The Garden of Organ


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Hepatitis C is a virus that destroys your liver – and the pace at which it’s infecting more and more of us around the world, especially America’s Baby Boomers, is growing rapidly. In fact, the rate of infection is the US grew by more than 150 percent from 2010 to 2013 and shows no signs of slowing.

A drug called Harvoni will manage your symptoms at a cost of $1,100 for every pill. And it’s shown side effects ranging from nausea and depression to insomnia and shortness of breath. Or you could get on the list of people waiting for a liver transplant and hope that a matching donor dies before you do, then face the risk that your body will reject the foreign organ.

But what if your doctor could take a few cells from your body and use them to grow your own new liver?  No waiting, no risk of rejection, no more hepatitis.

Those new livers are sprouting in medical labs around the world because medical researchers are doing a lot of gardening these days.

But they’re not growing snap peas or snapdragons.

Instead, they’re growing “organoids” — small sections of human organs that germinate in lab dishes. The purpose: Learn how organs grow, how disease develops and progresses, and to test treatments on actual human organs without endangering human subjects.

Take a disease like idiopathic pulmonary fibrosis. That’s when tissue inside the lungs stiffens and stops working. “Idiopathic” means that no one can explain the cause.

What if you could take fibrotic lung cells and put them through a genetic time machine that transforms them into young cells, before the disease began? You could watch the disease develop step by step, test various theories about the cause, then try possible cures without endangering an animal or a person with a risky drug or procedure.

That’s what organoids make possible.

Eventually, scientists expect to be able to regrow new organs for individuals from a person’s own “seed cells,” then swap out the spent organ for the new. A few decades in the future, it could be routine to bank cells from various parts of your body, or even your umbilicus. When you grow into an adult with a failing organ or chronic condition, the saved cells could be cultured into a replacement organ.
There’d be no hunt for a donor, no danger of organ rejection.

That’s a particular hope for lungs, and not just because of fibrosis.

Lung diseases are among the top four causes of death worldwide. As a result, lungs are among the most commonly transplanted organs. In the US alone, more than 30,000 lungs find new owners each year. Many more could — more than 120,000 people are on waiting lists for lung transplants. But the number of lucky recipients is limited by the difficulty in finding donors. Matching the biochemical compatibility of giver and receiver is hit and miss.

The best way to solve the problem is to grow your own. And researchers are beginning to harvest an initial crop.

For example, tissue engineers at UCLA’s Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research gathered lung stem cells and painted them on glass beads to give the tissue structures a three-dimensional shape. The stem cells organized themselves into air sacs identical to those found in human lungs.

That’s important because lung tissue grown as a flat mass in a Petri dish doesn’t function the same way as the three-dimensional structure found in real lungs.
Another barrier has been lungs’ diversity; they consist of various kinds of tissues and cells, each with a specialized job. It’s been difficult to grow lung organoids with cells that spontaneously specialize.

A BREAKTHROUGH MOMENT

But last spring, a team at the University of Michigan Medical Center reported feeding lung tissue a special diet that helped it rise off the bottom of the dish to form spheroids and begin to divide into two kinds of lung cells.

Scientists can’t grow an entire lung yet, in part because it’s hard in the lab to nurture blood vessels to support growing tissues. But they have enough to begin to study the progression of diseases such as pulmonary fibrosis.

At Wake Forest University, a team of bio-researchers programmed stem cells to grow into heart cells, then built heart-like structures using a 3D printer. The structures are now barely wider than a human hair. But the scientists will improve the heartlets so they can be used to study the causes and progression of cardiac disease — and test the effects of drugs on real human-heart tissue.

SEED CELLS SHOW PROMISE

Organoids have grown out of scientists’ increasing dexterity in using stem cells. They are the “generic” cells that specialize to become teeth or hair or a pancreas as they mature, depending on the chemical signals they receive. Embryonic stem cells can grow into almost any kind of tissue; they just need a certain collection of biochemical signals to tell them whether to become teeth, skin or pancreas. Adult stem cells are found in mature organs; they can be stimulated to make more of the kind of cells they already are.

Just as important, the body’s cells carry in them the knowledge of how to organize. No one needs to tell them which kind of cell goes where; they already know. So, instead of scientists needing to build an organoid, the cells do that on their own.
To grow organoids, scientists are using “induced pluripotent” stem cells. These are specialized cells that have been genetically reprogrammed using a Nobel Prize-winning technique to return to their unspecialized state.

In early days, these stem cells were used to grow mats of specialized tissue. To coax the mats into three-dimensional shapes that worked more like real organs, the mats were grown on scaffolds, such as the glass beads at UCLA. Now, as scientists learn to nourish the stem cells with just the right biochemical concoctions, the cells are beginning to behave much as they do in a developing embryo or in a healthy adult — differentiating into specialized cells with different jobs and organizing themselves just as they do in a growing embryo.

