- Email: [email protected]
Crystal myth
Microbes and Infection 17 (2015) 169e172 www.elsevier.com/locate/micinf
Highlight
Crystal myth* Then the Lord God formed a man from the dust of the ground and breathed into his nostrils the breath of life, and the man became a living being. At least, so says Genesis about Adam. Apart from maybe not being exactly the noblest imaginable origin, myths and legends claiming that living beings (e.g. humans) arose from inert matter, preferentially clay, are surprisingly abundant all over the planet, abundant enough for a Wikipedia page of their own [2]. According to Ying Shao, the goddess Nu¨ Wa made rich people from yellow earth and poor ones from mud, in the Qur'an, man is made from clay and the Jewish folklore relates various appearances of golems, beings made of stone or clay. Maybe there is a certain fetich about the first bottom-up manmade tools, kneaded with clay 20,000 years ago in China, yet, there seems to be nothing more remote from “life” than a stone, or its more elegant version, a crystal. Nonetheless, both maintain close relations e countless creatures need them to build their (exo)skeletons [3] and for orientation, navigation and homing [4], others use crystals for detoxification purposes, and organic compounds tend to stick on them and tickle the immune system, as suggested by the present article of Yolanda Corbett and colleagues [1]. Pharmaceutical researchers take advantage of them for drug delivery [5], computers are complex networks of silicates, and we owe to crystals and their unique physical properties our deepest insights into the very structure of life thanks to the technique of crystallography, 2014 having been declared “The International Year of Crystallography” by the United Nations [6]. But there might be an even more intimate relationship of crystals and life. Defining the latter has given the run-around both to scientists and philosophers since ages, the same goes for the hypotheses about how on earth it appeared [7,8]. In compensation of an undisputed definition, at least some basic characteristics were described, among those, the concept of genes and the ability to make copies of oneself. Almost two decades ago, the chemist and biologist Graham Cairns-Smith outlined a credible hypothetical scenario based on these properties where the first genes on this planet are no other than … clay crystals. “Odd, Watson e very odd!” is the first line of his book, sounding rather like Sir Arthur Conan Doyle. As a matter of fact, Seven clues to the origin of life is “a scientific detective story” that exposes its deduction both in a rigurous and enthralling way. Clay crystals replicate as they grow, each
molecular layer serving as a matrix for the next one, they break, disseminate and keep growing, so much for the replicability. Moreover, they differ in shape, size and may contain defects, leading to different properties such as stickiness, allowing for a primitive form of natural selection. And finally, many crystals are quite good at clinging to organic molecules and catalyzing chemical reactions, thus enabling the takeover of the primary, mineral “genetic” information by secondary, organic molecules such as for example polysaccharides and later RNA, while things like cell membranes and cytoplasm for their part are later acquired conveniences [9]. The ideas are attractive, proving them however is another problem. In the meantime, a handful of physicists have been toying around with the life-issue [10] and the computations of one, Jeremy England, lately got some attention in the public media [11] (with a year's delay though compared to the initial scientific publication [12]). According to the physicists' point of view then, another property of a crop of carbon atoms belonging to anything alive is that they are better at extracting energy from their environment and giving it off as heat than a crop of carbon atoms belonging to anything not alive. Or, in order to act up a little bit by quoting the second law of thermodynamics e the one telling that everything tends naturally to become the most chaotic possible e living systems excel in staying halfways organized by increasing the entropy of their surroundings. Packed into a nice and complicated-looking mathematical formula, the theory more or less suggests that fueling a group of atoms long enough with an external energy source (let's say, the sun) while bathing in some medium to be disorganized (let's say, the ocean) will sooner or later make them assume a more lifetypical conformation via a process called “dissipation-driven organization”. This hypothesis, as original as speculative, points towards the emergence of life from inanimate matter not being such an unlikely event after all. “You start with a random clump of atoms, and if you shine light on it for long enough, it should not be so surprising that you get a plant”, said Mr. England allegedly. Just in case, I placed a graphite crystal under my desk lamp. Up to now, it has not made any attempts to crawl away.
* Article highlight based on “Involvement of Nod2 in the innate immune response elicited by malarial 1 pigment hemozoin” by Y. Corbett at al. [1].
