Archive for the 'Medicine' Category

Milk, Prions and Evolution

ResearchBlogging.orgPrion protein (PrP) is the focus of some neurodegenerative diseases. It is believed that misfolded prion protein (PrPsc, or “scrapie”) is the infectious agent responsible for bovine spongiform encephalopathy (BSE), and Creutzfeldt-Jacob disease (CJD), among others. PrPsc propagates by conversion of normal (healthy) prion protein (PrPc).

Several questions arise in the research community. Two of them are: a) can prions be transmitted from domestic animals into humans, and b) how the prion protein propagates inside a healthy subject. Food safety is a major concern. Milk and their derivatives are a subject of study, because of their wide consumption in most countries. A study [1] from Didier and coworkers shows that the normal prion protein is detected in mammary gland and milk fractions of cow, goat and sheep. PrPc protein is detected in all milk fractions (skimmed milk, acid whey, cream) in goat and sheep. Although the authors failed to detect PrPc in bovine milk, they refer to other study that successful detected the protein in bovine milk using a different approach. Some conclusions of this study are that analytical methods to detect the prion protein should be improved (hopefully, at an industrial scale), to avoid the variability between studies, specially considering the high levels of prion protein detected in cream fractions and the widespread use of cream in cooking.

Scrapie in milk?

Another conclusion is that the prion protein exist at low levels in mammary gland and milk. Even detecting PrPc in milk requires hard work (enrichment of protein concentration, for example). But someone expect that PrPsc should exist at even lower levels, specially in asymptomatic animals. Then, PrPsc can be undetected in an industrial quality control. What happens if the common assumption that infectious prion protein is not present in milk is wrong? There is evidence of infectious prion transmission via milk; Timm Konold and colleagues published evidence in lambs fed with infected and healthy milk, but using lambs from a genotype with high susceptibility to scrapie [2], observing high levels of infection. Thinking in human population, if  populations with genetic susceptibility to scrapie are identified, then health measures should be implemented in those populations to avoid the exposure to potentially contaminated milk and cream.

Once inside the cell, then what?

A few days ago, a comment in Science raised the question  “What makes a prion infectious?” [3]. The article referred to two papers published recently. One of them raises interesting questions regarding the possibility of disease development after drinking contaminated milk, for example. A research team from the Department of Infectology in the Scripps Institute, showed that prions in cell culture are able to “evolve” [4]. Prions, viewed as infectious agents, exists as strains, which are a specific conformer of the protein, and they are able to multimerize forming seeds. One hypothesis, called “protein-only”, assumes that each strain is associated with a different conformer of PrPsc, and the infectious agent is composed of a misfolded conformer exclusively (without cofactors). Many strains can exist, since many conformers are able to arise from PrPc misfolding. Experiments from the work of Li and colleagues shows that, indeed, these strains exist, and they were able to identify prions strains sensitive to swainsonine (inhibitor of the formation of N-linked glycans). In a series of experiments they showed that the strains identified in a time-lapse isolated from a cell line infected with a brain homogenate changed over time: in the first days, they identified swa-resistant strains (and competent for R33, a neuroblastoma-derived cell line), but then they identified swa-insensitive and R33-incompetent, after they transferring to PK1 cells. These and remaining experiments suggests that the prion population changed over time, and there are different strains that can “compete” if the growth conditions are advantageous to a specific strain.The authors, based in their results, conclude that prions show the hallmarks of Darwinian evolution: they are subject to mutation and to selective amplification. Obviously, these findings are relevant to Medicine, since drug discovery should consider the fact that, in disease conditions, the raise of a infectious prion can lead to mutation (more likely by binding of a prion to some cellular cofactor leading to a small variations in the misfolded structure) of some monomers, causing strain evolution, some of which can growth in the presence of some drug, replace the remaining strains and lead to resistance.

It is evident that we are far from understand the biochemical and molecular foundations of scrapie disease and mechanism, and the new evidence suggest a complex scenario, specially regarding to the deveolpment of new drugs to fight the clinical symptoms and the CJD and BSE diseases.


