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If measured from beginning to end, the DNA in our cells is too long to fit into the cell’s nucleus, explaining why it must be constantly folded and packaged. When it is time for cell division, and the genetic information needs to be passed on to the next generation, DNA must be packed particularly tightly, else serious consequences for a cell’s viability might ensue. In a trans-European team effort, researchers from the Max Planck Institute of Molecular Physiology in Dortmund (MPI), the Netherlands Cancer Institute, and the Human Technopole in Milan have now discovered a molecular switch that regulates DNA packing into the typical sausage-shaped chromosomes observed during cell division. The discovery of this central mechanism for cell division has many potential applications in medicine and biotechnology.

From spaghetti to sausages

Our DNA is constantly being packed and unpacked. And there is a good reason for this: depending on its packing state, it performs different functions in the cell nucleus. For most of its life – this is the time between two cell divisions – our chromosomes look like a disordered, tangled pile of spaghetti, which makes it accessible to be read. When a cell needs to make a copy of itself, a process called “cell division”, the chromosomes must be neatly separated, aligned and then distributed to the daughter cells. However, this would be impossible with DNA in spaghetti form. That’s why the DNA strands are wrapped as tightly as possible in preparation for cell division: multiple loops and spirals form compact, neatly-disentangled, sausage-shaped chromosomes with their characteristic X shape, approximately 10,000 times shorter than the original DNA strands.

Packing chromosomes too early

Whether our genes can be read or distributed without errors depends on whether the DNA condenses at the right moment.”

Duccio Conti, postdoctoral researcher in Andrea Musacchio’s department at the MPI and co-first author of the study

Packing tightly the DNA at the wrong time can lead to severe consequences for the cell and for the organism – for example, uncontrolled DNA packing is associated with primary microcephaly. However, how DNA condensation is triggered and controlled when cell division begins remained unknown until now.

A timely molecular switch

‘It was only through the intensive collaboration of our three groups that we were able to discover how DNA condensation during the cell cycle is regulated by a unique molecular switch,’ says Alessandro Borsellini, postdoctoral researcher in Alessandro Vannini’s group at Human Technopole and also co-first author of the study. The researchers identified the proteins that regulate condensin II – which is known to drive chromosomes packing in cell division – going onto chromosomes. Two proteins compete mutually for binding to condensin II: when MCPH1 (or microcephalin) binds, condensin II cannot go to the DNA, when M18BP1 binds, condensin II can bind to the DNA and make loops. During the time between cell divisions, microcephalin binds to condensin II and keeps it inactive, causing the DNA to look like spaghetti instead of sausages. When the cell begins to divide, the key enzyme CDK1 is activated and phosphorylates both microcephalin and M18BP1, causing a switch of binding partners. Condensin II is thus activated and able to pack the spaghetti into sausage-shaped chromosomes.

‘For the first time, we understand one of the mechanisms that control DNA packing at the beginning of cell division. This not only clarifies a fundamental process of life, but may also contribute to better understanding of errors in the packing process in the future and, ideally, to their prevention,’ summarises Beccy Harris, postdoctoral researcher in Benjamin Rowland’s laboratory at the Netherlands Cancer Institute and co-first author of the study.

Two types of rivers

Earth scientists have long divided rivers into single and multi-channel categories, and generally investigate the two separately. While neither type clearly outnumbers the other, most of the world’s largest rivers are multi-channeled. The notable exception is the single-channel Mississippi River, in the United States, where a lot of river research has occurred.

Most field research has focused on single-threaded rivers, partly because they’re simpler. Meanwhile, experimental work has focused on multi-threaded rivers due to the challenges of recreating single-threaded channels in laboratory tank experiments.

It was while working on one of these tank experiments at University of Minnesota’s St. Anthony Falls Laboratory that Chadwick got the inspiration for this study. While examining multi-channel rivers in the lab, he noticed that they were constantly widening and splitting. “I was banging my head on the wall because I kept measuring more erosion than deposition. And that was not what we’re taught in school,” he recalled. “That led me to read some old books from the Army Corps and other sources about examples where there’s more bank erosion than deposition.” Eventually, he became curious whether this occurred in nature.

It was a classic example of the scientific method: “You generate a hypothesis in a laboratory setting and then you’re able to test it in nature,” said co-author Evan Greenberg, a former doctoral student at UCSB who received the prestigious Lancaster Award for best dissertation.

MIT researchers have developed a new bionic knee that can help people with above-the-knee amputations walk faster, climb stairs, and avoid obstacles more easily than they could with a traditional prosthesis.

Unlike prostheses in which the residual limb sits within a socket, the new system is directly integrated with the user’s muscle and bone tissue. This enables greater stability and gives the user much more control over the movement of the prosthesis.

Participants in a small clinical study also reported that the limb felt more like a part of their own body, compared to people who had more traditional above-the-knee amputations.

