Doron Lancet: The Origin and Synthesis of Life

"One of the greatest challenges of Synthetic Biology is to chemically engineer a simplified self-reproducing system. Even the simplest of such systems, obtained by a top-down approach, i.e., by gradually simplifying present-day living cells appears to be irrevocably complex. Therefore, a bottom-up approach is more appropriate if Synthetic Biology's declared goal of combining science and engineering in synthesizing novel biological functions and systems is to be followed. Self-reproduction comes in two different flavors: one is the ability of individual molecules, such as DNA and RNA to generate their own copies. Indeed, many Synthetic Biology efforts rely on this unique attribute, attempting to develop and utilise molecular replicators such as a self-copying ribozyme. The other reproduction flavor is the capacity of entire cells to fission and form progeny. In our laboratory we take the latter route...Because present-day test-tube biochemistry is rather limited, we resort to computer simulations...This approach echoes new developments in the realm of systems chemistry, a joint effort of prebiotic and supramolecular chemistry, as well as theoretical biology and complex systems research to address problems relating to the origin and synthesis of life." --Doron Lancet

Since the investigation into who we are and where we came from increasingly involves creating a living cell with modern chemicals that may not have existed on early Earth -- should we even continue to call the research origin of life? Weizmann Institute professor Doron Lancet says this dichotomy of origin of life and synthetic life or artificial life is itself artificial, and that scientists exploring origin of life are indeed working in artificial life science as well, including him. Moreover, Lancet does not see much difference between origin of life science building a living cell from the bottom-up and synthetic biology working from top-down (think Craig Venter) -- meaning there is plenty of controversy ahead since scientists are predicting a protocell will likely become reality within the decade able to reproduce and interact with the environment (nobody knows how exactly until it's developed).

Doron Lancet has distinguished himself from many of his colleagues in the field by proposing that life on Earth could have started with any mix of chemicals and reproduced, and that it did not have roots in a replicating world of polynucleotides. His model -- metabolism came first -- does not rely on RNA and DNA.

Lancet's ideas for this approach to life's origin were dubbed, the "garbage bag world" by Freeman Dyson in his book Origins of Life a dozen years ago. Dyson still shares Lancet's perspective on this, as well as Alexander Oparin's 1920s cell-first thinking, and says life may have reproduced this way for over a billion years or more before the appearance of RNA.

Over the last 15 years, Doron Lancet has been doing the math on these concepts as part of his "Lipid World" investigations using a computer system he calls GARD (Graded Autocatalysis Replication Domain).

In 2010, a PNAS paper by Eors Szathmary (of the Altenberg 16) and colleagues (not Altenberg 16) challenged Lancet's GARD model saying it did not exhibit evolution because compound genomes lost properties.

However, Lancet et al. counter that after reexamining the Szathmary analysis and focusing on clusters of composomes "appreciable selection response was observed for a large portion of the networks simulated."

Lancet has more recently noted further in an email to me:

"The paper by Szathmary et al. has examined a very special (and to a large degree untenable) case of our model, which casts a shadow on the critique. I should at the same time say, that like many other simulated models of evolution, GARD is far from being ideal, and will require long research to make it show what we call "open ended evolution." We are working exactly on this point. . . ."

Lancet says he spends his mornings investigating genetic diseases, afternoons thinking about "the quiet little pond" of origin of life research, and evenings speaking to public audiences about science.

Doron Lancet received his BSc in Chemistry and Physics from Hebrew University of Jerusalem and his PhD in Chemical Immunology at Israel's Weizmann Institute of Science. He did postdoctoral work at Yale and Harvard.

Lancet is currently Ralph D. and Lois R. Silver Professor of Human Genomics at the Weizmann Institute in Rehovot, where he also teaches bioinformatics. He is director of Israel's National Knowledge Centre for Genomics and of the Crown Human Genome Center at Weizmann. Lancet also serves as president of ILASOL (Israel Society for Astrobiology and the Study of the Origin of Life). He is a member of the editorial board of Biology Direct and the advisory board of the Lifeboat Foundation as well as a member of HUGO (Human Genome Organisation) and EMBRO (European Molecular Biology Organisation).

His pioneering of olfactory signals led to his receiving the R.H. Wright Award in Olfactory Research in 1998. Other awards include the Hestrin Prize from the Israel Biochemical Society (1986) and the Takasago Award of the American Association for Chemoreception Sciences (1986). Lancet is the author of more than 180 scientific papers including several patents.

