Probable Impossibilities, page 6
In 1968, at the age of fifteen, young Szostak began his undergraduate studies at McGill. His particular engagement with biology was sparked by a summer program for undergraduates at the Jackson Laboratories on Mount Desert Island, off the coast of Maine, where he analyzed the thyroid hormones of mice. In the early 1970s, Szostak began his graduate studies at Cornell. There, he worked with the DNA of yeast. Over the next decade and a half, that work deepened and spread, culminating in Szostak’s discovery of how the vulnerable ends of yeast chromosomes, and indeed all chromosomes, are protected by molecules called “telomeres”—work for which he won the 2009 Nobel Prize in Physiology or Medicine (shared with Elizabeth Blackburn and Carol Greider).
By the mid to late 1980s, the field of yeast biology was getting too congested for Szostak. “I had a growing feeling that my work in yeast was becoming less significant, in the sense that other people would inevitably end up doing the same experiments we were doing in a few months or years at the most,” he recalls. From the beginning of his career, Szostak had always tried to avoid direct competition with other scientists. So, still in his thirties, with his Nobel Prize–winning work already under his belt, he began shifting his focus to RNA (ribonucleic acid), a molecule very similar to DNA and thought to be its ancestor in the evolution of life. Since then, Szostak and the researchers in his lab have been at the forefront of the creation of life from nonlife. Some of their major achievements include the creation of cell membranes from simple chemicals and a demonstration of how these membranes could grow and divide under simple chemical and physical processes, and a partial understanding of how RNA can be replicated within a primitive surrounding membrane.
Biologists are not in complete agreement about when to declare a particular smidgeon of matter “alive.” In general, the requirements include some kind of surrounding membrane (what Szostak calls a “compartment”) to separate the organism from the outside world and to confine the most critical molecules in close proximity, the ability to utilize energy sources, the ability to grow, the ability to reproduce, and the ability to evolve. In a 2001 paper in the prominent journal Nature, Szostak and colleagues identified four vital ingredients of a minimal living cell: a compartment, an embedded molecule like RNA or DNA that is able to replicate, a means for that replication, and some kind of interaction between the compartment wall and the replicating molecule so that they can help each other in response to the forces of Darwinian evolution. What distinguishes Szostak’s work in this field from the work of many other synthetic biologists is that Szostak wants to create a living cell from scratch, using only the simple molecules present in the primordial Earth, what he calls “prebiotic” molecules. By contrast, most other labs start with complex molecules that have been snatched from existing life-forms and have already had the benefit of natural selection and evolution over hundreds of millions of years.
Although ambitious and laser focused, Szostak is exceptionally modest about his achievements. Near the beginning of his autobiographical statement upon receiving the Nobel in 2009, he says: “Although I have had some degree of success as a scientist, it is hard to say precisely why.” He is also exceptionally generous in giving credit and support to others. “One of the delights of the world of science,” he says, “is that it is filled with people of good will who are more than happy to assist a student or colleague by teaching a technique or discussing a problem.” He refers to his second graduate student, Andrew Murray, as “a brilliant and energetic student who was fun to talk with about any conceivable experiment.” About another of his students, he recalls, “I had the good fortune to ‘inherit’ one of [Harvard chemist Jeremy Knowles’s] graduate students, Jon Lorsch, who migrated to my lab and did outstanding work on ribozyme selections and mechanistic enzymology.” A photograph of Professor Szostak with his students in a quite plain-looking room at the Harvard Medical School shows twenty smiling young people, some standing, some kneeling, most wearing jeans. In the middle of this happy family is the professor. By his humble demeanor, he is one of them.
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I visited Professor Szostak in his office and lab in July 2019. His office, on the fourth floor of the Richard B. Simches Research Center of the Massachusetts General Hospital, is a small room barely large enough to hold a small couch, a small table, a small desk piled high with papers and documents, and a bookshelf with biology books and bound volumes of his students’ theses. When I met him, he was wearing a sweat-stained blue linen shirt and rumpled khaki pants loosely drooping from his waist. He has thinning hair and wears glasses. He speaks in a soft, almost hesitant voice, clearly passionate about his work while at the same time not endowing any sentence with the slightest exaggeration or presumption of importance. “People get all tied up in knots about defining life,” he told me. “That doesn’t help us. I care about the process and pathway from simple to complex. Where along the way you draw the line and call the thing ‘alive’—different people draw the line at different places. If it can start evolving, I would call it alive.” Evolution and natural selection are powerful driving forces. Szostak points out that any biological molecule will naturally undergo mutations, some positive and some negative. Given the right chemical environment, evolution then happens automatically. “Once you have one element that has an advantage, there is a huge pressure to drive replication…When somebody figures it out [how life started on Earth], it’s got to be a bunch of simple things.” He smacked his hand against his head in a eureka gesture. “It happened all by itself on primitive Earth. It can’t be that hard.”
