Soon, artificial human organs may be used to personalize drug prescriptions

By Alyssa
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By: Quartz creative services

 

A team in Luxembourg has developed a machine that can mimic the physical and biological conditions inside your digestive system. Just add a pinch of your personal microbiome and watch how your body would react to certain foods or drugs. Is this the future of personalized medicine?

At a microscopic level, about 100 trillion bacteria live in and around your body, with a large proportion residing in your gut. The kind you find in yogurt and fermented tea, Lactobacillus acidophilus, is one of the most common, but there are hundreds of varieties. Each individual has a slightly different mixture of bacteria, and it’s known as your “microbiome.”

Medical research has begun to pay more attention to these gut flora since 2012, when the NIH, FDA, and DARPA began funding studies into machines which might explore the link between your microbiome and your risk for diseases like diabetes, obesity, IBD, and Crohn’s. Even some neurodegenerative diseases have been shown to have some link to your bacterial cocktail, and research suggests these critters have an effect on your everyday cognitive functions, too.

Until recently it has been impossible to actually use these gut flora outside the body—to simulate a real human reaction to a drug compound, for example. If put in just the right environment, such a simulation could help doctors predict an individual’s response to pharmaceuticals, foods, allergens, supplements, and environmental factors, opening up the promising possibility of creating personalized treatments that could drastically reduce the likelihood of disease, drug interactions, and costly post-hoc treatments.

The implications for drug personalization are particularly profound. According to the FDA, adverse drug reactions are the fourth largest cause of death in the United States, causing over 106,000 deaths annually. Stimulated human organs, such as a machine-based human gut, offer the opportunity to run predictive pharmaceutical tests on the efficacy and safety of various drug compounds. The findings from such tests could inform which drugs doctors choose to administer to patients and reduce the likelihood of drug interactions in individuals being treated for more than one condition.

 

What’s so hard about simulating a human organ?

“In the gut, you have really strict requirements in terms of the oxygen concentrations,” says Pranjul Shah, PhD and cofounder of Orgamime, the Luxembourg-based biotech startup whose gut-on-a-chip machine received wide acclaim in June 2016 following the publication of its white paper in the journal Nature.

The challenge, Shah says, is reproducing the exact bacterial habitat as it exists inside the intestines, a complex task. “Human cells need oxygen to survive and thrive, [but] the bacteria need to be in a steep, zero-oxygen environment,” says Shah. In the gut, two environments—aerobic and anaerobic—exist within a few microns of each other. It’s hard to build a machine from plastic and simulated mucous that can do the same thing. “This gradient is so steep that many other systems which have tried to do that have failed to achieve it,” he says.

Plus, the machine needs to reproduce the physical changes caused by food material passing by, an effect called “shear.” “The bacteria are used to some kind of shear in the gut because it’s a constantly pulsating environment,” says Shah.

 

Will gut-on-a-chip machines change what you choose to eat?

The food industry, rife with pseudoscience, will also be transformed. While machines like Orgamime’s can facilitate personalization of drug compounds, they could also be used to verify food manufacturers’ health claims, or definitively prove whether ingredients like high-fructose corn syrup are actually bad for humans.

“There have been a couple of papers which came out very, very recently that say that artificial sugars—not natural sugars, but artificial sugars—are really a big problem,” says Shah. The true link between high-fructose corn syrup, gut flora, and diabetes might be deduced using gut machines like Orgamime’s. Shah, whose family has a history of diabetes, has already stopped consuming high-fructose corn syrup. “If you get the Mexican Coca-Cola, it’s real sugar,” he says. “Even when I’m traveling in the US, if I have an option, I ask for the Mexican Coke.”

Also on trial will be yogurts, the health claims of which will have to be substantiated with data, Shah predicts. “We’re getting a lot of requests from companies which are selling off-the-shelf probiotics which claim to boost your memory or help you lose weight,” he says.

Straight-up bacteria might even become a food group, of sorts. Bacterial transplants, already shown to be effective for treating the GI tracts of immuno-suppressed individuals, might become commonplace for all patients after a surgery or bout of illness. Family members might lend you their strains, or doctors might mix up completely artificial cocktails as substitutes and test their effects in a machine. The point is, it will be highly customized to you.

“A most suitable donor could be chosen based on your genetic makeup, the current system of bacteria that you have, and your diet, your stress level, your lifestyle, and the environment that you live in,” says Shah.

 

How can we prove the gut-on-a-chip actually works?

Shah began working full time on his machine in 2011 alongside Orgamime’s cofounder Sivakumar Bactavatchalou. Though it began while Shah was a PhD student in life sciences, the project now incorporates recent advances in electrical engineering, IT, and 3D printing. It is comprised of eight computer-controlled bacteria chambers, each of which mimics a different segment of the human intestinal tract.

