For a few years, I've taken a breather from HU while focusing on full life rather than my CLL. I'm stepping up to post a new podcast from Dana Farber Hospital, which I found fascinating. Particularly for those on Venetoclax, or considering the drug, I couldn't resist sharing it. The Season 2 Trailer provides a little history about the physician who discovered that the BCL-2 protein prohibits apoptosis (cell death), way back in 1998, setting the stage for seeking a way to inhibit the inhibitor. Listening to this history is interesting background for the next podcast about BCL-2 Inhibitors.
Even if the Season 1 podcasts may not specifically be about CLL, they all provide greater understanding of the passion some physicians have to find treatments. I am grateful to them all. Imagine where we would be without them.
Welcome back Starsafta, good to hear from you again.
Good to see transcripts of the Dana Farber podcasts.
Actually the story of BCL-2 goes back a decade before the Dana Farber research, to the Walter and Eliza Hall Institute, which is Australia's oldest medical research institute. Here's a snip from discovery.wehi.edu.au/timel...
A cancer revolution
It used to be thought that cancer was simply due to too many cells being created. Professor David Vaux discovered that some cancers are due to the opposite process: not the birth of too many cells, but to genetic errors that prevent unwanted cells from dying when they should.
In 1987, when Vaux began his PhD in the laboratory of Professor Jerry Adams and Suzanne Cory, “it was generally thought that cancer genes were just normal genes that regulated cell growth. But when they were mutated, they caused cells to proliferate in an uncontrolled way.”
His task was to work on a gene called Bcl-2, which was suspected to be a cancer gene because it was often altered in lymphomas, a type of malignancy of the white blood cells. He wanted to prove whether it was a cancer gene, and to find out how it actually worked. “The expectation was that this gene encoded a growth regulator that caused cancer when it was mutated,” he says.
“My task was to find out, ‘Is Bcl-2 another oncogene [cancer gene]? If you put it into cell and turn it on, does it make the cell divide more rapidly and generate leukaemia cells?’”
Disappointment leads to amazing find
The answer, initially, was a disappointing No. But, after persisting with different kinds of testing, Vaux discovered how Bcl-2 worked: “Rather than stimulating cell division, it stopped cells from being able to kill themselves.
“In our bodies we produce a million new cells every second, in the skin, intestines, blood etc. But, so you don’t end up the size of a planet, you also need to get rid of a million cells a second. Normal cells activate an inbuilt self-destruct mechanism called apoptosis. It’s sort of a time-bomb that allows a cell to kill itself. We discovered that failure of cell death was an important cause of cancer in humans.”
Vaux made transgenic mice that expressed lots of Bcl-2, thinking, “These mice will develop lymphoma.” It turned out that while the mice did have too many B cells (the type of white blood cells that make antibodies), they usually didn’t die of lymphoma. His colleague, Professor Andreas Strasser, found that these mice died of a disease that resembled lupus (where the body’s immune system becomes overactive and attacks healthy tissue). This suggested that cell death is needed to remove cells that can cause autoimmune disease.
A milestone in cancer
Vaux’s 1988 paper showing that Bcl-2 is an inhibitor of apoptosis sparked huge interest in the field of cell death and was hailed as a milestone in the study of cancer genes. In 2003 he was awarded the Victoria Prize for his work.
Love your allegiance to Australian research, Neil. It's not a competition. Since Korsmeyer is no longer with us to share when and how he learned about the BCL2 protein inhibiting apoptosis, would it make you feel better if we acknowledge that maybe he knew about Vaux's work? We can all thank those in his lab who took the information and found a way to inhibit the inhibitor.
After taking Idelalisib in a clinical trial in 2014, and Imbruvica for 4.5 years, I've now been on Venclexta for 22 months. It's a relief to be free of all the annoying little side effects of the BTK inhibitor. So far so good. I'm still alive and functioning.
