Technology Day 1999 - "The Human Body: Emerging Medical Science and Technology"

HECHT: For those of you who don't know me, I'm Bill Hecht. I know most of you. I'm a member of the class of '61. And I'll explain the red coat in a moment. I would like to say that the job of Executive Vice-President of the Alumni Association has aged me so much that I deserve one of these. But not quite true.

Many years ago, the class of 1924 elected me an honorary member. And unfortunately, none of the 30 survivors of that class are with us today. And therefore it's incumbent upon me to represent that class. So I may be the spryest member of the 75th reunion class here.

Although when they're here, I have to be very careful. They have been known to take me to the Faculty Club and produce the fact that they're much better survivors at some things than I am. We do. Okay. Then I'm in real trouble, because I'm supposed to wear this coat with a freshman tie all the time.

My principal job is to introduce the President of MIT. But I wanted to tell you all that the person who we owe a great debt to is not with us today. That's Phil Sharp. Phil, as you know, is currently and soon to not be chairman of the biology department here at MIT, a Nobel Laureate, and an extraordinary man, who called us several months ago after actually helping us put this program together, and asked permission not to be here because he's receiving an honorary degree in Sweden. And we gave him permission not to be here.

The other thing I want to say is that Bob Weinberg, distinguished member of our faculty, fellow alumnus, has a family issue and will not be at the question and answer period, but will join us and speak as well.

My job is really to call you to order and introduce my favorite honorary alumnus and his favorite bride-- his only bride, actually-- also an honorary alumna. And that's Chuck and Becky Vest. And Chuck will introduce the morning program. Let's welcome Chuck Vest.

[APPLAUSE]

VEST: Well I'm not as fast on my feet as our commencement speakers yesterday, Bill. But I have to tell you a funny story, because at lunch yesterday, with Tom and Ray Magliozzi-- Click and Clack-- our great commencement speakers, were there with all their families toward the back end of the room. And our chairman, Alex d'Arbeloff, was introducing people. And he was of course reading from a long list of their family who were present with them. And he introduced Tom's wife. And apparently, couldn't hear too well in the room, because when he introduced, two women stood up in the back.

And quite appropriate, quite appropriately, Alex looked back and he says, Tom, I don't understand. I announced your wife was here, and two women stood up. What's going on? Without a millisecond delay, Tom said, the other two couldn't come today.

But I've only got one. I guarantee. But it really is a great pleasure to welcome you to what I know is going to be a really extraordinary morning discussion led by four really extraordinary people whom I will introduce in just a few moments. But before doing so, I want to say that this really is a terrifically exciting time at MIT. And I hope you're going to get a little sense of that during your day or two with us here.

It's exciting. It's measured by the achievement of our undergraduates, by the strength of the new class that we have just admitted. I could give you a whole lecture on that. And actually I'm going to. But no this morning.

The significant change in growth of our physical campus. I think you're really going to be quite astounded at what you're going to see as literally a transformation in much of MIT's campus over the coming decade. The continued diversification of our educational and research agendas and their focus on the future, and our interaction with the national and global communities that we serve in so many ways.

The academic year that has just ended has been challenging, as always, and yet very, very fruitful. Early in the spring, for example, we had in a single 24-hour period visits to our campus by US Secretary of Energy Bill Richardson, Bill Gates, and Prime Minister Zhu Rongji of China.

In many ways, representing the breadth of what we do here, starting with fundamental science, because Bill Richardson was here to visit the Bates Laboratory. Bill Gates, of course, representing the future of computing and the role of entrepreneurship in our world today. And Premier Zhu Rongji, I think, very symbolic of the fact that MIT is deeply engaged on a global scale, and indeed, provides an important world platform for leaders.

Granted, of course, that the roster of campus visitors in those two days were a little bit more high profile than usual. But frankly, not by much. I could easily have sighted any other month in the past year to illustrate that 1999, MIT, as it always has been, an exciting and engaged institution.

