In the Zone

As Robert Frost’s poem posits, humankind will always seek to extend its reach. In a literal sense the poem, only a few lines of which we’ve quoted, is about a peach tree planted too far north. But its message has a timeless figurative meaning. Seventy years ago, Frost’s depiction of the hubris of planting a fruit tree beyond its climatic limits may have had the commonsense ring of truth. One can see the reader mulling it over: “Ah, yes, too cold. What were they thinking?” Or, “How foolish to expect this would work out well.”

“In the twenty-first century and beyond, human ambition will be bound only by the laws of physics, the rules of logic, and our descendants’ own sense of right and wrong.”

If Frost were with us today he might reconfigure his poem, updating it, exchanging transplanting a tree with transforming a cell, cloning an embryo, or creating genes in a computer. Now it is not a zone of adaptability we consider; it is changing the code of life, in essence engineering life from the roots up or, more accurately, from the cell out.

Even though the setting and method have changed, the question hasn’t: Are there roughly zones—limits we should not cross?

Plug-and-Play

Frost died in 1963, a decade before the advent of gene splicing. Color television was a new marvel. It was the midpoint between the discovery of the structure of DNA in the early 1950s and the first genetically engineered cell in the early 1970s.

Now almost 40 years old, the concept of genetic engineering through gene recombination, or recombinant DNA, is the foundation on which much of the biotech industry has been built. Early efforts at genetic modification led to the creation of bacteria that could synthesize human insulin. Miraculous as that seemed at the time, it isn’t too difficult from today’s perspective. In fact, it could be performed in an elementary school science class with little specialized equipment: the human gene for making the protein is cut and pasted into the bacterial genome and is thus recombined. It works because, just as an MP3 file can be read by any appropriate player, so the universal character of the genetic code makes any gene “playable” by any cell. Biotechnology merely takes advantage of the remarkable plug-and-play nature of the genetic system of life.

Of course, this was all new territory then, a leap forward—and not without detractors. Initial safety concerns were addressed in a kind of grassroots gathering in 1975. The Asilomar Conference is noted for its effectiveness in generating scientific agreements concerning how research should move forward. Those who continue to advocate that science should regulate science also see it as a benchmark, in that participants didn’t hinder laboratory work by jostling over ethics or messy political issues.

Beyond Recombination

A key player at Asilomar was Paul Berg. In accepting the 1980 Nobel Prize in Chemistry, he reiterated the pivotal nature of the scientific work: “The development and application of recombinant DNA techniques has opened a new era of scientific discovery, one that promises to influence our future in myriad ways.” Berg, a pioneer of the recombinant technique along with Steven Boyer and Stanley Cohen, noted later that “it was like an avalanche behind us” as other scientists used the new tools for both research and profit.

Controversies today have turned to patents: who owns the genes, the processes and the created organisms? The U.S. Supreme Court approved the first patented organism in 1980—a bacterium engineered to eat oil as an aid in oil-spill clean-ups. The first patented animal was DuPont’s transgenic OncoMouse (1988). Harvard researchers engineered the mouse to develop cancer and thus serve as a drug-testing platform. Others produced a mouse designed to lose its hair, for use in baldness studies. In that instance, however, the European Patent Office denied a patent because the potential human benefits did not outweigh the cost to the mouse.

Meanwhile genetic modification of plants has become common, with patented staples such as GM corn, soybeans, canola and cotton out-performing natural forms. Many still oppose this trend, though protest tends to wax and wane as world grain supplies peak or dwindle. The reality is that all domesticated crops are manipulated in the sense that they are the products of intense breeding programs. In terms of agriculture, we rely on very little that we have not in some way altered. Of course, the kind of alteration that is now in full swing is of a different order than has been the case for millennia. But as more consumers accept GM as the newest breed, the fear of so-called Frankenfoods fades.

Deaf to our debates on the safety issues of mixing genes from different species, nature carries on, however. Crops built to withstand herbicides or make their own pesticides give way to weeds becoming hardier and pest species growing immune to the very herbicides and pesticides that GM organisms were designed to tolerate and make more effective. As ecologist Paul Ehrlich has warned, “Nature bats last.”

