黑料网爆吃瓜

These proteins were not supposed to exist. Yet, there they were. As we started to learn more about them, researchers wondered if we hadn鈥檛 stumbled upon new targets for treating diseases like cancer.

If wellness fads abided by their own horoscope, we could say 2025 was the Year of the Protein. The macronutrient was shoved everywhere: inside of cereals, milk cartons, even pasta. Everyone wanted more protein.

But proteins are simply the building blocks of the human body. They make up much of the infrastructure of our cells鈥� cityscape. They make life possible.

Proteins are encoded in stretches of DNA we call genes, much like how an architectural plan dictates how to build a house. We have scanned our genome鈥攁nd the genome of many, many other species鈥攖hese past couple of decades, and you would think we had identified all of our protein-coding genes, roughly听. We certainly knew what to look for.

Now, though? We鈥檙e discovering what looks like proteins coming out of DNA stretches that shouldn鈥檛 be producing them. They have been here all along yet were invisible to our tech-enhanced eyes鈥攎uch like the imperceptible dark matter that seems to make up most of the weight in our universe.

They are one of the hottest things in molecular biology right now, the type of discovery one researcher tells me that comes maybe once or twice in a scientific career.

They are called dark proteins, and clinical trials are already underway to squeeze some good out of them.

Unveiling the dark proteome

听Proteins, which are chains of amino acids, tend to be long. But in the 2000s, researchers stumbled upon听听that were unnaturally short. In fact,听, found in the fruit fly, held a lot of power: when disrupted, significant defects in the fly鈥檚 anatomy would be observed. That a protein this small could have such a biological impact was the first major awakening that leads us to dark proteins.

The second one has to do with where tiny proteins can come from.

Imagine walking onto a construction site, sure of what they鈥檙e building, and finding out that the crew is also erecting walls that were not on the plans you saw. When asked, they would show you new paper plans, which you had never seen before. Worst of all, they would tell you this is routine. It had always been this way.

In 2009, Nicholas Ingolia, working in Jonathan Weissmann鈥檚 lab, managed to capture听. Ribosomes are the construction crew of our cells: tiny but mighty factories that read transcripts from our genes and translate them into proteins. That messenger RNA used in many of the COVID-19 vaccines? That鈥檚 a transcript, and it鈥檚 the ribosome that translates it into a protein.

And when he actually looked at what was coming out of ribosomes, he and his team saw molecules that looked like short proteins鈥� but that they had never encountered before.听

Major publications in the last few years put this discovery firmly on the map, and the phrase that caught the eye of the scientific press was 鈥渄ark proteins.鈥� They鈥檙e not dark because they鈥檙e evil or because they necessarily cause diseases; the 鈥渄ark鈥� is analogous to dark matter which exists but can鈥檛 be seen. When we think of all of the dark proteins contained in the human body, we call it the dark proteome. (If you鈥檙e a structural biologist, yes, I know, the phrase carries听听for you. Sorry.)

鈥淲hat I think the misunderstanding is is that this is something that a small number of people are doing without a larger buy-in. That鈥檚 not the case at all. I think this is super important.鈥� I interviewed Dr. John Prensner for this, and this is what he wanted to make clear. Prensner is a physician-scientist and pediatric hematologist-oncologist currently at the University of Michigan and one of the leading researchers in the expanding field of dark proteins.

The buy-in he鈥檚 referring to is the roughly 25 academic sites all over the world working on dark proteins through the听, on the executive board of which Prensner sits. The consortium earlier this month published a听听in听Nature听outlining the steps to studying these dark proteins, even giving them a proper scientific name: peptideins (roughly pronounced PEP-tuh-deenz). It鈥檚 a contraction of 鈥減eptide鈥� and 鈥減rotein.鈥� (They originally considered 鈥減eptein鈥� before learning it was the name of a听听in Thailand.)

鈥淧eptidein鈥� is a linguistic waystation, a temporary assignment to a scientific limbo. When they are first detected, these dark proteins are called peptideins because we don鈥檛 know what their role is. If they can be convincingly shown to behave like a traditional protein, then they will be called as such鈥攐r a 鈥渕icroprotein,鈥� since these peptideins tend to be quite short. When a protein is made up of fewer than 100 amino acids, it is听. So, a dark protein is scientifically called a peptidein when its function is unknown, but if it can be proven to behave like a protein, it will be reclassified as a microprotein.