During that same month, for example, just a few of the research accomplishments that were announced I might point to. Professor Elfatih Eltahir in civil and environmental engineering reported that records of the Nile River's height can be used to put recent occurrences of El Nino into an interesting historical perspective, yet another contribution to our understanding of the changes in global weather patterns.

Professor Maria Zuber, earth atmospheric and planetary science and three of her MIT colleagues were preparing to unveil a precise new topographic map on the surface of Mars that you probably have seen in the newspapers recently, based on data obtained by instruments aboard NASA's Mars Global Surveyor spacecraft.

And at the Harvard MIT division of Health Sciences and Technology-- HST-- graduate student Jennifer Elisseeff reported that her research team had developed an injectable liquid cartilage that may someday be used in a wide variety of orthopedic and plastic surgical procedures and therapies.

Today's program is going to focus on one of the most important areas at MIT-- the interaction of science, engineering, and medicine to produce extraordinary advances in our understanding of the human body. Before we begin, however, I'd like to take just a few moments to remind you that this immensely valuable field of inquiry is just one facet of the larger scientific and engineering revolution being played out here.

Biology and medicine are understandably a focus of a great deal of our attention today. And it will be even more so as we go forward. But no one at MIT who has been at MIT for long will recognize immediately that advances in these fields are closely interrelated with advances across a broad range of scientific and technological disciplines, all of which interweave together.

So before we delve specifically into the worlds of biotechnology, medicine, and health care, I'd like to take just a few moments to give a slightly larger context of MIT's current agenda.

As my colleagues and I look to the world ahead, I think it's clear that the end of science is nowhere in sight, despite catchy book titles of recent vintage. We are under the search for gravity waves. We're looking for anti-matter galaxies. We're moving ahead in the exciting fields of genomics, and neuroscience, and cognition, and learning. Quantum computing is beginning to come onto the horizon here at the Institute. And I suggest you don't really get me started on my excitement about these and so many other things on the horizon or we won't get to the main program.

Innovation. Looking for innovation and technology and business and organization is clearly the key theme of what is going to be driving economies, whether it be of cities, states, regions, nations, the whole globe.

New integrative approaches to large complex systems and problems and structures are going to have to be developed to attack such serious problems as global scale manufacturing, the issues of our global environment, and so forth. Research universities are increasingly going to be just about the only source of fundamental research and scholarship in the United States. That's been our role for 40 years. But folks, we're pretty much the only game in town today when it comes to truly basic science.

A new paradigm of research university is about to emerge. And I really believe that MIT is at the cutting edge of this. One that plays much more importantly together as partners with industry and with government to work on these complex issues in an objective and measured way.

Of course, it's a future in which the ubiquitous, instantaneous flow of information in digital form is just permeating everything-- the way we live, the way we work, the way we learn, the way we entertain ourselves. And that, of course, is going to have profound effect on education. But nonetheless, I deeply believe, as I know most of my colleagues at MIT do, that despite this, the residential campus experience is still going to be the most important way of educating the best and brightest young men and women. There's just nothing that replaces this incredible magic and synergy of bringing these bright young 18, 19, 20-year-old people together to learn in a very intense academic environment.

The security and quality of our lives is going to increasingly depend on building a coherent, productive society, one formed hopefully around common values, yet one that also revels in the rich diversity of its membership. We are going to need to educate new leaders with abilities, values, and desire to apply the knowledge they develop here, to apply it wisely and creatively to the betterment of the human condition.

So as we look forward, we know that MIT must continue to be a place that attracts the best and brightest-- the best and brightest students, the best and brightest faculty, the best and brightest staff to assist them in doing their work and carrying out their mission. We must be committed to excellence, of course, as we always have been.

But MIT also must distinguish itself by thriving on change. This is not an age in which staying steady, staying still, is going to be the most important thing. We must lead, as I've already said, in developing these new, more integrative modes of scholarship and learning and action. We must be even more adept than we already are at bringing together industry, government, and academia to solve major problems facing the world.

