Instead of trying to compensate for failing organs, what if we could readily replace diseased or injured body parts with brand-new versions made in the lab? Researchers working in the field of regenerative medicine have already made amazing progress, creating artificial organs and miniature labs-on-a-chip. The return on investment for this area of research is expected to be dramatic: better understanding of how diseases develop and spread, accurate screens for testing new drugs, and cell-based therapies for diabetes, arthritis, Parkinson’s disease, and many other conditions that affect millions of Americans.

NIH researchers have already created miniature "hearts" that beat rhythmically in a culture dish and contain all the different cell types that make up a human heart. Scientists have also developed a lung-on-a-chip. When intermittent suction is applied, the cells in this thumb-sized device flex and stretch rhythmically just as they do in our lungs when we breathe. For individuals with kidney failure, the potential of using their own skin cells to build a new kidney might now be within reach – given years of hard work and the necessary research investment.

What are regeneration and regenerative medicine?

Regeneration is the natural process of replacing or restoring damaged or missing cells, tissues, organs, and even entire body parts to full function in plants and animals. Scientists are studying regeneration for its potential uses in medicine, such as treating a variety of injuries and diseases. Researchers also hope to learn more about the human aging process through studies of regeneration. This rapidly advancing field is called regenerative medicine.

What organisms can regenerate?

All living organisms have some ability to regenerate as part of natural processes to maintain tissues and organs. Some animals have extensive regenerative abilities. For example, the tiny freshwater animal called Hydra can form two whole bodies after being cut in half. The axolotl, or Mexican salamander, is an animal with a backbone that can regenerate the form and function of almost any limb, organ, or other body part.

More complex animals such as mammals have limited regenerative capacities. These include:

• Forming thick scars in tissues and skin to promote the healing of injured or amputated body parts.
• Regrowing hair and skin.
• Healing a bone fracture by using new tissue to knit the bone pieces together.

How do different organisms regenerate?

Organisms regenerate in different ways. Plants and some sea creatures, such as jellyfish, can replace missing parts by extensively remodeling their remaining tissues.

Some animals such as lobsters, catfish, and lizards replace missing parts by first growing a blastema. The blastema cells rapidly divide to form the skin, scales, muscle, bone, or cartilage needed for creating the lost limb, fin, or tail.

In other animals, including humans, organs such as the liver undergo what’s called compensatory hypertrophy. When part of the liver is removed or destroyed, the remaining portion grows to the original size and allows the liver to function as it did before. Our kidneys, pancreas, thyroid, adrenal glands, and lungs compensate for organ loss in a similar, but more limited, way.

Research organisms that are particularly useful for studying regeneration include the blue-and-white-striped zebrafish and the planarian, a type of flatworm. The zebrafish can replace a damaged or lost fin; and can also repair significant damage to its heart, pancreas, retina, brain, and even spinal cord.

The planarian uses organogenesis on a very large scale to regrow its entire body from a tiny fragment of its tissue if that piece of tissue contains one single neoblast. Humans have the same genes and pathways used by these animals; however, scientists don’t yet fully understand how to turn on or start such extensive regeneration in humans.

The National Institute of General Medical Sciences (NIGMS) funds research to understand how regeneration works at the basic level, and why some organisms have less regenerative capacity than others. By studying regeneration in other species, scientists may learn more about how the human body heals and discover our regeneration pathways to repair damaged hearts or to even replace lost limbs.

What role do stem cells have in regeneration?

Stem cells play an important role in regeneration because they can develop into many different cell types in the body and renew themselves millions of times, something specialized cells in the body—such as nerve cells—cannot do. The primary roles of stem cells are to maintain and repair the tissue in which they’re found. Scientists are exploring whether a person’s own stem cells could “grow” replacement tissue that wouldn’t be rejected by the body’s immune system.

How is regeneration related to aging?

Throughout an organism’s life, its cells regenerate. But as part of the aging process, this ability gradually declines. To better understand the changes that occur, scientists are studying animals that show few signs of aging throughout their lifespans. Sea urchins, for example, can reproduce and regrow damaged parts throughout their lives. Because they maintain these abilities, sea urchins may help scientists answer questions about human aging as well as regeneration.

What are tissue engineering and regenerative medicine?

Tissue engineering evolved from the field of biomaterials development and refers to the practice of combining scaffolds, cells, and biologically active molecules into functional tissues. The goal of tissue engineering is to assemble functional constructs that restore, maintain, or improve damaged tissues or whole organs. Artificial skin and cartilage are examples of engineered tissues that have been approved by the FDA; however, currently they have limited use in human patients.

