Tuesday, July 12, 2016

In Memoriam: Al Knudsen, a modest, under-recognized founder of cancer genetics (and more)

My first job was a young faculty member was in the Graduate School of Biomedical Sciences, at the University of Texas Health Science Center in Houston.  Our small Center for Demographic and Population Genetics was part of the Graduate School, and it was small enough that we got to know, and interact with, the Dean.  And what a dean he was!

The great, and good Al Knudsen (1922-2016).  Google images.
It was a small graduate school, so Dr Knudsen still was active in research, cancer research. One of the first talks I heard down there in Houston, when I still didn't have my first pair of cowboy boots, y'all, was an interesting idea about the causes of cancer.

Radiation was a known carcinogen, as were some chemicals, and there were various ideas about how carcinogenesis worked at the gene level. The basic idea was that these agents caused genetic mutations that led cells to misbehave, and though abnormal, escape detection by the immune system. More mutations meant more cancer risk, and this was consistent with 'multi-hit' ideas of cancer. More mutations took longer to accumulate, which was consistent with the increasing risk of cancer with age.  But genetics was still very rudimentary then, compared to now, direct testing primitive at best. And there were some curious exceptions.  An interesting fact was that some cancers seemed familial, arising in close relatives, and typically at earlier ages than the sporadic versions of what seemed to be the same type of tumor.  Why?

One example was the eye cancer retinoblastoma which arose in children or young adults, mostly in isolated cases; but there were affected families in which Rb was often present at birth.  Knudsen's idea was that in affected families one harmful allele was being transmitted, but the disease did not arise until a second mutation occurred.  Al published a quantitative mutational model of the onset age pattern in a PNAS paper in 1971, just before I myself had arrived in Houston, but by chance I had heard him present his work at the time of my job interview.

The basic idea was a 2-hit hypothesis, in which you could inherit one Rb mutation, and then only had to 'wait' for some one of your embryonic retinal cells to suffer the bad luck of a hit in the normal copy in order for a cancer to develop.  That waiting time accounted for the earlier onset of familial cases, because they only had to 'wait' for one mutation, whereas sporadic cases needed to experience two Rb hits in the same cell lineage.

This was a profound insight.  It allowed for cancer genetic findings, in which some forms of cancer clustered in families (e.g., some breast and colorectal cancers). Yet most cases were sporadic.  It was shown roughly at that time, by clever work in those crude days of human genetics, that tumors were clonal--the tumor, even when it had spread, was the descendant of a single aberrant (mutated) cell.

It did not take long for this sort of thinking, along with various methods for detection, to find the Rb gene....and other genes related to cancer.  This eventually included genomewide tests for loss of detectable variation based on microsatellite sites, continued to confirm the idea, far beyond those types of cancer that seem to be caused largely by changes in a single gene. The idea of somatic mutation caused by environmental factors, was complemented by the idea that it is common to inherit genotypes that are partially altered but insufficient by themselves to cause cancer, so that the tumor only arises later in life, after environmentally-caused (or stochastic) further mutations occur.

Knudsen's basically 2-hit idea was quickly generalized to 'multi-hit' models of cancer, and the discovery that cancers in a given individual were clonal led to models in which combinations of inherited mutations (present in every cell) and those that occurred somatically, seemed to account for the basic biology of cancer.  Many of the individual genes whose mutation puts a person at very elevated risk of one or more forms of cancer have since been identified, and newer technology has allowed their functional nature (and reason for their role in cancer) to be found.  Some are involved in DNA repair or control of cell division, and it's understandable why their mutational loss is dangerous.

The sources of variation in these genes may vary, but cancer as a combination of inherited and somatically generated mutations is a, if not the, prevailing general model for its biological nature and epidemiology, and shows why tumors are somatic evolutionary phenomena at the gene level.  But his nugget of an idea triggered much broader work in human genetics that, once technology caught up to the challenge, led to our understanding (and, too often, convenient ignoring) of the role of combined inherited and somatically induced variation as a major cause of the common, complex disorders for which genomewide mapping has become a routine approach.

I was still in Houston when Dr Knudsen moved to the Fox Chase Cancer Center in Philadelphia.  We missed him, but over the following decades he continued to contribute to the understanding of cancer.  His inspiring, gentle, and generous nature was an exception in the snake-pit that has become so common in the 'business model' of so many biomedical research circles.

Al's foundational work earned him many honors.  But he didn't get one that I think he richly deserved: his quiet, transformative role in understanding cancer, and the much broader impact on human genetics that followed as a result, deserved a Nobel Prize.

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