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Tissue Chip for Drug Screening Program

Finding the ‘Tipping Point’ to Permanent Kidney Damage

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left: A ring of DAPI surrounds clusters of CDH1 and PODXL. right - a ring of DAPI surrounds a matrix of PDGFRβ
Caption: Kidney organoids. Left, markers of the kidney’s filtering units called nephrons (purple, light blue, green); right, markers of the kidney’s connective tissue, or stroma (red and yellow). Credit: Gupta N., Science Trans. Med (2022)

Healthy human kidneys filter more than 30 gallons of blood each day on average, efficiently removing extra fluid and harmful toxins from the body. If injured, the kidneys have a remarkable capacity for repair. And, yet, in more than one in seven U.S. adults, including disproportionately people with diabetes and hypertension, the daily wear and tear on these vital organs has passed a “tipping point” toward irreparable damage and the onset of chronic kidney disease (CKD) [1].

Defining this tipping point has been a major challenge for a variety of technical reasons. But in a study just published in the journal Science Translational Medicine, researchers have discovered a molecular switch involved in controlling the transition from normal tissue repair to incomplete, or permanent, damage [2]. The NIH-supported researchers also suggest a possible drug candidate to control this switch and slow the progression of CKD.

Also impressive is that the team broke through these longstanding technical problems without probing or testing a single person with CKD. They made their discovery using kidney organoids, or miniature human kidneys, that are grown in a lab dish and naturally model the repair process that takes place in our bodies.

The latest findings come from a team led by Ryuji Morizane, Massachusetts General Hospital and Harvard Medical School, Boston. The researchers recognized that earlier studies in animal models had identified processes involved in kidney injury and repair. But so far, there’s been limited success in translating those discoveries into clinical advances. That’s because many potential treatments that have appeared safe and effective in animal models have proven to be either damaging to the kidneys or ineffective when studied in humans.

To continue the search, the Morizane lab generated human kidney organoids from induced pluripotent stem cells (iPSCs) and other sources that include multiple essential renal tissue types. Using their tiny human kidneys, Morizane and colleagues, including first author Navin Gupta, sought the molecules responsible for the transition from complete to incomplete kidney repair.

The team repeatedly exposed kidney organoids to the cancer chemotherapy drug cisplatin, which can damage the kidneys as an unwanted side effect. Afterwards, examining single cells from the organoid, the researchers looked for underlying changes in gene activity associated with the transition from kidney repair to permanent kidney damage.

All told, their studies identified 159 genes in 29 different pathways that activate when kidneys fully repaired themselves. They found that many of those genes, including two called FANCD2 and RAD51, grew less active as kidney damage became irreversible. These genes encode proteins that are known to play a role in a process whereby cells repair broken strands of DNA.

Further study of stored biopsied kidney tissue from people with diabetic kidney disease, the most common cause of kidney failure, corroborated the organoid data tying a loss of FANCD2 activity to incomplete repair of kidney tissue. That’s encouraging because it suggests the new discoveries made in kidney organoids exposed to cisplatin may be relevant to people suffering from various forms of kidney injury.

One of the big advantages of organoid studies is the ability to rapidly screen for promising new drug candidates in the lab. And, indeed, the researchers found that a drug candidate called SCR7 helped to maintain FANCD2 and RAD51 activity in chemotherapy-injured organoids, preventing irreversible damage.

While much more study is needed, the findings suggest a potentially promising new way to prevent the kidneys from reaching their “tipping point” into permanent damage, CKD, and the risk for kidney failure. They also suggest that further studies in kidney organoids may lead to treatments targeting other kidney diseases.

These latest findings also highlight important progress in human tissue engineering, with implications for a wide range of conditions. In addition to making fundamental new biomedical discoveries as this new study has done, one of the great hopes of such efforts, including NIH’s National Center for Advancing Translational Sciences’ Tissue Chip for Drug Screening, is to improve predictions of whether new drug candidates will be safe or toxic in humans, speeding advances toward the most promising new therapies.