Regenerative medicine is a broad field that includes tissue engineering but also incorporates research on self-healing – where the body uses its own systems, sometimes with help foreign biological material to recreate cells and rebuild tissues and organs. The terms “tissue engineering” and “regenerative medicine” have become largely interchangeable, as the field hopes to focus on cures instead of treatments for complex, often chronic, diseases.

This field continues to evolve. In addition to medical applications, non-therapeutic applications include using tissues as biosensors to detect biological or chemical threat agents, and tissue chips that can be used to test the toxicity of an experimental medication.

How do tissue engineering and regenerative medicine work?

Cells are the building blocks of tissue, and tissues are the basic unit of function in the body. Generally, groups of cells make and secrete their own support structures, called extra-cellular matrix. This matrix, or scaffold, does more than just support the cells; it also acts as a relay station for various signaling molecules. Thus, cells receive messages from many sources that become available from the local environment. Each signal can start a chain of responses that determine what happens to the cell. By understanding how individual cells respond to signals, interact with their environment, and organize into tissues and organisms, researchers have been able to manipulate these processes to mend damaged tissues or even create new ones.

The process often begins with building a scaffold from a wide set of possible sources, from proteins to plastics. Once scaffolds are created, cells with or without a “cocktail” of growth factors can be introduced. If the environment is right, a tissue develops. In some cases, the cells, scaffolds, and growth factors are all mixed together at once, allowing the tissue to “self-assemble.”

Another method to create new tissue uses an existing scaffold. The cells of a donor organ are stripped and the remaining collagen scaffold is used to grow new tissue. This process has been used to bioengineer heart, liver, lung, and kidney tissue. This approach holds great promise for using scaffolding from human tissue discarded during surgery and combining it with a patient’s own cells to make customized organs that would not be rejected by the immune system.

How do tissue engineering and regenerative medicine fit in with current medical practices?

Currently, tissue engineering plays a relatively small role in patient treatment. Supplemental bladders, small arteries, skin grafts, cartilage, and even a full trachea have been implanted in patients, but the procedures are still experimental and very costly. While more complex organ tissues like heart, lung, and liver tissue have been successfully recreated in the lab, they are a long way from being fully reproducible and ready to implant into a patient. These tissues, however, can be quite useful in research, especially in drug development. Using functioning human tissue to help screen medication candidates could speed up development and provide key tools for facilitating personalized medicine while saving money and reducing the number of animals used for research.

Regenerative medicine harnesses the body’s growth and healing properties to repair or replace damaged cells, tissues, or organs. Researchers are drawing on the fields of stem cell and developmental biology, bioengineering, material science, and gene editing, among others, to develop safe and effective regenerative therapies. Dental, oral, and craniofacial regenerative medicine holds great promise for treating a variety of injuries, conditions, and diseases, including repair or replacement of teeth, cartilage, joints, bone, and other tissues.

NIDCR supports research to develop evidence-based regenerative medicine therapies and speed their translation from the laboratory to the clinic.

Examples of NIDCR-supported research include:

• Microengineering blood vessels –developing techniques to grow nutrient-carrying blood vessels that more effectively integrate with implanted cells and tissues, thereby promoting survival of engineered tissue.
• Generating stronger cartilage – exposing cartilage cells in the laboratory to physical forces like those that occur naturally during development to produce cartilage that’s nearly as strong as natural cartilage.
• Jumpstarting clinical trials – accelerating promising regenerative therapies by investing in infrastructure to improve the efficiency of preclinical studies, which are required before testing new treatments in humans. NIDCR established the multidisciplinary Dental, Oral, and Craniofacial Tissue Regeneration Consortium (DOCTRC) to achieve this goal and currently supports two resource centers to facilitate the translation process.
• Building bone from scratch – using stem cells from human fat tissue to grow bone that can successfully integrate into surrounding tissue in an animal model.
• Gene therapy to treat dry mouth –re-engineering salivary gland cells to producea water channel protein called aquaporin, thereby increasing the flow of saliva to alleviate dry mouth. This regenerative therapy is being tested in a clinical trial in people whose salivary glands have been damaged by radiation therapy used for head and neck cancer treatment.

What is a research organism?

A research organism can be any creature that scientists use to study life. Examples range from single-celled organisms such as bacteria to more complex ones such as mice. Researchers funded by NIGMS use research organisms to explore the basic biology and chemistry of life.