In 2003, Szostak and his colleagues demonstrated that a common mineral clay called montmorillonite, formed from volcanic ash and used in cat litter today, could accelerate the assembly of cell “compartments” needed for life using only the simple molecules available in the primordial Earth. Montmorillonite seems to be an extraordinary catalyst. It was already known that it could help assemble RNA molecules from their basic building blocks. Now, Szostak and his colleagues found that simple molecules called fatty acids, when placed in contact with the clay, bond together to form membranes. The membranes then automatically close up and assemble tiny fluid-filled sacs, or compartments, which could possibly contain replicating molecules like RNA or DNA. Furthermore, in the presence of the clay, these microscopic sacs grow all by themselves by incorporating other fatty acids. Evidently, the surface of the clay has special geometrical and chemical properties that catalyze these reactions. Szostak and his colleagues also showed that passing the tiny sacs through a material with small pores would cause them to divide, in a sense “reproducing.” Thus, he had demonstrated creation, growth, and reproduction of a cell compartment.
Almost immediately after his paper was published in Science, it was widely popularized in the press. For example, The New York Times published an article about the work titled “How Did Life Begin?” and Scientific American published an article titled “Clay Could Have Encouraged First Cells to Form.”
Szostak wanted to tell me a story about this discovery. After it was picked up by the news media, he received a “flood of emails” from fundamentalists saying they were pleased he had proven that God can create life from clay, just as mentioned in the sacred books. “I am not religious myself,” he said and smiled at the irony. “I hope that when we succeed, it will eventually seep into the culture that the creation of life is totally natural, and we don’t need to invoke anything magical or supernatural…What I don’t get is how religious people can say that they know how God did that.”
While we talked, several of Professor Szostak’s students and colleagues quietly worked in the lab just outside his office. His current research group consists of sixteen students and postdocs. The major part of the lab occupies part of a large room housing a dozen or so long shelves cluttered with various bottles and chemicals. Below the shelves are worktables. On one worktable I saw a computer screen, an open notebook and pen, and several Post-it notes stuck to the wall and shelf. Adjoining this large room are a few smaller rooms with mass spectrometers (which measure the ratio of mass to electrical charge of tiny particles and thus help identify them); centrifuges; an oxygen-free zone, contained within an airtight hood and used to simulate the oxygen-free atmosphere of the early Earth; and a sophisticated nuclear magnetic resonance (NMR) machine to measure the structure of molecules. As I stood gaping at the NMR machine, Szostak mentioned that he would like to have two, as a backup when one of them is temporarily down.
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Szostak and many other biologists who study the origin of life subscribe to a view called the “RNA world.” This concept, first proposed by biologist and biophysicist Alexander Rich in 1962, holds that the first replicating molecule in the early history of Earth was not DNA but RNA. The two molecules are chemical cousins. They differ in a few ways. In modern cells, most DNA is a double-stranded helix while most RNA is single-stranded; one of the four letters of the genetic alphabet used by the two molecules is different; and the backbones of the two molecules incorporate slightly different sugar molecules. (The sugar molecule found in DNA derives from the simpler sugar molecule in RNA, another reason why many biologists believe that RNA came first.) Both RNA and DNA store information for the reproduction of the organism. Unlike DNA, RNA has other duties in the cell. It reads the information on the DNA molecule and then carries that information to another part of the cell where proteins are made.
The RNA world hypothesis got a big boost in the early 1980s when biologists Thomas Cech and Sidney Altman independently showed that RNA was not simply a passive messenger of information but could catalyze reactions and help create molecules on its own. This discovery solved a long-standing chicken-and-egg-type conundrum: certain proteins are needed to make DNA, but DNA is needed to make those proteins. RNA could do both: store genetic information for the cell and also rebuild itself. RNA could be both the carrier of the map and the mapmaker.
Being single-stranded, RNA is more subject to attack and degradation by outside chemicals. It is not as stable as DNA. Over time, in the process of Darwinian evolution, RNA would have been replaced by DNA as the principal bank of genetic information. But in the beginning, according to RNA world, RNA might have been the principal molecule of replication.
Szostak believes that a primitive cell might not need much more in its innards than a strand of RNA and some simple chemicals to serve as raw construction materials. How that construction occurs is not yet understood—a major obstacle for understanding how to create life from nonlife. “In my view, the critical problem right now is to understand the chemistry that enabled the first mode of RNA replication,” says Szostak. In other words, exactly how does the replication molecule, carrying all the blueprints for the cell, replicate itself? Szostak says that it is easy to replicate RNA using protein enzymes (catalysts) and other complex molecules that have been developed over millions of years of evolution. But he wants to know how life began. He is trying to show how RNA replication could have happened on the primitive Earth, with only the simple molecules then in existence. “Our approach has a ways to go: so far, we can copy short stretches of an RNA template to generate a complementary strand in the form of an RNA double helix. However, our ability to copy RNA is limited to very short lengths, and we cannot yet do multiple cycles of copying, in other words, copy the copies. Indefinite replication within protocells is our goal, because we think that with replicating RNA inside replicating vesicles [membrane compartments], we would have a system capable of evolving in a Darwinian sense.”
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The study of how life began on Earth, and the related attempt to create life from nonlife in the lab, raise all kinds of philosophical, theological, ethical, and social issues. Many of these issues have been anticipated in science fiction, in academia, and in religious conferences and institutions. But with the successes of Szostak and other synthetic biologists, these matters are receiving new attention.
