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Pier Luigi Luisi: Origin of Life Mindstorms Needed

Pier Luigi Luisi: Origin of Life Mindstorms Needed

By Suzan Mazur
December 19, 2012


"Of dreams we live" -- Pier Luigi Luisi

The work of Pier Luigi Luisi continues in the best tradition of Italian visionaries of science and the humanities, Alberti, da Vinci, Galileo, Michelangelo. Luisi is currently chair of biochemistry at the University of Roma Tre and director of the Luisi lab, which focuses on Origin of Life, cell models and the self-organization and self-reproduction of chemical and biological systems. He has been particularly masterful at organizing scientific conferences in Europe -- 20 of them in the last 10 years -- with a cross-cultural approach to Origin of Life as well as other aspects of science and philosophy. He is known for his annual Cortona Week, which he describes as "a living organism" integrating science and the humanities and featuring a "gallery of original, often fantastic and occasionally odd, strange speakers." Luisi's aim has been to use Cortona Week to showcase future world class leaders who are "internally richer."

Pier Luigi Luisi is author of 10 books, among them: The Emergence of Life: From Chemical Origins to Synthetic Biology; Mind and Life; Giant Vesicles (P.L. Luisi, P. Walde (eds.)); Chemical Synthetic Biology (P.L. Luisi, C. Chiarabelli (eds.)); and with Pasquale Stano, The Minimal Cell (P.L. Luisi, P. Stano (eds.)). Luisi is also the author of 500 scientific papers.

His PhD is in chemistry, summa cum laude, from the University of Pisa. Pier Luigi Luisi did postdoctoral work at the University of St. Petersburg in the former Soviet Union and continued his research at the University of Uppsala, the Macromolecular Center Strasbourg, and was Research Fellow at the Institute of Molecular Biology in Eugene, Oregon. He was Extraordinarius of Macromolecular Chemistry at ETH-Zurich, founded the Swiss Colloid Group, and co-founded (with P. Pino and J. Meissner) the Institute of Polymers at ETH-Zurich, where he served three times as Chair.

My interview with Pier Luigi Luisi follows.

Suzan Mazur: You co-organized the San Sebastian Origin of Life conference in 2009. What are some of the significant developments since then? Is the Origin of Life field now "exploding"?

Pier Luigi Luisi: The main point about Origin of Life is we cannot yet conceive how that happened. We have a picture by which from inanimate through a series of increases of structure, complexity, functionality, slowly we arrive at the first cell or protocellular structure capable of reproduction, making copies of themselves. But in terms of concepts -- in terms of the big question: How did life arise on our Earth? -- I haven't seen in the last few years, or in many years, any progress. Some technical progress, maybe, doing better than before.

Suzan Mazur: Is the problem not enough funding to do the research?

Pier Luigi Luisi: No, no, no, it is not. The problem is, I would say, in the mind, in the capability, although funding is always a consideration. If I had $1 million, I would gladly give this money to somebody with a clear notion of how the passage from nonlife to life arose.

For example, the most popular view of Origin of Life, by way of the RNA world, to me and to many others is and always has been a fantasy. This is the theory by which self-replicating RNA arose by itself. Self-replicating also means Darwinian evolution. This, according to the story, produces ribozymes, nucleic acid also capable of catalysis. Ribozymes capable of catalyzing the synthesis of DNA and protein. How did self-replicating RNA arise? And, even granted that, how do we go from this to our DNA/protein cells? It is all in the air, still.

This is the story told to students and to me and is something without any scientific ground.

Suzan Mazur: It's remarkable to hear you say that.

Pier Luigi Luisi: Yes I know, and sometimes people think I'm a little too negative and pessimistic, but I co-organized this meeting on Open Questions about the Origins of Life in Spain. I organized already three of them. I haven't seen any conceptual progress. I insist on the term "conceptual."

Suzan Mazur: Are you currently coordinating a European COST action for another Origin of Life conference?

Pier Luigi Luisi: Well, we are always planning more conferences of this type. The meetings do not cost much. We can do it with $30,000. A researcher I contacted is trying to find this money for another one. We think it is useful to focus on what we do not yet understand, and ask why. And as I say, it is not the technical side that is the main problem. It is not the money problem either. We still need some basic conceptual breakthrough.

One missing chapter from the story is how the first enzymes or the first nucleic acids came about in many identical copies. Because if you want to do some chemistry, prebiotic or not, you cannot do it with one single molecule. You need concentrations.

Take self-replicating RNA. You cannot make self-replication with one single molecule. You need enough material to build an active binary complex so that one molecule can replicate. So you need at least a phantomole concentration. But even 10 minus 12 molar means, avogadro's number being 10 to the power of 23, several million of identical or quasi-identical molecules in one microliter.

