One Big Science Man: What is (Im)Possible for Scientists with Money?

Craig Venter knows a lot, but there is also a lot that Craig Venter does not know. He knows the sequence of the human genome, having led the private-sector efforts to complete the project back in 2000. In the process, he showed that he also knows how to piss off a lot of people, prompting his critics to label him an egomaniac, and James Watson (of DNA double-helix fame) to say: “He’s Hitler.”

Since the initial hullabaloo of the sequencing race – which concluded more or less in a tie between Venter and “the government” – Venter has set his sights on sundry scientific undertakings, the magnitude of which has reinforced the egomaniac tag. Magazine profiles of Venter often relate Venter the person – a rebellious surfer, a flashy Californian – to Venter the scientist – a fearless “disruptor” in the hackneyed Silicon Valley sense. Yet Venter’s iconoclasm has rubbed off less popularly than that of, say, Elon Musk.

Recently under flak has been Venter’s for-profit enterprise Human Longevity Inc, which offers a comprehensive health service marketed for CEOs and professional athletes. For $25,000, HLI will sequence your genome (or more likely your boss’s boss’s boss’s genome) and also perform just about every advanced test known to medical science, at the end spitting out a digital avatar of the patient, with a supposedly close-to-complete synopsis of every aspect of their health. Despite its promising, ambitious aspects, HLI has drawn the criticism of the medical establishment. Rita Redberg, a cardiologist at the University of California, San Francisco, has said there is “absolutely no evidence that any of those tests have any benefit for healthy people.”

Needless to say, Craig Venter is not Hitler. He does think in grandiose schemes and sees his personal role in them as central. In his eyes, he rescued the human genome project from government inefficiency, completing in just three years a project that supposedly had fifteen years left to go.  How much should we care that Craig Venter thinks quite highly of himself if he is insistently pushing innovative science forward? Beyond changing health care, he has plans to tackle fossil fuel dependency and to sequence the DNA of the world’s oceans (yes, all of it).

After winning the NBA championship in 2008 as a member of the Boston Celtics, superstar Kevin Garnett semi-famously roared, “Anything is possible…ANYTHING IS POSSIBLLLLLLE.” But with all due respect to KG, some things are surely impossible, even in athletics, where records once considered beyond reach (e.g. the four-minute mile) are regularly smashed. In sports, money doesn’t buy success, though it can help. But what about science? Provided enough money, is anything possible?

There is perhaps no single project that Craig Venter would consider beyond his limitations, although it is unlikely he will accomplish all of his schemes. In his ambition, Venter’s “egomania” is not actually unorthodox, but reflects the lofty expectations of science in the twenty-first century. Look at the Cancer Moonshot Initiative, introduced by Obama in the 2016 State of the Union with the aspiration: “Let’s make America the country that cures cancer once and for all.” The Moonshot represents a cultural mentality about science not distinct from, but aligned with, Venter’s arrogance: throw enough money and brains at a scientific problem, and inevitably you fix it. After all, this worked for John F. Kennedy’s moonshot. Riding that classic Camelot confidence, the assumption seems to be that, with enough money, anything is in fact possible.

But I daresay this attitude is a tad inflated, and in support I will focus on just one example that will occupy the rest of our time here. At its core is Craig Venter. The question, broadly, is as follows: what are the essential components for creating life?

It is easy to paint Craig Venter as an explorer, a maverick, but of course he exists in various contexts. One of these is the field of synthetic biology, an emerging discipline that approaches biology as something to be designed and constructed, not merely understood. The allure of playing God has attracted a particularly male streak of narcissism and the field is populated by a patriarchy of hotshots. Its ranks include one Cambridge-based professor who once suggested in writing that a “particularly adventurous human female” could be used to carry an in-vitro fertilized Neanderthal baby. Within this culture of ego, of blurred lines between science serving humanity or humanity serving science, Venter is a more ordinary figure. Where many scientists see the present world and the problems in it, synthetic biologists see utopias that may veer into dystopias, depending on your perspective.

One of the promises of synthetic biology is that we might one day design and construct living cells to do a variety of jobs – like turning agricultural waste into biofuel, or detecting contaminants in drinking water – to cherry-pick a few of the more benevolent possibilities. In service of this, synthetic biologists would like to design a “minimal genome,” the most basic set of instructions required for a cell to function properly. This lean cell could then be accessorized with genetic additions to make it efficiently perform a specific task: for instance, you could add the enzymes necessary for processing plant matter, turning the cell into the aforementioned factory for biofuels.

Yet making the simplest cell possible turns out to be an extremely complex task, and one that drives at a fundamental question: which genes are essential for cellular life? Humans have ~25,000 genes, but mice have all of the features of mammals and require only 20,000 genes. Bacteria like E. coli have around 5,000. The question is: how low can you go?

If you’re Craig Venter, you can approach this problem in a couple of ways. You can say, “well, what do cells need to do?” and identify genes that give instructions for proteins that will accomplish these core tasks: for instance, the ability to translate RNA messages, or the ability to turn glucose into energy. The problem with the strategy just described is that it presumes we know enough about how cells function to be able to list all of the essential processes. But in fact, every cell does a lot that we know nothing about. We can write down genomes, but huge swaths of the letters are still gibberish, even to the Venters among us.

The more pragmatic approach, and one that avoids the problem of ignorance, has two steps: 1) take the smallest genome that we can find in nature and 2) strip genes away from it until it no longer works. But even answering the first part is not so straightforward.

The smallest genomes in the world belong to viruses. The bacteriophage MS2 gets along fine with just four genes. But many question whether viruses can even be considered living things, or at least independently living things. Since viruses require cellular hosts to make more copies of themselves, they require not only their own genes but also the genes of their hosts.

