A retrovirus illustration.
Even with groundbreaking advances in cancer treatment and research over the past two centuries, the problem remains that some cancer does not respond to treatment. A subset of patients experience recurrence or metastasis, even when the original tumor is detected at an early stage.
"Why do some tumors evolve into metastatic disease that is then capable of spreading, while other tumors do not?"
Moreover, doctors are not able to tell in advance which patients will respond to treatment and which will not. This means that many patients endure conventional cancer therapies, like countless rounds of chemo and radiation, that do not ultimately increase their likelihood of survival.
Researchers are beginning to understand why some tumors respond to treatment and others do not. The answer appears to lie in the strange connection between human life at its earliest stages — and retroviruses. A retrovirus is different than a regular virus in that its RNA is reverse-transcribed into DNA, which makes it possible for its genetic material to be integrated into a host's genome, and passed on to subsequent generations.
Researchers have shown that reactivation of retroviral sequences is associated with the survival of developing embryos. Certain retroviral sequences must be expressed around the 8-cell stage for successful embryonic development. Active expression of retroviral sequences is required for proper functioning of human embryonic stem cells. These sequences must then shut down at the later state, or the embryo will fail to develop. And here's where things get really interesting: If specific stem cell-associated retroviral sequences become activated again later in life, they seem to play a role in some cancers becoming lethal.
"Eight to 10 million years ago, at the time when we became primates, the population was infected with a virus."
While some retroviral sequences in our genome contribute to the restriction of viral infection and appear to have contributed to the development of the placenta, they can also, if expressed at the wrong time, drive the development of cancer stem cells. Described as the "beating hearts" of treatment-resistant tumors, cancer stem cells are robust and long-living, and they can maintain the ability to proliferate indefinitely.
This apparent connection has inspired Gennadi V. Glinsky, a research scientist at the Institute of Engineering in Medicine at UC San Diego, to find better ways to diagnose and treat metastatic cancer. Glinsky specializes in the development of new technologies, methods, and system integration approaches for personalized genomics-guided prevention and precision therapy of cancer and other common human disorders. We spoke with him about his work and the exciting possibilities it may open up for cancer patients. This interview has been edited and condensed for clarity.
What key questions have driven your research in this area?
I was thinking for years that the major mysteries are: Why do some tumors evolve into metastatic disease that is then capable of spreading, while other tumors do not? What explains some cancer cells' ability to get into the blood or lymph nodes and be able to survive in this very foreign, hostile environment of circulatory channels, and then be able to escape and take root elsewhere in the body?
"If you detect conventional cancer early, and treat it early, it will be cured. But with cancer involving stem cells, even if you diagnose it early, it will come back."
When we were able to do genomic analysis on enough early stage cancers, we arrived at an alternative concept of cancer that starts in the stem cells. Stem cells exist throughout our bodies, so in the case of cancer starting in stem cells you will have metastatic properties … because that's what stem cells do. They can travel throughout the body, they can make any other type of cell or resemble them.
So there are basically two types of cancer: conventional non-stem cell cancer and stem cell-like cancer. If you detect conventional cancer early, and treat it early, it will be cured. But with cancer involving stem cells, even if you diagnose it early, it will come back.
What causes some cancer to originate in stem cells?
Cancer stem cells possess stemness [or the ability to self-renew, differentiate, and survive chemical and physical insults]. Stemness is driven by the reactivation of retroviral sequences that have been integrated into the human genome.
Tell me about these retroviral sequences.
Eight to 10 million years ago, at the time when we became primates, the population was infected with a virus. Part of the population survived and the virus was integrated into our primate ancestors' genome. These are known as human endogenous retroviruses, or HERVs. The DNA of the host cells became carriers of these retroviral sequences, and whenever the host cells multiply, they carry the sequences in them and pass them on to future generations.
This pattern of infection and integration of retroviral sequences has happened thousands of times during our evolutionary history. As a result, eight percent of the human genome is derived from these different retroviral sequences.
We've found that some HERVs are expressed in some cancers. For example, 10-15 percent of prostate cancer is stem cell-like. But at first it was not understood what this HERV expression meant.
Gennadi V. Glinsky, a research scientist at the Institute of Engineering in Medicine at UC San Diego.
(Courtesy)
How have you endeavored to solve this in your lab?
We were trying to track down metastatic prostate cancer. We found a molecular signature of prostate cancer that made the prostate tumors look like stem cells. And those were the ones likely to fail cancer therapy. Then we applied this signature to other types of cancers and we found that uniformly, tumors that exhibit stemness fail therapy.
Then in 2014, several breakthrough papers came out that linked the activation of the retroviral sequences in human embryonic stem cells and in human embryo development. When I read these papers, it occurred to me that if these retroviral sequences are required for pluripotency in human embryonic stem cells, they must be involved in stem cell-resembling human cancer that's likely to fail therapy.
