Organoids and especially brain organoids, which are made from pluripotent stem cells, are one of the most interesting developmental biology technologies of the last half a dozen or so years. Still some folks can’t help but get carried away when thinking about brain organoids it seems.
A new Science paper from a team led by UCSD’s Alysson Muotri has stirred things up the last few days.
Brain organoids
Various organoid methods have yielded solid advances in biomedical science via some intriguing papers. I tend to find the papers on human brain organoids to be especially interesting. This is probably because of my lab’s work in this area and my interest in brain growth.
At the same time, there have been some papers that have gotten way overblown to the point of hype in media coverage. One issue is the tendency to see brain organoids as too similar to brains. Brain organoids, also known as cortical organoids or “mini-brains”, are not brains, not even shrinky-dinked ones.
I see them as akin to some portions of the fetal brain, depending on the protocol. They are great, novel tools but as with any technology there are limitations. Nothing’s perfect.
For me the new Science paper on brain organoids with a Neanderthal twist is something I haven’t quite been able to find a home for in terms of how to categorize or think about it. A true big deal or overblown? Probably more the latter.
Let’s go through it, but first some brief background on Neanderthals.
Us vs. Neanderthals?
Neanderthals were humans but of a slightly different species than us Homo sapiens sapiens. They are classified as either Homo sapiens neanderthalensis or Homo neanderthalensis. It’s unclear what happened to Neanderthals as a species.
There seems to be some fascination on the part of us “modern” humans with Neanderthals. Maybe it’s understandable that we wonder about our fellow humans of the past. We also have some small percentage of Neanderthal DNA because of past mating between the two species so that may add to the interest.
There is a propensity for pop culture to view Neanderthals as somehow less advanced than us, but I’m not clear on how convincing the evidence might be to that effect.
There is also the pejorative term “neanderthal” that is applied to a person acting badly or crudely. Has science escaped this stereotyped view of Neanderthals? Even the use of the term “modern” sometimes has an odd ring to it when applied to humans.
Science pub on human brain organoids with “Neanderthal” variant
The new pub Trujillo, et al. in Science got big attention this week. It’s entitled “Reintroduction of the archaic variant of NOVA1 in cortical organoids alters neurodevelopment.”
The paper in essence argues that a Neanderthal variant of a particular gene, NOVA1, when gene-edited into human pluripotent stem cells, results in brain organoids made from the stem cells that have different phenotypes. See image of the different organoids side by side above.
The work got splashy international media coverage, but my instant reaction on first glancing at it was that this could be less concrete of a finding than it was often portrayed in the media. It feels like it got hyped.
From the summary with the paper:
“The genomes of Neanderthals and modern humans are overall very similar. To understand the impact of genetic variants that are specific to modern humans, Trujillo et al. performed a genome-wide analysis to identify 61 coding variants in protein-coding genes. Identifying the gene encoding the RNA-binding protein NOVA1 as a top candidate for functional analyses, they introduced the archaic gene variant into human pluripotent stem cells and generated brain organoids.”
It’s also worth mentioning that the “Neanderthal” gene variant is not specific to Neanderthals. It is also present in other vertebrates including mice and chickens (see screenshot from the paper itself above). So could you call the variant brain organoids “chicken brain organoids”? Not really since the rest of the sequence is human, but I think you get the point.
Someone else helpfully also pointed out to me that there are also some of us “modern” humans walking around today with the “Neanderthal” NOVA1 variant. As with many things in science, this variant is not so simple.
Note that Muotri has done some other high-profile human brain organoid work including related to autism, which he discuss in the video below, and is co-founder of a small organoid-focused biotech called TISMOO.
Same brain organoids can vary substantially
As someone whose lab is making human brain organoids and examining different gene-edits, I appreciate the effort that went into this paper. But I also wonder if the phenotype is definitely specific to Neanderthals. How could we know?
Will the phenotype will be reproducible?
Could there be experimental issues that explain some of the reported phenotypes? The authors did discuss important caveats so that’s a plus.
Based on my experience just with human brain organoids in general, the team’s archaic NOVA1 variant-containing organoids don’t look wildly atypical from just regular human brain organoids made from iPS cells. Maybe a somewhat less healthy batch. Their “modern” brain organoids look rather smooth and round too. Quite a lot depends on the stage of the organoid process for all of this and each batch can turn out somewhat different even starting with the same cells.
Mechanisms?
In terms of molecular and cellular mechanisms for how a variant in NOVA1 could impact organoid phenotypes, the paper is unclear. The phenotype may even not be related to the NOVA1 protein’s known RNA-binding function.
Splashy papers without strong mechanistic data make me a little more skeptical.
Organoids are not brains and brains are not minds
This article by Carl Zimmer in NYT on the organoid paper is worth a read. It does a good job on the topic.
However, I see the title, “Tiny Blobs of Brain Cells Could Reveal How Your Mind Differs From a Neanderthal’s“, as having overstated things.
Could this Science paper actually teach us about how our minds differ? Not really.
A mind is, of course, a different thing than a brain and then an organoid as mentioned earlier is not a brain. I guess the key word in the title is “could.”
In the big picture, the phenotypes in this Science paper also do not necessarily fit in with what is known about Neanderthals or their brains. Neanderthals had bigger brains and they weren’t somehow bumpier then ours.
Looking ahead, many of the question marks here will be resolved by future research.
My lab cultured rat neural precursors in little balls in the 1980s. We affectionately called them “brain balls”. My point is that we never considered them to be brains. They were merely a better way to culture neurons- they survived and matured better than when attached to a dish. It is tempting to call them things like “mini-brains” but they resemble brains only in having neurons and perhaps glia. The neurons in the brain are conduits for signals- they are part of networks that include inputs and connections with other types of neurons. Neurons do not have a function in isolation. Except perhaps for a neuron replacement therapy!
Looking at the original paper, the right image appears to be homozygous archaic in the proliferation phase, and the right I am having difficulty matching. I think it is homozygous archaic maturation phase, an enlarged version of the panel in the paper, but I am not entirely sure.
How are those images being used? If they were in a press release purporting to show differences between modern and archaic, I fear that they are being used in a misleading manner,
One problem that I see with the above images is the lack of scale bars. I can’t tell from the image if the Neanderthal organoids are smaller or not. There is a difference in morphology, but I have no idea what that means.
Some of the images in the paper itself have scale bars, but not all. Also, some of the data are statistically analyzed, while some are not, and there’s a fair amount of N=1. It’s also not clear from my reading of the paper how deeply they looked for off-targets from their CRISPR.