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Sci-Tech

Using Laser Technology to Detect Cancer Cells

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We’ve come a long way since hearing Dr. Evil of Austin Powers’ movie fame describe “a sophisticated heat beam, which we call ‘a laser’ ” to take over the world, or sitting in awe watching Jedi knights in Star Wars blast through enemies using lightsabers.   

Now in real life, lasers are being used to detect cancers cells. 

Cancer tumors have the ability to break off of their primary site and spread from their primary organ to other sites of the body via the bloodstream and lymphatic system.  The spreading of cancer, known as “metastasis”, is the leading cause of cancer-related death.  Although, there are currently blood tests designed to detect cancer cells in the blood, known as circulating tumor cells, these test many times cannot pick up minimal cancer cells released early on.   If these current tests return as positive, this frequently means that there is a high level of cancerous cells in the blood that have spread to other organs.

However, the diagnosis and treatment of these cancer cells in the blood may soon change.

  In a recent study published in Science Translation Medicine, researchers have devised a laser that can detect these malignant cells and ‘zap’ them from outside of the body.  The current standard methods of detection have limited sensitivity for picking up minimal cells at early stages of the disease, therefore possibly missing an opportunity to eliminate them at a treatable juncture.   A team led by biomedical engineer Vladimir Zharov, director of nanomedicine at the University of Arkansas for Medical Sciences, has developed a method in hopes of changing that modality.

In studies with melanoma, they have coupled a laser with an ultrasound detector to create a ‘Cytophone,’ a device that identifies cells acoustically. 

To break it down, a laser is first shined on the surface of a person’s skin, penetrating right into some of the near-surface blood vessels.  The passing melanoma cells will then ‘heat up’ because of their darker pigment and create a small ‘acoustic wave’ that then gets picked up by the ultrasound detector.   Melanoma cells absorb more of the energy from the laser because of their dark pigment, allowing them to heat up quickly and expand.

This devised method can pick up a single circulating tumor cell per liter of blood, which makes this up to approximately 1,000 times more sensitive than other available methods of detection that typically examine only about 7- 8 milliliters of a sample of blood.  Additionally, the cytophone was able to detect small clots of blood that could potentially grow and lead to another set of harmful consequences. 

They have tested this on 28 patients with melanoma and 19 healthy volunteers. 

Researchers were able to discover that within as little as 10 seconds and as long as 1 hour, the cytophone was able to detect circulating tumor cells in 27 of the 28 patients.  It also did not return any false positives on the healthy volunteers.  Moreover, it was found that when the energy level of the laser was turned up (still to a safe intensity) that the amount of circulating tumor cells came down over the hour, without causing any side effects. 

Although the mechanism will likely not destroy all of the patient’s cancer cells, it can help in several different ways.  Initially, it can be used in high-risk individuals as a screening tool to detect cancer cells in the blood.  Similar to mammograms in breast cancer, it can be added to skin checks in patients that are at high risk for melanoma.  While undergoing treatment, it could potentially be used to monitor the effects of that particular treatment, in addition to or separate from imaging and other blood tests, to determine if the circulating cancer cells in the blood are decreasing.   Following the completion of treatment, it can be used to monitor for relapse of disease. 

Even though this has been tested recently in melanoma, and the dark pigment of melanin plays a role in its detection, Zharov and his colleagues are currently working to develop methods of ‘tagging’ other cancer cells with small nanoparticles to be able to ‘heat up’ and be distinguished from the normal cells.  This study holds promise but it now needs to be expanded to in a larger population including patients with a higher content of melanin.  For the Silo, Jerry McGlothlin.

Movies aside, the future holds promise in the new hope of using lasers to fight off the evil invasions of metastasis.

About Joshua Mansour, MD…

Dr. Joshua Mansour is a board-certified hematologist/oncologist working and in the field of hematopoietic stem cell transplantation and cellular immunotherapy in Stanford, California. In June 2019 he was a recipient of the ‘40 Under 40 in Cancer’ award. Abstracts, manuscripts, and commentaries by Dr. Mansour have been published in more than 100 esteemed journals and media outlets including Canada Free Press, Today’s Practitioner, Physician’s News, and KevinMD. He has given countless presentations at conferences and other institutions, and he has helped design and implement clinical studies to evaluate current treatment plans, collaborated on grant proposals and multi-institutional retrospective studies that have been published. Joshua Mansour. M.D. has been featured on Fox Television.

Sci-Tech

Researchers Control Mammalian Cells With Sound For First Time

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Salk researchers pinpoint a sound-sensitive mammalian protein that lets them activate brain, heart or other cells with ultrasound
LA JOLLA—Salk scientists have engineered mammalian cells to be activated using ultrasound. The method, which the team used to activate human cells in a dish and brain cells inside living mice, paves the way toward non-invasive versions of deep brain stimulation, pacemakers and insulin pumps.

