Dr. Andrew Maniotis is a popular personality at conferences, an artful presenter, and unquestionably a controversial figure in science.

He is a cell biologist, who is principally interested in the process of cell division and especially how it may result in cancer.

He grew up in Detroit, studied in Iowa and obtained his PhD at the University of California, Berkeley. He then spent 6 years at Harvard Medical School working with Prof. Ingber and Prof. Folkman. Maniotis was instrumental in the experimental demonstration of the theory of ‘tensegrity’ as applied to living cells. It's an idea which actually comes from Buckminster Fuller, the architect. This work, published by the Proceedings of the Academy of Sciences of the USA in 1997 caused a scientific and an editorial was written about it in the journal Science later that year. He is now moving to the University of Illinois in Chicago.

Shebang's Jack Klaff spoke to Dr. Andrew Maniotis during a conference in Banff, Canada.
Prof. Jack Tuszynski of Starlab organised the Conference; we at Shebang would like to express our gratitude to Professor Tuszynski for his editing and advice in connection with this piece. Many thanks also to Lee Grimard for transcribing it.

Jack: Now, Andrew

Andrew: Jack

Jack: You work with extremely high-powered microscopes and you twiddle away inside cells. I have been going around for a long while asking the same question, maybe at last I have found someone who can help. What does a gene actually look like?

Andrew: It looks like a - one of my most critical enemies called it once at a conference I gave - he said "it looks like a bunch of snot to me" and that's exactly right. I mean he was right it does look like a bunch of mucus, like connected snot, in its living state. Very much like that

Jack: Now wait, you’re describing the gene there?

Andrew: The chromosomes and the chromatin — the complex of genes and proteins in the nucleus. You can't see the genes.

Jack: But then where are the genes? You almost got me excited then.

Andrew: The genes are in there.

Jack: In the bunch of snot?

Andrew: Yes, in there; There are many of them, you know.

Jack: Why do people say the genes are ‘on the chromosome’ rather than "in’ it." I don’t understand that, although it does make you think of them written ‘on’ the chromosome.

Andrew: That's because of our nomenclature not because of the way it is. Because the gene is buried in this whole entanglement of wires and strings that are all wound up around each other. Its somewhere deeply buried in that, in there. A haystack of chromatin.

Jack: And the stuff people call ‘junk’, the stretched of chromosome between the genetic information, you don't believe that's junk?

Andrew: No of course not, because that connects the coding genes together. And without those connections - its been shown a number of times, and it makes perfect sense — the hereditary units would be like astronauts who go out in their space crafts. If they don't have a lifeline attached to their waists they're going to float off. If you want to maintain a system that is characterized by fidelity over millions of years, like those clams I was talking about, you don't want too much change; so you want to tether all these stretches of genes together. Much of the genome - the exons that most people think are junk, and which aren't being sequenced in the genome project because they aren't appreciated as the lifelines — must be critically important, because these regions hold the coding sequences together. They should be looked at; very carefully. But that's the essential feature of how these chromosomes are positioned, and how the coding genes are organized. But, it's the continuity in the chromosomes that explains their most interesting features; it is the continuity and the fidelity in the process that gives life.

Jack: Great. Thank you for that. Now, my friend: cancer. Let’s start with you telling us about it.

Andrew: Well cancer has had a number of different definitions over a period of time. People have been aware of cancer for centuries and have had different ideas about it. But, essentially, because of certain observations the field has ‘canalized’ in certain directions. The belief is that that somehow a change occurs in the instructions in the cell. Well, people equate instructions with genes. And genes are the heredity unit so people who were studying cancer took care to look at genes, and an intensive look for certain specific genes And then viruses came along that were shown to cause cancer in chickens.

Well, what it all adds up is that the genes don't cause cancer. But they are players. It’s worth thinking about the way they train certain medical students nowadays. The give them some facts. They tell them that on a hot summer day in August in New York City the sidewalk cracks frequently and there's a lot of infant mortality, because infants can't stand the 100 degree temperatures on a hot August day. Would you therefore say that sidewalk cracking causes infant mortality? No. You wouldn't, no rational person would.

I'm a professor of continuity essentially. I'm not a professor of biochemistry, or cell biology or anthropology. I study the continuity of life essentially, and its discontinuity, because from that wellspring I find, just as Watson and Crick found, when they illustrated the structure of DNA, with their models, that there's a continuity, that explains the whole thing.

That's why semi-conservative replication works, that's why this strand can make that strand, why heredity works. You can see how it all happens by paying attention to the structural chemical bonds between this side of the ladder and that side of the ladder, and finding the best fit. I don't know where the next continuity or discontinuity will come from. So, why should you say that a certain mutation in a certain gene causes cancer, when we find these mutations in some people that have the cancer but not in others?

Nobody has yet found, as far as I'm aware, a correlation that is better than 50% between cancer and any specific gene mutations. You’re probably going to find some other correlation. That is consistent across all cancers which are aggressive is that they are disorganised. That would be confirmed by some of the leading cancer experts in the world. It's not a controversial point. There's something about cancer’s disorganization that is a consistent feature. We’ve found there are major differences between the human cancers and experimental tumors developed in animal models. We look at human cancers; we relate the cancer to whether they live or die over a long period of time, because we have figured out how to get into those data bases. And we have the material from their tumors preserved.

And we find that there is a consistent feature. And the patterns allow you to analyze the tumor, even to predict the outcome of the tumor from a very early stage. So that when you look at a tumor you can begin to see by its pattern whether its going to kill the patient or not. Tumors have bad cells in them; they can also have good cells, as well as cells that aren't so bad, that aren't dangerous. So you can make diagnosis based on the good cells, or the cells which aren’t too bad and you can tell somebody they don't have a malignancy because maybe the malignant region of the tumor is missed by the biopsy. The patterns that we are characterising get around or circumvent limited sampling errors because if the patterns that we find associated with malignancy are present anywhere in a tumor then that tumor is aggressive. We’d like to take these cells and try to make them behave like better citizens. To return to their more mutualistic interactions within the tissue. You do this by a reverse process, by giving them the information that, somehow, they are lacking.

Jack: And the big discovery that caused such a stir?

Andrew; The big discovery is that a new hypothesis emerged in cancer biology about 20 years ago to the effect that tumors grow and prosper by being ‘perfused’ with the host blood. The idea was born by Judah Folkman and others that if you could cut off the blood supply of a growing tumor, then you could starve that tumor. You can maintain people on anti-angiogenesis [angiogenesis is the growth of new blood host blood vessels from pre-existing host blood vessels] regimes, in addition to other therapies, and by cutting off the blood supply you can actually reverse the tumor.

That was the hypothesis, and fully expecting to find this to be the case in a very specialized system I started working. (A specialized deadly eye tumor that lacks any lymhpatic vessels) It was a specialized path in order to eliminate some of the variables.

I found that tumors find ways of growing without any evidence of invading blood vessels from the host. Instead our group found that the aggressive tumors reorganise into a collection of small spheres similar to a bunch of grapes and they mimic what appears to be a para-circulation through the juxtaposition of the spheres. And through deregulation of the tumor cells. Non aggressive tumors do not do this.

Jack: Even if you cut off the blood supply?

Andrew: Without the need for new growth of hosts vessels. And so that was a major breakthrough. I proposed the mechanism; I offered an explanation of how it happened.