March happens to be National Kidney Month, and it’s especially important to raise awareness because 90 percent of people with CKD don’t even know they have it. So, if you or a loved one is at risk for CKD, be vigilant. Meanwhile, the work continues through studies like this one to find better leads to help control CKD.

References:

[1] Chronic kidney disease in the United States, 2021. Centers for Disease Control and Prevention.

[2] Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair. Gupta N, Matsumoto T, Hiratsuka K, Garcia Saiz E, Galichon P, Miyoshi T, Susa K, Tatsumoto N, Yamashita M, Morizane R. Sci Transl Med. 2022 Mar 2;14(634):eabj4772

Links:

Chronic Kidney Disease (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)

National Kidney Month 2022 (NIDDK)

Morizane Lab (Harvard Medical School, Boston, MA)

Tissue Chip for Screening (National Center for Advancing Translational Sciences/NIH)

NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Biomedical Imaging and Bioengineering; National Center for Advancing Translational Sciences


Body-on-a-Chip Device Predicts Cancer Drug Responses

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Body-on-a-Chip
Credit: McAleer et al., Science Translational Medicine, 2019

Researchers continue to produce impressive miniature human tissues that resemble the structure of a range of human organs, including the livers, kidneys, hearts, and even the brain. In fact, some researchers are now building on this success to take the next big technological step: placing key components of several miniature organs on a chip at once.

These body-on-a-chip (BOC) devices place each tissue type in its own pea-sized chamber and connect them via fluid-filled microchannels into living, integrated biological systems on a laboratory plate. In the photo above, the BOC chip is filled with green fluid to make it easier to see the various chambers. For example, this easy-to-reconfigure system can make it possible to culture liver cells (chamber 1) along with two cancer cell lines (chambers 3, 5) and cardiac function chips (chambers 2, 4).

Researchers circulate blood-mimicking fluid through the chip, along with chemotherapy drugs. This allows them to test the agents’ potential to fight human cancer cells, while simultaneously gathering evidence for potential adverse effects on tissues placed in the other chambers.

This BOC comes from a team of NIH-supported researchers, including James Hickman and Christopher McAleer, Hesperos Inc., Orlando, FL. The two were challenged by their Swiss colleagues at Roche Pharmaceuticals to create a leukemia-on-a-chip model. The challenge was to see whether it was possible to reproduce on the chip the known effects and toxicities of diclofenac and imatinib in people.

As published in Science Translational Medicine, they more than met the challenge. The researchers showed as expected that imatinib did not harm liver cells [1]. But, when treated with diclofenac, liver cells on the chip were reduced in number by about 30 percent, an observation consistent with the drug’s known liver toxicity profile.

As a second and more challenging test, the researchers reconfigured the BOC by placing a multi-drug resistant vulva cancer cell line in one chamber and, in another, a breast cancer cell line that responded to drug treatment. To explore side effects, the system also incorporated a chamber with human liver cells and two others containing beating human heart cells, along with devices to measure the cells’ electrical and mechanical activity separately.

These studies showed that tamoxifen, commonly used to treat breast cancer, indeed killed a significant number of the breast cancer cells on the BOC. But, it only did so after liver cells on the chip processed the tamoxifen to produce its more active metabolite!

Meanwhile, tamoxifen alone didn’t affect the drug-resistant vulva cancer cells on the chip, whether or not liver cells were present. This type of cancer cell has previously been shown to pump the drug out through a specific channel. Studies on the chip showed that this form of drug resistance could be overcome by adding a second drug called verapamil, which blocks the channel.

Both tamoxifen alone and the combination treatment showed some off-target effects on heart cells. While the heart cells survived the treatment, they contracted more slowly and with less force. The encouraging news was that the heart cells bounced back from the tamoxifen-only treatment within three days. But when the drug-drug combination was tested, the cardiac cells did not recover their function during the same time period.

What makes advances like this especially important is that only 1 in 10 drug candidates entering human clinical trials ultimately receives approval from the Food and Drug Administration (FDA) [2]. Often, drug candidates fail because they prove toxic to the human brain, liver, kidneys, or other organs in ways that preclinical studies in animals didn’t predict.

