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Designer Genes, the Bacteria in Our Guts, and Precision Medicine

In the near future, we will routinely have our genetic material analyzed; late in the next decade, we will be able to download and “print” at home medicines, tissues, and bacteria custom designed to suit our DNA and keep us healthy. In short, we will all be biohackers and amateur geneticists, able to understand how our genes work and how to fix them. That’s because these technologies are moving along the exponential technology curve.

Scientists published the first draft analysis of the human genome in 2001. The effort to sequence a human genome for the first time was a long and costly one. Started by the government-funded Human Genome Project and later augmented by Celera Genomics and its noted scientist founder, Craig Venter, the sequencing spanned more than a decade and cost nearly $3 billion. Today, it is possible to completely sequence a human genome for a cost of less than $1,000 and to do so in less than a day. There are even venture-backed companies, such as 23andMe, that sequence parts of human DNA for consumers, without any doctor participation or prescription, for as little as $99.

We can expect the price of DNA sequencing to fall to that of a regular blood test in the early 2020s and, shortly thereafter, to cost practically nothing. Again, what makes this possible is that the computers that sequence DNA are becoming faster and more powerful in parallel with development of the microprocessors that power them, which double in speed and halve in price every eighteen to twenty-four months. Ultimately, someone will build a sensor-packed dongle and a smartphone application that can do it in the field, in seconds: prick your finger; parse your DNA; done.

By the mid-2020s, sequencing DNA will probably become part of a normal health panel. Your genome will be part of what doctors look at to determine treatments and potential risks. This will be more accurate than any other tests.

A team of scientists published a study in The New England Journal of Medicine documenting that fetal DNA testing was ten times better at predicting cases of Down syndrome (trisomy 21) than the standard blood test and ultrasound screening were,⁷⁶ and five times better at predicting Edwards syndrome (trisomy 18), a mutation arising from an error in cell division that in the early months and years of life results in more complications, which are more potentially life-threatening, than those of Down syndrome.

At leading cancer-treatment centers all over the world, scientists are using DNA tests to find out whether a patient’s tumor carries clinically useful mutations that make cancers vulnerable to particular drugs and to match individual patients with available therapies or clinical trials that will most benefit them. Treatments developed for one type of cancer are being used to treat other cancers with similar gene mutations.

It is not all smooth sailing, though. Scientists have suffered a number of agonizing setbacks in the arena of genomically targeted drugs. Compounds that caused cancer to go into remission by focusing on molecular targets in cancer cells, for example, failed to deliver a permanent cure and allowed the cancer to return in a more aggressive form. Regardless, there is hope for better outcomes; we can expect more progress in curing cancer (and other diseases) in the next five years than there has been in the past fifty years.

We will be able to surmount the obstacles in developing safe, effective techniques and technologies to reverse genetic mutations because a lot is happening at the same time. With the numerous genomic data already available and the ability to sequence at will, scientists are experimenting, learning from mistakes, and quickly moving on to new ideas. They will soon decipher the complex relationships between DNA and biological processes with the help of artificial intelligence and Big Data analytical tools. Increasingly precise knowledge and deepening understanding of DNA will lead to a wholesale shift in how we think about medicine and health, and we will move from broad-stroke to personalized health care.

The Big Shift in Medicine: From Broad Stroke to Precision Genomic Targeting

In 1972, Richard Nixon declared a war on cancer. The president wanted to be able to declare cancer eradicated, much as we have since declared smallpox and polio. It was a noble but quixotic fight. Doctors understood, even then, that cancer is not a single disease, yet treatments such as chemotherapy and radiation tended to focus more on location and gross processes than on specific cellular biology.

Today, cancer remains very much with us, but investigation of this broad class of illnesses has helped spark a wholesale shift in medical thinking that extends well beyond it.

Breast cancer, for example, as not only doctors but many patients now understand, comprises a genetically diverse realm of ailments that are in many ways biologically unrelated. High-profile celebrities such as actress Angelina Jolie may opt for radical mastectomies when they discover that they carry genes that promise a high likelihood of a particularly rapacious cancer’s appearance in their breasts later in life, but this may not be the most appropriate response.

Eric Green, director of the National Human Genome Research Institute, explains that cancer is essentially a genomic disease. “Instead of classifying cancers by the tissue where they are first detected—colon, breast, or brain—doctors are beginning to categorize cancer by its genomic characteristics and select treatments based on the signature of different mutations. This approach promises to treat patients with the most effective medicines while minimizing undesirable side effects, especially when chemotherapy is unlikely to help,” he said to me in discussing this technology’s future.