[1] Didier A, Gebert R, Dietrich R, Schweiger M, Gareis M, Märtlbauer E, & Amselgruber WM (2008). Cellular prion protein in mammary gland and milk fractions of domestic ruminants. Biochemical and biophysical research communications, 369 (3), 841-4 PMID: 18325321

[2] Konold T, Moore SJ, Bellworthy SJ, & Simmons HA (2008). Evidence of scrapie transmission via milk. BMC veterinary research, 4 PMID: 18397513

[3] Supattapone S (2010). Biochemistry. What makes a prion infectious? Science (New York, N.Y.), 327 (5969), 1091-2 PMID: 20185716

[4] Li J, Browning S, Mahal SP, Oelschlegel AM, & Weissmann C (2010). Darwinian evolution of prions in cell culture. Science (New York, N.Y.), 327 (5967), 869-72 PMID: 20044542

Swine Flu, Update 2: Outbreak in Chile?

I have no time these days to spent in my blog (because I’m writing my PhD research project), but I have to say something about the Swine Flu outbreak in Chile.

Last Friday, officially, Chile was free of Swine Flu cases. The Health authorities reported no cases confirmed in Chile, and all the safety measures had worked. Chile has only one International Airport, so the control of arrival is easy.

However, Saturday night, we find out about the first confirmed case. One woman, who travelled to Central America, became infected. Also, another woman who travelled with the first infected. On Sunday, we had three cases. The measures were to contact to all the passengers from the respective flight, above one hundred people. And that’s was the beginning.

The most disturbing situations was about to come. One children was reported as positive to AH1N1 virus. The case is interesting to molecular virologists and medical doctors in Chile: the children did not travelled outside Chile, neither anybody in his family. The parents told to the press that the boy did not established contact with any peopel who could be suspect of being infected. And, even more, the boy recovered in his house, without specific treatment. The press quickly renamed the boy as “Super Clemente”.

Despite the state of Clemente, several children became infected in a school in Vitacura, a well established and wealthy place in Santiago. And, in less than 72 hours, Chile has eleven cases confirmed, most of them children. Some of this children are students of the same school of Clemente. Some of them are students from schools near the Clemente’s school, and this is disturbing because the virus is infecting quickly to the population. Today, some schools are closed, and the Health authorities are expecting to have more confirmed cases in the next hours.

According to WHO (Report #34), Chile is the country in the 11th place in number of cases confirmed, following USA (5815), Mexico (3648), Canada (496), Japan (261), Spain (111), UK (102), Panama (71), France (16), Germany (14) and Colombia (13). However, Chile achieved these 11 cases in just 72 hours. Santiago is one of the cities with the highest pollution in the world, and every winter we have thousands of people infected with seasonal viruses and several deaths. That makes the Chilean scenario more dangerous that we think.

Note added on proof: just a few hours after I published the previous post, the number of positive cases in Chile increased from 11 (at 09:00 am) to 24 (published at 20:00).

Swine Flu, Update

First of all, thanks to the team and people of Nature Blogs for accept my blog in their list!

Second… Being a Grad Student, usually I have little time to dedicate to post something really interesting and good-quality content. Today, it’s one of these days (the workbench took all of my day… and now I am getting ready to sleep). But I wanted to recommend these links about the Swine Flu on Nature and Science.

First, an interview from ScienceInsider with Ruben Donis, chief of the molecular virology and vaccines branch at the CDC. I tried to investigate about the genetics of the virus, but it seems that I have to wait to see a paper in a Journal. Anyway, Donis talks in the interview about some interesting features of the virus, and about the history of the Swine Flu. Also check the special from Science here.

Second, the special from Nature is also interesting. By the way… this blogger lives in Chile. Sometimes, here we hear things like “we are so far from everything… we are isolated and safe”. But in the news I watched about the first confirmed case in Peru, next to us. Chile has been very efficient so far in the preparation for the disease and the checking of the tourists and travellers in the International Airport. By now, there are about 42 cases in our country; 16 of them have been ruled out; 26 are being studied, and several of them are people who travelled to Mexico or USA. I guess the meetings and courses around there will suffer by now.

About Stem Cells and the Holy Grail

A recent news article in Nature caught me into deep thoughts. The article reviewed some of the main developments in the field of induced Pluripotent Stem (iPS) cells. The formula seems simple: I have my “whatever” cell, and by introduction of a cocktail of genes, eventually I will find out that three or four genes are able to reprogramming the cell.

However, it seems that not every tale about iPS cells is so simple. Several issues are of the concern of scientists and medical doctors. For example, the efficiency of the production of the iPS cells, and the purity. Also, whether this cells will induce the formation of teratomas or tumours. I strongly recommend the News Article by Monya Baker in Nature [1] to read about the subject.