And in order to do all these things, we're absolutely convinced that we must have a strong presence of engagement with the arts, the humanities, and the social sciences. We must expand our technological and organizational capabilities, but also be very much attuned and concerned about the moral and ethical issues that the rapid progress of technology and its effect on our lives is going to have.

And finally, we continue to follow a very important philosophy. It says that MIT is first and foremost an American institution, born and bred and developed here in the United States and by the United States, but in order in the 21st century to be the very best possible university, focused largely on science and engineering and management. We must be engaged globally. We must have a cosmopolitan student body and faculty. And we must be engaged with our colleagues around the world.

As always, MIT's pursuit of this vision will be ably shaped and guided by a brilliant and talented faculty. And the best way to demonstrate the continuing excitement and rich promise of MIT's future is just that, to let the faculty speak for themselves.

Our four colleagues who will lead this morning's discussion are truly extraordinary in every dimension-- in brilliance and accomplishment, and contribution to human welfare, as good and engaged people, and as teachers and mentors for the next generation. They really make us all proud to be part of MIT.

Now in order to move forward efficiently, I'm simply going to introduce all of our speakers now, and then turn the platform over to them to guide the discussion for the rest of the morning.

Let me begin with Bob Langer. Robert S. Langer Jr, class of 1974 as a Kenneth J. Germeshausen, Professor of Chemical and Biomedical Engineering. The scope of Bob's interests and achievement ranges so widely that he is the only active member of the US National Academies of Science and Engineering, and the Institute of Medicine.

A pioneering researcher in bioengineering techniques, his work has led directly to numerous improvements in medical care, including the development of implantable polymer wafers that release time-controlled doses of medication to treat tumors and other localized illnesses.

He has also successfully developed artificial skin therapies to help burn victims. More recently, he and MIT colleagues, Professor Michael Cima and John Santini, have announced the development of the new microchip that can be programmed to release specific doses of multiple medications. This so-called pharmacy on a chip as a wide variety of potential applications, and has already garnered considerable national and international interest.

Bob's work has already yielded some 350 patents. And his extraordinary productivity has earned him a Lemelson MIT Prize for Excellence in Invention and Innovation.

Bob Weinberg. Robert A. Weinberg, class of 1964. The Daniel K. Ludwig professor of cancer research at MIT. He's a founding member of the Whitehead Institute for Biomedical Research.

A leading specialist in the study of the genetic basis of cancer, professor Weinberg has made a number of major advances in understanding the genetic mechanisms to control or inhibit cell growth. Bob's internationally acclaimed work is designed to lay the foundation for a new generation of cancer therapies. In the evolving effort to understand and control human cancer, his discoveries have marked a crucial watershed, and earned him an enduring place of honor among cancer researchers.

He also has just received another enduring place of honor here at MIT. Just three weeks ago, he received the Killian Faculty Achievement Award-- the highest award bestowed by our faculty on one of its colleagues. And also, if I might editorialize a little bit, something I value very deeply about Bob is that he does something that is incredibly important. He is a remarkable communicator of the science of cancer to the lay public, something that I just cannot overstate how important the kind of writing he does for a more lay-oriented audience is.

David Page. Dr. David C. Page is professor of biology, Associate Investigator at the Howard Hughes Medical Institute, and an adjunct faculty member of the Harvard MIT Division of Health Science and Technology. Like Bob Weinberg, David is also a member of the Whitehead Institute where he chairs a task force on genetic testing, privacy, and public policy.

As an adviser to numerous governmental bodies, he is one of those rare and invaluable scientists who combine first-rate research with genuine public leadership on science-related policy issues. His research is focused on mapping the Y chromosome as a promising avenue toward understanding and treating a number of chromosome-based disorders, including infertility. In recognition of his achievement in biomedical science, David received the 1997 Amory prize from the American Academy of Arts and Sciences.

