Recently, I have been working on an essay for my last year in college.  I titled it: “Parkinsonism: Disease and Treatment”, scary enough? NO!!??  I turned it in, anyway. In it, I identified the neurodegenerative disease that targets the basal ganglia and deprives it of the inhibitory neurotransmitter (NT), dopamine. No dopamine means no balance between the excitatory action of the NT, Acetylcholine, and the inhibitory action of dopamine, leading to the well-known clinical picture of parkinsonism that Jankovic (2007) gave the acronym TRAP: Tremor at rest, Rigidity, Akinesia/bradykinesia and Postural instability.

Parkinsonism can be classified into:

1. Primary/idiopathic “of unknown cause” which is mostly due to degeneration of dopaminergic neurons (a.k.a Parkinson’s disease)
2. Secondary to viral infection as encephalitis & meningitis; drug-induced, e.g., antipsychotics; or due to brain damage caused by trauma, anesthetics,  or toxins as MPTP (a contaminant of street-drugs).

You may know that the Nobel Prize associated with Parkinson’s disease didn’t go to Dr. James Parkinson who described it in an essay he wrote back in 1817 calling it “The Shaking Palsy”.  It went jointly to Arvid Carlsson, Paul Greengard, and Eric R. Kandel in 2000 (To find out more about the story, here’s the Nobel lecture by Dr. Carlsson). Carlsson and colleagues discovered dopamine as a potential NT in 1957. After that, in 1960, Hornykiewicz and his postdoctoral fellow, then, Ehringer observed the decrease of dopamine levels in Parkinson’s disease patients, and levodopa successful trials started after that, in 1961.

What does Dr. Warren, the scientist whose discoveries led to a paradigm shift in physiology, who said out loud that peptic ulcer is an infectious disease caused by Helicobacter pylori, the gut bacteria? What does he have to do with parkinsonism? Note that: J. Robin Warren and Barry J. Marshall also won Nobel prize in medicine for 2005 for their discovery.

Helicobacter-induced parkinsonism!!

What I am trying to say here—and didn’t say in my essay—is that there is a hypothesis, Helicobacter-hypothesis, that strongly provides another cause of idiopathic parkinsonism, which will not be idiopathic any more, and this cause is H. pylori (Altschuler, 1996). Or to be more accurate, I will say parkinsonism associated with H. pylori. Dobbs and colleagues have carried out well-controlled studies and observed a significant conversion in patients with Parkinson’s disease from malignant into benign parkinsonism after successful eradication of their H. pylori, even with no levodopa administration. The rationale behind this theory is that: H. pylori induces an autoimmune reaction against mitochondria, then a systemic inflammatory response with the whole gang of inflammatory mediators and antibodies reaching and crossing the deficient areas or areas with increased permeability of the blood-brain barrier, causing parkinsonism. And the blood profile can prove the Helicobacter-hypothesis.

Tags: Arvid Carlsson, blood profile, essay, Helicobacter pylori, Helicobacter-hypothesis, idiopathic, J. Robin Warren, James Parkinson, levodopa, Nobel Prize, Parkinson's disease, parkinsonism, shaking palsy, systemic inflammatory response, TRAP

I had the chance to attend the international conference BioVision Alexandria 2010 held at the Bibliotheca Alexandrina Conference Center in Alexandria, Egypt, from 12-15 April 2010. I really want to share with you the >50 talks that I attended, given by Nobel laureates and other remarkable scientists specialized in health-related topics.

I will start with this talk by Dr. Richard Roberts, who received the Nobel Prize in Physiology or Medicine in 1993 for the discovery of split genes and mRNA splicing in 1977. He is now joint Research Director at New England Biolabs. Dr. Roberts entitled his talk: “Collaborating to bridge the gap between computation and experimentation”. I will try to sum it up for you.

I. Let’s start with stating this fact that Genomics is rapidly taking over the field of biology, at the research level at least.

Examples:

1. Sequencing of the human genome or “The Human Genome Project” provides the basis of the emerging field “personalized medicine”.
2. Plant genomics are unbelievably important for food and –maybe- for energy production purposes, unicellular plants mostly.
3. Ocean organisms are very interesting, as they produce potential new antibiotics and many other useful substances.
4. Bacteria and archaea are making up to 50% of the living biomass.

Bacteria are everywhere, they live in the oceans, the soil -plants require them for nitrogen fixation- animals and us; our gut, skin, nose and mouth. Most of these bacteria we know absolutely nothing about because we can’t grow them on cultures.

But this is about to change now thanks to DNA sequencing.

II. So, the core of today’s science is DNA sequencing… but unfortunately, DNA sequencing has its drawbacks.

1) DNA sequencing is getting faster and cheaper in a rate that is exceeding our ability to understand the function or the biochemical pathways of every single gene sequenced. Or, if we’re really lucky, we can make a guess –based on sequence similarity– that this gene, for example, encodes for a “hydrolase”, but just a hydrolase with no clue about the exact biochemical pathways it’s involved in or its substrate.