Great to hear how well you are doing on venetoclax. Indeed, we can thank the very many researchers who, over 3 decades, were involved in bringing venetoclax to market for the treatment of CLL. Venetoclax was so effective, the risk of Tumour Lysis Syndrome nearly ended an early CLL clinical trial. There was a precursor treatment, navitoclax, en.wikipedia.org/wiki/Navit... which wasn't selective enough and affected platelets due to an off target effect. Someone with CLL on that trial switched away from navitoclax last year I think.
I appreciate that research into better treatments for us should be a collaborative approach - which it very much is nowadays and perhaps I should have acknowledged that. Prior to the 90s, I expect it was considerably harder to find prior research. We didn't have fantastic free access to search via on-line research publication tools like PubMed, though there were proprietary tools with varying coverage. Importantly there was gopher in 1991 prior to the establishment of the Netscape browser in December 1994, which kick started the World Wide Web. Before then, researchers needed access to suitable journals, which arrived perhaps monthly or quarterly and required considerable time to check through them for prior research. Your research library may not have had sufficient funding to purchase all the periodicals requested by researchers!
For those who are interested, here is a paper from 1997, showing the researchers who were recognised as establishing the importance of BCL-2 in apoptosis control, including Vaux and Korsmeyer:-
The anti-apoptosis function of Bcl-2 can be genetically separated from its inhibitory effect on cell cycle entry
The ability of Bcl-2 to promote cell survival is well established (Vaux et al., 1988; Cory, 1995; Korsmeyer, 1995; White, 1996), but only recently has its influence on the cell cycle begun to attract scrutiny. In vitro Bcl-2 overexpressing cells that resist apoptosis when deprived of an obligate growth factor cease cycling (Vaux et al.,1988; Nunez et al., 1990) and are surprisingly slow to start proliferating again upon stimulation with growth factor (Marvel et al., 1994; O’Reilly et al., 1996)."
Everybody is standing on the shoulders of someone else these days, if none other than at least on the shoulders of his primary school teacher 😁 Hello Petra!
I love history research! If I was younger and feeling less ill, I might have wagered over a pint or three.
PubMed did not have much on Kormeyer or Vaux before 2000. So I used Google Scholar.
David Hockenbery, Gabriel Nuñez, Curt Milliman, Robert D. Schreiber, and Stanly J. Korsmeyer of the Howard Hughes Medical Institute in St. Louis, MO, wrote a letter to Nature that was published 22 November 1990, titled:
Bcl-2 is an inner mitochondiral membrane protein that blocks programmed cell death
In reference 10, they cited D. L. Vaux, S. Cory, and J. M. Adams of the Walter and Eliza Hall Institute in Nature volume 335; pp440-442 from 29 September 1988:
Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells.
My search is certainly not definitive - it found what was available. I do see an earlier BCL-2 paper by Korsmeyer in Google Scholar regarding the subject of Vaux's paper, mutation t(14;18) - translocation of part of the IGH gene with part of the BCL-2 gene. That had been researched in regard to follicular lymphoma as far back as 1985 by others, such as M L Cleary and J Sklar:
Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18.
1985 Nov
Online indexing of papers was getting more common in the late 1990s, but catching up on older papers took awhile. There certainly could be other papers that Google Scholar doesn't know about.
So I can only say that as of 1990, Korsmeyer cited Vaux, and that the BCL-2 area of the genome was being researched by several other people as well, including M L Cleary and J Sklar Thank God for nerds!
Both Korsmeyer and Vaux had both been down into the intimate genetic details of a wide variety of things using slow, manual methods of genetic sequencing for about a decade in the 1980s. The Human Genome Project that published the first (almost) entire human genome in 2003 no doubt built on their work and others.
For our next futile primacy discussion, we could consider one of my favorite debates, "Who invented television?" Or not.
Yes, the Dr's at Dana-Farber are so awesome as I'm sure of all the Dr's at all the Centers around the world are too. It takes certain types of folks to be that Earthbound Angel with the determination to help so many. Ty for sharing!
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