The Future of Organ-Chip Technology Is Bright

Biologist and bioengineer Donald E. Ingber doesn’t have time to sleep. As the founding director of The Wyss Institute for Biologically Inspired Engineering at Harvard University, finding time outside of work hasn’t gotten easier with age. At 67, his morning still starts at 5 a.m., running through a pile of emails that seems to grow larger by the day.

By lunch, he’s already revised the budget for a crucial government grant and met with postdoctoral fellows regarding work on various research projects. Ingber also deals with unexpected issues, like immigration and political turbulence, that he never dreamed would fall under his purview. Recently, when a scientist he hired from Germany came with his wife and child and was turned away at Logan Airport for having an Iranian passport, Ingber spent the morning wrangling with the Harvard visa office, trying to get him back into the country.

He’s as much a CEO as he is a scientist. He takes Biologist and bioengineer Donald E. Ingber doesn’t have time to sleep. As the founding director of The Wyss Institute for Biologically Inspired Engineering at Harvard University, finding time outside of work hasn’t gotten easier with age. At 67, his morning still starts at 5 a.m., running through a pile of emails that seems to grow larger by the day.

Ingber’s work was previously featured in Discover, when we covered the development of the so-called “lung-on-a-chip” and “body-on-a-chip.” One of his latest projects is the “vagina-on-a-chip.” These minute devices, made up of clear polymer and about the size of a USB thumb drive, contain hollow “micro-fluidic channels” lined with living cells that mimic the body’s organs. Each organ-on-a-chip uses human tissue kept vital with a circulatory system that allows the cells to remain alive.

Using such tiny renderings of living human organs, Ingber has shown that in many ways chip technology is more effective — and humane — than using animal models. The chips are also less variable than using human subjects.

When researchers use chips to test a drug therapy or the toxicity that medications may have on certain organs, they can control for variables like changes in drug levels over time, physical stresses, and oxygen levels, as well as factors such as genetics or even work history, that they can’t always control for in humans. They can also move more efficiently and quickly on drug testing if humans or animals aren’t in the mix.

The Wyss Institute, which opened in 2009, has been on the frontlines of research bent on solving real-world challenges. Ingber recently met with Discover over video chat to explain the utility of organ-chip technology and how his work is giving modern research a critical upgrade.

Q: Your vagina-on-a-chip has really taken off in the headlines, even breaking through to late-night television when The Late Show With Stephen Colbert gave you and the chip an irreverent shout-out. Why do you think it’s caught so much attention?

DI: I laugh because just that one Stephen Colbert mention brought more attention to women’s health than I ever could have dreamed. Bacterial vaginosis is a major cause of preterm birth and death, increased susceptibility to HIV, and other health issues prevalent in lower-resourced nations. In the U.S., impoverished communities are at a greater risk of HIV infection and poor health outcomes as a result of the disease.

The chip emulates the vaginal microbiome, which has a healthy state and also a dysbiotic, or unhealthy, state. In healthy women without bacterial vaginosis, lactobacillus crispatus is the dominant bacteria and in those in a dysbiotic state there’s less lactobacillus crispatus and a more diverse microbiota, including bacteria like gardnerella vaginalis.

The goal is to deliver the good bacteria to a patient with vaginosis through a cheap solution like engineered probiotics. The Gates Foundation is working with scientists to develop a mixture of strains of lactobacillus crispatus that can provide a simple fix to patients. But you can’t test the probiotic on mice because they don’t have the same microbiome or reproductive tract. In fact, there’s no animal model in which to test the drug therapy.

The Gates Foundation came to us to design a technology to test the drug therapy and the vagina-on-a-chip has worked incredibly well at filling this niche. There’s a large clinical trial that’s about to take place both in South Africa and at Massachusetts General Hospital in Boston where we’ll compare our results to the clinical results in patients. If it pans out, the chip can be used to develop improved formulations of the probiotic.

Q: I’ve heard that you’ve developed a similar chip for the cervix. How would this translate into treatment?

DI: The cervix chip looks very much like a real cervix in terms of mucus production and its response to changes in hormones that come with a woman’s menstrual cycle. The technology can also be used to study HIV as well as cervical cancer and other viral infection models.

We know that those with vaginosis are more susceptible to certain viral infections like HIV, but a model like this could help us figure out why. Using the cervix and vagina chip, we can control each parameter individually, which you can never do in people. For example, researchers have long thought that cervical mucus played a role in vaginosis, but we don’t know for sure because the mucus is always there. But with the chip you can control for this by cutting mucus production and then noting its impact.

Q: Did you really use a cigarette-smoking robot to test the impact of smoking?

DI: We did. Normally when researchers test the effects of cigarette smoking on the body, they use nicotine extracts and add them to cells in a petri dish. But smoking isn’t just measured by the way tobacco impacts the cells; the rate at which we inhale along with a host of other factors also impacts health outcomes. In order to more closely mimic the impact of smoking on the airways, we designed a cigarette-smoking robot that breathes as a human would, with pauses, pulses, and deep inhales.