He has written science columns for Haaretz, as well, and he and his Lancet Group developed the web-based encyclopedia on human genes called GeneCards.

Writing with Barak Shenhav, Doron Lancet contributed to the significant 2009 MIT text Protocells with a chapter called, "Compositional Lipid Protocells: Reproduction without Polynucleotides" (Protocells: Bridging Nonliving and Living Matter, editors: Steen Rasmussen, Mark Bedau, Liaohai Chen, David Deamer, David Krakauer, Norman Packard and Peter Stadler).

I spoke recently by phone with Doron Lancet in Israel. Our conversation follows.

Suzan Mazur: Would you bring us up to date on where you and your colleagues are now in testing your idea that life began in a "garbage bag world," as Freeman Dyson described it, of self-assembled metabolic creatures that possibly reproduced for a billion or so years without relying on RNA?

Also, since no one knows exactly what the conditions were on Earth wherever and whenever life emerged and we may never know, is yours an investigation into original life or an exercise in creating artificial life, a protocell?

Doron Lancet: Let's begin by talking about conditions for life's emergence. The specific conditions matter less. There should be some provisos, or general conditions without which I don't see how life could have begun. For example, if people tell you life began at a temperature of 25 degrees Centigrade, 110 degrees or 360 degrees (in suboceanic vents) -- this doesn't matter. What does matter is the principle of what would constitute acceptable molecular roots of life, and at the same time have sufficient simplicity to warrant emergence from an abiotic mixture of chemicals.

I would also state the following: We don't know, and we will likely never know what were actually the exact chemical substances that began life. But we can wisely guess what principles such chemicals had to obey.

One of the worst mistakes, in my opinion, and in the opinion of Freeman Dyson and to some degree also of David Deamer, is that people think of first life in terms of life as we know it today -- with 20 amino acids and four nucleotides, the latter being a rather elaborate molecule with a nitrogen base, a sugar and a phosphate. And they say: "That's how life should be. That's how life should have been from its inception." That's utterly wrong, in my view.

Suzan Mazur: Thank you. That's important to establish.

Doron Lancet: Let's discuss my ideas, then think about their testing. Dyson wisely called this general class of ideas the "garbage bag world." What Dyson meant by garbage bag world was the principle that any set of molecules could have jump-started life. That set of molecules need not have been polypeptides or amino acids or nucleotides or polynucleotides (such as RNA and DNA) or for that matter fats, lipids, sugars or any other of the known array of molecules entertained as those that began life.

A chapter in Dyson's book Origins of Life discusses the ideas of Alexander Oparin, the Russian biochemist who in the 1920s wrote a book that marked the beginning of modern thought about the origin of life. This is where Dyson writes about "garbage bag world," relating to Oparin's model of "coacervates," tiny chemical spheres that fuse, split and copy themselves In that context, Dyson describes a random collection of molecules in a bag that may contain catalysts causing the synthesis of other molecules that in turn act as catalyst to synthesize yet other molecules, thus allowing "garbage bag" copying.

I'd like to clarify the basic mechanism involved: Molecules, when left alone, may go in different chemical directions undergoing conversion from A to B to C to Z to Q, etc. If there is a catalyst around, it will direct reactions, making them more efficient and focused. So the idea is that when you have a bag of molecules, irrespective of what they are, the constituents will begin to interact and help each other form additional similes, paving the route to "bag replication." Attempting to provide evidence for this kept us busy for nearly two decades.

To quote Dyson, "the bag may be growing by accretion of fresh garbage from the outside, and the bag may occasionally be broken into two bags, when it is thrown around by turbulent motion. The critical question is then: what is the probability that a daughter bag produced from the splitting of the first bag with a self-reproducing population of molecules will itself contain a self-reproducing population?"

I share with Dyson the notion that such chain of events, while of low probability, is a likely path from dead chemicals to life, as indicated by our computer simulations.

Importantly, there may be billions of different bags of molecules formed in this ancient ocean, in the primordial soup, and very few of the bags will have the capacity to produce a simile of the entire bag when its molecules interact. These precious few unique bags with specific sets of molecules will feebly reproduce and may jump-start selection and evolution.

This is the set of ideas we have initiated and propagated, standing on the shoulders of giants like Freeman Dyson and Stuart Kauffman.

Suzan Mazur: How are you testing this idea currently?