Dr. Yolanda Corbett obtained her PhD on the activation of innate immune system, specifically the Toll Like Receptors, by
1. Biosketch e Dr. Yolanda Corbett
http://dx.doi.org/10.1016/j.micinf.2014.12.010 1286-4579/© 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
170
Highlight / Microbes and Infection 17 (2015) 169e172
P. falciparum at the University of Milan and the University of Massachusetts in 2006. Currently she is a research fellow in the department of public health, microbiology and virology at the University of Milan in the research unit of Donatella Taramelli. The team focuses on the identification of new antimalarials and the characterization of parasite products responsible of the induction of the inflammatory response during malaria.
with malaria hemozoin, because the mechanisms underlying NO production were still not clear. Based on literature data, we hypothesized that Nod2, IFN-g and hemozoin could be somehow related to produce NO, as shown for the bacterial component muramyl dipeptide (MDP). The hypothesis appeared to be correct and was verified by the experimental data. In a sense the results were not unexpected, but fit with the hypothesis we made. 3. How will the project go on? We are currently working on the effects that hemozoin has on this pathway. We are interested in looking at the hemozoin components (lipids, proteins, or the heme moiety) that are involved in the activation of Nod2. 4. What is the take-home message of the article? Hemozoin is immunogenic and with the present report we showed that it activates Nod2, directly or indirectly, for the production of NO. Although it seems that Nod2 has a minor involvement in the outcome of a malaria infection in the murine model this knowledge may help dissecting the multiple aspects of malaria pathogenesis and host immune response and eventually propose new pharmacological interventions where modulation of NO production is required. Do you have a personal motto, quote or leading sentence? Perseverance is one of the keys… 5. What advice would you give to the young next-generation scientists? Try always to do the best of yourself, be scientifically correct and do not give up. 6. What is your favorite hang-out method after a tough day at the lab?
2. Interview with Dr. Yolanda Corbett To go back home and stay with my family. 1. What triggered your interest in the response of Nod2 to hemozoin? Hemozoin is a parasite by-product from the catabolism of ingested hemoglobin, released into the host bloodstream after late stage parasite infection. Malaria hemozoin is considered a pathogen-associated molecular pattern (PAMP), and it has been shown to activate several pattern recognition receptors (PPRs), including the nucleotide-binding Oligomerization Domain [Nod])-like receptor (NLR) family members, to elicit immune responses. Nod2 is a member of the NLR family, involved in several infectious diseases as well as in the pathogenesis of malaria more than in the resolution of the disease. We asked ourselves how hemozoin could contribute to trigger this activity during the blood stage of the infection.
7. In your opinion, what are the three most important (scientific) discoveries of the last decade? - Adult skin cells that act like embryonic stem cells. - RNA interference, a method to block the effect of individual genes in cells. - Human genome mapping 8. If you could travel back in time e what historical personality would you like to meet and what scientific discovery to assist to?
2. What was your first reaction when you faced the results? Did you expect them?
I would like to meet Robert Koch, and assist to his simple experiment to check if the bacillus of anthrax was able to multiply by itself. He spent hours observing through the microscope and he saw that suddenly the bacillus start multiplying. This event is considered one of the most important of the history of microbiology.
It was an enjoyable feeling to discover that Nod2 was involved in the production of NO upon macrophages stimulation
9. If you could travel forth in time e what eventual invention would you like to check out?
Highlight / Microbes and Infection 17 (2015) 169e172
I would like to see the development of an effective vaccine against malaria caused by P. falciparum, and maybe to participate.
Background Hemozoin, also called “malaria pigment” is a pure crystalline form of b-hematin whose chemical formula is C68H60N8O8Fe2. Blood-feeding parasites digest host hemoglobin and release free heme, the iron atom inside a porphyrin ring, which is toxic to cells due to its pro-oxidant properties. Hemozoin formation is crucial for parasite survival, thus many treatment attempts against malaria focus on inhibiting this process.
References [1] Corbett Y, Parapini S, D'Allessandro S, Scaccabarozzi D, Rocha BC, Egan TJ, et al. Involvement of Nod2 in the innate immune response elicited by malarial pigment hemozoin. Microbes Infect 2014. http:// dx.doi.org/10.1016/j.micinf.2014.11.001. [2] http://en.wikipedia.org/wiki/Creation_of_man_from_clay. [3] Nagasawa H. The molecular mechanism of calcification in aquatic organisms. Biosci Biotechnol Biochem 2013;77(10):1991e6.
