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Even allowing for the fact that these were lilliputian brains, they were not behaving at all according to plan. From the first days of the tiny lab-grown organs’ development, primitive “progenitor cells” romped out of their birthplaces in the deep interior and quickly turned into neurons and glia, specialized cells that do the brain’s heavy lifting, from thinking and feeling and moving to boring old neurological housekeeping. But the cells were jumping the gun.

In healthy developing human brains, progenitor cells spend a good chunk of prenatal existence simply reproducing, vastly increasing their numbers and postponing becoming other brain cells. The impatient progenitor cells, however, were in cerebral organoids — minuscule 3-D versions of the brain — created from the cells of people with Huntington’s disease in hopes of mimicking the patients’ actual brain development decades earlier.


It was new evidence that, in their understanding of this devastating genetic illness, scientists know only half the story: In addition to being a neurodegenerative disease, it is also neurodevelopmental, starting in the womb. These recent findings and other research are spurring a radical rethinking of Huntington’s, with implications for the age when any potential cure is likely to be most effective.

“It’s not conclusive, but there is suggestive evidence that neurodevelopment is altered in Huntington’s disease,” said neurobiologist Mahmoud Pouladi of the National University of Singapore, who led the organoid work. If so, then if scientists discover a way to repair the mutant gene or remove the aberrant molecules it makes, “the earlier you intervene the better it should be.”

In contrast, today’s most-watched clinical trials in Huntington’s include only adults, often middle-aged ones, reflecting the belief that most mutation carriers can reach their 30s or beyond cerebrally unscathed. In fact, doctors and advocacy groups strongly discourage genetic testing for Huntington’s in anyone under 18, presuming there’s nothing to be gained. According to the genetic-testing guidelines from the Huntington’s Disease Society of America, “Predictive testing of minors currently has no medical benefits and the possibility for psychosocial harm and lowered self-esteem is high.”


The new understanding is surprising because Huntington’s has long seemed like a prototypical neurodegenerative disease, one in which the brain’s circuits, especially those that control movement and cognition, begin to fall apart in early to middle adulthood. Exactly when that happens depends on the severity of the genetic mutation, which is a sort of DNA stutter — repeats of the nucleotide sequence CAG in a gene named HTT, which makes a protein called huntingtin.

Three dozen repeats of the sequence are normal; 40 or more generally result in Huntington’s symptoms in the person’s 30s, including abnormal walking, involuntary movements, loss of coordination, memory loss, delusions, difficulty thinking and understanding, irritability, and compulsive behavior. All are due to neuronal death in the movement-controlling striatum as well as the cerebral cortex. More than 60 repeats bring symptoms by adolescence.

If nothing else, the fact that people can live normal lives for decades without suspecting they have the Huntington’s mutation (unless they undergo genetic testing) seemed to confirm that, like Alzheimer’s or Parkinson’s, the disease ravages once-healthy brains, but doesn’t strike before then.

An animation explaining how Huntington’s disease works. Dom Smith/STAT

Experiments with both simple collections of neurons growing in lab dishes as well as cerebral organoids grown from the stem cells of Huntington’s patients, and therefore harboring the DNA stutters, are now undermining that belief. Cerebral organoids in general reprise the development of the donor’s brain, growing from a few cells to a structure with millions, and dozens of cell types, circuits, and layers — a complex entity capable of spontaneously generating brain waves.

“Since the mutation is with you from conception, it makes sense that there could be deleterious effects on the brain from the beginning,” said biologist Virginia Mattis, who led studies at Cedars-Sinai Medical Center in Los Angeles of lab-grown neurons produced from Huntington’s patients’ stem cells. But effects on the young brain are subtle, she cautioned, and “just because it is neurodevelopmental doesn’t mean that all hope is lost.”

In one of the most detailed studies of brain development in Huntington’s, Pouladi and his colleagues produced cerebral organoids from two kinds of stem cells. One batch came from human embryonic stem cells, from donated IVF embryos that had the Huntington’s mutation and were otherwise going to be discarded. The others came from pluripotent stem cells derived from Huntington’s patients, through a Nobel-winning technique that reverts ordinary skin or other adult cells back to an embryonic state.

In both cases, the genesis cells had mutations of different severity (45, 65, or 81 CAG repeats). After at least 21 days, the organoids reached the size of apple seeds, about 2 millimeters across, and were beginning to mimic the brain development of a 4-month fetus in terms of which structures are emerging.

One of the more striking findings was the failure of progenitor cells to remain in the hollows where they originated and replicate with abandon. Instead, Huntington’s cerebral organoids showed “premature neurodifferentiation,” Pouladi said, migrating abnormally early to their ultimate homes in the brain organoid, giving birth to neurons (a process called neurogenesis), and differentiating into specialized cells. The more CAG repeats, the more significantly the progenitors abandoned proliferation too soon.