As I mentioned earlier, the usefulness of DNA sequencing has expanded from its role in pure research to use in diagnostics, clinical practice, and drug development broadly. The large amounts of data are enabling scientists to identify key genetic predispositions to more than 5,000 of the inherited diseases resulting from mutations in a protein-encoding gene. In an extensive research program, the Centers for Mendelian Genomics is working to find the genomic bases of these diseases, which collectively afflict 25 million Americans. Its researchers reported in a paper in August 2015 that they had identified mutations in 2,937 genes and were making as many as three discoveries a week because of “next-generation” DNA-sequencing technologies.⁷⁷

Though the technology isn’t perfect yet, Sloan Kettering Hospital is using IBM Watson to help deliver personalized treatment plans for patients. Watson pores over all the literature, studies a myriad of drug interactions, and sifts through treatment outcomes for patients with similar genetic makeup, background, and cancer strains to identify the best possible course. This is something a physician simply cannot do in a reasonable period.

The Sloan Kettering offering highlights another key shift, to using A.I. to make the doctors smarter and let them focus on the medical aspects that require a human touch and judgment. But, though A.I. systems may be able to tell a doctor the highest-outcome chemotherapy regime, the computer cannot help patients make a decision as to whether to continue treatment that makes them feel horrible and offers a slight chance of recovery. Medical decisions about very serious illnesses are ultimately human decisions, and for that we still very much need the help of doctors, nurses, and others with true empathy. (It will be a long, long time before A.I. can eliminate these jobs.)

The new era of precision medicine and granular understanding of the interplay of all genetic material and environmental stimuli has enlivened quests for extreme longevity. Google (whose holding company, Alphabet, was created in 2015), for example, has Calico, a subsidiary focusing on radical life extension; and Craig Venter is one of the cofounders of a company called Human Longevity, which is working on extending the healthy human life span through genomics-based stem-cell therapies that mitigate the diseases of aging. This company is sequencing hundreds of thousands of genomes and incorporating data from functional-MRI scans that capture views of and data from processes inside a living human body in order to match genetic processes with in vivo biological ones.

The next big medical frontier after genomics is also already on the horizon: the microbiome, the bacterial population that lives inside your gut. This is a field that I am most excited about because it takes us back to looking at the human organism as a whole. Scientists are coming to the conclusion that the microbiome may be the missing link between environment, genomics, and human health. They are discovering connections between what types of bacteria live inside your body, how your genes behave, and how healthy you feel.

Microbiome: Bacterial Rainforest in Your Gut

Many children are born with genetic predispositions to type-1 diabetes. Though some of those infants become diabetic in their earlier years, others do not. A key reason for this may lie in the microbiome. In February 2015, researchers from MIT and from Harvard University released the results of the most comprehensive longitudinal study yet of how the diversity and types of gut flora affect onset of this type of diabetes.⁷⁸ The scientists tracked what happened to the gut bacteria of a large number of subjects from birth to their third year in life, and found that children who became diabetic suffered a 25 percent reduction in their gut bacteria’s diversity. What’s more, the mix of bacteria shifted away from types known to promote health toward types known to promote inflammation.

Correlation is not causation, but the results added to evidence that the bacteria in our intestines have a strong effect on our health. In fact, manipulating the microbiome may even become more important than genomics and gene-based medicine. Unlike genomics and gene therapy, which require a relatively heroic effort to induce physiological changes, tweaking the microbiome appears to be relatively straightforward and safe: just mix up a cocktail of the appropriate bacteria, and transplant it into your gut.

One of the hottest topics in medicine has been the successful treatment of Crohn’s disease using fecal transplantation. This autoimmune disorder of the digestive tract ruins the lives of millions of sufferers in America. The solution is still being researched, and there could be other complications, but it appears to be relatively simple: take a small sample of feces from a healthy person, mix it up in a blender with some water, and give the Crohn’s victim an enema of the fecal cocktail.⁷⁹ I know that it sounds disgusting; but, so far, the treatment has proven extremely effective. Similar research is being conducted on other diseases.⁸⁰ Every week studies are published that illustrate the power of the microbiome to foster a healthy immune system and fend off disease.

