
Building a new protein to fight brain tumours
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Building a new protein to fight brain tumours
Did you know that scientists can build new proteins in much the same way that you can build something out of Lego? Professor Lali Medina-Kauwe, a biomedical scientist at Cedars-Sinai Medical Center in the US, uses this analogy to explain how she created a new protein that can carry drugs into the brain to fight tumours. Her incredible research is paving the way for new treatments for brain cancer.
Talk like a biomedical scientist
Bioengineering — the process of artificially creating or altering a biological molecule
Bio-particle — a bioengineered molecule
Blood-brain barrier — the layer between the brain and its blood vessels, which prevents substances passing from the blood into the brain
Intravenous — delivery (e.g., of a drug) through the bloodstream
Organ chip — an artificial device that mimics an organ, made from stem cells grown on a scaffold that develop into cells of the organ of interest
Stem cells — unspecialised cells that can develop into specialised cells
Therapeutic — relating to the healing and treatment of diseases
Tumour — a mass of abnormal cells which, if cancerous, is harmful
The average survival rate for a cancerous brain tumour is only 35%. This is partly because it is very hard to get drugs into the brain to fight the tumour. The blood vessels in your brain are surrounded by a tight shield, known as the blood-brain barrier, which stops harmful substances in your blood from passing into your brain. However, this protective shield also prevents helpful substances, such as therapeutic drugs, from reaching the brain. “This is a problem because many strategies for treating cancer, such as chemotherapy, rely on delivering the drug to the tumour through the bloodstream, known as intravenous delivery,” explains Professor Lali Medina-Kauwe, a biomedical scientist at Cedars-Sinai Medical Center. “Unfortunately, the blood-brain barrier prevents intravenous drugs from reaching the brain.”
This means doctors cannot use intravenous drugs to treat brain tumours, as the drug will never reach the tumour as it cannot enter the brain. To overcome this problem, Lali has bioengineered a new protein molecule that can pass through the blood-brain barrier, detect cancerous cells in the brain and deliver drugs to destroy them.
How did Lali build a new protein?
Lali built her new protein by piecing together different segments of other proteins, in a similar way to how you might construct something from Lego! “Different pieces with different shapes can be connected in different ways resulting in a construction with a new form or function,” explains Lali. “I used this approach to piece together parts of proteins found in nature to form a new protein that serves a unique biomedical function.”
First, Lali found a protein that is attracted, like a magnet, to a cell surface feature called HER3. HER3 was known to be found on aggressive tumour cells, but Lali’s research team discovered that HER3 is also found on the blood-brain barrier. By including the protein segment that is attracted to HER3, Lali’s new protein is pulled across the blood-brain barrier and is then attracted to aggressive brain tumour cells.
Next, Lali attached a protein segment that would allow her bioengineered protein to enter cancerous cells. “I studied how a common cold virus enters cells, and I isolated the protein that enables cell entry,” she says. “This protein allows itself to be swallowed by cells to gain entry, then uses an escape mechanism to avoid being digested by the cell.” Finally, Lali attached a third protein segment that can carry therapeutic cargo, such as cancer drug molecules.
“The result is a bio-particle that uses the HER3 targeting, cell entry and cargo transport functions to cross the blood-brain barrier and seek out tumours for the delivery of cancer therapy,” explains Lali. However, once she had developed this tumour-invading protein, she still had lots of work to test its ability to cross the blood-brain barrier and effectively deliver treatments to brain tumours.
How did Lali test delivery across the blood-brain barrier?
To test how her protein crossed the blood-brain barrier, Lali and her research team used an organ chip. Organ chips mimic organ function as they consist of stem cells grown on an artificial scaffold that are programmed to develop into whichever type of cells the scientists want to study. In this case, Lali’s team collaborated with Dr Clive Svendsen’s team in the Regenerative Medicine Institute at Cedars-Sinai who created an organ chip that mimicked the human blood-brain barrier. “The chip was designed so that the stem cells developed into a blood-vessel-like tube overlain by neuron cells, thus resembling a blood vessel in the brain,” explains Lali. “We injected our bio-particles into one end of the tube and examined whether the particles would flow to the other end or pass through the wall of the tube and enter the neuron layer resembling the brain.” The team found that a substantial portion of the injected bio-particles passed through the wall of the tube and entered the neuron layer, suggesting that, in the human body, the protein will pass through the blood-brain barrier.
Reference
https://doi.org/10.33424/FUTURUM588
How did Lali test her protein’s ability to target brain tumours?
Lali then needed to demonstrate that if her protein was delivered intravenously, it would accumulate in brain tumours. She and the team attached a fluorescent tag to the protein molecules, then injected them into the tails of mice with brain tumours. By imaging which parts of the mice became fluorescent and checking the bio-particle content in each organ, the team showed that the protein accumulated in the brain tumours rather than in other organs in the body.
Finally, the team repeated the same experiment, only this time they used the cargo transport function of the bio-particle to deliver cancer drugs to the tumours. “Our results showed that the bio-particle treatment reduced tumour growth in the mice, while sparing healthy brain tissue and other organs,” says Lali. This is fantastic news, as current chemotherapy treatments for cancer are toxic for healthy cells as well as tumours.
The success of Lali’s bioengineered protein holds great promise for advancing the treatment of brain tumours. The next step will be to take her research from the lab and test it in humans. “By providing a more efficient and effective route of crossing the blood-brain barrier and entering tumours, I hope that my bioengineered protein will one day be used in the clinic to improve therapeutic treatment of brain tumours.”