Martha Constantine-Patton. All of us at MIT are absolutely delighted that the next speaker in this sequence-- Martha Constantine-Patton-- will be joining MIT's biology faculty as of July 1. She is one of the nation's leading researchers and teachers in neuroscience, and has received among many other awards and honors, the Matilda [INAUDIBLE] Award in Neuroscience, The Society of Neuroscience Young Investigator Award, and received a John Simon Guggenheim fellowship.

Currently a professor of molecular, cellular, and developmental biology at Yale, doctor Constantine-Patton has served as director of Yale's interdepartmental neuroscience training program. Under the auspices of the National Institute of Mental Health, she has also served as director of two different programs in neuroscience training and behavioral science and studies-- one at Yale, and the other at the Woods Hole Marine Biological Laboratory.

We are honored that she has been able to come up to Cambridge to join us for Tech Day in advance of her formal arrival on campus. So it's my pleasure now to simply turn the stage over to my colleagues. I'm going to turn the stage over to Bob Weinberg. I just made a decision. Bob, come on up.

[APPLAUSE]

WEINBERG: Thank you, Chuck, for that kind introduction. I'm most pleased and flattered to be here on this occasion of my own 35th reunion. I've been here now almost 40 years. And I must say when I first came, biology was only a minor variation on the MIT theme. It was a relatively minor part of MIT's research and teaching agenda. And it's grown enormously since then, to the extent that the MIT Department of Biology is now amongst the top five in this country, and likely in the world, which is an extraordinary testimonial to how things change here in no small part due to the farsightedness of some of our leaders.

I think, in fact, that this enormous expansion is due to two separate factors. First came the discovery of the DNA double helix in 1953 by Watson and Crick. Watson and Crick are still around. They're still alive and kicking and active in the field of biology. And I imagine 200 or 300 years from now, one will look back on this era in which we live as having been as important in terms of its watershed effects on science as was, for example, the discovery of the laws of physics by Isaac Newton 300 years ago.

So we live in an era which really is epoch-making in terms of the opening up the explosion of a new field of science. I'm very impressed by the fact that we live in this time of Watson and Crick. Although I must say most people are much more impressed by the fact of all the work here at MIT goes on the same city as does the garage work of Tom and Ray Magliozzi-- Click and Clack, the Tappet brothers. That's for them, ultimately, a more impressing fact.

In the early 1960s, there was the recruitment of a large number of faculty to the biology department and related areas. And this has resulted in this rich harvest of research, some of which I wish to discuss now, and by implication, work of other laboratories at MIT.

My focus this morning is on how we have come to understand the origin of human cancer. That is, what provokes this disease, and what prospects does this give us in the long run for understanding how to control it.

And in order to elaborate on that theme, I want to begin by discussing one important lesson we've learned. And that lesson, which has been long in coming, is that cancer is not an inevitable consequence of the human condition, but rather that the incidence of cancer occurs at vastly different rates in different sub-populations of humanity. And in saying that, I refer to begin to the discovery in the end of the 18th century by a London physician that chimney sweeps who had worked in their youth--

AUDIENCE: [INAUDIBLE] can't hear.

WEINBERG: Oh. They promised me-- are we okay now?

AUDIENCE: No.

WEINBERG: Is that right?

[LAUGHTER]

I was about to swallow it. Okay. That men who had worked as chimney sweeps in their youths in the soot of the London chimneys came down with cancer of the scrotum at very high rates-- an otherwise very rare kind of malignancy. The first insight-- the first connection-- into the fact that a specific exposure was connected with the onset of a disease, rather than this disease was simply a spontaneous accident.

And over the ensuing 200 years, the evidence of connections between the onsets of certain kinds of cancer and specific exposures has accumulated largely through the work of epidemiologists. Here, for example, is the incidence of cancer of the mouth and throat among women, which we see is concentrated in the Southeastern part of the United States, not because of heredity, but because as you might speculate, of the habit of chewing tobacco in that sub-population.