To prove their simulation was accurate, Shah and Bactavatchalou conducted two published clinical studies (one in Europe, one in South America) to see if they could predict human subjects’ reactions to probiotics. Patients were first endoscoped to take a sample of gut material, then given six weeks of probiotic therapy with a live culture known as Lactobacillus rhamnosus, or LGG, commonly found in yogurt.

In gut science, one marker of impact for a probiotic supplement is your body’s secretion of proteins called cytokines, which send signals to other cells. Whether or not these cytokines are pro-inflammatory—a sign the body is being attacked, and invoking an immune response to deal with the threat—can be assessed by looking at the RNA excreted by the cytokines.

When Shah tested his patients’ RNA secretions alongside the Orgamime simulated gut, the results were identical. “We took the same bacteria, same type of cells, same conditions—and we see exactly the same genes to be influenced in our system at the molecular level,” Shah says.

 

What this means for existing drugs

About 30 percent of new pharmaceuticals fail in human clinical trials despite promising animal tests, according to the NIH. Orgamime’s technology could call into question every compound discarded by drug companies over the past 50 years. Those compounds can now be re-assessed for usefulness as a result of the more accurate simulated-human testing that has become available. Anywhere from 300,000 to 500,000 discarded compounds could be re-tested.

“I expect every pharmaceutical industry will open up their closets to startups,” says Shah.

But first, the FDA must approve the validity of machines like Orgamime’s. The department has announced it will begin clinical trials sometime in 2017. “If something like this happens,” says Shah, “it’s going to be the biggest game changer in the field of medicine, at least in the drug testing and development, in the last 50 years.

 

To discuss this and other topics about the future of technology, finance, life sciences and more, join the Future Realities discussion on LinkedIn.

This article was produced by Quartz creative services and not by the Quartz editorial staff.

The tiny scale of medical breakthroughs

By Catherine
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Written by Catherine Bolgar

 

Nanomedicine takes advantage of its extremely small size—“nano” being one-millionth of a millimeter—to target drugs inside the body, fight cancer and other diseases, regenerate cells and provide contrast for medical imaging. As a result, nanomedicines hold out hope of curing hard-to-treat diseases. However, it also triggers fears, not least about whether they are safe for patients and the environment, and whether they are sufficiently regulated.

To date, about 40 nanomedicines have been approved by the U.S. Food and Drug Administration and about 20 by the European Medicines Agency, says Patrick Boisseau, nanomedicine program manager at the French Atomic Energy Commission and chairman of European Technology Platform on Nanomedicine. A further 130 nanomedicines are in clinical trials. It can take more than a decade for a drug, including nanomedicines, to receive regulatory approval.

However, despite this progress, much public discussion relating to nanomedicine is in fact based on their confusion with engineered nanomaterials, mostly inorganic materials produced by industry in large quantities.

“Most of the reactions expressed by citizens are directed at these [engineered] materials because products aren’t labeled and people don’t know whether appropriate toxicological studies have been performed as to whether the nanomaterials are safe for humans or the environment,” Mr. Boisseau says.

The only link between nanomaterials and nanomedicines,” he adds, “is the need to develop specific analytical techniques because the nanoscale is very, very small.”

Materials may behave differently at nanoscale, which is why nanotechnology is potentially so powerful, but also why ensuring safety, especially of nanomedicines, is so difficult, says Michael Schillmeier, professor of sociology, philosophy and anthropology at the University of Exeter in the U.K. and nanomedicine specialist.

“We can’t say nanomedicine is safe or not safe because nanoparticles can be very different, depending which nanoparticles are involved and how they interact with their environment,” he says. “Just by being nanoscale, they can be more toxic, more reactive, more resistant to erosion. There is no one nanoparticle.”

While materials may act differently on the nano scale compared with the macro scale, there can also be variations within a single substance. Nanomedicines’ impact can differ depending on their size, shape and texture. The trick is to understand whether such differences are positive or negative.

“We went to laboratories and toxicologists and found they often lack technologies or know how to sufficiently test and characterize nanoparticles,” says Prof. Schillmeier.

However, if clinicians discover specific properties of nanomedicines compared with macro forms of those drugs, they are required to inform regulators, Mr. Boisseau says.

“The body is a fantastic machine,” he adds. “Particles below five nanometers are filtered by the kidneys and quickly eliminated in urine, depending on whether the nanomaterial is organic or inorganic. Already, regulation for all medicines requires you to explain how your medicine is eliminated.”

The fact that the body doesn’t degrade inorganic particles can be useful in medicine. Metallic nanoparticles, for example, are injected into advanced cancerous tumors to enhance radiotherapy and destroy more cancer cells without increasing the radiation dose, he notes.

“If the patient is already 60 years old and, without treatment, could expect to live six months, and with it six years, then the regulator says the benefit is higher than the risk,” Mr. Boisseau says. “It would be different for treating young children because we do not know if children can live for 60 or 70 years with metallic nanoparticles in the body.”