171
In A Nutshell Stimulation of interferon-g-primed murine macrophages with natural hemozoin induced a dosedependent production of nitric oxyde (NO) dependent on the inducible nitric oxyde synthase. The effect disappeared in macrophages knocked out for either NOD2 or its adaptors RIP2 or CARD9. Synthetic hemozoin elicited lower NO-production without differences between wild-type and NOD2KO macrophages. Natural hemozoin induced cytokine and chemokine production independently on the presence of NO2. / Organic parasite components present in natural hemozoin, other than the crystal, induce NO-production via the NOD2 receptor and its adaptors. / NO- and inflammatory cytokine-production due to synthetic hemozoin are NOD2-independent.
[4] Kirschvink JL, Walker MM, Diebel CE. Magnetite-based magnetoreception. Curr Opin Neurobiol 2001;11:462e7. [5] Steed JW. The role of co-crystals in pharmaceutical design. Trends Pharmacol Sci 2013;34(4):185e93. [6] Jaskolski M, Dauter Z, Wlodawer A. A brief history of macromolecular crystallography, illustrated by a family tree and its Nobel fruits. FEBS J 2014;281(18):3985e4009. [7] Morange M. Life explained. Editions Odile Jacob; 2008. [8] Schr€odinger E. What is life?. CambridgeUP; 1944.
172
Highlight / Microbes and Infection 17 (2015) 169e172
[9] Cairns-Smith AG. Seven clues to the origin of life. CambridgeUP; 1986. [10] Fujiki M. Mirror symmetry breaking of silicon polymers e from weak bosons to artificial helix. Chem Rec 2009;9:271e98. [11] http://www.businessinsider.com/groundbreaking-idea-of-lifes-origin2014-12?IR¼T. [12] England JL. Statistical physics of self-replication. J Chem Phys 2013;139(12):121923.
Sophia H€afner Univ. Paris Diderot, Sorbonne Paris Cite, UMR 7216 CNRS, Epigenetics and Cell Fate, 75013 Paris, France E-mail address: [email protected] 20 December 2014
Highlight
Crystal myth* Then the Lord God formed a man from the dust of the ground and breathed into his nostrils the breath of life, and the man became a living being. At least, so says Genesis about Adam. Apart from maybe not being exactly the noblest imaginable origin, myths and legends claiming that living beings (e.g. humans) arose from inert matter, preferentially clay, are surprisingly abundant all over the planet, abundant enough for a Wikipedia page of their own [2]. According to Ying Shao, the goddess Nu¨ Wa made rich people from yellow earth and poor ones from mud, in the Qur'an, man is made from clay and the Jewish folklore relates various appearances of golems, beings made of stone or clay. Maybe there is a certain fetich about the first bottom-up manmade tools, kneaded with clay 20,000 years ago in China, yet, there seems to be nothing more remote from “life” than a stone, or its more elegant version, a crystal. Nonetheless, both maintain close relations e countless creatures need them to build their (exo)skeletons [3] and for orientation, navigation and homing [4], others use crystals for detoxification purposes, and organic compounds tend to stick on them and tickle the immune system, as suggested by the present article of Yolanda Corbett and colleagues [1]. Pharmaceutical researchers take advantage of them for drug delivery [5], computers are complex networks of silicates, and we owe to crystals and their unique physical properties our deepest insights into the very structure of life thanks to the technique of crystallography, 2014 having been declared “The International Year of Crystallography” by the United Nations [6]. But there might be an even more intimate relationship of crystals and life. Defining the latter has given the run-around both to scientists and philosophers since ages, the same goes for the hypotheses about how on earth it appeared [7,8]. In compensation of an undisputed definition, at least some basic characteristics were described, among those, the concept of genes and the ability to make copies of oneself. Almost two decades ago, the chemist and biologist Graham Cairns-Smith outlined a credible hypothetical scenario based on these properties where the first genes on this planet are no other than … clay crystals. “Odd, Watson e very odd!” is the first line of his book, sounding rather like Sir Arthur Conan Doyle. As a matter of fact, Seven clues to the origin of life is “a scientific detective story” that exposes its deduction both in a rigurous and enthralling way. Clay crystals replicate as they grow, each
