Cancer Treatment Through Biochemical Engineering of Histones and Their Binding Proteins

I want to spotlight the work of Professor Karmella Haynes. I heard an interesting interview with her on The Leap, which got me interested in her work on epigenetics and synthetic biology.

Her work uses engineered proteins to reactivate silenced tumor-suppressing proteins and potentially stop cancer cells from spreading.

Here’s my basic understanding of the biology. In one sense, cancer is a disease where cells divide and proliferate more than they should. One way that organisms can prevent this is through that activity of tumor suppressing proteins. These proteins can work by either repairing mutated DNA, or triggering programmed cell death (apoptosis). There are genes that code for those proteins, and those genes are supposed to get transcribed and then translated into functional proteins. But sometimes, something suppresses the transcription of those tumor suppressing genes. Scientists have noticed that at these suppressed genes there is sometimes more of particular versions of histones. Histones are proteins that package DNA – you can picture them as spools that DNA wraps around. So Haynes’ lab has engineered a fusion protein that binds to those versions of histones. By binding the histones, the genes for tumor suppressing proteins are more available for transcription. Cancer cells should either get repaired or destroyed. The hope is that clinicians will someday be able to treat patients with these engineered proteins. That would allow the patient’s own internal systems to express more of these tumor suppressing genes, which will in turn reduce the spread of tumors in patients.

I want to dive into some of the details of her work, as shown by this paper from 2023. Haynes and her colleagues describe one of these fusion proteins, and how it worked against difficult cancers, like triple-negative breast cancer. In the paper, they call their fusion protein “Synthetic Reader-Actuator” or SRA for short. SRA has three parts. At the N-terminal there is region that binds the particular type of histone associated with silencing these tumor suppressor genes. Then there is a region that binds transcription initiation factor. And finally there’s a segment that localized the molecule to the cell’s nucleus.

For those (like me) who aren’t oncologists: triple-negative breast cancer is hard to treat because it lacks the hormone receptors and the HER2 protein. This makes several of the common drugs ineffective.

The work for this paper was all in vitro, because the technology is still in early stages. Still, in well plates and liquid cultures, they noted smaller clusters formed by experimental cancer cells. The cells also failed to invade culture materials. Genes associated with apoptosis and DNA repair showed twice the activity after treatment with their engineered fusion protein.

Scientists are also working on patenting ways of modifying the types of histones that Haynes and her colleagues were targeting in their research. This published patent application – 20250277266 Chromatin profiling compositions and methods – describes ways of isolating and profiling histones. The basic idea is to

1. use substrates that bind the histone

2. binding a nucleic acid barcode to the histone,

3. amplifying the target nucleic acid sequence, along with whatever it’s now attached to

4. analyzing the target sequence that’s stuck to the barcode

The patent application describes this as five steps. To me, conceptually, it makes more sense as just these four steps. I have outlined them above.

The application is written with three independent claims, and thirty claims in total. There are two main differences among the independent claims. The first is whether there is a connector targeting nucleosome DNA. They define the “connector” as a sequence that can hybridize with a complimentary sequence on any adapter a practitioner of this technique might be using. The second main difference among the independent claims is whether there is a nucleosome binding conjugate. By “nucleosome binding conjugate,” they mean a nucleotide barcode that a practitioner is using.

There are other related patent applications pending, of course. I’ll keep an eye on how these patent applications advance, and what further work is coming out of Haynes’ lab.

And, always, keep in mind that I’m not a lawyer. Nothing in this post is legal advice.