LIVER REPLACEMENT PROMISE

Like people with failing lungs, many more people with dying livers could survive if organs were available. But livers have been hard to grow outside the body; most liver cells can’t survive a day in the lab. Until now.

At Yokohama City University in Japan, a research team fashioned stem cells that were precursors of liver cells. They mixed those cells with a support system of cells that send biochemical signals telling the pre-liver cells to mature. The mix grew into mini-livers about the size of peanut kernel that could survive up to eight weeks in a dish.

The group’s hope is to grow and implant enough of these liver “buds” into a failing organ that the buds take over and, eventually, grow together into a new liver. Trying the idea in mice, the researchers embedded a dozen buds and watched them tap into the mouse’s blood supply, grow to maturity and take on many of the liver’s ordinary functions. Even in mice whose livers had been killed by a toxic drug, most survived when the buds were implanted.

Clinical trials could begin by 2020, first targeting children.

THE BRAIN GARDEN

Brain organoids offer a special promise. Brain disorders from autism to Alzheimer’s disease don’t surrender their secrets easily.

Now, culturing a few cells from a person’s defective brain region could grow enough of that part of the organ to study a disease and test treatments — even testing a range of treatments on an individual’s cells to see which is most effective in that particular case.

Although the first organoids — mini-gu
ts — were grown in 2009 in a Netherlands lab, it wasn’t until 2013 that tiny brain sections sprouted. Researchers in a Vienna lab noticed that brain cells they grew on a flat plate were clumping together. They kept gently washing the clumps with nutrients; the bits grew into globs not quite an eighth of an inch. When scientists looked inside the globs, the cells were differentiating into specific brain regions and functions.

A member of the team was investigating microcephaly, a deformity in which babies are born with abnormally small heads — a particularly grotesque result of the zika virus. She took skin cells from persons with the condition, reprogrammed them to become stem cells, then gave the cells biochemical signals that told them to become neural organoids. She found these organoids were stunted compared to normal brains. The finding opened a new avenue of research into the condition’s origins and for thwarting zika’s effects.

At Yale, another group grew mini-brains to study autism. Researchers took stem cells from the normal fathers of children with autism. They cultured both sets of cells to become brain organoids. They found that cells inhibiting biochemical signals were growing faster in the autistic brainlets than in normal ones. When they added certain biochemicals, the normal balance of growth was restored. The discovery has led some to whisper about a possible cure.

Similar hopes are blooming for breakthrough insights into other brain-based conditions from Parkinson’s disease to schizophrenia.

THE ETHICS OF MEDICAL GARDENING

Medical researchers aren’t much concerning themselves with the ethics of growing and keeping organoids. A lab-grown bit of liver or lung has no ability to register pain or discomfort, much less self-awareness.

But a beating human heart in a dish, even if it’s only a little portion of a heart, is something different. When an experiment ends and it’s time to dispose of the tissue and stop the heart, are you killing a human entity? It certainly can feel that way.
Medical ethicists already are looking ahead to ethical issues, most of which fall into two areas.

The first deals with brain organoids. Most of us, and many neuroscientists, see the brain as the seat of awareness, personality and consciousness. Brain cells in the lab already are dividing and specializing, organizing themselves into structures that mimic portions of the brains in our heads. At what point can that little bit of brain become aware — whatever “awareness” means?

Fortunately, most scientists agree that brains can’t become aware or conscious without sensory input. Organoids have none, but, in at least one case, scientists have linked a brain organoid with a bit of retinal tissue to see what would happen. That, according to some ethicists, is a big step down the slippery slope toward creating a mind in a dish.

The second ethical jungle surrounds the issue of embryos in a dish. Papers published in scientific journals indicate that, under the right conditions, stem cells in a dish can become “germ layers” — the first stage of development of an embryo. Other researchers foresee the ability to culture a cluster of stem cells into a fully formed creature, from slug to human.

That gets sticky; many nations forbid research on embryos of any kind. The Court of Justice of the European Union has set clear guidelines banning any kind of experimentation that could grow an embryo in a lab. The European Patent Office forbids “immoral inventions.”

Organoid research will face these questions soon. The Wake Forest team that printed heart organoids also connected them to liver organoids as part of a project to eventually lay the full range of human organs on a chip. It’s part of a government-funded project to test the integrated impacts of diseases and potential treatments all along the human organism.

If you have the full collection of human organs, even if only partial organs, on a chip, is it a human entity? Do laws governing human experimentation or treatment of embryos pertain?

We will face these conundrums eventually. For now, scientists will grow their buds and bits — and that’s enough to test new generations of cures, spark new hope for those needing transplants, and gain new understandings of the intricate processes that turn a mass of cells into a human being.   TJ

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