As BOCs are put to work in testing new drug candidates and especially treatment combinations, the hope is that we can do a better job of predicting early on which chemical compounds will prove safe and effective in humans. For those drug candidates that are ultimately doomed, “failing early” is key to reducing drug development costs. By culturing an individual patient’s cells in the chambers, BOCs also may be used to help doctors select the best treatment option for that particular patient. The ultimate goal is to accelerate the translation of basic discoveries into clinical breakthroughs. For more information about tissue chips, take a look at NIH’s Tissue Chip for Drug Screening program.

References:

[1] Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics. McAleer CW, Long CJ, Elbrecht D, Sasserath T, Bridges LR, Rumsey JW, Martin C, Schnepper M, Wang Y, Schuler F, Roth AB, Funk C, Shuler ML, Hickman JJ. Sci Transl Med. 2019 Jun 19;11(497).

[2] Clinical development success rates for investigational drugs. Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J. Nat Biotechnol. 2014 Jan;32(1):40-51.

Links:

Tissue Chip for Drug Screening (National Center for Advancing Translational Sciences/NIH)

James Hickman (Hesperos, Inc., Orlando, FL)

Hesperos, Inc.

NIH Support: National Center for Advancing Translational Sciences


If I Only Had a Brain? Tissue Chips Predict Neurotoxicity

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Image of neurons, glial cells, and nuclei

Caption: 3D neural tissue chips contain neurons (green), glial cells (red), and nuclei (blue). To take this confocal micrograph, developing neural tissue was removed from a chip and placed on a glass-bottom Petri dish.
Credit: Michael Schwartz, Dept.  of Bioengineering, University of Wisconsin-Madison

A lot of time, money, and effort are devoted to developing new drugs. Yet only one of every 10 drug candidates entering human clinical trials successfully goes on to receive approval from the Food and Drug Administration (FDA) [1]. Many would-be drugs fall by the wayside because they prove toxic to the brain, liver, kidneys, or other organs—toxicity that, unfortunately, isn’t always detected in preclinical studies using mice, rats, or other animal models. That explains why scientists are working so hard to devise technologies that can do a better job of predicting early on which chemical compounds will be safe in humans.

As an important step in this direction, NIH-funded researchers at the Morgridge Institute for Research and University of Wisconsin-Madison have produced neural tissue chips with many features of a developing human brain. Each cultured 3D “organoid”—which sits comfortably in the bottom of a pea-sized well on a standard laboratory plate—comes complete with its very own neurons, support cells, blood vessels, and immune cells! As described in Proceedings of the National Academy of Sciences [2], this new tool is poised to predict earlier, faster, and less expensively which new or untested compounds—be they drug candidates or even ingredients in cosmetics and pesticides—might harm the brain, particularly at the earliest stages of development.


Bioengineering: Big Potential in Tiny 3D Heart Chambers

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iPS human heart

Caption: Heart microchamber generated from human iPS cells; cardiomyocytes (red), myofibroblasts (green), cell nuclei (blue) 
Credit: Zhen Ma, University of California, Berkeley

The adult human heart is about the size of a large fist, divided into four chambers that beat in precise harmony about 100,000 times a day to circulate blood throughout the body. That’s a very dynamic system, and also a very challenging one to study in real-time in the lab. Understanding how the heart forms within developing human embryos is another formidable challenge. So, you can see why researchers are excited by the creation of tiny, 3D heart chambers with the ability to exist (see image above) and even beat (see video below) in a lab dish, or as scientists  say “in vitro.”

iPS heart cells video

Credit: Zhen Ma et al., Nature Communications

To achieve this feat, an NIH-funded team from University of California, Berkeley, and Gladstone Institute of Cardiovascular Disease, San Francisco turned to human induced pluripotent stem (iPS) cell technology. The resulting heart chambers may be miniscule—measuring no more than a couple of hair-widths across—but they hold huge potential for everything from improving understanding of cardiac development to speeding drug toxicity screening.