molecular layer serving as a matrix for the next one, they break, disseminate and keep growing, so much for the replicability. Moreover, they differ in shape, size and may contain defects, leading to different properties such as stickiness, allowing for a primitive form of natural selection. And finally, many crystals are quite good at clinging to organic molecules and catalyzing chemical reactions, thus enabling the takeover of the primary, mineral “genetic” information by secondary, organic molecules such as for example polysaccharides and later RNA, while things like cell membranes and cytoplasm for their part are later acquired conveniences [9]. The ideas are attractive, proving them however is another problem. In the meantime, a handful of physicists have been toying around with the life-issue [10] and the computations of one, Jeremy England, lately got some attention in the public media [11] (with a year's delay though compared to the initial scientific publication [12]). According to the physicists' point of view then, another property of a crop of carbon atoms belonging to anything alive is that they are better at extracting energy from their environment and giving it off as heat than a crop of carbon atoms belonging to anything not alive. Or, in order to act up a little bit by quoting the second law of thermodynamics e the one telling that everything tends naturally to become the most chaotic possible e living systems excel in staying halfways organized by increasing the entropy of their surroundings. Packed into a nice and complicated-looking mathematical formula, the theory more or less suggests that fueling a group of atoms long enough with an external energy source (let's say, the sun) while bathing in some medium to be disorganized (let's say, the ocean) will sooner or later make them assume a more lifetypical conformation via a process called “dissipation-driven organization”. This hypothesis, as original as speculative, points towards the emergence of life from inanimate matter not being such an unlikely event after all. “You start with a random clump of atoms, and if you shine light on it for long enough, it should not be so surprising that you get a plant”, said Mr. England allegedly. Just in case, I placed a graphite crystal under my desk lamp. Up to now, it has not made any attempts to crawl away.
* Article highlight based on “Involvement of Nod2 in the innate immune response elicited by malarial 1 pigment hemozoin” by Y. Corbett at al. [1].
Dr. Yolanda Corbett obtained her PhD on the activation of innate immune system, specifically the Toll Like Receptors, by
1. Biosketch e Dr. Yolanda Corbett
http://dx.doi.org/10.1016/j.micinf.2014.12.010 1286-4579/© 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.
170
Highlight / Microbes and Infection 17 (2015) 169e172
P. falciparum at the University of Milan and the University of Massachusetts in 2006. Currently she is a research fellow in the department of public health, microbiology and virology at the University of Milan in the research unit of Donatella Taramelli. The team focuses on the identification of new antimalarials and the characterization of parasite products responsible of the induction of the inflammatory response during malaria.
with malaria hemozoin, because the mechanisms underlying NO production were still not clear. Based on literature data, we hypothesized that Nod2, IFN-g and hemozoin could be somehow related to produce NO, as shown for the bacterial component muramyl dipeptide (MDP). The hypothesis appeared to be correct and was verified by the experimental data. In a sense the results were not unexpected, but fit with the hypothesis we made. 3. How will the project go on? We are currently working on the effects that hemozoin has on this pathway. We are interested in looking at the hemozoin components (lipids, proteins, or the heme moiety) that are involved in the activation of Nod2. 4. What is the take-home message of the article? Hemozoin is immunogenic and with the present report we showed that it activates Nod2, directly or indirectly, for the production of NO. Although it seems that Nod2 has a minor involvement in the outcome of a malaria infection in the murine model this knowledge may help dissecting the multiple aspects of malaria pathogenesis and host immune response and eventually propose new pharmacological interventions where modulation of NO production is required. Do you have a personal motto, quote or leading sentence? Perseverance is one of the keys… 5. What advice would you give to the young next-generation scientists? Try always to do the best of yourself, be scientifically correct and do not give up. 6. What is your favorite hang-out method after a tough day at the lab?
2. Interview with Dr. Yolanda Corbett To go back home and stay with my family. 1. What triggered your interest in the response of Nod2 to hemozoin? Hemozoin is a parasite by-product from the catabolism of ingested hemoglobin, released into the host bloodstream after late stage parasite infection. Malaria hemozoin is considered a pathogen-associated molecular pattern (PAMP), and it has been shown to activate several pattern recognition receptors (PPRs), including the nucleotide-binding Oligomerization Domain [Nod])-like receptor (NLR) family members, to elicit immune responses. Nod2 is a member of the NLR family, involved in several infectious diseases as well as in the pathogenesis of malaria more than in the resolution of the disease. We asked ourselves how hemozoin could contribute to trigger this activity during the blood stage of the infection.