Some medicines use nano properties to deliver drugs more efficiently to where they’re needed in the body. Often the drugs are strong, such as chemotherapy for cancer, but better-targeted delivery can make drugs work better while lessening side effects. Eventually, nanomedicine might make personalized medicine possible.

For now, research is focusing on drugs coated with nanotechnology that better target cancer and other diseases and distinguish between cancer cells and healthy cells, Prof. Schillmeier says.

Nanomedicine is not revolutionizing medicine, but may improve it.”

Meanwhile, pharmaceutical companies are looking at developing new nanomedicines or innovative nano-delivery systems for old drugs, Mr. Boisseau says. “Most people don’t care whether they have nanomedicine or not,” he notes. “They just care about therapeutic solutions that will treat them with the fewest side effects and best outcome.”

 

Catherine Bolgar is a former managing editor of The Wall Street Journal Europe. For more from Catherine Bolgar, contributors from the Economist Intelligence Unit along with industry experts, join the Future Realities discussion on LinkedIn.

Photos courtesy of iStock

Controlling the genetic genie

By Catherine
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Written by Catherine Bolgar

Advances in genetic sequencing techniques and discoveries about our DNA are helping to identify inherited diseases, and someday may lead to treatments or personalized medicine. But can regulation keep up with the science, securing the health benefits, while protecting those whose test results bring bad news?

Genetic tests promise great insights. They may diagnose disease or find the mutated gene responsible. They can detect whether a genetic disorder could be passed on to children, and which disorders in newborns might need early treatment. And tests can identify biological relationships, as well as victims of crime or catastrophe.

There are about 4,000 to 5,000 diseases that can be tracked back to a mutation in a known gene,” says Alastair Kent, director of Genetic Alliance U.K., in London. “There are probably more but the gene hasn’t yet been identified. They are rare, and most are incredibly rare.”

About 80% of inherited diseases become apparent soon after birth or in early childhood, he says, and most are fatal by age five. There are about 400 rare genetic conditions for which treatments can improve and prolong life, and some recent therapies may cure some people, Mr. Kent says, but “it’s too soon to tell.”

The most prevalent diseases caused by a single gene are Down syndrome, blood-related disorders such as thalassemia, sickle-cell anemia and hemophilia, followed by cystic fibrosis, Tay-Sachs disease, Fragile X syndrome and Huntington’s disease.

Cystic fibrosis treatments have improved life spans, but Huntington’s, a degenerative brain disorder, has no cure—and anyone with the genetic mutation is certain to get the disease. Understandably, people want to test for a late-onset genetic disease usually because a family member already has it. Knowing whether they too are carriers could influence important life decisions, such as whether to have children or retire.

However, you can’t just say, “do my genome,” Mr. Kent notes.

Having a defective gene, such as APOE-e4 for Alzheimer’s, or BRCA1 for breast cancer, doesn’t always lead to the disease. Women with BRCA1, for example, sometimes choose to have a mastectomy to reduce the risk.

Given the difficulties associated with such decisions, most countries try to protect genetic privacy. The European Union requires patient consent for disclosure of genetic information and bans discrimination based on genetic features. In the U.K., insurers have agreed not to ask for predictive genetic test results except for policies above £500,000 ($757,000). In the U.S., the Genetic Information Non-Discrimination Act prohibits discrimination by employers or insurers on genetic grounds.

Companies that conduct genetic tests directly for consumers also guard client privacy. 23andMe, a personal genetics company (named after our 23 pairs of chromosomes) based in Mountain View, Calif., has more than a million genotyped customers. Their data is stripped of personal identifiers such as name, address or email, and aggregated with other data, according to Emily Drabant Conley, vice president of business development.

Though the volume of genetic data is expanding, testing can accomplish only so much. “We don’t have the knowledge to interpret the information that comes out of sequencing except in a relatively small proportion of cases,” Mr. Kent notes.

While some genetic mutations will always result in the related disease, in many cases, it’s not possible to give an exact risk of developing a disorder or to predict its severity. Genetic alterations are not always informative—after all, we all have DNA variations.

“Certain conditions and diseases are genetically determined. There are a number of Mendelian diseases that are almost completely determined by your genes—for example, conditions like Tay-Sachs, cystic fibrosis, and sickle cell anemia. In other cases, genetic factors may increase or decrease a person’s risk for a particular condition, but environmental and lifestyle factors also play a role,” Ms. Drabant Conley says.

In 2009, an Italian court reduced the prison sentence of a convicted murderer after discovering that he carried genetic variants associated with a predisposition to aggressiveness.

“But if you look at people who carry that mutation, some have a fairly aggressive personality but others are successful entrepreneurs,” says Mr. Kent. “You have to be extremely careful in associating complex behavioral characteristics with underlying genetic structures.”

Catherine Bolgar is a former managing editor of The Wall Street Journal Europe. For more from Catherine Bolgar, contributors from the Economist Intelligence Unit along with industry experts, join the Future Realities discussion on LinkedIn.

Photos courtesy of iStock



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