Dr. Roberts gave this interesting simile that getting more and more DNA sequences of bacteria is like getting a car with a list of all its parts with no idea about how they fit together or how they work. Biology is about understanding how life works. If we’re talking about synthesizing life today, we have to understand how life works first. He dreams that before he dies, he can understand how a very simple bacterium actually works, what is the chemistry that is going on there?

So, the first problem is in the very rapid growth in DNA sequencing without a similar growth in annotation/renaming/finding the function. Here’s a quite older graph showing the growth of sequence databases and annotations from 1982 till 2006, close to the one Dr. Roberts presented, from 1995 till 2009. If you can get to a newer one, please do not hesitate to comment on the post and add its link.

2) The computer is not enough! Do the biochemistry in the lab! In spite of the large amount of money spent on sequencing different organisms; we still are not making any progress in understanding them. This might be that when we get the DNA sequence, translate it into its corresponding amino acid sequence, our best shot then is to compare it to the existing protein sequences in the databases to know how it looks like what and thus predict its function. If two protein sequences look the same, there’s a chance, not a guarantee, that they have the same function, because if there’s a one amino acid difference, they may have different substrates and thus different functions. How to tell? The computer is not enough! Do the biochemistry in the lab! This will lead us to the third problem.

3) All substrates are not available to all labs all the time. So, one lab can’t determine the function of all genes on earth. He gave this example: if you want to assay a specific disaccharide hydrolase; to determine its substrate, you need to have disaccharide combinations of all possible sugars and test it on them.

4) Lack of good funding for biochemistry. Funding agencies think that biochem- is an “old-fashioned” field! They are funding the more appealing genome-wide studies, which is very superficial.

III. Dr. Roberts’ suggestions for a solution: “COMBREX”
Identifying Protein Function—A Call for Community Action.

Dr. Roberts and colleagues have got an NIH fund in October 2009 to establish COMBREX (maybe: COMputational Biology Reading EXperiments). The work flow will be very much like this:

Step1: Establishment of a database. From 1200 complete bacterial and archaeal genome sequences, computational biologists groups generate protein families/domains of unknown function (DUFs), predict the function based on sequence similarity and establish a database.

Step2: Coordination of the efforts between biochemistry labs, experimentalists/biochemists (young grads, even technicians) offer a proposal to test those predictions, gain an exclusive access to those genes of interest for 6 months + a small grant (5,000-10,000 USD) to carry out single gene studies. If we know one protein’s function, we know the function of the whole protein family.

Step3: Making of a Wikipedia-type page for suggestions and predictions.

Step4: Establishment of a journal to publish the findings.

IV. What genes should we focus on/start with?

Dr. Roberts suggested this list, which is ordered in a descending order:

1) Genes abundant in many many different organisms; in humans, animals, bacteria… etc. Those are likely to have conserved important functions.

2) E. coli, the most widely used and so-called “the best studied” organism, we can make a full characterization of it.

3) Helicobacter pylori, to understand the biochemistry of such an important pathogen that we know nothing about.

4) Identify cloned, translated and frozen open reading frames (ORFs) products.

V. Who can help?

Dr. Roberts said almost everybody, computational biologists to predict, biochemists to test, geneticists, as personnel university students -even high school students it can help them to get a genuine science project-, retired professors to supervise and maybe get back to the lab, and funding agencies.

You can watch this talk and most of the conference’s talks via the Bibliotheca Alexandrina webcast.

Tags: annotation, Bibliotheca Alexandrina, biochemistry, BioVision Alexandria 2010, COMBREX, database, DNA sequencing, domains of unknown function, drawbacks, DUFs, E. coli, Helicobacter pylori, human genome project, New England Biolabs, Nobel laureates, open reading frames, ORFs, Richard Roberts, sequence similarity, synthetic life

Meeting a scientist is like reading many books in few minutes, books of science and books of life. To me, though, meeting Dr. Niyaz Ahmed ⁽¹⁾ was like reading a library. He is one of the most active advocates for Open Access (OA) and open evaluation of science. His support for OA is not just by words, but through sharing effectively in such purpose as he is a section editor of Microbiology and Genomics in PLoS ONE and a chief editor in Gut pathogen, the official journal of ISOGEM (the International Society for Genomic and Evolutionary Microbiology), in Sassari, Italy, of which Dr. Ahmed is a co-founder and the General Secretary. ISOGEM members work on developing post-genomic ideas to serve the public health and the environment. Dr. Ahmed is one of the faculty members of Faculty of 1000 Biology, the expert guide to the most important advances in biology.