What was one of the biggest aha moments in your cancer research?
Several major labs around the U.S. took advantage of The Cancer Genome Anatomy Project, which made it possible to have access to about 12,000 individual human tumors across a spectrum of 30 or so cancer types. This is the largest set of tumors that's ever been made available in a comprehensive and state of the art way. So we now know all there is to know about the genetics of these tumors, including the long-term clinical outcome.
"When we cross-referenced these 10,713 human cancer survival genes to see how many are part of the retroviral network in human cells, we found that the answer was 97 percent!"
These labs identified 10,713 human genes that were associated with the likelihood of patients surviving or dying after [cancer] treatment. I call them the human cancer survival genes, and there are two classes of them: one whose high expression in tumors correlates with an increased likelihood of survival and one whose high expression in tumors correlates with a decreased likelihood of survival.
When we cross-referenced these 10,713 human cancer survival genes to see how many are part of the retroviral network in human cells, we found that the answer was 97 percent!
How will all of this new knowledge change how cancer is treated?
To make cancer stem cells vulnerable to treatment, you need to interfere with stemness and the stemness network. And to do this, you would need to identify the retroviral component of the network, and interfere with this component therapeutically.
The real breakthrough will come when we start to treat these early stage stem cell-like cancers with stem cell-targeting therapy that we are trying to develop. And with our ability to detect the retroviral genome activation, we will be able to detect stem cell-like cancer very early on.
How far away are we from being able to apply this information clinically?
We have two molecule [treatment] candidates. We know that they efficiently interfere with the stemness program in the cells. The road to clinical trials is typically a long one, but since we're clear about our targets, it's a shorter road. We would like to say it's two to three years until we can start a human trial.
Dr. May Edward Chinn, Kizzmekia Corbett, PhD., and Alice Ball, among others, have been behind some of the most important scientific work of the last century.
If you look back on the last century of scientific achievements, you might notice that most of the scientists we celebrate are overwhelmingly white, while scientists of color take a backseat. Since the Nobel Prize was introduced in 1901, for example, no black scientists have landed this prestigious award.
The work of black women scientists has gone unrecognized in particular. Their work uncredited and often stolen, black women have nevertheless contributed to some of the most important advancements of the last 100 years, from the polio vaccine to GPS.
Here are five black women who have changed science forever.
Dr. May Edward Chinn
Dr. May Edward Chinn practicing medicine in Harlem
George B. Davis, PhD.
Chinn was born to poor parents in New York City just before the start of the 20th century. Although she showed great promise as a pianist, playing with the legendary musician Paul Robeson throughout the 1920s, she decided to study medicine instead. Chinn, like other black doctors of the time, were barred from studying or practicing in New York hospitals. So Chinn formed a private practice and made house calls, sometimes operating in patients’ living rooms, using an ironing board as a makeshift operating table.
Chinn worked among the city’s poor, and in doing this, started to notice her patients had late-stage cancers that often had gone undetected or untreated for years. To learn more about cancer and its prevention, Chinn begged information off white doctors who were willing to share with her, and even accompanied her patients to other clinic appointments in the city, claiming to be the family physician. Chinn took this information and integrated it into her own practice, creating guidelines for early cancer detection that were revolutionary at the time—for instance, checking patient health histories, checking family histories, performing routine pap smears, and screening patients for cancer even before they showed symptoms. For years, Chinn was the only black female doctor working in Harlem, and she continued to work closely with the poor and advocate for early cancer screenings until she retired at age 81.
Alice Ball
Pictorial Press Ltd/Alamy
Alice Ball was a chemist best known for her groundbreaking work on the development of the “Ball Method,” the first successful treatment for those suffering from leprosy during the early 20th century.
In 1916, while she was an undergraduate student at the University of Hawaii, Ball studied the effects of Chaulmoogra oil in treating leprosy. This oil was a well-established therapy in Asian countries, but it had such a foul taste and led to such unpleasant side effects that many patients refused to take it.
So Ball developed a method to isolate and extract the active compounds from Chaulmoogra oil to create an injectable medicine. This marked a significant breakthrough in leprosy treatment and became the standard of care for several decades afterward.
Unfortunately, Ball died before she could publish her results, and credit for this discovery was given to another scientist. One of her colleagues, however, was able to properly credit her in a publication in 1922.