Doron Lancet: How do you test black holes and galaxies? Often by mathematical formulations and computer simulations, to do what you can hardly do in a laboratory, as is the case for the multi-million years of life's origin.

Suzan Mazur: You're largely relying on computer chemistry rather than bench chemistry.

Doron Lancet: Yes. Mainly. I say mainly because there are experiments we and others do to prove aspects of our theory.

Suzan Mazur: Do you consider your investigation one into origin of life or of creating artificial life?

Doron Lancet: Both. It's more origin of life because this question really challenges us. And it is very far from being solved.

Suzan Mazur: Would you say the origin of life community is largely focused on discovering first life or creating artificial, autonomous life, a protocell?

Doron Lancet: These two worlds interact with each other.

Suzan Mazur: Are scientists in pushing for origin of life research funding looking to solve the mystery of the origin of life or to create artificial life?

Doron Lancet: This dichotomy is artificial. Every scientist who works on the grandiose question of how life began sees how answering some of the questions addressed above will be useful in constructing artificial life. Many of us are interested in both aspects. We are interested in the big question that is far from being solved, and we're interested in the down-to-earth agenda items related to potential mechanisms that can lead to artificial life. It is very difficult to get funding for the grandiose question, so a lot of us get our funding for topics related to synthetic or artificial life.

Suzan Mazur: You're saying it's easier to get funding for artificial life research than origin of life research?

Doron Lancet: The simple short answer may be yes. But we have to define what artificial life is. Artificial life typically is taking part of existing life and making very simple systems in which these existing parts play important and relevant "games." This may also be a valid route to understanding primordial events.

Bottom-up artificial or sythethetic life uses materials (e.g., protein and DNA) from present day life, as does top-down synthetic life.

But there is another kind of bottom-up research. Our own 15-year old model called GARD (Graded Autocatalysis Replication Domain), is a concrete chemical system of fat-like substances (lipids), whose behavior is emulated by a set of non-linear equations. When run in a computer such systems exhibit the capacity to replicate, to undergo mutations and selection and rudimentary evolution. GARD's focus is on molecules not necessarily present in life now. As in the garbage bag world, our "Lipid World" molecules are contained in "bags" and exert catalysis on each other, to enact "bag reproduction"

Using the principles governing the interaction of these molecules, we are investigating whether this can lead to a simile of life, entities with sufficient chemical complexity to be called "primitive life." The interactions within such systems can be described by linear or non-linear mathematical equations alike.

Admittedly, the molecular bags described by our GARD model start out very simply and to show a valid path of scrutiny, need to become more and more accurate, with a higher and higher specificity and fidelity. The question is: What is the simplest conceivable collection of molecules endowed with these capacities that show rudiments of selection?

Suzan Mazur: And this selection that you're talking about is artificial selection, since you're dealing with an artificial situation. Right?

Doron Lancet: When you describe something with an equation and simulate it in a computer, it is not necessarily less natural than nature itself. You can simulate the formation of a planet from a nebula. You can simulate the formation of the moon from the Earth. The atomic bomb has been designed to explode according to physical-mathematical equations. Are these equations "artificial"? The same may apply to equations that describe selection, be it in a population of present-day insects or in early protocells.

Notably, without a computer, galactic dynamics or protocell dynamics may encompass a million years, which we cannot wait for. Computer simulations may often be the only way!

Suzan Mazur: But I don't think I got an answer as to whether it's more difficult to get funding for artificial life experiments or origin of life experiments.

Doron Lancet: More difficult for origin of life.

Suzan Mazur: What is the point of inventing artificial, autonomous life?

Doron Lancet: I thought we were going to discuss origin of life?

Suzan Mazur: You said you're looking at both.

Doron Lancet: The reason for investigating artificial life is double. One of the best ways to understand life is laboratory generation of simpler life. And artificial life can also help in understanding the origins of life. That's why I'm interested.

Suzan Mazur: But how might artificial life, the protocell, revolutionize medicine, industry and information science? Isn't that why there's an investigation into artificial life -- applications and commercial opportunities?

Doron Lancet: Artificial life and synthetic life -- these are very, very broad domains. At one extreme are applications potentially important to medicine, how to cure disease, the circuitry of gene expression, etc. Understanding how life began on early Earth is at the other extreme. In between is a whole graded spectrum. Whether rung 30 of the ladder is more important than rung 40 is not what's significant about the story.