These examples give some historical perspective to the newest form of engineering: to create genes and cells digitally. The first such synthetic organism was announced in May 2010 by J. Craig Venter and funded by Synthetic Genomics, Inc. It’s important to note that Venter’s group did not achieve spontaneous generation of life. Still, the new degree of genetic manipulation is remarkable. After sequencing a bacterial genome and recording it as a digital file, they edited the file, just as one edits a text. At one point they inserted a salient quote attributed to physicist Richard Feynman: “What I cannot build, I cannot understand.” Of course, they wrote it in code using the DNA language of A, T, C and G, but they made their point: Now we can build what we want; we are not reliant on only what nature gives us to work with.

The researchers plugged their handmade genome into another type of bacterium and booted up the cell using the new software. “We refer to such a cell controlled by a genome assembled from chemically synthesized pieces of DNA as a ‘synthetic cell’, even though the cytoplasm of the recipient cell is not synthetic,” Venter and his coworkers explained in their report. Venter’s goal is to build cells that will be useful to humans by, for example, ameliorating disease through new vaccines. Asked about potential downsides, he replied at a press conference, “It’s not clear there are any.”

How to Play God

When once asked whether understanding DNA leads to playing God, James Watson, co-discoverer of the double helix, infamously answered, “If we don’t play God, who will?” And so, in a way, we have.

“When a bioengineer intervenes for nontherapeutic ends, he stands not as nature’s servant but as her aspiring master, guided by nothing but his own will and serving ends of his own devising.” 

Perhaps believing that God was out of touch or otherwise occupied, humanity has always striven to make the world a better, more comfortable place. Biblical passages, even if seen only as a record of secular hopes, speak to this eternal desire: the wolf and the lamb together at peace (Isaiah 11:6); spears turned into pruning hooks (Micah 4:3); a new heart (Ezekiel 36:26); victory over death (1 Corinthians 15:54); a new heaven and earth (Revelation 21:1). While today these may have lost some of their familiarity, the imagery holds out compelling possibilities. But with these, the Bible also conveys in Genesis the story of humankind’s eating from the tree of the knowledge of good and evil. Can we trust our decision-making when we have determined to, so to speak, go it alone?

Those who see the biblical promises as prophetic statements of things to come, endpoints that God alone can bring to fruition, often accuse those on science’s frontier of overstepping their bounds. Indeed, for those who also take seriously the statement “Nothing that they propose to do will now be impossible for them” (Genesis 11:6b), it seems clear that we have a responsibility to limit ourselves—to accept certain boundaries and refuse to cross them. Could it be that “playing God” is not so much about doing all the things we can think to do, but more about caution, more about wisdom and self-control?

In whatever light one views human beings—whether our creative consciousness is the byproduct of evolution or the key attribute of being created “in the image of God”—we must take responsibility for what we know. The heretofore hidden powers we have wrested from the natural world are now our powers. It is an unfortunate foible of human nature to lean toward expediency, so the need to walk with care is often neglected, irrespective of underlying belief. Only sporadically do we overcome this common shortcoming as individuals; even less likely would one expect it of an entire group.

Surprisingly, however, walking with care was exactly what the President’s Council on Bioethics focused on when in 2002 it began looking deeply at the range of possible futures that lay at our biotechnological fingertips. “Such exploration is unlikely to result in a large number of policy recommendations, but that is not its aim,” wrote Gilbert Meilaender, professor of theology at Valparaiso University and a member of the council throughout the tenure of U.S. president George W. Bush. “The aim, rather, is to help the public and its elected representatives think about the implications of biotechnological advance for human life. . . . The Council thought of the task of public bioethics not as protecting scientific research from oversight but as enriching public deliberation about the place of research in our common life together.”