In one episode of Star Trek: The Next Generation, Commander Data fractures a part of himself and stares at the bare tangle of wires and computer chips protruding from his wrist. Although Data is a machine, viewers have come to regard him as human. He looks human. He acts toward other characters with compassion and sweetness. He appears to know right from wrong. Something unsettles us about this scene, not so much because Data is hurt, but because he, and we, suddenly see inside his mechanism. The secret of his being hangs open in the air. All the complexities of his bodily actions and thoughts, the subtle depths of his feelings, the seemingly infinite mysteries of a living being, have been graphically reduced to so many amperes of current flowing through these protruding wires, to particular patterns of zeros and ones within these computer components. We feel affronted. We feel some kind of violation of the natural order of things.
In our age of rampant technological advance—with small boxes that can transmit our words and images over vast distances through space, with other devices that improve our hearing and sight, with drugs that alter our thoughts and personalities, all of it human-made—the lines between the “natural” and the “unnatural” have become blurred. One might argue that since we human beings are “natural” and our brains and their capacities evolved “naturally,” then anything we make is “natural.” Others disagree. What are the differences, if any, between an organism created in Jack Szostak’s lab and an organism found in the moist soil under a rock?
Micah Greenstein, a prominent rabbi in Memphis, Tennessee, says unequivocally that an organism created in a lab would not have a soul. “Soul is the life force within all living beings which cannot be quantified,” says Rabbi Greenstein. “It is the animating feature of all life-forms. Dogs have souls. They cry and offer compassion and love like humans. Human souls are gifted with the ability to take care of other life-forms and the planet itself. Were we able to construct a new life, I believe no process could ‘breathe’ into a proto-human or proto-dog the soul of which I speak. Call it personality, call it the unique signature of each human being. In a beautiful midrash, the rabbis speak of the difference between a coin creator and God. A coin maker puts the same mark on each shekel and they are exactly the same. God breathes ‘soul’ into every human, the same gift of spirit in every human being, yet no two people are exactly alike. Each is a unique signature of the One.”
A related concern for theists is that the human creation of living organisms seemingly transgresses into territory and knowledge reserved for God. This concern has a long history. In Milton’s Paradise Lost (1667)—written in the age of Newton and the beginnings of modern science—when Adam questions the angel Raphael about celestial mechanics, Raphael offers some vague hints and then says that “the rest / From Man or Angel the great Architect / Did wisely to conceal, and not divulge / His secrets to be scann’d by them who ought / Rather admire.” In 1996, when the British embryologist Dr. Ian Wilmut cloned a lamb (named Dolly) from an adult sheep’s cell, it was undoubtedly a success for science, but ethical and theological alarms sounded all over the world. The sheep’s human manipulators were described by The New York Times as having “pried open one of the most forbidden—and tantalizing—doors of modern life.” Cloning is a complex issue, and one has to distinguish between therapeutic cloning (to treat illnesses) and reproductive cloning (to produce new organisms). On the subject of human cloning, most religious groups are adamantly opposed, or highly suspicious. But even with Dolly, many were disturbed when the achievement was announced. Dozens of articles had the phrase “playing God” in the title. Even today, according to a recent Gallup survey, 66 percent of Americans think it is “morally wrong” to clone animals, while 31 percent say it is “morally acceptable.”
Ruth Faden, professor of biomedical ethics at Johns Hopkins University and founder of the Berman Institute of Bioethics at that university, frames the question of human-made organisms in terms of their “moral status.” An entity’s “moral status” determines its rights and value and sets parameters for how we human beings are morally obligated to treat it. The term has gained currency in the twentieth century with the abortion debate and questions about whether a human embryo has moral status. Professor Faden discussed the issue with me specifically in relation to synthetic biology. “Does it matter how life is formed?” she said. “Certainly it matters scientifically. But does it matter for the entity that is created? Should it be treated any differently from something we just found under a rock? For some people, in the ethical domain there is a big line between organic and inorganic entities. Living matter has value in ways that inorganic matter does not. There is a huge debate over who has moral status.” Faden says that for people of faith, “we may be redefining where the spark of life is.” She adds that “for many nonreligious people, it is not the soul that matters but sentience,” suggesting that the dividing line between deserving some level of moral status and not is whether the organism has feelings and consciousness. Consciousness and self-awareness are not easy to pin down, but wherever one draws the line it is likely that at some point in the future biologists will have the ability to create a sentient living being.
At least for the creators and writers of Star Trek, Commander Data has moral status. Did the creature brought to life by Victor Frankenstein have moral status? Does a computer with the ability to learn and speak have moral status? In Rabbi Greenstein’s view, none of these entities would have a soul, but some of them would be sentient, however one defines that word. The Buddhist monk Yos Hut Khemacaro, who played a major role in rebuilding the monkhood in Cambodia in the 1980s and 1990s, told me that Buddhists, who do not believe in a soul, have no problem with human-made life-forms and would accord them “morality, value, and dignity if we see the same characteristics as ‘natural’ living beings.”