Scientists decide which organism to study based on their research questions. Worms and zebrafish, which can regrow missing or injured body parts, are used to learn how cells and tissues regenerate. Insects such as fruit flies and honeybees are important research organisms for learning how genes and the environment interact to affect behavior. Sea urchins are able to reproduce and regrow body parts throughout their lives, making them of interest to scientists who study aging.

Scientists can study animals in ways that they cannot study people. For example, animal studies conducted in the lab allow scientists to control temperature, humidity, light, diet, and other factors that might affect the outcome of the experiments. These rigorous controls allow for more precise understanding of the biological factors being studied and provide greater certainty about experimental outcomes when pursuing additional studies.

What are model organisms?

Model organisms are a small group of research organisms that serve as a proxy for understanding the biology of humans. Examples include yeast, fruit flies, worms, zebrafish, and mice. Many aspects of these organisms’ biology are similar to ours, and much is already known about their genetic makeup. For these and other reasons, studying model organisms helps scientists learn more about human health.

Why are model organisms useful for studying diseases?

The natural course of a disease in humans may take dozens of years. In contrast, a model organism can quickly develop a disease or some of its symptoms. That allows researchers to learn about the disease in a much shorter time.

When scientists discover a link between a particular gene and a human disease, they typically find out what that gene does in a model organism. This information can provide important clues about what causes a disease. It also can help researchers develop potential diagnostic tests and treatments that are later tested in clinical trials. Mice, for example, have served as a model for studying the genetics of Down syndrome, cystic fibrosis, heart disease, and cancer.

Any NIH-funded study that involves animals or humans must follow laws, regulations, and policies to ensure participants’ welfare and minimize risks stemming from the research.

How has work with research organisms influenced human health?

Much of what we know about biology comes from studies using model and other research organisms. In addition to advancing knowledge of our own biology, these studies have led to the development of new tools doctors can use to diagnose and treat disease. Here are a few of the many examples from NIGMS-funded research:

• Yeast studies sorted out how cells divide. They revealed the orderly sequence of events that cells use to duplicate their contents and multiply, a process called the cell cycle. Millions of people with cancer have benefitted from this information, because many cancer drugs interfere with the cell cycle.
• Yeast studies clarified how genes are turned on or off and informed our understanding of diseases that occur when genes are active at the wrong time or in the wrong cell.
• Studies in fruit flies and tiny worms taught scientists new things about how fertilized eggs develop into complex organisms.
• Research with bacteria, viruses, and yeast revealed how all living things pass on their genes to offspring. This work detailed the ways cells copy DNA and repair mistakes made during the copying process.
• Researchers have used laboratory mice and rats for decades to test drugs. Basic research with rats also has taught us much of what we know about cancer-causing molecules.
• Studies with fruit flies, bread mold, bacteria, and mice identified the basic components of circadian clocks, which drive daily biological rhythms. The research revealed connections between these clocks and sleep deprivation, obesity, diabetes, depression, and other human health conditions.
• Studies using research organisms produced powerful tools that scientists use in human health studies worldwide. Examples include DNA chips for studying all the gene activity in a cell and the CRISPR tool for editing DNA in living organisms.

What more can research organisms tell us?

Scientists continue to work toward understanding all of the molecular processes that underpin human biology and health. They are currently using research organisms to see how these animals fix damaged pieces of DNA, regenerate missing or injured body parts, and pass certain genetic changes to their offspring.

Studying research organisms can also help reveal molecular changes that are associated with diseases and show the connections between certain diseases that seem unrelated.

How are computer models used?

Computers can serve as virtual laboratories that advance biomedical knowledge in areas such as infectious disease spread and drug interactions in the body. With virtual labs, scientists can perform experiments that are difficult to do in actual labs. They also can quickly identify factors that are important to include in lab-based experiments. Researchers use computer simulations to track biological processes in cells and research organisms. This allows them to computationally test, for example, the possible effects of drugs on those processes. The drugs that seem the most promising can then be studied in living cells or organisms.

Because the computer models are so complex, researchers need to use high-performance computers. Often, these computers run for weeks at a time, generating millions of different possible outcomes.

No single set of results or single computer model can accurately predict an outcome. Therefore, researchers often ask the same questions using different models. When multiple models yield similar results, scientists have more confidence in the predictions.

Can computer models replace research organisms?

Computer models have limits. Researchers create them based on what they already know about a process or disease. Scientists use information and data gained from real-world experiments to enhance computer models and predictions to help design additional experiments. Thus, computer modeling and lab experiments go hand in hand—both are needed to advance our understanding of health.