But what about the genomes of cellular life forms? The problem remains. The smallest known cellular genome is that of Tremblaya princeps, a bacterium that lives inside the mealybug. Tremblaya has 120 genes. The relationship here is not parasitic but symbiotic, with both the mealybug and Tremblaya performing chemical tasks for one another. Moreover, there is another bacterium found living inside of the Tremblaya bacteria called Moranella endobia that also contributes to the symbiotic relationship. All three players, and the three sets of genes they each bring to the table (which total in the thousands), are essential for the community to survive.

Where many people draw the line, and it is a very thin line etched on some very fine sand, is with Mycoplasma genitalium. M. genitalium has 525 genes and can grow independently in a laboratory setting, unlike the viruses or Tremblaya. However, M. genitalium is naturally found as a resident of animal intestines, and it owes its lean genome to an evolutionary history that has provided a generous abundance and diversity of nutrients, allowing M. genitalium to lose many nutrient-making genes over time with no consequence. Because these nutrients can also be supplied in a laboratory, M. genitalium can live “independently” in this environment.

Life, and the genomes underlying it, do not exist in isolation. Instead, life forms rely and feed on one another, from the sub-cellular scale to the ecosystem scale, perhaps to the cosmological scale, if you like to think that way. As such, defining the “essential” genes for life is not a fixed target, but one that depends greatly on the environment around a given life form. That Mycoplasma can live “independently in a laboratory” is a paradoxical claim, as that laboratory setting is a product of humans and the 25,000 genes that enable us.

It would seem that we have to concede, that the scientific question, “What genes are required for cellular life?” is in fact impossible to answer. The same may ultimately be true for questions like “How do we cure cancer?” or “Why do we have dreams?” Questions are sentences – they have tone, employ rhetoric (even unintentionally), and have a whole ton of implicit assumptions. For instance, when we talk about whether a gene is “required” we are assuming this is black or white, rather than a property that may depend on a number of contextual factors. It would be silly to expect a scientific answer to every question, even if we use the proper jargon.

But this does not mean that we cannot try to tether questions down, to ground them in specifics that are conducive to performing experiments.  We can pursue the practical application of creating a close-to-minimal cellular genome that can survive and replicate in a laboratory setting, all the while conceding that it may not be The Minimal Cell, because maybe that term doesn’t actually make sense.

So intrepid folks like Craig Venter march on, armed with money, pipettes, and a team of researchers to do the actual pipetting. They chose Mycoplasma (not M. genitalium, but the closely-related M. mycoides) and asked: how many genes are essential for life, even in that silver-spoon laboratory setting?

The work of Venter’s team, published in Science in March of 2016, offers a complicated and unsatisfactory answer to a vague and arbitrary question. To follow the narrative of their research is to see the fits and starts of scientific endeavor.

First, Venter’s team used mutagenesis screens: a method to delete genes one at a time and classify them as essential, non-essential, and quasi-essential (not necessary for the cell to live but necessary for the cell to divide).

Then, Venter’s team synthesized an entirely new genome from scratch, omitting all of the genes considered to be non-essential by the mutagenesis screen. They inserted this newly designed genome into the body of an existing cell, to see if the new software could effectively operate the cell without any glitches.

Instead, the cell just died. This is largely due to an issue called synthetic lethality. The screen mutates genes one at a time, but some of the cell’s functions can be carried out by either of two genes. Each of these genes might be labeled as non-essential when deleted individually, but when you get rid of both, the cell dies. The “essentiality” of any given gene depends on the presence of other genes. While it is possible to test 525 individual deletions, it is impossible to test the more than 10 quadrillion combinations.

In short, there is no neat or elegant way to approach the problem of minimizing a genome. Whether egomaniacal or persistent, Venter’s team pushed on. They partially battled the obstacle of synthetic lethality by breaking the genome into eight pieces, and testing the modifications in each segment when combined with a 7/8 normal background. This method made the problem more manageable by mapping where synthetic lethal pairs were in the genome. Even more significantly, Venter’s lab made serious technical strides in their ability to synthesize whole genomes from scratch. They can now synthesize an entire bacterial genome in about three weeks, one hundred times faster than with their previous technology. With this enhanced speed, his team rapidly designed, assembled, and tested many variations of the genome, each time shaving more genes away. At various stages along this path, they repeated the screen to see if the changes they had made turned a non-essential gene into an essential one, or even vice versa.

The end result? A functional genome consisting of 473 genes, a bit smaller than the 525 of M. genitalium. Yet this symbolic victory veils a more important finding, which is that of the 473 genes essential for life, we know next to nothing about the functions of 149 of these genes. Craig Venter, or anyone else, does not know how to read one third of the manual for life,  a manual whose definition is arbitrary at best. Yet knowing what we do not know has tremendous value in itself. Following up on these unknown genes will have real impact for both understanding biology and for creating synthetic biological applications, like the lean cell.

In one sense, Craig Venter created the first synthetic minimal genome. But the story does not read as a triumphant success. It’s more like a series of compromises and frustrating trial-and-error. On the one hand, this is because science is hard. It requires much more than money. It requires mistakes, arguments, wasted days, and a lot of hard work. But even this characterization is to aggrandize the process of science too much, as if it is only about doggedness, as if no question is beyond our human limitations.

The scientific questions we ask – in our imperfect, subjective human words – often steer our research half-blindly. They may be guided by implicit and naïve assumptions, like the idea that any one life form can operate “independently,” an assumption perhaps rooted in our inflated estimation of our autonomous selves, of what we can do with time and money. But the questions themselves may provide answers of a different type, as their subjectivity stores inerasable human instincts; like the pugilism revealed in the “fight against cancer,” the desire to label and extinguish a perceived enemy, to put a face on our confusion and suffering.

 

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