Professor Lali Medina-Kauwe
Department of Biomedical Sciences, Cedars-Sinai Medical Center, USA
Fields of research: Biomedical science, bioengineering, nanobiology
Research project: Bioengineering a new protein molecule that can cross the blood-brain barrier and deliver drugs to brain tumours
Funders: US National Institutes of Health (NIH), National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), Department of Defense (DoD), Avon Foundation, Komen Foundation, American Cancer Society
About biomedical science
Biomedical science is a multidisciplinary field that combines medicine, biology, chemistry and engineering to improve human health. It involves understanding how cells and organs function and what happens when this goes wrong, and finding better ways to treat diseases. Biomedical science is an extremely rewarding field to work in as laboratory research can have significant real-world applications. “I enjoy using my skills in innovation, creativity and bioengineering to solve biomedical problems,” says Lali.
A day in the life of a biomedical scientist
As well as being an experimental laboratory where Lali develops new bio-particles, her lab also operates as a biomanufacturing and pre-clinical testing facility where she produces her bio-particles on a larger scale and tests their therapeutic abilities in cells and mice. “My tumour-invading bioengineered protein is generated in bacteria, which grow (by fermentation) in large containers,” Lali explains. “A typical day might involve collecting these bacteria and cracking them open to isolate the protein.” Once the protein has been extracted from the bacteria, it is purified then stored at -80 °C until the team is ready to use it in experiments.
The rest of the day looks different depending on what experiments Lali and her team are conducting. “If we are preparing bio-particles for an experiment, we will mix the protein with the therapeutic cargo of interest,” she says. “If we are performing experiments on lab-grown tumour cells, we will prepare the tumour cells in dishes, add bio-particles to them and monitor how they respond under a variety of conditions. If we are performing experiments in mice with tumours, we will monitor their health every day and use imaging techniques to measure tumour growth.”
Pathway from school to biomedical science
At high school, study biology and chemistry. “Biology, molecular biology and biochemistry will provide a foundation for biomedical science work,” says Lali.
At university, study an undergraduate degree in biomedical science, biomedical engineering, biology or biochemistry. You can follow this with a master’s degree and PhD if you want to become a research scientist.
“Re-discover the cell!” advises Lali. “The term ‘biomedical research’ implies that the research will have clinical applications to treat humans. As the cell is the smallest living unit of the body, it is important to know how cells work.”
Be proactive in looking for opportunities to gain hands-on experience in a lab. Reach out to scientists and explore programmes such as Cedars-Sinai’s INSPIRE, which offers paid summer internships for high school and undergraduate students: cedars-sinai.edu/education/professional-training-programs/internship/inspire.html
Explore careers in biomedical science
As a biomedical scientist, you could find yourself conducting research at a university, in a hospital or for a pharmaceutical company. Depending on your qualifications and level of experience, you could lead a research lab or work as a technician.
This article lists careers that you could pursue with a degree in biomedical science: prospects.ac.uk/careers-advice/what-can-i-do-with-my-degree/biomedical-sciences
This article explains how you can become a biomedical scientist: medicaltechnologyschools.com/biomedical-science/how-to-become-a-biomedical-scientist
Meet Lali
Raised in a family of artists in the 1970s, I was always trying to engineer things out of paper, cardboard and objects from around the house. I loved to build contraptions from trash, or to turn it into tiny furniture for a ‘mouse-house’. I would spend hours in my room – cutting, pasting, adjusting and losing all sense of time. I was always looking for an outlet to channel my creativity.
My teachers recognised my artistic and creative talents but overlooked my knack for the sciences. This reinforced my desire to take college classes in the sciences to see if this was a direction I wanted to pursue. As an undergraduate, I asked my molecular biology professor if I could work in her lab, and getting involved in research cemented my passion for science. From that point on, I was known as the student who was always in the lab and people started recognising me for my scientific endeavours.
My approach to making my tumour-invading protein was a continuation of my creative obsessions as a teenager, except now I repurpose parts of viruses and proteins to make devices for therapeutic delivery, and I work on a much smaller scale. When I learned how to generate novel proteins by piecing together segments of DNA, I became hooked on molecular bioengineering.
My goal is to bring an effective therapeutic to the clinic that can treat types of cancer for which there are currently few effective options, such as brain tumours. Accordingly, one of my proudest career achievements was being granted patents for my inventions, as these recognise the novelty and relevance of my proteins.
I grew up engaging with my cultural heritage through Hawai’ian and Polynesian arts, including music, dance, song and language. I continue this today, and I love experimenting with novel arrangements of traditional Hawai’ian songs fused to pop music. I perform these songs using the traditional singing style that my father taught me, while accompanying myself on the guitar, mandolin or ukulele. I also enjoy drawing and sketching, and I have illustrated a children’s book.
Lali’s top tips
1. Don’t compare yourself to others around you. You are not on their journey, and they are not on yours.
2. Observe the world around you. Don’t just rely on textbooks and the internet, make your own observations about what is happening.
3. Seek out how things work. Biomedical research procedures were once all performed manually using biochemical processes. Understanding the principles behind these will help you troubleshoot experimental problems and interpret data.
4. Be resilient. Scientific research often leads to unexpected findings, so be ready to embrace the unexpected rather than interpreting something as a ‘failure’.
Do you have a question for Lali?
Write it in the comments box below and Lali will get back to you. (Remember, researchers are very busy people, so you may have to wait a few days.)
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