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.
Silkworm silk is fragile, which limits its uses, but a few extra genes can help.
Today, biomimetics is everywhere. Shark-inspired swimming trunks, gecko-inspired adhesives, and lotus-inspired water-repellents are all taken from observing the natural world. After millions of years of evolution, nature has quite a few tricks up its sleeve. They are tricks we can learn from. And now, thanks to some spider DNA and clever genetic engineering, we have another one to add to the list.
The elusive spider silk
We’ve known for a long time that spider silk is remarkable, in ways that synthetic fibers can’t emulate. Nylon is incredibly strong (it can support a lot of force), and Kevlar is incredibly tough (it can absorb a lot of force). But neither is both strong and tough. In all artificial polymeric fibers, strength and toughness are mutually exclusive, and so we pick the material best for the job and make do.
Spider silk, a natural polymeric fiber, breaks this rule. It is somehow both strong and tough. No surprise, then, that spider silk is a source of much study.The problem, though, is that spiders are incredibly hard to cultivate — let alone farm. If you put them together, they will attack and kill each other until only one or a few survive. If you put 100 spiders in an enclosed space, they will go about an aggressive, arachnocidal Hunger Games. You need to give each its own space and boundaries, and a spider hotel is hard and costly. Silkworms, on the other hand, are peaceful and productive. They’ll hang around all day to make the silk that has been used in textiles for centuries. But silkworm silk is fragile. It has very limited use.
The elusive – and lucrative – trick, then, would be to genetically engineer a silkworm to produce spider-quality silk. So far, efforts have been fruitless. That is, until now.
We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
Spider-silkworms
Junpeng Mi and his colleagues working at Donghua University, China, used CRISPR gene-editing technology to recode the silk-creating properties of a silkworm. First, they took genes from Araneus ventricosus, an East Asian orb-weaving spider known for its strong silk. Then they placed these complex genes – genes that involve more than 100 amino acids – into silkworm egg cells. (This description fails to capture how time-consuming, technical, and laborious this was; it’s a procedure that requires hundreds of thousands of microinjections.)
This had all been done before, and this had failed before. Where Mi and his team succeeded was using a concept called “localization.” Localization involves narrowing in on a very specific location in a genome. For this experiment, the team from Donghua University developed a “minimal basic structure model” of silkworm silk, which guided the genetic modifications. They wanted to make sure they had the exactly right transgenic spider silk proteins. Mi said that combining localization with this basic structure model “represents a significant departure from previous research.” And, judging only from the results, he might be right. Their “fibers exhibited impressive tensile strength (1,299 MPa) and toughness (319 MJ/m3), surpassing Kevlar’s toughness 6-fold.”
A world of super-materials
Mi’s research represents the bursting of a barrier. It opens up hugely important avenues for future biomimetic materials. As Mi puts it, “This groundbreaking achievement effectively resolves the scientific, technical, and engineering challenges that have hindered the commercialization of spider silk, positioning it as a viable alternative to commercially synthesized fibers like nylon and contributing to the advancement of ecological civilization.”
Around 60 percent of our clothing is made from synthetic fibers like nylon, polyester, and acrylic. These plastics are useful, but often bad for the environment. They shed into our waterways and sometimes damage wildlife. The production of these fibers is a source of greenhouse gas emissions. Now, we have a “sustainable, eco-friendly high-strength and ultra-tough alternative.” We can have silkworms creating silk six times as tough as Kevlar and ten times as strong as nylon.
We shouldn’t get carried away. This isn’t going to transform the textiles industry overnight. Gene-edited silkworms are still only going to produce a comparatively small amount of silk – even if farmed in the millions. But, as Mi himself concedes, this is only the beginning. If Mi’s localization and structure-model techniques are as remarkable as they seem, then this opens up the door to a great many supermaterials.
Nature continues to inspire. We had the bird, the gecko, and the shark. Now we have the spider-silkworm. What new secrets will we unravel in the future? And in what exciting ways will it change the world?
This article originally appeared on Freethink, home of the brightest minds and biggest ideas of all time.