The lack of specific policy directives, and especially of recommendations that researchers be given carte blanche or that “science knows best,” continues to stoke an undercurrent of criticism among scientists. For instance, at the 2010 International Society for Stem Cell Research conference in San Francisco, Vision found that many still dismiss the Council’s work as biased, the odious product of authorship stacked in favor of “Christian morality” and the Bush doctrine of restricted stem-cell research. Some still complain that funding restrictions beyond those set by a scientific consensus have been an unnecessary roadblock to progress. It is ironic that the Bush policy was actually more liberal, in fact opening sources of federal funding to human embryonic stem-cell research, than U.S. law had previously allowed. [As this article goes to press, it appears that the Obama administration’s policy of allowing greater latitude in federal funding for research may be disallowed on legal grounds. The exact implications of the August 23 ruling are currently uncertain.]

Criticism from each side notwithstanding, research continues apace. It is only wise to follow the developments, because we all move together; like cells in a body, we are separate, but we are one. As individuals we may not feel a need to know or to participate in the discussion. But as a 2003 report by the President’s Council on Bioethics notes, “because the choices made by some can, in their consequences, alter the shared life lived by all, it behooves all of us to consider the meaning of these developments, whether we are privately tempted by them or not” (“Beyond Therapy: Biotechnology and the Pursuit of Happiness”).

An Age of Control

We live in a new age, a time Sir Ian Wilmut calls the “age of biological control,” where he believes the notion of something being biologically impossible is obsolete. Wilmut, along with colleagues at the Roslin Institute and the biotech firm PPL in Edinburgh, Scotland, in 1996 created the first mammal cloned from an adult body cell. Although there were several others (lambs that were not only cloned but genetically modified as well), Dolly became the best known. She proved that a totally differentiated adult cell contained a complete genome. Of course, it was the ideas of creating duplicates and cloning people that spawned the greatest intrigue.

Surely by now, however, we all understand that even though a clone may share the donor’s genetic make-up, every individual is, well, individual—the unique product of genetic, environmental and experiential inputs. Cloning is not going to be a good hedge against the things we fear most: disease and death. Nevertheless, when the topics of gene engineering, chromosome-making, stem-cell injection and genomic analysis are jumbled together, almost anything seems possible.

Of course, all things are not yet possible. Even the most likely stem-cell-based regenerative medicine remains a long-range goal with many short-term research objectives still to be met. These include understanding how the cells work to generate healing from a biological perspective, and how they perform in patients.

“You have to be pragmatic in your approach, as well as apply the best and most rigorous science that you can,” says Clive Svendsen, director of the Cedars-Sinai Regenerative Medicine Institute in Los Angeles. “There is one group of people that says, ‘We need to know everything about this before we can possibly touch a patient.’ And there is another that says, ‘I don’t care about anything; put the cells in, because the patient is dying.’ I say, let’s have a rational plan backed up by statistical evidence that something has an effect; but once we get to a certain point, let’s proceed with that ‘something’ to a clinical trial.”

Habits of Life

While the goal of healing degenerative disease such as diabetes, Parkinson’s and ALS is a hopeful and positive good end, the means of reaching that goal remains cloudy. By distracting ourselves with dystopian scenarios (of, say, new species of humans bred and grown in bottles like a production line of colas, or genetic castes designed for the duller or more dangerous jobs of the future), we may miss the real downside of what already exists. How far do we go with pre-implantation genetic analysis? What of the fate of embryo “leftovers” from in vitro fertilization clinics? Is the intentional creation and destruction of human embryos as a source of new lineages of stem cells a good idea?

But we may miss the upside as well. A new embryo-like stem cell, called an iPS cell (induced-pluripotent stem cell) can be reprogrammed from a patient’s skin cell. The potential to create new cell lines useful for studying disease in human cells and not just animal models is an encouraging step. The idea is to “recapitulate” the course of disease, says Fred Gage of the Salk Institute in San Diego, with the aim of learning how the disease happened, the interplay of genes and biochemistry. True cures will be possible only if the actual workings of the diseased cells are revealed. Then it may one day be possible to access those mechanisms and retune them.