You would then need a mechanism to make this self-replicating RNA to start the whole story, and I believe there is no conceivable way yet how this can be done.

Until somebody actually finds a way by which randomly produced RNA begins to self-replicate in not one single molecule but in a thermodynamically-driven process, the RNA world is baseless. It is not satisfactory to think that replicating RNA came from the prebiotic soup by itself -- as implicitly, even if they don't write so -- most of the RNA world people assume.

Suzan Mazur: You're not comfortable with computer chemistry.

Pier Luigi Luisi: I do not believe in computer chemistry for the origin of life. I want to see some bench chemistry experiments, and I want to see cellular life arising at least conceptually. This means a network of chemical reactions based on bench chemistry that go from simple amino acid to, for example, a specific primary sequence in many identical copies.

Suzan Mazur: Would you describe your current research?

Pier Luigi Luisi: Yes. I'm also interested in RNA, but approaching it in a different way. We are working in chemical synthetic biology. Our lab is researching two directions. One is construction of what we call a minimal cell. A minimal cell is a cell which has minimal and sufficient complexity, namely the minimal and sufficient number of components to be alive.

Suzan Mazur: Are you building from bottom up?

Pier Luisi Luisi: Yes, but not completely from bottom up because we use extant nucleic acid and proteins. We put those inside a shell, a liposome. We are investigating what the minimal and sufficient number of enzymes and nucleic acids are to make this minimal living cell.

Consider that the simplest microbial cell on our Earth contains several thousand components, a minimum of three hundred, four hundred genes. In a microbe there are something like 10,000 different molecular structures in many copies, an enormous complexity. And it is precisely the complexity that elicits the question: Is this complexity necessary for life or can you make life with a much simpler structure?

This question relates to the origin of the first cell, which could not have started with 10,000 components of 500 genes inside. So what was the beginning of complexity to make life?

Suzan Mazur: Working with existing, with modern material, doesn't that interfere with discovering what life was like originally?

Pier Luigi Luisi: Yes. That's why I say that research on minimal cells is not the study of the origin of life, but rather the study of the origin of the first cells once nucleic acids and proteins were already there. And we don't know how. But we start from then, so it's not really a bottom-up approach because we start in the middle of the way.

Suzan Mazur: But you consider this a protocell.

Pier Luigi Luisi: Yes, we can call it a protocell. It's a very vague term. It's something prior to the first fully-fledged biological cell, which was capable of three things. The trilogy of life -- self-maintenance, self-reproduction and evolution.

Suzan Mazur: How soon do think you will make this minimal cell?

Pier Luigi Luisi: In our lab in Italy, we along with other researchers -- Yomo in Japan and some people in the US -- made a protocell containing a minimal set of enzymes, 37 enzymes with a total of about 90 macromolecular components. This is all inside a liposome. The liposome is capable of making proteins, which is one basic function of the cell. So it is a protocell in the sense that although it is not yet a living cell, because what we have done, we and other groups, is not yet developed self-reproduction and evolution, but this minimal cell is capable of metabolism.

Suzan Mazur: You mention Yomo in Japan, is that Tetsuya Yomo at Osaka University?

Pier Luigi Luisi: Yes. Tetsuya is a good friend of mine. Very smart. Very intelligent person.

Suzan Mazur: So the replication is something that is down the road.

Pier Luigi Luisi: It is down the road.

Professor Ueda is the one in Japan who discovered this minimal enzyme kit, which he called the pure system. He's trying to modify this minimal set of enzymes so the set of enzymes reproduces itself. But it is still down the road. Maybe there will be 50 or so macromolecules instead of 37, still a great complexity.

It's one or two orders of magnitude simpler than the simplest living bacterial cell, like E. coli, which has inside thousands of components. However, it is still difficult to think that a structure with 100 macromolecular components can be the origin of life.

Suzan Mazur: How many labs are working on the protocell?

Pier Luigi Luisi: I know of five, six, maybe seven. Not more. Let me mention the lab of Yomo in Osaka, Ueda in Tokyo, Noireau and Libchaber at Rockefeller, Jack Szostak in Boston, Dave Deamer [now working with NASA's Winona Vercoutere through a grant from US businessman Harry Lonsdale].

But then there is supporting research. There are groups of very good biophysicists who are looking at molecular crowding inside the cell, for example. There are people who study permeability of membrane bilayers. These groups do not say they are making a minimal cell, however their research is very important. So this is one direction.

