Talk like a cancer biologist

Acute myeloid leukaemia (AML) — a type of blood cancer that occurs when stem cells divide uncontrollably instead of changing into specialised blood cells

ATP — the molecule that provides energy for cellular processes

Chemotherapy — cancer treatments that use small molecules to stop the growth or drive the death of cancerous cells

Electrochemical gradient — a difference in electrical charge and chemical concentration across a membrane, which is the driving force for ions to move across the membrane

Mitochondria — small structures within cells that convert energy from food into ATP

Stem cell — a cell with the potential to develop into many different types of specialised cells

“I run a lab with the ambitious goal of curing cancer,” says Dr Kelsey Fisher- Wellman, a cancer biologist at Wake Forest University School of Medicine. “While this is likely unattainable in one lifetime, it’s motivating to have this goal as my guiding star.” But Kelsey never set out to cure cancer. As a teenager with a love of baseball and bodybuilding, his dream was to pursue a career as a strength and conditioning coach, and he worked as a personal trainer while studying exercise science at university. However, an internship with the university football team was not as inspiring as he had hoped, so he tried another internship, this time in a scientific research lab. “That decision was a turning point for me,” he says. “I discovered a love for lab science, and from that moment on, I was hooked.”

Battling blood cancer

After completing his university education and exploring different research opportunities, Kelsey began investigating leukaemia, a type of blood cancer. Cancer occurs when abnormal cells divide uncontrollably. Your blood contains different cell types, including red blood cells that carry oxygen around the body, white blood cells that fight disease, and platelets that clot the blood following injury. “All these blood cells begin life as stem cells in bone marrow,” says Kelsey. “As these stem cells grow and divide, they change shape and function to become specialised blood cells.”

But the specialisation process does not always work as it should. “A DNA mutation in a developing cell can prevent it from maturing,” explains Kelsey. “The cell gets stuck in an immature stage and begins dividing uncontrollably.” This marks the beginning of acute myeloid leukaemia (AML), a type of blood cancer. The immature cells fill the bloodstream, outnumbering the specialised healthy blood cells to the point that the body can no longer function properly. AML symptoms include tiredness and shortness of breath, vulnerability to infection, and excessive bleeding when injured.

When it comes to blood cancers, the cancerous cells exist in isolation in the blood or bone marrow, unlike cancers that exist as solid tumours. This makes targeted treatments much more challenging. “Since there’s no lump to surgically remove, treatment relies entirely on chemotherapy,” says Kelsey. “The challenge with AML is that chemotherapy usually kills most of the cancerous cells, but not all of them. A small number survive at undetectable levels, only to begin multiplying again after treatment stops – a process known as relapse.” Additionally, the surviving cells develop resistance to the chemotherapy drugs, so if relapse occurs, chemotherapy is no longer effective. As a result, AML is fatal for over 70% of older adults diagnosed with the disease.

Treatments for AML have remained largely unchanged for decades, so better options are desperately needed. Kelsey is taking a closer look at AML cells to identify key differences in how healthy and cancerous cells function. He hopes this knowledge can inform the development of new treatments that exploit these differences.

Mysterious mitochondria

Mitochondria, often called ‘the powerhouse of the cell’, are found in every cell in the body, except for red blood cells. “Mitochondria convert the energy stored in food into a form that our cells can use – a molecule called ATP,” explains Kelsey. “This energy powers everything our cells do, from moving muscles to thinking thoughts.” Mitochondria also have a key role in resource management. They manage supplies of important molecules that cells need to grow and function (such as proteins and fats), and they send signals to the cell’s nucleus to coordinate the cell’s actions based on available resources and energy levels.

Kelsey’s research has shown that mitochondria play a crucial role in the effectiveness of chemotherapy for treating AML. “Triggering cell death often involves damaging the mitochondria,” says Kelsey. “So, we want to develop a treatment that damages the mitochondria of AML cells, but not healthy cells.” This requires discovering the differences between mitochondria in these two cell types.

To achieve this, Kelsey and his team developed a tool known as ‘mitochondrial diagnostics’, a set of lab tests that allows them to create a detailed picture of the mitochondria in cells. This includes which proteins are present in mitochondria, how they are arranged, and how they help the cell survive. “Once we have this information, we look for weak points where AML mitochondria are vulnerable,” says Kelsey. “Then we can design treatments that target those vulnerabilities.”

Is running in reverse the key to treatment?

Using mitochondrial diagnostics, Kelsey and his team made a surprising discovery. “Normally, mitochondria create ATP, and this process is driven by an electrochemical gradient across the mitochondrial membrane,” explains Kelsey. “But AML cells do something unusual – they run this process in reverse.” Instead of making ATP, mitochondria in leukaemia cells consume it in order to maintain the electrochemical gradient. “We discovered that this gradient is essential for AML cells’ survival, especially when under attack from chemotherapy,” says Kelsey. “If we disrupt this process, the AML cells become more sensitive to treatment.” He hopes this discovery will lead to new treatments for leukaemia that target the cell’s energy system.

Kelsey and his team will continue to investigate the mitochondrial differences between AML and healthy cells. “The more we learn, the better we can design treatments that take advantage of these differences,” he says. “The goal is to develop therapies that destroy the mitochondria inside AML cells while leaving healthy cells unharmed. I believe this precision approach to cancer treatment could hold real promise for improving outcomes for patients with acute myeloid leukaemia.”

Dr Kelsey Fisher-Wellman
Associate Professor, Department of Cancer Biology, Wake Forest University School of Medicine, USA

Field of research: Cancer biology

Research project: Comparing mitochondria in healthy and cancerous cells to develop treatments for leukaemia that target these differences

Funder: US National Cancer Institute (NCI) Grant numbers: P01CA302570, R37CA278826, R01CA299332

Website: fisherwellmanlab.com

About cancer biology

Cancer biology is the study of the biological mechanisms underlying cancer development and how to address them through treatment. These mechanisms are wide-ranging, from the genetic and molecular foundations of cancer (such as the role of DNA mutations), to how cancerous cells grow, spread and cause illness. According to the National Cancer Institute, two in five people in the US will develop cancer in their lifetime, so developing new and improved ways to detect and treat the disease is essential for a healthy society.