Figure 1: Microproteins and proteins are different based on how many amino acids they contain.

(Here鈥檚 an aside for the linguistically minded who are wondering why I am using the word 鈥渕icroprotein鈥� and not 鈥減eptide.鈥� Feel free to skip. Peptides are indeed short chains of amino acids, basically short proteins. But peptides don鈥檛 have a clear cut-off point in terms of their length. Many of us will say they have to be shorter than 100 amino acids to qualify, but there is no scientific consensus on this length. More importantly, peptides are typically born of听cleavage.听If you think of a protein as a bit of twine and you cut it in two, the halves would be called peptides. Peptides are made from longer starting material that needs to be processed; microproteins, by comparison, are encoded as such, no cleavage needed. That鈥檚 the big difference.)听

All of this discussion on what to call them obscures an important question: how were these dark proteins invisible to us for so long?

It boils down to rules.

We thought we knew what the rules were for a stretch of DNA to code for a protein. There was a particular sequence of letters that said 鈥渟tart here.鈥� Well, it turns out that you don鈥檛 necessarily need this sequence to produce a protein. The instructions to make dark proteins are in parts of the DNA听that shouldn鈥檛 code for proteins鈥� at least according to what we thought we knew.

You may remember the term 鈥渏unk DNA,鈥� which was popular in the media during the Human Genome Project. Our DNA has genes, which code for proteins, and much of the rest was, at the time, hit with the dismissive label of 鈥渏unk DNA.鈥� Some sort of evolutionary holdover, perhaps, or the equivalent of packing material. Some of this junk DNA codes for dark proteins, it turns out.

But other dark proteins are encoded very near actual genes, in regions that are involved in the regulation of these genes. It鈥檚 like buying one of those steel model kits鈥攚here you twist off tiny pieces of metal and painstakingly assemble them into the Eiffel Tower or the Millennium Falcon鈥攁nd finding out that the instructions can also be folded into a tiny 3D model.

So, dark proteins exist鈥攚ith over a hundred properly documented in humans and thousands more being explored. But what exactly do they do?

鈥淎 fundamentally different biology鈥�

I spoke to Dr. Marie Brunet, who works at the genetics service of the Department of Pediatrics of the University of Sherbrooke and who carries research into dark proteins. 鈥淲e鈥檙e moving from 鈥榳hat exists鈥� to 鈥榳hat does it do鈥�,鈥� she said, summarizing where the field had been and where it was headed.

Some peptideins have enough evidence for us to say that they are simply short proteins that were previously missed because of their size and because of how they are encoded in our DNA.

But a large swath of peptideins may turn out to be protein-like听in structure only. They may, as has been hypothesized, only exist to gum up the ribosome. If you send phony architectural plans to a construction crew and tell them to make them a reality pronto, they will waste time doing this, and house construction will be delayed. For a cell, this might be desirable. Cells are not producing every protein all the time. Protein production is carefully regulated through a dozen different means: peptideins might be one more way of doing it, by clogging up the ribosome temporarily. In these cases, the peptidein itself is worthless and has no function; it鈥檚 the DNA coding for it that鈥檚 important.

I asked Prensner about this, and his hunch鈥攁nd it is simply his own personal hypothesis鈥攊s that, indeed, a minority of peptideins will be shown to be traditional proteins, while the听majority听of peptideins will be shown to have 鈥渁 fundamentally different biology.鈥�

Brunet was keen to remind me that different peptideins will have different reasons for existing鈥攎uch like, I would add, how different guests staying at the same hotel have their own reason for being there: work, vacation, an unexpected holdup from a delayed flight. One peptidein will be shown to behave like a protein. The next one will turn out to be a temporary artefact from a cancer cell whose biology is out of whack. The next one still will be an artefact of normal biology, where a bit of DNA is translated by the ribosome and then immediately degraded. Yet others will carry unknown functions for a while as scientists puzzle over them. It鈥檚 a spectrum.

Figure 2: What a newly discovered peptidein (also known as a dark protein) may be doing in the body.

But not knowing what they do will not stop scientists from trying to do something with them now.