The second direction is in chemical synthetic biology, an area we call "never born proteins." An important question in the origin of life in general, in evolution, is why did nature do things in one way and not the other. Why this and not that? One of these questions pertains to proteins.

Now the proteins of our life are only a few thousand billion. You would say this is an enormous number. Yes, but this is a ridiculously small number when compared to the possible number of proteins. If you take a protein with a hundred residues and you consider that each residue can be 20 different structures, 20 different amino acids, then the number of chains with the length of 100 can be 20x20x20 -- 20 to the 100th, which is 10 followed by 100 zeros, or more. Compare to 10 to the 14th for the number of proteins on Earth. In other words, the known number of proteins corresponds roughly to a grain of sand in the Sahara, compared to all sand of the Sahara.

How did these few proteins come about? These, and not some others?

In our lab we are constructing proteins which were "not born," did not exist previously and we are comparing them to the proteins that do exist on Earth. This, in order to understand whether our proteins on Earth have something basically different from the random library of never born proteins.

Suzan Mazur: What have you discovered so far?

Pier Luigi Luisi: It's easy to make a library of proteins, but it's very difficult to obtain these proteins in a milligram or microgram amount in pure form. The few that we've made are proteins that are completely similar to the protein of our Earth. They are folded, are thermodynamically stable and soluable in water. They can be reversibly denatured. So we say in a provocative way that our proteins of life have nothing particular to show, which seems to corroborate the hypothesis that the proteins of our life on Earth are the product of contingency (once we used to say chance). This means that these proteins have not been chosen by a deterministic pathway but instead came out -- let's say in first approximation -- by accident, and then life was built on this structure that came out. It's a very strong idea, and has to do with the classic controversy between contingency versus determinism.

Is the origin of life a chance event or an obligatory deterministic pathway? We scientists are still divided on this question.

Suzan Mazur: What do you think is at the core of life? Is it algorithmic or nonalgorithmic? Is it autocatalytic sets or something else?

Pier Luigi Luisi: I take a phenomenological approach to this question of the Origin of Life. Instead of considering a theoretical algorithm and so on, I look at life where life is in its simplest form -- unicellular organisms. There the essence of life is metabolism based on self-maintenance.

Self-maintenance is the essence of life, is the capability of bacteria, the elephant, and the tree to each remain themselves despite the thousands and thousands of transformations going on inside their structure.

You remain always the same Suzan despite the transformations. This is possible because life remakes all those components that are being destroyed by metabolism.

You lose thousands and thousands of hemoglobin molecules every hour but they are remade from living cells, from the organized network of reactions inside you. It's what we call autopoeisis. You remain Suzan. You age a little in the process, but that's another question.

Suzan Mazur: That's fascinating to think about. Thank you.

What are your thoughts about the origin of body form?

Pier Luigi Luisi: It's a top down approach, what in philosophy of science is called downward causality. Genes are made by the living organism. Genes then make protein, proteins make tissue, tissue makes organs, organs make life. But when my body needs hemoglobin, it is not that the gene starts by itself to make hemoglobin. My entire body as a living organism decides how genes should be activated, with a lot of hormonal release and mechanics that make a signal arrive, which reaches the organs and tissues and activates the genes to make proteins. But this activation, this decisioin is a system property. So we are not our genes. We are the system that activates the genes.

It's systemic. Actually I'm writing a book now with Fritjof Capra titled: The Sytem's View of Life, which also emphasizes the system's view of society, ecology and medicine. We take the perspective that it is not the single individual -- be it a cell or a man or a city -- that is the real active agent, but the entire system which activates the individuals so that they make something for the whole structure. It's very important in all fields.

Suzan Mazur: You did your postdoctoral work in the former Soviet Union. Do you see a difference between the Russian perspective on Origin of Life and Western perspective?

Pier Luigi Luisi: The Russians started the Origin of Life field, beginning with the work of Alexander Oparin's book in 1924, The Origin of Life. Oparin was the first to invoke prebiotic molecular evolution. This, of course, was in the middle of the Russian vision of life, whereby Oparin was influenced by the Marxist dialectic, and by On the Origin of Species, the book by Darwin. Those were the two dominant visions of science because they were both without God. Very materialistic in a way.

After Oparin I do not see any major breakthroughs in Soviet Origin of Life science. In recent years, even before the big crisis in Russia 10, 15 years ago when all science was destroyed -- I was collaborating with some groups then on enzymes in micelles -- I have not seen any important Origin of Life experimental work coming from Russia nor do I see it in the literature. There are some theoretical papers but no important experiments.

Suzan Mazur: Do you think there's still a rivalry of sorts that persists between East and West in science and even between the US and Western Europe, in spite of the Internet, and in the case of East-West, despite the fact that the physical wall has been dismantled?

