If I expect change, it must start with me.
I favor sharing and working together to benefit society and humanity (see Scientist).
After a decade of hard work and personal sacrifices, I wrapped my works into packages and e-mailed them to the Toxoplasma international research community (Figure 1).
I hope the works done will be used to find cures.
If I expect change, it must start with me. The email sent out is shown.
Figure 1. The packages of the two-pronged strategy and personal plea were emailed to an international network of research groups who have published works on Toxoplasma.
Subject: Toxoplasma: Protein structure-functions and potential correlations with Brain Cancer, Epilepsy, Huntington’s and Alzheimer’s Diseases
Date: August 2, 2017
From: Huân M. Ngô, Ph.D.
Dear Colleague,
This communication provides the Toxoplasma research community a summary and opportunities from a research initiative.
1. The Questions.
I asked three basic questions. (1) What is the human brain gene network likely activated by the brain parasite Toxoplasma? (2) What are the neurological diseases correlated with brain parasitism? (3) What do we do about it?
2. The Progress.
A summary is described (now converted to Brain Parasite Toxoplasma page).
I answered Question 1 and 2 using a new paradigm. The ‘Gene-Environment’ paradigm changes to include a third component of ‘Development’.
I constructed the ‘Reconstruction-Deconvolution’ Model to get the complex answers. Our template points to the potential modulation of human brain pathways correlating to Brain Cancer, Epilepsy, Huntington’s and Alzheimer’s Diseases.
For Question 3, we focus on the structure-based approach for discovery of drugs against the brain stage of parasites. We develop a protein structural platform for the Toxoplasma community. Our effort produced 12 crystallographic structures of Toxoplasma enzymes (Drug Discovery page). We hope it helps with functional studies and to develop drugs against Toxoplasma brain parasitism.
We examined the structure-function of two multifunctional enzymes (Enolase 1, GAPDH1) and a non-metabolic role of a pseudoenzyme (TgDPA). Enolase 1 and TgDPA are specific bradyzoite proteins.
GAPDH1 publication is one of the most complete protein structure-function studies to date. We used the molecular and biochemical repertoire (Dubey et al 2017).
3. Opportunities for Structure-Function Studies.
All 12 protein structures are open to the research community. We invite colleagues to use them to pursue (a) structure-functions and essentiality, and (b) compound screening for drug leads. See Doc 2 (Drug Discovery page) for additional details.
As far as we know, our collaborators for the 3 published structural studies have no further plans for these enzymes, but please check with them to avoid any conflicts. They are: (1) Bradyzoite pseudoaldolase (Dr. Martin Boulanger, U. of Victoria), (2) Enolase 1 (Dr. Stan Tomavo, U. de Lille), (3) GAPDH1 (Dr. Marc-Jan Gubbels, Boston College).
Only ornithine aminotransferase (PDB accession 5UPR) is being pursued further by Dr. Richard Silverman (Northwestern U.) with ligand studies and by Dr. Rima McLeod with cat stage studies. We encourage other researchers to pursue its structure-function with other biological experiments.
Please contact Dr. Wayne Anderson (CSGID) for information about clones and limited purified proteins. Dr. Anderson will retire August 31 of 2017. You can then contact the new Co-Director, Dr. Karla Satchell (k-satchell@northwestern.edu)
4. Opportunities for Neurological Disease Studies.
The proposed correlation between Toxoplasma brain parasitism and noted neurological diseases is a hypothesis that will require rigorous testing & critique from the research community (see Brain Parasite Toxoplasma page).
If proven true, the brain gene networks provide a starting point for further validation and therapeutic approaches.
I completed the Reconstruction-Deconvolution analysis in July of 2015. The manuscript has been entangled further in a web of politics. I hope it will be published soon in whatever form it takes.
I’m interested in advancing the community's evaluation of this hypothesis. We should advance finding cures for these devastating neurological diseases. As a colleague, you can request directly a copy of my last revision of this manuscript. You can judge for yourself the hypothesis and data.
5. The future
We have enjoyed over 4 decades of developing basic research of Toxoplasma as an interesting cellular, molecular and immunological model. Only within the last decade have we started to examine its neurobiological, endocrinological, and psychiatric bases.
I welcome the influx of researchers from outside of our classical parasitology training. I am encouraged by the increasing efforts from Asia, Middle East and South America to develop diagnostics, vaccines and drugs, which have been lackluster in North America and Europe.
I plead passionately to my colleagues that we need to re-shift our focus to finding cures for Toxoplasma brain parasitism and correlating brain diseases. Please think of our research as more than ‘it’s such an interesting organism to study’.
If proven true, we have the moral obligation to find drugs and vaccines for people suffering from Brain Cancer, Epilepsy, Alzheimer’s, Huntington’s Disease (and Schizophrenia).
Addendum. The Credentials
Since I don't follow the normal professional route and an unknown name to most people, I’m obliged to highlight several key contributions in parasitology. A CV will be attached.
* As a graduate student, I propose and wrote with my PhD advisor the novel synthesis of the membrane cytoskeletal motif in protozoans. We expanded his discovery of the articulins in Euglena to other free-living and parasitic relatives. It provided the base for the discovery of structural proteins in the Apicomplexan cortical skeleton, such as the IMCs.
Bouck and Ngô, 1996, Int. Rev. Cytology 169: 267-318.
* As a postdoc at Yale, I synthesized the convergence of endocytic and secretory pathways in rhoptry biogenesis.
Ngô et al., 2004, Molecular Microbiol 52:1531-41.
* In a serendipitous collaboration with a neighboring lab at Yale, Dr. Elisabetta Ullu and I discovered RNA interference in African trypanosome.
Ngô et al., 1998, PNAS 95: 14687-14692.
After my postdoc, I left research to build a model science education program for our inner-city kids in New Haven, Connecticut.
The brain parasitism work mentioned above is from the last decade from which I learned new disciplines of neuroscience, structural and systems biology.
To bring this research initiative to this point, I worked out of my home in New Haven, USA. I depleted my own retirement fund to learn and work independently. Due to my cavalier attitude to my professional development, I cannot continue the normal research route.
I hope you can find your own resources to collaborate in pursuing these studies, such as a structural biology collaborator. If not, I would consider servicing as a consultant, but I emphasize that it’s NOT required. The projects are open to the community.
I hope this body of works provides a solid foundation for others to continue our common mission of finding cures for over 2 billions humans infected with brain parasitism.
Best regards,
Huân