Dr. N. Ahmed’s early start was in India as he graduated in Veterinary Medicine and obtained his Masters degree in Animal Biotechnology, then his PhD in Molecular Medicine. Currently, he is also based in India, in Hyderabad University as an Associate Professor of Biotechnology and a staff scientist in the Center of DNA Fingerprinting and Diagnostics in Hyderabad. This is not everything about him, his homepage reveals more, especially those pioneer achievements in the research world in India, like being a co-principal investigator of the Mycobacterium W genome program, India’s first whole genome sequencing project, and the most amazing part of his research is working on Helicobacter pylori chronological evolution and phylogeographic analysis.

Having read about all these achievements, I had many questions in mind, but, knowing how busy he is,  I tried to reduce them to the following few questions that cover different areas of his activities.  Dr. Ahmed generously agreed to answer them all.

Dr. Niyaz Ahmed, any microbiologist would be honored to meet you, and so am I. I am one of the “Micro Writers” blog members; we are young enthusiastic students from Faculty of Pharmacy, Cairo University in Egypt, mostly undergraduate and some graduate students, who are looking from the blog window towards the research world. Most of us wished someday to become scientists; “Micro Writers” is like the first real step on the right way. Our blog focuses on different areas of microbiology. It is like a message by students so far from Egypt, but hopefully from other places as well, to students all over the world. I read a lot about your achievements, especially those concerning the H. pylori phylogeographic analysis. As you have a great experience in research, reviewing articles and especially because you own a blog, I would like to ask you a few questions, and get them published with your answers on the blog, in order to teach and guide not only us, but the all students from everywhere.

• N.A.: I am very much enthused by your offer and would like to be interviewed at Micro-Writers blog. Please let me know your questions and I would try to answer them all.

Since you are working on the population structure of H. pylori, and on their chronological evolution, can the phylogeographic analysis of bacterial strains lead to infection control or innovative treatment? If yes, how?

• N.A: It may not directly lead to product development as such, but, it can definitely explain how the spread-patterns of this organism are? and that has a lot of bearing on infection control in terms of tracking the infection sources. Also, knowing separate lineages in greater details offers accurate diagnostic development which in turn helps keep a tab on their emergence or otherwise.

If phylogeographic analysis can teach us about migration of some strains from one place to another, can we use it in a reverse way? I mean can we use this analysis to learn about the origin of mankind, and his migration routes?

• N.A.: Indeed, we can do that. For a bacterial parasite to become a surrogate marker of human history (including migrations), it needs that its population structure mimics with that of the host. It is now established that H. pylori has most probably coevolved with its human host and thus its population structure is juxtapose to the human population structure. Therefore, we can use it as a marker of human history and geography.

Concerning the unpublished ideas of your studies, which suggest that bacterial proteins may be able to perform both the immune stimulatory and immune evasion tasks, the simple question is, do you think bacteria are smart? Do they have that smart controlling machinery that is able to distinguish between all these factors?

• N.A.: The term ‘smart’ is reserved for humans. However, we can say that bacteria are highly adaptable. Several bacterial traits such as quorum sensing, community interactions (such as that seen in biofilm formation), molecular mimicry, immune evasion, dormancy etc. definitely point towards their being ‘intelligent’.

You talked about the host-pathogen relationship. I would like to add one more suggestion, which is that bacteria may face the immune system or the host body as a community of workers, not as independent cells. It is like the idea of sociomicrobiology in biofilms. Does this social behavior apply to other communities of bacteria other than bioflims, e.g. the community of H. pylori cells against the human defense system in the stomach?

• N.A.: Indeed there is a body of evidence coming in via both in vitro and in vivo observations that H. pylori cells tend to form biofilms which is favored by gastric mucin and by mutations of luxS, and the cagE type IV secretion gene. This observation is important to understand H. pylori’s resistance to host immune responses and antibiotics, and in microenvironmental pH homeostasis which conditions and streamlines the growth and survival of H. pylori in vivo.

You mentioned at your homepage that strains of H. pylori in the Southern Asia are not life-threatening in the same time they may cause gastric cancer in the West. Do you think the lifestyle in Southern Asia, especially the food (extra-spicy food), might lead to evolution of these non-lethal strains, and vice versa in case of the western lifestyle?

• N.A.: It is observed that high incidence of H. pylori in India (nearly 98%) does not positively correlate with the rates of invasive outcomes and life-threatening consequences of the infection (cancer). It is possible that the food that is eaten here (rich is herbs and vegetables) has some protective advantage in terms of governing the micro-environmental conditions at the niches colonized by H. pylori. Another aspect is genetic susceptibility or resistance to gastric cancer which is to be considered as well.

Adoption of open access (OA) in science, isn’t it a huge responsibility, with great challenges, most probably the funding challenge? I mean, who will pay always for open access science?