The findings were published in Nature Communications on February 9, 2022.” Going wireless is the future for just about everything,” says senior author Sreekanth Chalasani, an associate professor in Salk’s Molecular Neurobiology Laboratory. “We already know that ultrasound is safe, and that it can go through bone, muscle and other tissues, making it the ultimate tool for manipulating cells deep in the body.” About a decade ago, Chalasani pioneered the idea of using ultrasonic waves to stimulate specific groups of genetically marked cells, and coined the term “sonogenetics” to describe it.

In 2015, his group showed that, in the roundworm Caenorhabditis elegans, a protein called TRP-4 makes cells sensitive to low-frequency ultrasound. When the researchers added TRP-4 to C. elegans neurons that didn’t usually have it, they could activate these cells with a burst of ultrasound—the same sound waves used in medical sonograms. When the researchers tried adding TRP-4 to mammalian cells, however, the protein was not able to make the cells respond to ultrasound. A few mammalian proteins were reported to be ultrasound-sensitive, but none seemed ideal for clinical use.

So Chalasani and his colleagues set out to search for a new mammalian protein that made cells highly ultrasound sensitive at 7 MHz, considered an optimal and safe frequency.” Our approach was different than previous screens because we set out to look for ultrasound-sensitive channels in a comprehensive way,” says Yusuf Tufail, a former project scientist at Salk and a co-first author of the new paper.

The researchers added hundreds of different proteins, one at a time, to a common human research cell line (HEK), which does not usually respond to ultrasound. Then, they put each cell culture under a setup that let them monitor changes to the cells upon ultrasound stimulation. After screening proteins for more than a year, and working their way through nearly 300 candidates, the scientists finally found one that made the HEK cells sensitive to the 7 MHz ultrasound frequency.

TRPA1, a channel protein, was known to let cells respond to the presence of noxious compounds and to activate a range of cells in the human body, including brain and heart cells.

But Chalasani’s team discovered that the channel also opened in response to ultrasound in HEK cells. “We were really surprised,” says co-first author of the paper Marc Duque, a Salk exchange student. “TRPA1 has been well-studied in the literature but hasn’t been described as a classical mechanosensitive protein that you’d expect to respond to ultrasound.” To test whether the channel could activate other cell types in response to ultrasound, the team used a gene therapy approach to add the genes for human TRPA1 to a specific group of neurons in the brains of living mice.

When they then administered ultrasound to the mice, only the neurons with the TRPA1 genes were activated.Clinicians treating conditions including Parkinson’s disease and epilepsy currently use deep brain stimulation, which involves surgically implanting electrodes in the brain, to activate certain subsets of neurons.

Chalasani says that sonogenetics could one day replace this approach—the next step would be developing a gene therapy delivery method that can cross the blood-brain barrier, something that is already being studied. Perhaps sooner, he says, sonogenetics could be used to activate cells in the heart, as a kind of pacemaker that requires no implantation.

“Gene delivery techniques already exist for getting a new gene—such as TRPA1—into the human heart,” Chalasani says. “If we can then use an external ultrasound device to activate those cells, that could really revolutionize pacemakers.”For now, his team is carrying out more basic work on exactly how TRPA1 senses ultrasound.

“In order to make this finding more useful for future research and clinical applications, we hope to determine exactly what parts of TRPA1 contribute to its ultrasound sensitivity and tweak them to enhance this sensitivity,” says Corinne Lee-Kubli, a co-first author of the paper and former postdoctoral fellow at Salk.

They also plan to carry out another screen for ultrasound sensitive proteins—this time looking for proteins that can inhibit, or shut off, a cell’s activity in response to ultrasound.

The other authors of the paper were Uri Magaram, Janki Patel, Ahana Chakraborty, Jose Mendoza Lopez, Eric Edsinger, Rani Shiao and Connor Weiss of Salk; and Aditya Vasan and James Friend of UC San Diego.

The work was supported by the National Institutes of Health (R01MH111534, R01NS115591), Brain Research Foundation, Kavli Institute of Brain and Mind, Life Sciences Research Foundation, W.M. Keck Foundation (SERF), and the Waitt Advanced Biophotonics and GT3 Cores (which receive funding through NCI CCSG P30014195 and NINDSR24).

About the Salk Institute for Biological Studies:
Every cure has a starting point. The Salk Institute embodies Jonas Salk’s mission to dare to make dreams into reality. Its internationally renowned and award-winning scientists explore the very foundations of life, seeking new understandings in neuroscience, genetics, immunology, plant biology and more. The Institute is an independent nonprofit organization and architectural landmark: small by choice, intimate by nature and fearless in the face of any challenge. Be it cancer or Alzheimer’s, aging or diabetes, Salk is where cures begin.

Featured image: Neurons (magenta) in the mouse brain. The Chalasani lab made specific neurons express TRPA1 (white), so they can be activated by ultrasound.