While many biologists take the reductionist view of disease—looking for the chemical switches to shut down problems and restart normal function—we know this is incomplete. “I think disease is totally a matter of context,” Susan Fitzpatrick, vice president of the James S. McDonnell Foundation, told Vision. Our problems may have cellular markers, but is what we see a cause or an effect? “Aspects of a particular question can be explored in models,” she says, but “at some point it all has to be brought back to a cell in a tissue, in an organ, in an organism, and the interactions at every level with the various environments encountered.”

Clearly there are broad influences that contribute to a person’s vulnerability to degenerative diseases. Because many are age-related, it would also make sense to seek out the characteristics common to healthy seniors. Dan Buettner, explorer and National Geographic writer, traveled the world to study pockets of centenarians. Collecting his findings in his book The Blue Zones, Buettner focused on lifestyle, not cells. Rather than excising broken tissue or bombarding the body with toxins to subdue wayward cells, Buettner suggests a different clinical path. “Cut out the toxic people in your life,” he advises, “and spend time and effort augmenting your social circle with people who have the right values and a healthy lifestyle.”

Leon Kass, chairman of the President’s Council on Bioethics from 2001 to 2005, adds that quality of life also means more than being free of disease. “It is not mere life, or even a healthy life, but rather a good and worthy life for which we must aim. And while poor health may weaken our efforts, good health alone is an insufficient condition or sign of a worthy human life.” This is a challenging statement because it asks us each to consider the purpose of life itself. What is a life for? “We must strike a proper balance,” Kass continues, “a balance that can only be furthered if the approach to health also concentrates on the habits of life.”

A Tree Is Known by Its Fruit

There is a feeling that new science is necessary to fix the problems created by old science. At the heart of Venter’s work is a desire not simply to repair what degenerative disease does to the body but to undo the damage we have done to the world. Even civilization itself can be seen as toxic, a pox—not simply from an ecological point of view but as itself degenerative or degenerating, teetering on the edge of collapse because we have built it with technologies whose long-term consequences we really did not understand. Venter’s offering of made-to-order life is meant to facilitate positive change, a seed planted for a better future. “We need new ways to alter our future, or we aren’t going to have one,” he says.

We have created a fast-paced, impatient world with which most of us are deeply intertwined and on which all of us depend—a dependence that goes beyond the interchange of food and water. Our wired umbilicals interconnect, rooted in human systems and cultures, thirsty for pulses of electronic media that power our working and leisure lives. When we have a free moment, a weekend perhaps, we want to go-go-go some more. But there is little time to think, and even less time to consider how this hectic pace changes and affects us psychologically and physically.

The point of a poem, and the enduring appreciation for the timelessness of a poet such as Frost, is that it provides something to think about, a pause worth taking. In our science- and technology-driven world, we seldom have a moment to reflect and consider that it is not the scientist but the artist who has the better grip on ambition and the drivers of human nature. Maybe we live in a comfort zone of naïve trust, unwilling to attend to the challenges brought about by our discoveries and our desires, hopeful that others might determine the boundary lines.

“Biotechnology,” suggests the “Beyond Therapy” report, “like any other technology, is not for anything in particular. Like any other technology, the goals it serves are supplied neither by the techniques themselves nor by the powers they make available, but by their human users. Like any other means, a given biotechnology once developed to serve one purpose is frequently available to serve multiple purposes, including some that were not imagined or even imaginable by those who brought the means into being.”

Yes, there are roughly zones. While our desires to investigate may be boundless, and we may feel that limits exist only to be overcome, we need to corral and temper those desires. Not all ideas will lead to where we want to go. That curiosity is the accelerator of human invention is undisputed; it makes us who we are and is at the core of all we do and have done. But an accelerator needs to be paired with a brake, a means to slow down, so we have time to judge and adjust. After all, contentment is also a healer.

A wise planter does not plant with abandon, without thoughtfulness; he selects his field and the appropriate crop carefully. Pushing forward without doing so, he knows, would yield bitter fruit.