein in more detail then and found the decline of MKRN3 expression in the arcuate nucleus (area of the hypothalamus to control GnRH secretion) is necessary for the increase of GnRH secretion. Without GnRH puberty can not take place. By which stimulus the decline of MKRN3 is initiated has not been described. It is discussed whether MKRN3 acts directly on GnRH secretion or on kisspeptin, neuromedin B or dynorphin, known mediators of GnRH secretion. It can not act on GnRH expression since the GnRH neurons only reach with their axons into the arcuate nucleus where their release is controlled by other neurons and mediators.

This is a nice paper, adding valuable information to people concerned with the mechanisms of puberty. Recommended!

New Malaria drug with DDD107498

Biochemistry, Malaria

200 millions of cases and more than 500000 death are worth every effort to deal with the world wide pest named malaria. A report in nature from a multicentric group with the Welcome Trust and Glaxo has found a new drug with the so-far non-attractive name DDD107498, which has excellent non-clinical parameters. It is drug specifically active against the translation elongation factor 2 (eEF2) of Plasmodium falciparum . 

DDD107498

A patent for the drug is filed (PCT/GB2009/002084).

Wrong splicing of the androgen receptor as the cause for polycystic ovary syndrome (?)

alternative splicing, androgen, Biochemistry,

It has since long been suggested that androgen receptor changes are at the origin of the polycystic ovary syndrome (PCO), which affects about 7 % of fertile women and is a major cause for infertility; good proof, however, has been lacking. Wang and colleagues from the Hangzhou University in China have now presented in PNAS from April 15 this year a convincing report that alternative splice variants (ASV) occur in women with PCO but not in those without. 

Alternative splicing occurs when there are several acceptor sites for the RNA lariat during splicing, where the introns are excised from the heteronuclear RNA and the RNA is cut to the messenger RNA. Or there are mutations at the sites supposed to be brought together that the splicing mechanism can no longer work.

It is very suggestive that the ASV occuring in the androgen receptor are causative for the disease. It is very much supprising that this finding has taken so much time to be discovered. This lets one think about lack of basic scientific knowlege in the medical community at large. It should be necessary to have scientists advisors assisting medical researchers not beeing able to look beyond their own nose.

An important paper and a must.

Man and dog – bonding and evolution

Oxytocin

Science from April 17, this year, has two feature articles by David Grimm about men and his dog, one perspective article and a report that shows how men-dog but not men-wolf bonding is intensifierd by oxytocin.

One feature article: Dawn of the dog is most instructive about the process in science itself, fighting over data, sparring with opponents, and reconsiliation to a common task with the help of a third party, the other one: How the wolf became a dog is summarizing the different text, the perspective paper by MacLean and Hare shows the implications of the report: How the oxytozin loop between men and dog might shape the bonding and even help in pathological situation like autism and posttraumatic stress. A nice sentence from the feature is “if the dog is staring at you, it might not be after your sandwich!”

The whole bunch of articles is a pleasue to read.

Regulatory T cells and AIRE expressing cells do the job of tolerance

Cell physiology, Immunology, tolerance

T lymphocytes require education in order to distinguish between self and nonself. This education is maintained by thymus stromal epithelial expressing the autoimmune regulator gene (AIRE). These cells express proteins from throughout the organism not in promotor regulated way, but in a epigenetically controlled statistically mode, the only cells that do so. This has as a consequence that these cells present on their surface each a part of the possible plethora of self peptides in the context of MHC class I molecule. T cells which react with them do recognize self and should be suppressed lifelong to avoid autoimmunity.

In a paper by Yang and colleagues from the Benoist/Mathis laboratory at Stanford it is now reported, that early regulatory T cells are additionally required to maintain the protection against autoimmune diseases. If the cells are lacking due to the absece of AIRE expression, a disease called autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy or
autoimmune polyglandular syndrome 1 is the consequence. The News and Views contribution by Tanaka and Sakaguchi explains this in detail.  This is a nice addition to the problem of tolerance and and might be an important step to development of tolerance to foreign antigens as well. That would be required to make gene therapy sustainable.

A must!

Identical twins? only genetically

antibody repertoire, B cell, immunization

The twin research has intrigued researchers since the beginning of scientific research. Are two “identical” twins really identical? Immunologists had their doubts and epigeneticists (those who study epigenome characteristics) as well. 

A paper in PNAS by Wang and colleagus from S.D.Boyd’s group at Stanford earlier this year confirms the doubts the immunologist had. They have analyzed the B lymphocyte repertoire in identical twins who had been immunized with the virus Varizella zoster. Being close and sharing sequences, the repertoires against Varizella differed, however. Recombination of light and heavy chains and somatic mutation generated a unique individual pattern, as one would have predicted. The recombination and somatic mutation events are thus, at least partially, independent of the genetic environnement where they take place and thus generate a unique individual repertoire by which the individuum could be recognized.

It is nice that finally evidence for this foreseeable result has been accumulated. Recommended!

 

Prolactin acts on stem cells – understanding circannual behaviour?

Biochemistry, Cell physiology, Circadian Clock, Endocrinology, Prolactin

Prolactin is the hormone that regulates mammary gland development in man. However, in animals it is the main functional regulator to transmit the physiological reaction to the seasons, its expression is dependent on the day length, which is measured in calendar cells close to the hypophyseal stalk, and which activate prolactin expression when the day time increases, and vice versa.

How prolactin could in turn influence different functions such as increase in mating behaviour, coat colour changes or molt, the song in birds, e.g., has been an open question. A minireview in Molecular Endocrinology by Sackmann-Sala and colleagues from the  Institut Necker in Paris, France, may shed light on this issue. They show that in humans, mice, and rats prolactin acts on stem cells in a tissue specific way. The tissues in question are reproductive tissues, but apart from that also special regions of the brain, and peripheral tissues.

If each of the functions as mediated from the progeny of individual stem cells, then a stimulating role of the pleiotropic prolactin activities is easily understood. The paper does not address this question, but it opens a new way of thinking.

For this reason, do not miss it if you are concerned with circannual regulation.