“A prosthesis that’s tissue-integrated — anchored to the bone and directly controlled by the nervous system — is not merely a lifeless, separate device, but rather a system that is carefully integrated into human physiology, offering a greater level of prosthetic embodiment. It’s not simply a tool that the human employs, but rather an integral part of self,” says Hugh Herr, a professor of media arts and sciences, co-director of the K. Lisa Yang Center for Bionics at MIT, an associate member of MIT’s McGovern Institute for Brain Research, and the senior author of the new study.

Tony Shu PhD ’24 is the lead author of the paper, which appears today in Science.

Better control

Over the past several years, Herr’s lab has been working on new prostheses that can extract neural information from muscles left behind after an amputation and use that information to help guide a prosthetic limb.

During a traditional amputation, pairs of muscles that take turns stretching and contracting are usually severed, disrupting the normal agonist-antagonist relationship of the muscles. This disruption makes it very difficult for the nervous system to sense the position of a muscle and how fast it’s contracting.

Using the new surgical approach developed by Herr and his colleagues, known as agonist-antagonist myoneuronal interface (AMI), muscle pairs are reconnected during surgery so that they still dynamically communicate with each other within the residual limb. This sensory feedback helps the wearer of the prosthesis to decide how to move the limb, and also generates electrical signals that can be used to control the prosthetic limb.

In a 2024 study, the researchers showed that people with amputations below the knee who received the AMI surgery were able to walk faster and navigate around obstacles much more naturally than people with traditional below-the-knee amputations.

In the new study, the researchers extended the approach to better serve people with amputations above the knee. They wanted to create a system that could not only read out signals from the muscles using AMI but also be integrated into the bone, offering more stability and better sensory feedback.

To achieve that, the researchers developed a procedure to insert a titanium rod into the residual femur bone at the amputation site. This implant allows for better mechanical control and load bearing than a traditional prosthesis. Additionally, the implant contains 16 wires that collect information from electrodes located on the AMI muscles inside the body, which enables more accurate transduction of the signals coming from the muscles.

This bone-integrated system, known as e-OPRA, transmits AMI signals to a new robotic controller developed specifically for this study. The controller uses this information to calculate the torque necessary to move the prosthesis the way that the user wants it to move.

“All parts work together to better get information into and out of the body and better interface mechanically with the device,” Shu says. “We’re directly loading the skeleton, which is the part of the body that’s supposed to be loaded, as opposed to using sockets, which is uncomfortable and can lead to frequent skin infections.”

In this study, two subjects received the combined AMI and e-OPRA system, known as an osseointegrated mechanoneural prosthesis (OMP). These users were compared with eight who had the AMI surgery but not the e-OPRA implant, and seven users who had neither AMI nor e-OPRA. All subjects took a turn at using an experimental powered knee prosthesis developed by the lab.

The researchers measured the participants’ ability to perform several types of tasks, including bending the knee to a specified angle, climbing stairs, and stepping over obstacles. In most of these tasks, users with the OMP system performed better than the subjects who had the AMI surgery but not the e-OPRA implant, and much better than users of traditional prostheses.

“This paper represents the fulfillment of a vision that the scientific community has had for a long time — the implementation and demonstration of a fully physiologically integrated, volitionally controlled robotic leg,” says Michael Goldfarb, a professor of mechanical engineering and director of the Center for Intelligent Mechatronics at Vanderbilt University, who was not involved in the research. “This is really difficult work, and the authors deserve tremendous credit for their efforts in realizing such a challenging goal.”

A sense of embodiment

In addition to testing gait and other movements, the researchers also asked questions designed to evaluate participants’ sense of embodiment — that is, to what extent their prosthetic limb felt like a part of their own body.

Questions included whether the patients felt as if they had two legs, if they felt as if the prosthesis was part of their body, and if they felt in control of the prosthesis. Each question was designed to evaluate the participants’ feelings of agency, ownership of device, and body representation.

The researchers found that as the study went on, the two participants with the OMP showed much greater increases in their feelings of agency and ownership than the other subjects.

“Another reason this paper is significant is that it looks into these embodiment questions and it shows large improvements in that sensation of embodiment,” Herr says. “No matter how sophisticated you make the AI systems of a robotic prosthesis, it’s still going to feel like a tool to the user, like an external device. But with this tissue-integrated approach, when you ask the human user what is their body, the more it’s integrated, the more they’re going to say the prosthesis is actually part of self.”

The AMI procedure is now done routinely on patients with below-the-knee amputations at Brigham and Women’s Hospital, and Herr expects it will soon become the standard for above-the-knee amputations as well. The combined OMP system will need larger clinical trials to receive FDA approval for commercial use, which Herr expects may take about five years.

The research was funded by the Yang Tan Collective and DARPA.