What dark proteins mean for you

Reading the papers of the dark protein literature, I couldn鈥檛 help but notice how many authors are involved, in one way or another, with biotech companies focused on developing new ways to treat diseases. Both industry and academia are interested in quickly translating this knowledge of the dark proteome into the clinic. Two applications are already being considered.

First, diagnostics. If a dark protein can be shown to be tied to a specific cancer, for instance, and nothing else, then detecting it鈥攁s part of a robust diagnostic test with few false positives and false negatives鈥攚ould mean you likely have this cancer.

Second, therapeutics. It may sound premature: after all, there is little we know about dark proteins鈥� roles in the body. Shouldn鈥檛 we study this more before talking about treatment potential? But if a dark protein is present, like a flag, at the surface of a cancer cell and is not present at the surface of a healthy cell, an immunological therapy can in theory be devised against it. We can train immune cells to recognize this flag as the enemy and to attack the cells bearing it inside the body. This is something that is already being done with traditional proteins. Our realization of the existence of dark proteins simply expands the repertoire of potential targets, and at least听听is already testing this hypothesis.

Hope is important, but adequately calibrated hope is perhaps more valuable. Yes, dark proteins are promising, but there are significant challenges ahead, and听听out of Columbia University and published last year zeroes in on them. Because of their small size, they are difficult to detect by mass spectrometry. The vast majority of them appear to get degraded inside the cell very quickly after their synthesis, which reduces the chances the peptidein itself plays a role. Very few of them, so far, are supported by more than one study: there is a lack of substantial overlap, something听听in the field of microRNAs, which also held promise for diagnostics and therapeutics. And when we add a tag to a dark protein in order to see where it goes in the cell, the tag itself may alter its localization because of how small the dark protein is, thus giving us false answers.

There is another hurdle: many of the rigorous papers I read on dark proteins were for studies that had received NIH funding. The National Institutes of Health are the main health research body of the U.S. government. They have been gutted under the Trump regime.

Dark proteins represent yet another example of a basic-research finding that appears to be trivial. Why should we invest money into studying 鈥渘oncanonical open reading frames,鈥� areas in the DNA that听shouldn鈥檛听produce proteins? Why should we pay to account for everything that comes out of our ribosomes? It can seem like nerdy knowledge gathering with no real value.

But nerdy knowledge gathering听has听value, in and of itself, and on top of that, you never know which part of it may end up transforming cancer care in the near future.

Evolution in action

I will end with a hypothesis Brunet slipped in toward the end of our interview and which gave me goosebumps. There is something uncanny about these dark proteins. They look like proteins but are very short; many of them get degraded before they have a real chance of doing something; and they come out of places in our genome that should not be coding for proteins. It鈥檚 like Bizarro World for molecular biology, some sort of weird laboratory our cells have set up inside of themselves. We could dismiss all this as artefactual nonsense鈥攁nd many scientists听did听before enough evidence had accumulated that we had missed something genuine.

But Brunet asks a stunning question: 鈥淎re we witnessing evolution in real time?鈥�

It鈥檚 known as听de novo听gene birth, a sort of immaculate conception for genes, an exotic and mostly theoretical idea that genes can be born from scratch. Those weird dark proteins we are now witnessing鈥攐r at least听some听of them鈥攎ight be one way in which novel genes are born, especially since many human dark proteins are not seen in other species. Dark proteins are 鈥渘oncanonical,鈥� meaning they are not recognized as being part of the canon of existing proteins. They currently exist outside of the consensus. 鈥淪ome of these peptideins,鈥� Brunet told me, 鈥渕ay be not-fully-finished copies of proteins. They may still be evolving. They may well be the canonical proteins of the future.鈥�

Let鈥檚 keep an eye on them, now that we know they exist.

Take-home message:
- Dark proteins, recently renamed peptideins, are molecules present in our body that look like short proteins but that are made from stretches of DNA that were not thought to code for proteins.
- Researchers are still figuring out the roles that these peptideins play in the body: some have turned out to be genuine proteins, while others may have no role at all or may play roles in our biology that we don鈥檛 even know about yet.
- Some of these dark proteins represent new targets that could potentially help doctors diagnose people with certain diseases or even treat them by training immune cells to recognize a dark protein associated with a specific disease.