What you eat, too, affects what is in your gut. A study published in the journal Nature found that changes in diet can cause dramatic shifts in the microbiome within three or four days.⁸¹ “We found that the bacteria that lives in people’s guts are surprisingly responsive to change in diet,” Lawrence David, assistant professor at the Duke Institute for Genome Sciences and Policy, and one of the study’s authors, told Scientific American. “Within days we saw not just a variation in the abundance of different kinds of bacteria, but in the kinds of genes they were expressing.” The researchers noted shifts in the volume of bile acid secreted. Most surprisingly, they found that bacteria native to food we eat can handle the bile bath and colonize our guts when we eat foods, such as cheeses or meats, that are happy homes to bacteria.

As this discovery illustrates, diet is important, but though it may help motivate them, getting people to alter their diets is exceptionally hard. (That’s why most diets fail, right?) But we may be able to work around that by creating ways to change the microbiome balance in our bellies using supplements or other delivery mechanisms. And here’s where a rapid pace in scientific advances pays off: a wide-ranging analysis of microbiomes to identify bacterial population patterns in the guts of millions of people could provide a blueprint for the gut contents of disease sufferers and healthy people. This census could inform treatment efforts and allow doctors to more effectively manipulate the microbiome. So a yogurt a day may keep the doctor away, and a tummy full of the right sorts of cheese may be better medicine for many metabolic syndromes than pharmaceuticals or other lifestyle changes.

Genomic medicine, gene-targeted drug development, and microbiome manipulation all depend on the ability to read DNA. But a few years ago we pushed past simply reading DNA and began writing it: creating life forms that did not naturally evolve.

Altering Life Itself: The Rise of Synthetic Biology

A computer-designed virus that cures a fatal disease, new types of bacteria capable of synthesizing an unlimited fuel supply or of wiping out every person on Earth, customized biotoxins targeting the genome of the U.S. president, engineering an Olympic athlete for height and strength from the first days of inception: science fiction? Actually, we’re well down that road. When looking back in history a hundred years from now, we will probably recognize this as the greatest historical shift in genetics: the transition from reading and understanding DNA to editing it in living organisms and creating entirely new organisms using chromosomes created de novo from DNA base pairs.

In May 2010, Craig Venter announced that his team had, for the first time in history, built a synthetic life form by creating entirely novel DNA. Christened Mycoplasma mycoides JCVI-syn1.0, also known as “Synthia,” the slow-growing, harmless bacterium was made of a synthetic genome with 1,077,947 DNA base pairs. To make Synthia, Venter’s team inserted a synthetic genome into a cell containing no DNA.

The technology that Venter used to “write” the genes of this new organism is the equivalent of a laser printer that can “print” DNA. DNA has a fairly simple structure, with a double helix comprising two chains of nucleic acids, linked in pairs. A number of DNA print providers, such as Thermo Fisher Scientific, Bio-Cat and GenScript, offer DNA synthesis and assembly. Current pricing is by the number of amino-acid base pairs—the chemical components of a gene—that are to be assembled. From 2003 to 2015, assembly costs plummeted from $4 to 10 cents per base pair.

More recently, in January 2018, researchers at UCLA surprised the scientific community with a new technique called DropSynth, which enables scientists to build hundreds of genes at once. The technique, because it requires no specialized equipment, is expected to reduce the cost of printing a gene from about $150 to $2.⁸²

Tinkering with our genetic material is, however, a risky thing. We don’t even know how little we know about the effects of altering a single gene.

From the 1940s through the discovery of DNA’s double-helical structure in the 1950s and even into the twenty-first century, it was generally assumed that each gene took the form of a single recipe for building a single protein: one gene, one protein, which quickly became the central dogma of what has been called the “new synthesis” of biology, a synthesis of the understanding that Darwinian selection and Mendelian genetics have given us.

The one-gene-one-protein central dogma of the modern synthesis of biology, though it continues to pervade our common beliefs about genetics, underwent serious modification when scientists realized that many proteins comprise several polypeptides, each of which was coded for by a gene. The dogma then became “one gene, one polypeptide.”

But the discovery in the 1970s that a single gene can code for more than one protein sounded the entire dogma’s death knell. We now know that a single gene can contain the instructions for building not just one protein but tens of thousands of proteins, instructions selected according to the dictates of non-gene DNA segments in response to the organism’s genuine needs—or chemical derangements (largely accounting for many instances of degenerative disease such as cancers).

As some have observed, this potential for vast protein diversity raises the possibility that cells are able to identify themselves individually within the organism: an entire realm of possibilities undreamt of because we didn’t know the function of non-gene DNA segments and had no notion of their role in choosing gene-splicing permutations.