Using real cigarette smoke, researchers are able to closely mimic how cigarette smoke being inhaled by the robot would damage cells flowing through an airway chip. When we compared the results of our study with a composite of nine patients who were healthy with the exception of cigarette smoking, we found that the robot’s results were strikingly similar to that of human patients.

Q: Why has sepsis become a focus of your research?

DI: I’ve always compared science to cooking, in that it’s a creative process where you keep folding in ingredients. One research idea often folds into another, and that was the case with sepsis. Microfluidics is the behavior of fluids running through microchannels that can flow side-by-side without mixing. In the same way, if you flow blood and sterile saline together on a chip, they don’t mix.

With sepsis, the inflammatory reaction in your body stimulates the production of cytokines, which cause the condition. If you’re able to remove the pathogens that are stimulating the inflammatory response earlier, you can prevent sepsis.

We engineered a protein added to the saline solution that could do just that: magnetically bind to pathogens and remove them from the blood. Later we immobilized that protein on a clinical dialysis instrument, which recently moved into clinical studies in patients. The hope is that this might help save at least some of the 270,000 people who die in the U.S. annually from the condition.

Q: Can you discuss your work developing treatments for radiation injuries?

DI: We were funded by Biomedical Advanced Research and Development Authority [BARDA], the U.S. government agency whose role is biothreat reduction and defense. They stockpile drugs that would be useful in a mass-scale crisis, such as a radiation disaster.

We worked on bone marrow, lung, and intestinal chips where we could test the impact of a radiation injury. Similar to the microbiome, animal models don’t work on radiation because they don’t have the same reaction to it [as humans].

The chips also showed that certain parts of the human body were more resistant to radiation. For example, cells in the bone marrow chip were very sensitive while those in the intestinal chip were moderately sensitive and those in the lung chip were resistant.

What’s more, levels of radiation sensitivity on each organ chip match what we see in humans. We’re also in the midst of using the chips to test a number of compounds that suppress radiation injury and could be used in the event of a nuclear disaster.

Q: In an era of remote work, do you think the collaborative nature of The Wyss Institute allows for more innovation?

DI: The Wyss Institute is a unique place in that we are a translation-focused institute, meaning we strive to have a near-term impact. We’re not trying to do open-ended, exploratory research; we’re trying to solve problems. We need both and I’ve done both. But our near-term perspective allows us to find solutions. We’ve had a Science or Nature paper published every month since we’ve been open. The way we’re structured is to do collaborative research and interdisciplinary work. It’s very different from academia in that we’re not split up into departments or schools. We’re a separate institute that’s part of Harvard but also collaborates with 12 institutions including MIT, Boston University, Tufts, The University of Massachusetts Amherst, and all of the Harvard hospitals as well as institutions in Europe.

When someone comes to us with a challenge, like BARDA or the Gates Foundation, we can combine the most bizarre and quirky collection of researchers who you would never think would fit together on a project. When you bring together brilliant minds who have never worked on a project, it allows them to look at a problem in a different light, finding solutions that haven’t been identified before.

Q: Your research goes far beyond studies into producing applicable technology. Why is this important?

DI: You can’t impact the world unless you can get people to put the money behind bringing it to patients. It’s not only money. Scientists often think they’re selling out when they get a patent, but if you don’t have a patent, you’ll never get the funding to bring a project to fruition. We have 4,000 patents. We’re run like a midsized company made up of 58 start-ups. It’s how capitalism works and it’s an important aspect of innovation.

We have our own strategic intellectual property attorney onsite whose role is to provide feedback to researchers to help them make their work patentable. And we have our own business-development team to guide scientists along the right path for their research and provide tips for strengthening an idea. We also ask our researchers to come up with a vision — or a first application of a project — so that their thoughts are focused throughout the process. Then we fund them so that they can build a team around the idea.

Q: You’ve been laying the groundwork for a future of drug testing and research without animal testing. What’s the latest on this?

DI: The recently passed FDA Modernization Act allows for the use of organ chips and other human-relevant technologies for drug testing rather than animal models. This was the first time that the FDA has provided guidance on the subject since 1939, and it’s a long time coming.

After doing research on animals as a grad student and as a postdoc, I consciously wanted to work on the development of in-vitro models. If you’ve ever had dogs and cats, doing research on them is painful, and nonhuman primates are worse. There’s also a shortage of nonhuman primates because of COVID, where so many were used to develop drugs and vaccines. This has garnered enormous interest in organ chips. Additionally, because of ethical concerns, primate centers have closed globally.

The most important thing is designing drugs that are more effective, safer, cheaper, and faster, but at the same time, we can save animal lives. And as an animal lover, this work has been tremendously gratifying to me personally.

This interview has been edited for length and clarity.

This story was originally published in our July August 2024 issue. Click here to subscribe to read more stories like this one.

Source : Discovermagazine