Pier Luigi Luisi: I don't think there's a difference in terms of real concepts. There is a difference, however, in terms of style of writing. I'm referring to papers in all kinds of journals. Americans are much more hyper, it's a kind of free will style. The European way of writing and presenting papers is more Germanic, more sound and down to earth.

Take for example the popularity of the RNA world in the US, a theory which lacks grounding, at least for the moment.

Suzan Mazur: It's incredible to hear you say that because there's a four-day Origin of Life conference in January at Princeton University featuring the RNA world.

Pier Luigi Luisi: Yes. I know of that. It is important, and at the same time to me it's old stuff. Conceptually, I don't see much progress. The origin of life, until now, remains a mystery.

Suzan Mazur: How is science is funded in Italy? Do the Italian people share in the decisionmaking process about allocation of public funds in science? Do citizens sit on your national science panels or is it like in the US where the public funds science but the scientists control it?

Pier Luigi Luisi: In a way it's a very simple answer. In Italy since many years, the funds for research have been almost non-extant. After 30 years of working in Zurich at ETH, I came back to Italy, and the dramatic difference is that here there is no money coming from the government for research. Or very, very little. There are typically something like 100 applicants for three or four grants.

Suzan Mazur: Do you have a national science organization like the National Science Foundation?

Pier Luigi Luisi: There is something like that but it has very, very little money.

Suzan Mazur: Does the public participate or are there scientists only on the panel?

Pier Luigi Luisi: Only scientists.

Suzan Mazur: It's like the United States. So in Italy you've got corporations and private philanthrophy financing research?

Pier Luigi Luisi: It's peer-review of projects.

Suzan Mazur: Do you have legislation in Italy as we do in the US where we have a virtual "commercial usurpation of the whole scientific enterprise"?

Here in the US we have something called the Bayh-Dole Act where a corporatization of universities was allowed to take place with companies acquiring monopoly rights to products developed by scientists funded by the public. So the public is left out of the profit and the information plus the public has to pay again for the product following development to use it.

Pier Luigi Luisi: We have no private money funding our universities, the little that comes, comes from the government.

Suzan Mazur: Corporations don't have partnerships with universities and monopoly rights to products developed by scientists?

Pier Luigi Luisi: There is very little and only for very applicative projects. For basic science you will not find anything like that.

We do have the advantage that there is no inference of non-science groups, but the problem is there is no money. Let me add that in Italy or Germany or France, most of the money for research comes from the European foundation. My research in Italy has been supported by international grants coming from the European Union or from the Human Frontier. This is how most of the research in Italy is financed not directly from the government but from the European foundations.

Suzan Mazur: You emphasize wholeness in science. Would you explain?

Pier Luigi Luisi: It means what is important is not the structure but the relationships. In systemic science, if you have a society of people or a complex of cities or nations or if you look into the cell and have many molecules, what is important is not the single individual but the relations among all the components. The is the systems view.

It's just like you have a pond and a frog, and the frog in the pond can only see a couple of frogs around. But the bird's view, the eagle's view sees all components of the pond interacting with each other. The bird also sees the trees on the edge of the pond and that the water in the pond comes from the mountains and pollution from the nearby factory. All possible relationships are considered.

The systems view is that reality is the product of a series of relations. That is why it is not DNA alone, it is not molecules that determine life, but the whole systemic structure, the ensemble of relations that makes reality.

Why we are alive? What is the difference between a living horse and dead horse? A horse who just died? The dead horse is a fragmented structure, followed by decay.

In the living horse the organs talk with each other, the heart with the lungs with the kidneys with the brain with the arteries with whatever. All parts talk with each other, it is an integrated structure. There is a relation, this is the systems approach. It is this relation that keeps the living structure alive.

The same is true for a city, the same for a nation. This is the holistic view.


Suzan Mazur is the author of The Altenberg 16: An Exposé of the Evolution Industry. Her interest in evolution began with a flight from Nairobi into Olduvai Gorge to interview the late paleoanthropologist Mary Leakey. Because of ideological struggles, the Kenyan-Tanzanian border was closed, and Leakey was the only reason authorities in Dar es Salaam agreed to give landing clearance. The meeting followed discovery by Leakey and her team of the 3.6 million-year-old hominid footprints at Laetoli. Suzan Mazur's reports have since appeared in the Financial Times, The Economist, Forbes, Newsday, Philadelphia Inquirer, Archaeology, Connoisseur, Omni and others, as well as on PBS, CBC and MBC. She has been a guest on McLaughlin, Charlie Rose and various Fox Television News programs. Email:

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