Henrietta Lacks
onathan Newton/The Washington Post/Getty
The person who arguably contributed the most to scientific research in the last century, surprisingly, wasn’t even a scientist. Henrietta Lacks was a tobacco farmer and mother of five children who lived in Maryland during the 1940s. In 1951, Lacks visited Johns Hopkins Hospital where doctors found a cancerous tumor on her cervix. Before treating the tumor, the doctor who examined Lacks clipped two small samples of tissue from Lacks’ cervix without her knowledge or consent—something unthinkable today thanks to informed consent practices, but commonplace back then.
As Lacks underwent treatment for her cancer, her tissue samples made their way to the desk of George Otto Gey, a cancer researcher at Johns Hopkins. He noticed that unlike the other cell cultures that came into his lab, Lacks’ cells grew and multiplied instead of dying out. Lacks’ cells were “immortal,” meaning that because of a genetic defect, they were able to reproduce indefinitely as long as certain conditions were kept stable inside the lab.
Gey started shipping Lacks’ cells to other researchers across the globe, and scientists were thrilled to have an unlimited amount of sturdy human cells with which to experiment. Long after Lacks died of cervical cancer in 1951, her cells continued to multiply and scientists continued to use them to develop cancer treatments, to learn more about HIV/AIDS, to pioneer fertility treatments like in vitro fertilization, and to develop the polio vaccine. To this day, Lacks’ cells have saved an estimated 10 million lives, and her family is beginning to get the compensation and recognition that Henrietta deserved.
Dr. Gladys West
Andre West
Gladys West was a mathematician who helped invent something nearly everyone uses today. West started her career in the 1950s at the Naval Surface Warfare Center Dahlgren Division in Virginia, and took data from satellites to create a mathematical model of the Earth’s shape and gravitational field. This important work would lay the groundwork for the technology that would later become the Global Positioning System, or GPS. West’s work was not widely recognized until she was honored by the US Air Force in 2018.
Dr. Kizzmekia "Kizzy" Corbett
TIME Magazine
At just 35 years old, immunologist Kizzmekia “Kizzy” Corbett has already made history. A viral immunologist by training, Corbett studied coronaviruses at the National Institutes of Health (NIH) and researched possible vaccines for coronaviruses such as SARS (Severe Acute Respiratory Syndrome) and MERS (Middle East Respiratory Syndrome).
At the start of the COVID pandemic, Corbett and her team at the NIH partnered with pharmaceutical giant Moderna to develop an mRNA-based vaccine against the virus. Corbett’s previous work with mRNA and coronaviruses was vital in developing the vaccine, which became one of the first to be authorized for emergency use in the United States. The vaccine, along with others, is responsible for saving an estimated 14 million lives.
In the realm of cancer, Dr. Song is similarly setting his sights on another group of patients for whom treatment options are few and far between: people with solid tumors. Whereas some gradual progress has been made in treating blood cancers such as certain leukemias in past few decades, solid tumors have been even more of a challenge. But Dr. Song’s approach of using natural killer cells to treat solid tumors is promising. You may have heard of CAR-T, which uses genetic engineering to introduce cells into the body that have a particular function to help treat a disease. NKGen focuses on other means to enhance the 40 plus receptors of natural killer cells, making them more receptive and sensitive to picking out cancer cells.
Paul Y. Song, MD is currently CEO and Vice Chairman of NKGen Biotech. Dr. Song’s last clinical role was Asst. Professor at the Samuel Oschin Cancer Center at Cedars Sinai Medical Center.
Dr. Song served as the very first visiting fellow on healthcare policy in the California Department of Insurance in 2013. He is currently on the advisory board of the Pritzker School of Molecular Engineering at the University of Chicago and a board member of Mercy Corps, The Center for Health and Democracy, and Gideon’s Promise.
Dr. Song graduated with honors from the University of Chicago and received his MD from George Washington University. He completed his residency in radiation oncology at the University of Chicago where he served as Chief Resident and did a brachytherapy fellowship at the Institute Gustave Roussy in Villejuif, France. He was also awarded an ASTRO research fellowship in 1995 for his research in radiation inducible gene therapy.
With Dr. Song’s leadership, NKGen Biotech’s work on natural killer cells represents cutting-edge science leading to key findings and important pieces of the puzzle for treating two of humanity’s most intractable diseases.
Show links
- Paul Song LinkedIn
- NKGen Biotech on Twitter - @NKGenBiotech
- NKGen Website: https://nkgenbiotech.com/
- NKGen appoints Paul Song
- Patient Story: https://pix11.com/news/local-news/long-island/promising-new-treatment-for-advanced-alzheimers-patients/
- FDA Clearance: https://nkgenbiotech.com/nkgen-biotech-receives-ind-clearance-from-fda-for-snk02-allogeneic-natural-killer-cell-therapy-for-solid-tumors/Q3 earnings data: https://www.nasdaq.com/press-release/nkgen-biotech-inc.-reports-third-quarter-2023-financial-results-and-business
