Himanshu Brahmbhatt was staring at the results of a clinical trial that looked too good to be true. A co-founder and CEO of , a biopharmaceutical company, was running a small trial that was testing a fundamentally different approach to fighting cancer. Patients in the group had grim prospects. They had exhausted all other options. With nothing left to lose and not expecting any miracles, they enrolled in the trial. They wanted to give it one more chance. Now their scans showed their tumors had stopped progressing. Even more remarkable was they didn鈥檛 have the same type of tumors. They had malignancies affecting different organs鈥攍ungs, bladders, colons, pancreases鈥攁nd yet, they uniformly did well.
鈥淭hese people were facing death,鈥� Brahmbhatt says. 鈥淭hen we started seeing that they were actually succeeding. You could see in the scan that the tumor has stopped growing. It was a feeling of such extreme internal joy that it鈥檚 very difficult to describe.鈥�
The results may have appeared miraculous, but they were anything but. They stemmed from fundamental research into cell division that forms the basis of the EnGeneIC process. A longtime advisor to the company, Bruce Stillman, professor of biochemistry and president and CEO of 黑料吃瓜资源, has been studying the process of DNA replication, which plays a key role in cell division and cancer progression.
鈥淐ancer cells multiply out of control,鈥� says Stillman, who has devoted his career to studying DNA replication. 鈥淲hen a cell becomes a cancer cell, the very first thing that happens is the cells begin to divide without the normal controls. And the first thing that has to happen before the cell has to divide into two daughter cells is to copy the genome. So, the path that leads to cancer is in part dysregulation of the process that controls DNA replication.鈥� The abnormal DNA replication causes the accumulation of mutations in the genome that advances cancer. Interfering with the process of cell division has long been a focus for treating cancer, but because normal cell division is unavoidably affected also, many of these chemotherapies are toxic. EnGeneIC has figured out a way around this problem by combining a novel method of drug delivery with a way to stop DNA replication.
If this works, we won鈥檛 just cure one type of cancer. We would cure cancer across the board.鈥�
Himanshu Brahmbhatt, Ph.D.
Stillman was a graduate student when he understood that cell division, and DNA replication in particular, were key targets for treating cancer. That insight inspired him to switch careers from medicine to medical research. At the time, the science of DNA was a burgeoning field and there was a lot to discover; Stillman was a pioneer. He uncovered many of the mysteries of the genome replication process and what sets the copy machinery in motion. He has spent 40 years putting together the pieces of the molecular puzzle. 鈥淚 wanted to understand how this process really works,鈥� he says. And he did.
Deep inside the tens of trillions of cells that comprise your body, the DNA replication machinery is constantly speeding along in many tissues. In the bone marrow alone, 500 million red and white blood cells are produced every minute. There鈥檚 about two meters of DNA in each cell, neatly woven inside the nucleus. To keep the blood cell supply steady, about a billion meters of DNA must be copied every minute. 鈥淵ou could wrap that around the Earth along the equator about 25 times,鈥� Stillman says. It is inevitable that over the course of a person鈥檚 lifetime, this process will make mistakes鈥攕ome harmless, but others leading to malignant mutations. So, understanding the cogs of this complex machinery may hold the key to combating many cancers.
Stillman and his team discovered that the replication process starts with a set of six specific proteins called Origin Recognition Complex, or ORC. The proteins bind to the DNA at specific locations and recruit more proteins to help, forming what鈥檚 called the pre-replicative complex. This pre-replicative complex 鈥済ives permission鈥� to start DNA replication and many proteins begin copying the genetic material from their respective starting points. Once the job is finished, the pre-replicative complex is destroyed. Once the cell is ready to divide again, the complex is formed anew.