Digging deeper, Pouladi and his colleagues found one reason for that: Progenitor cells’ timing was off. They lingered in the growth phase of their life cycle before getting on to the business of reproducing. That stole time from the reproduction phase. The segue to differentiation began immediately after the abbreviated period of cellular reproduction. More CAG repeats predicted more lingering in the first phase, less time for proliferating, and more premature differentiation.

It’s another clue that “abnormal neurodevelopment may be a component of [Huntington’s disease] pathophysiology,” he and his colleagues wrote in a paper submitted to a journal.

More research is needed to determine whether that affects Huntington’s carriers in measurable ways, including in their cognition, movement, or emotional regulation. But one consequence of too-early differentiation is that the genes in the cortical neurons in the Huntington’s brain organoids have a different on-off pattern. Overall, their DNA activation is that of less mature neuronal development compared to brain organoids created from healthy people, which may lay the foundation for eventual neurodegeneration.

The organoids’ behavior might explain puzzling findings in people who have a Huntington mutation. As children, their head circumference, a measure of brain volume, is smaller than healthy children’s, yet they are decades from showing symptoms. As adults, also before symptoms, they have a larger cerebral cortex, smaller basal ganglia, and less white matter, which carries signals from one neuron to another and thereby creates functional brain circuits. Mutation carriers also have a larger striatum, the region most affected by Huntington’s. The organoids showed abnormalities that can cause all of these.

Neurons created from the stem cells of juvenile-onset Huntington’s patients — but not coaxed to form 3-D organoids — also had developmental abnormalities, Mattis and her colleagues found in their experiments. The connecting filaments, or neurites, “were shorter and less mature,” she said. “By 40 days we could see a real difference in their neurons” compared to those from healthy people, they reported last year.

Scientists at Cedars-Sinai are now moving beyond cells-in-dishes to three-dimensional cerebral organoids. Organoids “are better able to show the process of cerebral maturation,” Mattis said, especially spatial organization of brain cells.

One striking abnormality in the organoids is the oversized movement-controlling striatum. That’s also seen in children and adolescents who have the Huntington’s mutation but who won’t show symptoms for many years, scientists reported in September. The striatum’s size initially outstrips that in healthy young people, brain MRIs showed, but then begins a fast pullback between ages 10 and 14. That might be a harbinger of the eventual pathology that precipitates the involuntary writhing and jerking that characterizes Huntington’s. It was as if the structure overshot its goal and then overcompensated.

One reason why brain development might go off course in Huntington’s is the effect of the mutant protein on cells’ life cycles. Healthy huntingtin gathers up molecules deep in the cell nucleus that are required for cell division, Pouladi explained; the mutant protein fumbles that task, hobbling the proliferation of progenitor cells.

That keeps cellular structures that resemble starbursts from growing to normal size. The self-organizing starbursts, collections of neurons radiating out from a central point, differentiate into all of the brain’s specialized regions, Pouladi said. In normal brains and normal brain organoids, they exceed 400 microns in the earliest stages of development. But in his Huntington’s organoids, none did, and very few were larger than 200 microns. The starburst size gap was especially stark in the organoids’ forebrain, which in the full-size brain controls higher cognition such as problem solving, planning, and judgment.

“There is accumulating evidence that neurodevelopment is altered” in Huntington’s, said neuroscientist Scott Zeitlin of the University of Virginia School of Medicine and an expert on the disease. “But we don’t know yet if this causes any clinically relevant symptoms in people” or if the altered neurodevelopment somehow sets the stage for eventual neurodegeneration.

One reason early neurodevelopmental abnormalities do not necessarily cause symptoms is that one region of the brain can compensate for deficits in another. For instance, although the striatum loses volume during the tween years, the cerebellum (which also controls movement) compensates, said Dr. Peggy Nopoulos of the University of Iowa, who led the MRI study.

If abnormal neurodevelopment does contribute to the devastating adult symptoms of Huntington’s, then efforts to prevent, treat, or even cure the disease will need to focus much earlier than they now do, she said. An experimental therapy now being tested in a clinical trial, for instance, silences the HTT gene. Only adults are in the study, which isn’t unusual. But the growing recognition that Huntington’s is also neurodevelopmental suggests that treating earlier (assuming the gene-silencing drug candidate works) would be necessary “to maximize preventive therapy,” Nopoulos said, preserving normal neurodevelopment and forestalling neurodegeneration.

  • Articles like this show the importance of the Huntington’s Disease Youth Organization, a group focused on supporting, education and empowering young people who this article is pointing towards. In order for the Hd community to be prepared for these earlier in life trials, support and education for these young people and families will be crucial. Please visit the website to learn more:

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