What is wonderful about the story is that in the last century we've been able to understand life as a complex chemical system that we can make simpler and simpler without losing the properties or attributes of living cells.

The simplest living cell we know has 500 genes with molecular machines that convert DNA to RNA (RNA polymerase) and molecular machines that can read the RNA and synthesize proteins accordingly (ribosomes). It has membrane all around with many chemicals dissipated in it.

A protocell has yet to be made, but we can assume it will have very little of all of that, because the ribosome is such an utterly complex machine. There is no way it could be contained within an honest to god early protocell.

On the other hand, there are many other scientists, wonderful scientists, productive scientists who continue to take bags made of fat, lipid vesicles or liposomes and stick inside them a ribosome and an RNA molecule and some building blocks for protein and watch what happens. It cannot have been how life began, because the ribosome is too complex to have been there early on. Still it's important to look at this kind of protocell.

Suzan Mazur: Is what David Deamer is doing by mixing in the mononucleotides to come up with a replicating cell along the lines of what you envision regarding origin of life?

Doron Lancet: If you are asking could mononucleotides have existed inside a bag of fat on early Earth -- yes. But if you ask could the mononucleotides form orderly chains, including polynucleotides such as RNA or DNA, it's more complex because you need specific catalysts for that. But you can think of a way by adding a few other smart molecules that would then interact with each other to form short chains of polynucleotides.

Suzan Mazur: Is the public sufficiently informed about artificial life?

Doron Lancet: The public is utterly uninformed about science in general, including the serious attempts taking place to understand how life began. So let's try to make them informed.

Suzan Mazur: What should some of the societal concerns be regarding artificial life?

Doron Lancet: I see no problems. The artificial life that we discuss is so far from being able to do anything wrong or good that it's not an issue.

Suzan Mazur: But scientists are saying that within 10 years they're going to have a protocell. And, according to Artificial Life Editor Mark Bedau, although the immediate danger is low, these protocells will in the future "be able to metabolize material from their environments, reproduce, and evolve" and "could cause problems for human health or the environment" if control is lost.

Doron Lancet: Yes, there will be some entities that will be capable of making copies of themselves in a very simple way but this is not an issue. You can now kill people very easily with chemicals you synthesize in the lab, it doesn't have to be a protocell. Natural viruses kill people as much as designed viruses.

When it comes to protocells that we're trying to cook up in the laboratory, either by computer simulations or by experiments, these are very, very far from being dangerous.

Suzan Mazur: Do you think a certain percentage of research budgets regarding artificial life or even origin of life should be allocated to raise public awareness?

Doron Lancet: For science education, so people can read and share in the joy of scientific discovery.

Suzan Mazur: What about oversight of artificial life? Watch dog organizations.

Doron Lancet: Thirty years ago genetic engineering scientists were confined to laboratories that had 16 doors so nothing got out. It then went down to 10 doors, and then to 5. Now those doors have been continuously open for years and nothing happens. Artificial life is much less dangerous than recombinant DNA. Recombinant DNA speaks the same chemical language that controls our own cells. Artificial life, typically, speaks a foreign language and does not easily interact with cells in our human body, but I admit there would be exceptions.

Suzan Mazur: Do you think we'll see a protocell within 10 years? You've previously commented as follows:

"It is obvious that a primitive protocell in the form of an assembly of arbitrary organic molecules cannot be expected to undergo reproduction-like dynamic changes at rates that are measurable in standard devices." And that "it could take months, years, or even decades," meaning handing off the experiment to the next generation.

Doron Lancet: I was talking about a specific type of primitive protocell that, as mentioned above, uses a different "language" than present-day cells. Also, science is erratic and hard to predict.

We promised to cure cancer in 10 years 50 years ago, though we are much closer to finding a cure. And life is changing dramatically because of modern biomedicine and computer technology.

The humble effort we are making in our laboratories in terms of artificial life is not likely to have such immediate impact on our lives. But in the long term it will. In 10 years there will be first glimpses. I don't doubt that in 10 years something extremely important could happen, but this may still be very far from affecting our lives as much as biomedicine and computer technology.

What is nice about origin of life science is that it's a quiet little pond in the middle of the forest, away from the hustle bustle of the city of modern biomedical science. There people can contemplate the interface between chemistry and biology and how life could have emerged as well as how to create it. I don't think we have to worry about some kind of artificial life monster jumping out threatening human survival in New York, Tel Aviv or anywhere else.

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: sznmzr@aol.com

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