7. In your opinion, what are the three most important (scientific) discoveries of the last decade? - Adult skin cells that act like embryonic stem cells. - RNA interference, a method to block the effect of individual genes in cells. - Human genome mapping 8. If you could travel back in time e what historical personality would you like to meet and what scientific discovery to assist to?
2. What was your first reaction when you faced the results? Did you expect them?
I would like to meet Robert Koch, and assist to his simple experiment to check if the bacillus of anthrax was able to multiply by itself. He spent hours observing through the microscope and he saw that suddenly the bacillus start multiplying. This event is considered one of the most important of the history of microbiology.
It was an enjoyable feeling to discover that Nod2 was involved in the production of NO upon macrophages stimulation
9. If you could travel forth in time e what eventual invention would you like to check out?
Highlight / Microbes and Infection 17 (2015) 169e172
I would like to see the development of an effective vaccine against malaria caused by P. falciparum, and maybe to participate.
Background Hemozoin, also called “malaria pigment” is a pure crystalline form of b-hematin whose chemical formula is C68H60N8O8Fe2. Blood-feeding parasites digest host hemoglobin and release free heme, the iron atom inside a porphyrin ring, which is toxic to cells due to its pro-oxidant properties. Hemozoin formation is crucial for parasite survival, thus many treatment attempts against malaria focus on inhibiting this process.
References [1] Corbett Y, Parapini S, D'Allessandro S, Scaccabarozzi D, Rocha BC, Egan TJ, et al. Involvement of Nod2 in the innate immune response elicited by malarial pigment hemozoin. Microbes Infect 2014. http:// dx.doi.org/10.1016/j.micinf.2014.11.001. [2] http://en.wikipedia.org/wiki/Creation_of_man_from_clay. [3] Nagasawa H. The molecular mechanism of calcification in aquatic organisms. Biosci Biotechnol Biochem 2013;77(10):1991e6.
171
In A Nutshell Stimulation of interferon-g-primed murine macrophages with natural hemozoin induced a dosedependent production of nitric oxyde (NO) dependent on the inducible nitric oxyde synthase. The effect disappeared in macrophages knocked out for either NOD2 or its adaptors RIP2 or CARD9. Synthetic hemozoin elicited lower NO-production without differences between wild-type and NOD2KO macrophages. Natural hemozoin induced cytokine and chemokine production independently on the presence of NO2. / Organic parasite components present in natural hemozoin, other than the crystal, induce NO-production via the NOD2 receptor and its adaptors. / NO- and inflammatory cytokine-production due to synthetic hemozoin are NOD2-independent.
[4] Kirschvink JL, Walker MM, Diebel CE. Magnetite-based magnetoreception. Curr Opin Neurobiol 2001;11:462e7. [5] Steed JW. The role of co-crystals in pharmaceutical design. Trends Pharmacol Sci 2013;34(4):185e93. [6] Jaskolski M, Dauter Z, Wlodawer A. A brief history of macromolecular crystallography, illustrated by a family tree and its Nobel fruits. FEBS J 2014;281(18):3985e4009. [7] Morange M. Life explained. Editions Odile Jacob; 2008. [8] Schr€odinger E. What is life?. CambridgeUP; 1944.
172
Highlight / Microbes and Infection 17 (2015) 169e172
[9] Cairns-Smith AG. Seven clues to the origin of life. CambridgeUP; 1986. [10] Fujiki M. Mirror symmetry breaking of silicon polymers e from weak bosons to artificial helix. Chem Rec 2009;9:271e98. [11] http://www.businessinsider.com/groundbreaking-idea-of-lifes-origin2014-12?IR¼T. [12] England JL. Statistical physics of self-replication. J Chem Phys 2013;139(12):121923.
Sophia H€afner Univ. Paris Diderot, Sorbonne Paris Cite, UMR 7216 CNRS, Epigenetics and Cell Fate, 75013 Paris, France E-mail address: [email protected] 20 December 2014