The average human carries 20,000 different species of bacteria in his or her digestive system, according to scientists. These bacteria, collectively called the human microbiome, have been linked to a variety of ailments, including diabetes, obesity, asthma and autoimmune diseases. They also have been linked to depression and overall mental health.
Scientists can identify the bacteria by decoding DNA using genetic sequencing machines, ushering in the dawn of a new era in understanding human health.
Researchers in the US, Europe and China are racing to put the knowledge to work. The complexity is astonishing. Scientists do not know how the different populations of bacteria interact with each other, and they do not understand the specific mechanisms by which the bacteria impact the health of a human host. They do know, however, that people in different parts of the world have very different collections of bacteria inside them. They suspect that the various bacterial soups may help to explain why some nationalities are prone to diseases that rarely occur in others. And that has many scientists asking: Could we prevent or cure diseases by managing the mix of bacteria in a person’s gut?
THE COMPLEX UNKNOWN
As a pioneer in this field and head of the American Gut project, the world’s largest open-source science project to understand microbial diversity in the human digestive system, Rob Knight is one of the world’s leading human microbiome scientists.
“The complexity of the microbiome likely exceeds the complexity of cancer because of the sheer number of genes involved, the number of configurations and the number of attractions among cells,” Knight said. “Your microbes have way more genes than you do, and they have way more connections between them.”
In purely technological terms, one key to making sense of it all is to drive down the cost of deciphering a gene, which means continuing the revolution in DNA sequencing machines.
“The big challenge is really the DNA sequencing,” Knight said. “At the moment, each batch of DNA sequencing is expensive and you need to accumulate a lot of samples to put them into the sequencer.”
BGI, formerly known as the Beijing Genomics Institute, based in Shenzhen, China, is the world’s largest purchaser of DNA sequencing machines. BGI is exploring many genomics subjects, including the bacteria in the digestive systems of newborn children.
DECIPHERING THE DATA
The microbiome’s complexity, however, makes the well-chronicled big data challenge look like child’s play. The American Gut project uses DNA extraction protocols from MO BIO Laboratories, a privately held biotech company in Carlsbad, California. It then processes the results either on the University of California’s supercomputer network or on Amazon Web Services, a provider of cloud-computing services.
All of these fields – big data, supercomputing and cloud computing – are undergoing rapid evolution, and all are essential to making sense of the microbiome. “It’s kind of like asking what’s more important for a cake; is it the flour or the eggs or the sugar?” Knight said. “The reality is that you need all of them to be successful.”
To date, some 6,000 people have had their gut bacteria analyzed by the American Gut project, but the complexity of the data is difficult for anyone, even a medical doctor, to decipher.
Aside from technology, scientists who wish to unravel the microbiome’s secrets will have to change the way they conduct research, said David Agus, professor of medicine and engineering and director of the Center for Applied Molecular Medicine at the University of Southern California in Beverly Hills, as well as a leading cancer researcher who is expanding his work into the microbiome.
“My team has physicists, mathematicians, mathematic modelers and biologists all on one team,” Agus said. “We have to do something that was considered heretical a decade ago. We have to converge the sciences. That’s how we’re going to make breakthroughs in fields like this.”
“WE HAVE TO DO SOMETHING THAT WAS CONSIDERED HERETICAL A DECADE AGO. WE HAVE TO CONVERGE THE SCIENCES. THAT’S HOW WE’RE GOING TO MAKE BREAKTHROUGHS IN FIELDS LIKE THIS.”DAVID AGUS
CANCER RESEARCHER, UNIVERSITY OF SOUTHERN CALIFORNIA
Agus’ team relies on massively parallel computing, an advanced type of supercomputing that uses a large number of processors or separate computers to perform a set of coordinated computations simultaneously.
He argues that it is folly to insist on establishing every data point – for example, how one population of bacteria engages with another – because that is beyond the capabilities of even the most powerful supercomputers for the foreseeable future.
It is better, Agus said, to develop “coarse” theories based on approximations. One coarse theory is that, although no one understands the precise connection, tobacco smoking is almost universally acknowledged to increase the risk of lung cancer. Agus recommends a similar common-sense approach for the emerging microbiome field. “This is a complex emergent system,” he said. “You have to look at it in terms of modeling, not the reductionist approach, to try to understand every data point.”
Although the work is just beginning, some signs indicate how different industries will seek to profit. For example, one medical response to an antibiotic-resistant “super bacteria” called Clostridium difficile (or C. diff), which kills thousands of people a year, is the use of fecal microbiota transplants. A patient is, in effect, given a colonoscopic infusion of fecal microbiota from a healthy donor in an effort to clean out the C. diff.
While this method has been shown to be effective against C. diff cases in the US, the US Food and Drug Administration has not authorized it for any other bacterial imbalance. Some manufacturers have therefore developed pills containing treated fecal material that can be swallowed. The goal is the same: changing the gut’s bacterial balance.
Another exploding field is probiotics. Probiotics are taken orally to build up the number of “good” bacteria. One breakthrough discovered by Karl Seddon, who graduated from the University of Oxford (UK) with a master’s degree in biomedical engineering, allows probiotics to pass intact through the digestive tract until they reach the large intestine. Once there each dose, now the cornerstone of a UK-based company called Elixa Probiotic Limited, reportedly delivers 50 times more beneficial bacteria, compared to the average probiotic supplement. Following a six-day program, Elixa reports the regimen releases 3 trillion units of “good” bacteria into the user’s microbiome, compared with 10 billion with the average probiotic. Because it is considered a food supplement, Elixa’s capsules are available in many jurisdictions without a prescription.
CHANGING THE ECOSYSTEM
These techniques are blunt instruments, however, compared to the goal of achieving a deep understanding of exactly what is happening in the interactions among different bacteria and the human host.
Over the longer term, the big payoff could come when either pharmaceutical or food companies or both learn how to tweak existing products or develop new ones that impact the microbiome in ways that spur specific health outcomes. Currently, the food industry has a head start because pharma companies, as a rule, try to identify a specific molecule, patent it and then conduct clinical trials to win approval from government regulatory agencies.
The sheer mathematical complexity of the microbiome also may require a mixture of different substances to reshape it; a one-molecule solution may not prove effective, said Scott J. Parkinson, head of the Gastrointestinal Health and Microbiome group at the Nestlé Institute of Health Sciences in Lausanne, Switzerland. “People are becoming more and more aware that it isn’t a single bug you’re trying to change,” Parkinson said. “You’re actually trying to change an ecosystem.”
The vast possibilities are easy to imagine. If Nestlé, for example, could tweak its infant milk products – just one of its many product lines – for different types of children in different geographies, the result could be enormous health benefits and large sales.
“Nestlé and other food companies are investing a lot of money trying to figure out the future of the microbiome, as far as product development goes,” Parkinson said. “Maybe you think about products that combine knowledge about lipids, carbohydrates and proteins and target the microbiome at multiple levels to get the ecology we’re looking for in very specific patient populations. Then we could expand it and tailor-make products for various consumers or patients.”
Like Agus, Parkinson is skeptical that scientists will succeed in cracking open the microbiome’s secrets any time soon. At least for now, they will have to rely on the old-fashioned scientific method to formulate hypotheses about what works and then test those theories. The way an individual responds to a particular drug, for example, could serve as a marker that reveals clues about his or her microbiome.
The race is truly global, and it is picking up speed. Many people suffering with untreatable ailments hope answers come fast. ◆