• N.A.: Open Access is a reality and the most practical approach to augment knowledge sharing towards science education, research and the practice of medicine and agriculture. Developing countries that have brains but no library budgets and that have been until now deprived of access to knowledge will be at a great benefit with this OA revolution. I do not see any challenge here as funding agencies such as NIH, Howard-Hughes Institute and Welcome Trust have already started subsidizing costs for OA in a big headway.

You started in India; did you feel some bias (in the international journal publishing) towards some western countries (e.g., USA, Germany, France, UK, etc.)? Do you think that the researchers from the developing countries should be encouraged in a way or another, especially against the fees and restrictions of publishing?

• N.A.: I firmly believe that originality and novelty have no barriers. If your ideas are novel and your findings well defended, no one can stop them from seeing light of the day. Developing country scientists are equally respected – I can cite my own example, I was made Section Editor at PLoS ONE to oversee an extremely important area, microbial genomics; for this appointment, my affiliation and my geographical co-ordinates were not the important criteria but my standing in the field of medical microbiology, the efficiency with which I handled the issues and my professional commitment to the cause and ethos of OA publishing. However, there may be exceptions of which I have no idea. Nevertheless, this is a free world and if one has zeal and dedication, success is not that far. These days, publication restrictions based on novelty or being on ‘cutting edge’ or otherwise, are no issues. Developing country scientists are thus free to bring forward their research even on topics which may not be interesting to a few ‘glamour magazines’ of science, but they are welcome at descent venues such as PLoS ONE; they are free to even send in aspects of their folklore medicine, their local environmental problems, cropping, local biodiversity, energy production, their cultural and human anthropological aspects (and topics cutting across these) wherein no one is their competitor! Fees for publication is not a problem, PLoS and Biomed Central both waive off publication charges quite generously in almost all cases of genuine inability to pay.

In an old interview, you said that blogs are a good chance for young scientists to express their ideas for free, what about the older scientists in the developing countries who need more space to express their research activities, in the same time so many restrictions are imposed on them to get their papers published in the international journals?

• N.A.: Old, and young, all need to be part of the dialogue. Even for busy academics, blogs are extremely helpful although they are no alternative to a proper publication of results or viewpoints. Blogs can effectively blend zeal and enthusiasm of ‘young Turks’ with the experience and patient advice of the ‘old guards’. Academic institutions in the developing countries should support such portals wherein students and faculty discuss research to arrive on novel interpretations and provocative ideas in an interdisciplinary environment of learning and enabling.

As an editor and reviewer in so many journals, what is your advice to some young Egyptian researchers like us in the “Micro Writers” blog who work with the fewest capabilities and with minimal resources, to get our papers published in an easier way?

• N.A.: I love the Micro Writers Blog. You are the torch-bearers for all other undergraduate students in our countries of the developing world. My advice is try hard to deliver your best. Do not write on complaints – write about solutions! Do not present as Egyptian, or African, think globally, be a part of global community in the best interests of humanity, the environment and wellbeing of all creatures. I can quote from the Holy Qur’an: “Wallatheena Jaahadu Feena Lanahdiyannahum subulana” (The more you dedicate yourself and strive hard, the more will be the opportunities and paths widened for you from the Almighty). (2)

 

Finally, I would like to thank you Dr. Niyaz for the time you gifted for us to answer my questions with plentiful ideas, objects, and words. I am quite sure, each one who reads this interview will get benefited more than once.

Dr Niyaz Ahmed (left) co-ordinating a ‘student-scientist-administration’ meeting with Nobel Laureate Prof. Peter C. Doherty (center) and Australian High Commissioner to India, Mr John McCarthy (right).

 

———

(1): Dr Niyaz Ahmed, PhD

General Secretary,  ISOGEM
Section Editor, PLoS ONE
Chief Editor, Gut Pathogens
Assoc. Editor, Ann Clin Microb Antimicrobials
Assoc. Editor, Acta Veterinaria Scandinavica
Faculty Member, Faculty of 1000 Biology
Corres. Fellow, Eur Helicobacter Study Group

 

(2): EL-Qur’an El-Karim, chapter #29 (El-Ankaboot), verse #69.

Image credits: Dr. Niyaz Ahmed.

 

Tags: Academic institutions in the developing countries, bacterial dormancy, biofilm, Biomed Central, cagE type IV secretion gene, chronological evolution, developing countries, Egyptian researchers, Faculty of 1000 biology, gastric cancer, gastric mucin, Gut pathogen, Helicobacter pylori, host-pathogen relationship, Howard-Hughes Institute, Hyderabad University, immune evasion, ISOGEM, luxS, microenvironmental pH homeostasis, NIH, Niyaz Ahmed, open access, phylogeographic analysis, PLoS ONE, quorum sensing, smart bacteria, the Center of DNA Fingerprinting and Diagnostics, Wellcome trust