In a nutshell, we don’t know the limits of the new technologies, we can’t guess what lifetime effects a single alteration of a healthy gene will have on a single individual, and we have no idea at all what effects a novel gene in a sperm or ovum or fetus will have on future generations.

In the early 2030s, it will more than likely be possible to search for genetic designs on the web, download them to your computer, and modify and adapt them to your needs. Cold- and flu-vaccine designs as well as custom cures for pandemics will be available online globally upon release, and the process of printing them will be as easy as downloading an application on a smartphone. This technology may enable any of us to print our own treatment—or, more darkly, to become a backyard eugenicist.

You may recognize from the radio show A Prairie Home Companion the line “and all the children are above average.” The new average will be above the old one—for those who can pay for it. Should the U.S. government subsidize eugenic improvements to ensure a level playing field when the rich have access to the best genetics that money can buy and the rest of society does not? Will we enter a time when those who can afford it live far longer and healthier lives than those of lesser means because they can pay for a better genome?

Because of yet another genomics technology, we may face these questions sooner than we might think.

In 2014, Chinese scientists announced that they had successfully produced monkeys that had been genetically modified at the embryonic stage.⁸³ In April 2015, another group of researchers in China published a paper detailing the first ever effort to edit the genes of a human embryo.⁸⁴ The attempt failed, but it shocked the world: this wasn’t supposed to happen so quickly. And then, in April 2016, yet another group of Chinese researchers reported that it had succeeded in modifying the genome of a human embryo in an effort to make it resistant to HIV infection.⁸⁵ The scientists used a new technique, the CRISPR-cas9 system, which was developed in the United States by Jennifer Doudna, of UC Berkeley, and Feng Zhang, of M.I.T. Cas9 helps to snip out a piece of DNA from a cell and then enables the cell to stitch the ends back together. It can be used to edit out faulty parts of the DNA.

Better results have been achieved recently using a variant of CRISPR called base editing. In a 2018 study in China, researchers used base editing to remove and replace a single errant amino acid on a single gene. The procedure corrected a flaw that is the cause of Marfan syndrome,⁸⁶ a potentially fatal condition that weakens the connective tissues in the body and can result in heart failure.

The rough material cost of editing a gene using CRISPR is between $50 and $100. In other words, it’s a lot more expensive to go to an NBA basketball game than to edit a gene or to create a new DNA structure using CRISPR.

In the very near term, scientists hope to use CRISPR to edit human genes for therapies against cystic fibrosis and other hereditary fatal conditions. In the longer term, supporters of synthetic biology point to huge potential benefits. Freed from the slow-moving confines of evolution, we could potentially edit genes and build new ones to eradicate all hereditary diseases. We might respond quickly with genetic alterations to withstand horrific epidemics such as the Spanish influenza that killed tens of millions. And we might design plants that are far more nutritious, hardy, and delicious than anything that exists today.

Agronomists are undertaking genetic modifications of food that are reductive rather than additive, meaning that they are fixing or removing plant genes that generate undesired traits. This approach appears to be more palatable to critics who object to “Frankenfoods,” where researchers splice genes from one species into another (for example, food crops that produce organic pest killers by virtue of foreign genes added to their genomes.)⁸⁷

Reductive genetic modification does not, however, mitigate the considerable ethical and scientific concerns that abound over the release of genetically modified organisms into the wild. Plans to release genetically crippled mosquitoes in the southern United States to reduce the risk of tropical ailments that they host, for instance, met firestorms of concerns.⁸⁸ Altering the DNA of insects is controversial enough. The prospect of altering the genes of people—modern-day eugenics—has caused a schism in the science community. Regardless, this gene editing is now happening. Although we can’t yet reformat our genomes as we can our hard disks, we are approaching such a capability, and this is creating concerns even among the creators of the technologies. One of CRISPR’s inventors, Jennifer Doudna, came out strongly in favor of a cautious approach to modifying the human germline in 2015. “The idea that you would affect evolution is a very profound thing,” she said to the New York Times.⁸⁹

I personally love technology and have never before advocated slowing down technological development. But, in September 2015, I wrote a column for The Washington Post titled “Why there’s an urgent need for a moratorium on gene editing.”⁹⁰ I argued that we need to better understand the technologies and develop a consensus on what is ethical before allowing researchers to edit the DNA of human embryos.