Stillman鈥檚 group first discovered the ORC in yeast, experimenting with a strain called Saccharomyces cerevisiae, normally used to make bread, wine, and beer. (Notably, in 2020, he won a for his work, although it didn鈥檛 have anything to do with brewing鈥攖he prizes are awarded to the leading figures in the above disciplines as well as in art, medicine, history, and environmental and cognitive sciences.) As Stillman鈥檚 team kept studying the ORC phenomenon, they realized this ancient process works very similarly in humans. 鈥淚t鈥檚 remarkable to think that yeast and humans share the same process of DNA replication,鈥� Stillman says. 鈥淲e started off with yeast cells and we were able to walk through evolution and eventually get to the human genes.鈥�
Another key player in DNA replication is an enzyme called DNA polymerase. DNA polymerases synthesize the new DNA by adding nucleotides鈥攖he gene building blocks鈥攐ne by one to the growing DNA chain. 鈥淭here are about 15 polymerases involved in this procedure,鈥� Brahmbhatt says. 鈥淓ach of these polymerases does a different job inside that DNA replication process.鈥� If some of them stop working, the cell won鈥檛 be able to divide.
Knowing the key points in DNA replication has allowed scientists to ponder ways to jam the copying gears inside the rogue cells. At the biochemical level, gear-jamming isn鈥檛 an insurmountable task鈥攖oday scientists can forge a small molecule that can bind to some of the players and 鈥渄isable鈥� them. The real challenge was to deliver these molecules inside the cancer cells and no others. If these molecules ended up inside healthy cells, they would halt the normal replication processes, killing the cells鈥攁nd the person with them.
Scientists know cancers have an uncanny ability to travel through the body by slipping in and out of blood vessels to hitch a ride through the bloodstream. They do it by loosening the arterial walls and squeezing through. 鈥淣ormally, our blood vessel walls are all sealed pipes,鈥� Brahmbhatt says. 鈥淏ut around wherever the cancer is growing, the blood vessels are known to be very defective. They have got a lot of holes in them.鈥�
Brahmbhatt and his collaborator devised a clever ploy. They would send a Trojan horse into malignant cells and turn cancer鈥檚 own trickery against it.
The Trojan horse, in this case, is a product of a harmless bacteria that鈥檚 been genetically engineered to have specific qualities. When this genetically engineered bacteria divides, it yields a tiny non-living cell of 400 nanometers in diameter鈥攖he right size to slip through the damaged vessels and mingle with the tumors. To the nano-cell, Brahmbhatt and MacDiarmid affixed a 鈥渕olecular hook鈥� that the tumor grasps and swallows. The nano-cell is also packaged with 鈥渋nterfering鈥� RNA molecules鈥攄istant relatives of the RNAs used to create the first coronavirus vaccines. Known as siRNAs, the molecules interfere with the expression of specific genes. They can target some of the DNA replication enzymes and inhibit their function. Brahmbhatt says Stillman provided invaluable advice about which polymerases to target to kill malignant tumors.
Brahmbhatt and MacDiarmid tested the nano-cell assassins in mice and then in a small human trial. 鈥淭here was a big fear at first,鈥� Brahmbhatt says. 鈥淓verybody was frightened because these molecules have never been sent specifically into a human, and everybody knew that if this thing gets into the wrong cells鈥攎eaning into the normal cells鈥攊t could be fatal.鈥� That鈥檚 why the study鈥檚 first cohort included only people who had exhausted all other options.
When he looked at the first set of scans, Brahmbhatt recalls, 鈥渨hat we saw was something fantastic. With these molecules, which are inhibitors of DNA replication, we could extend their lives.鈥� More surprising was the fact that鈥攗nlike systemic chemotherapies鈥攖here were no toxic side effects. Currently, Brahmbhatt鈥檚 company, EnGeneIC, is preparing for the next phase of clinical trials.
Should the siRNA method prove its worth in larger trials, the public health impact will be much greater than just putting another anti-cancer compound on the market. Stunting DNA replication has the potential to become cancer鈥檚 universal treatment. The research Stillman did, as well as others who chose to study the fundamental biology of DNA replication, is now not only bearing fruit, but鈥攃ombined with the right delivery system鈥攈as the potential to change the cancer treatment paradigm. And that鈥檚 the beauty and importance of fundamental research, without which modern clinical applications would be impossible. 鈥淭oday, those discoveries have become critical,鈥� Brahmbhatt says. 鈥淚f this works, we won鈥檛 just cure one type of cancer. We would cure cancer across the board.鈥�
Written by: Lina Zeldovich, Science Writer | [email protected] | 516-367-8455