I share some of the enthusiasm about iPS cells. Working with primary cultures of stem cells is hard, slow and sometimes disappointing. For example, working with bone marrow derived stem cells is a slow process; from obtaining the sample until reaching a fourth passage, can take even four months, when cells are isolated from older donors (I worked with this model four years; I know what I’m talking about). If we can use these cells for the treatment of a disease, months can be lethal for the patient. Even so, cells are progressively loosing their “stemness”. iPS cells seems to circumvent some issues regarding efficiency. However, the artificial induction of a stemness state is a subject of relatively little study; by now, the focus of the scientists has been the improving of the methods for the development of the iPS cells, without worry about the mechanisms [1]. Then, the next step should be the further knowledge of mechanisms. In this scenario, Systems Biology should take an important place. We need to gain insight about what genes, what metabolic pathways, what proteins, what non-coding RNAs, what micro-RNAs, are being induced, are working, are being repressed.

From Bruneau Lab

From Bruneau Lab

Maybe a fresh approach is provided by the work by Takeuchi and Bruneau published online in Nature [2]. The authors showed that mouse mesoderm cells can be transdifferentiated into cardiac myocytes by the introduction of three genes: Gata4, Tbx5 (two cardiac transcription factors) and Baf60c (a cardiac-specific subunit of the BAF chromatin-remodelling complex). The novelty resides in that the authors further handle their work providing data about the mechanisms (something which is lacking in several other works): they show that Gata4 binds Tnnt2 and Nppa (cardiac genes) only in the presence of Baf60c, using chromatin immunoprecipitation. They even provide a model and a “minimal” regulatory gene network. This work can be considered a step forward in the way researchers are studying reprogramming. It is not a matter of just “we will insert these genes and quantify how fast the cells are induced to pluripotency”, but also the “how”. And it seems very reasonable thinking about the possible effect of the genes being introduced.


[1] News Feature Article:

Fast and Furious. M. Baker. Nature, 2009, Vol 458, pp. 962-965

[2] Takeuchi, J.K. and Bruneau B.G.

Directed transdifferentiation of mouse mesoderm to heart tissue by defined factors.

Nature, 2009, doi:10.1038/nature08039

[3] Bruneau’s Lab Page (including videos):

Swine Flu, reloaded

I found some interesting information about the Swine Flu outbreak in Science Insider [1,2]. Two topics are really disturbing: one of them is related with a previous outbreak in 1976. It seems that a swine flu strain swept from a military base in New Jersey, and several soldiers were infected. But only one soldier died. You can read more about this story in [2].
The second topic is very perturbing. The news from ScienceInsider claims that in USA, none of the suspected diseased people have died; all of them had a mild disease. However, in Mexico, 80 deaths are attributed to the virus. One should ask: Why? If these numbers are correct, why in one country, there are no deaths from a virus, but in the next country, there are so many? In this case, one can propose that economical factors are influencing in the outcome of the treatment. But, there is such a difference between USA and Mexico? I could accept a difference maybe between England and Bolivia, for example.
Maybe another explanation can be even more deep. Ona explanation regarding something even more powerful than economics: Single Nucleotide Polymorphisms (SNPs). There is no scientific fact to assume that two populations will have the same genetical background. And, indeed, some mutations are more prevalent in specific genes in specific populations. I have some knowledge about one specific gene: ATP7B. Mutations in this gene is related with the Wilson Disease, and more than 250 mutations have been reported. Strikingly, mutations are “country-specific”. Even between neighbor countries, the differences are surprising. A database with more than 300 mutations has been implemented. And this is only one example.
Being hard with this idea, I can imagine that the influence of genetic variations in the response to pathogens and drugs, for example, will be important when someone is analyzing two populations. And then, we have Genome-Wide association studies: the only available tool that we can use in a quick way to asses two population’s response to an infectious disease, in this case. Are we ready to develop and implement fast and global responses to global threats such as Swine Flu? Of note, a recent news in Science talks about a debate regarding the real value of genome-wide association studies, where some scientists are saying that these studies are not bringing valuable clinical information about diseases, and the trend seems to be the support to full-genome sequencing in patients. That approach could be very useful in the study of diseases such as cancer. But, when we are dealing with global outbreaks, as Swine Flu now, we need to handle all the information available. Including the properties in our genome that can influence the response of a country, or even the entire human kind, to a inminent threat.

References and links:

[3] Koenig, R. Science, 2009, April 24, Vol. 324, page 448.

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