We simply do not yet understand the potential unintended consequences of genomics editing. What if modifications result in terrible illnesses? What if they somehow modify brain chemistry to make a healthy genome of psychotic, remorseless superhumans? What if a synthetic bacterium escapes the lab and causes a widespread plague that kills millions?

A panel of distinguished scientists, in December 2015, expressed similar concerns. At a meeting convened by the National Academy of Sciences of the United States, the Institute of Medicine, the Chinese Academy of Sciences, and the Royal Society of London in Washington, the panel called for what would, in effect, be a moratorium on making heritable changes to the human genome.⁹¹ The International Society for Stem Cell Research went further, calling for a moratorium on all gene therapy. The academies said that it would be “irresponsible to proceed” until the risks could be better assessed and there was “broad societal consensus about the appropriateness” of any proposed change. They left open the possibility for such work to proceed in the future by saying that as knowledge advances, the issue of making permanent changes to the human genome “should be revisited on a regular basis.”

The academies, however, have no regulatory power; what they published were just guidelines. The many calls to stop the editing of embryos have been to no avail. They could not stop researchers in China.

In November 2018, a Chinese scientist from a university in Shenzhen claimed to have helped create the world’s first genetically edited babies. He told the Associated Press that twin girls were born in that month after he had edited their embryos using CRISPR to deliberately damage the CCR5 gene, which in normal health forms a protein doorway through which the HIV virus can enter a cell. This step toward genetically tailored humans was undertaken in secrecy and with the clear ambition of achieving a stunning medical first, and it resulted in one embryo with both copies of the CCR5 gene genetically damaged and one embryo with one intact copy.

So CRISPR babies are being manufactured heedless of the state of our ignorance of the broader effects of genetic tampering and heedless of the irreversibility of any damage this may do to future generations.

Humans are on the verge of finally being able to modify their own evolution. The question is whether they can use this newfound superpower in a way that is responsible and that will benefit the planet and its people.

The ethical problems extend to the way in which synthetic biology may open a Pandora’s box of national-security problems. Security futurist Marc Goodman says that it could lead to new forms of bioterrorism, with hitherto unseen forms of bio-toxins.⁹² These bio-threats may be nearly impossible to detect, because they can be customized to the genome of a certain person or groups of people. Goodman, who has worked on cybercrime and terrorism with organizations such as Interpol and the United Nations, says that the bio-threat potential is greatly underestimated. “Biocrime today is akin to computer crime in the early 1980s. Few initially recognized the problem, but one need only observe how the threat grew exponentially over time,” he says.

If the tools are there, criminals and terrorists will exploit them. They have embraced drones and cybercrime because they are useful, and they will exploit synthetic biology. So we will need new types of defenses against hostile synthetic bio-toxins or life forms. And we will need global agreements to stop governments themselves from “engineering” the perfect athlete or soldier.

Do the Benefits Outweigh the Risks?

As you have probably guessed, I am deeply concerned about the implications of indiscriminately editing the human genome. The primary risks arise from alterations of the germline: heritable genetic modifications. (Genetic therapies using CRISPR that will fix only in situ gene expressions and are not heritable are not nearly as problematic, being more similar to the familiar risks of new drugs and treatments.) Synthetic biology presents grave existential risks that we must examine and consider very closely before widely permitting artificially designed life loose outside the lab. A synthetic-biology experiment gone awry could unleash horrific disease or environmental damage that would be nearly impossible to stop.

Yes, I know that lives can be saved and diseases cured, and that we don’t have time to waste; but there needs to be a balance. To allow these technologies to function safely outside the lab, researchers must put in place multiple mechanisms to ensure that engineered organisms can be, for lack of better words, killed on demand, and quickly. I am advocating not that we cease progress, but that we slow it down until we understand the risks—and are sure that the benefits outweigh them.

In this light, the most promising and least controversial realm of breakthroughs discussed in this chapter is the ongoing analysis of the microbiome. Since this is more about restoring ancient healthy systems in our intestines that evolved naturally, rather than about permanently or radically altering life forms, the microbiome promises to be the least risky and perhaps the most important way to affect our health and quell the very lifestyle diseases that have proven so resistant to all manner of interventions. This will benefit everyone equally, will not lead to dependence on drugs and doctors, and will be affordable by all. It is where we must focus more energy—as we develop guidelines on how to safely use gene editing. Fortunately, the U.S. government agrees about the importance of doing so: the White House launched the National Microbiome Initiative in May 2016 to foster the integrated study of microbiomes across different ecosystems and committed more than $121 million for the research.⁹³