Or for example, cancer of the liver, which occurs at extraordinarily high rates in certain parts of Africa and Southeast Asia, but occurs relatively rarely, thankfully, in this country, a consequence one now realizes years later, of eating tainted grains and perhaps also of hepatitis B virus infection.

Other evidence from epidemiology comes from studies of lifestyle. For example, the description already in the early 19th century that breast cancer was a plague among the nunneries of Northern Italy, this being due, we now realize in retrospect, to the increased risk of the disease due to the fact that the nuns in the nunneries obviously bore no children, and as a consequence, had a two to threefold increased risk of breast cancer during their lifetimes.

And then there are the discoveries of epidemiology. Here, for example, is the risk of breast cancer in different countries across the world. And what we see is an extraordinary variability from one geographical location to another in the risk of breast cancer-- as much as a 20-fold difference. Not a twofold difference or 20% difference, but a 2,000% difference across the globe in the incidence of breast cancer.

On this graph, it's correlated on the abscissa-- you remember what that is-- with dietary fat intake. Some might conclude that eating more fat gives you more breast cancer. But we will not leap to that conclusion today.

I just want to impress on you the fact that different kinds of human cancer occur with enormously different frequencies for reasons that are not clear. But one thing is clear. These differences are not due to differences in inborn predisposition-- that is to say, in genetics-- because when individuals move from countries of low cancer incidence to countries of high cancer incidence, within a generation or two, their risk of cancer begins to approach to that of the people who've always lived in that country. So it's not as if these people are genetically less susceptible to this disease or, for example, to prostate cancer, which has a remarkably similar kind of spectrum.

Prostate cancer, until recently, has been as much as seven-fold more frequent in this country then it has in Japan, for example. And that's changing now due to changes in Japanese diet. Again, I'm wishing to leave you with the impression that the incidence of most kinds of disease cancer is highly variable, and that to the extent that we are susceptible to these cancers in this country, it's not simply that we're preordained to come down with cancer. There are aspects of our diet and our lifestyle and our environment, very largely diet and lifestyle in terms of smoking, which influence enormously disease incidence.

Here you can see yet another representation of that. Here's the incidence, for example, among males of stomach cancer over the last 60 years in this country. And you see it's gone down dramatically by six-fold. A testimonial to the powers of food preservation, the powers of refrigerating food and the deleterious effects-- at least as argued by some of food preservatives-- which keeps food from going moldy, and therefore protects our stomachs.

So next time you hear food preservatives maligned, think of this decrease in stomach cancer rates over the last 60 years. Here's another change in cancer incidence. This is the change in incidence, of course, of lung cancer, which is by now the greatest killer in this country.

At the beginning of this century, a case of lung cancer was so rare and unique that it would be paraded in front of a medical school class, the professor saying to the students that this was such an interesting disease that they likely would never again see another in their lifetimes.

Here is female cancer incidence over the last 60 years. And these are all age-adjusted incidents to take into account the aging of the population. We see here that, for example, stomach cancer has gone down dramatically. Cervical cancer has gone down due to the pap test. Lung cancer has gone up, and by now exceeds the rate of death in women from breast cancer. And here's an amusing kind of curve. The rate of breast cancer mortality over the last 60 years among women, age adjusted, has changed absolutely not at all.

So the next time you hear about a cancer epidemic in this country, remember that if you subtract away the effects of smoking and tobacco, that the rates of most kinds of cancer in this country have either remained static or gone down. We're not being overwhelmed by an increased cancer risk. And nor is there any evidence that environmental pollution causes any more than a minute fraction of tumors in this population.

Here's another way of depicting the connection between lifestyle and cancer. Here the number of deaths that are caused every year in this country-- this was several years ago-- from smoking. The effects probably of secondhand smoke. And this is a little uncertain.

Here's the number of American deaths in all of World War II or in Vietnam. So the annual death rate for smoking in this country-- much of it due to cancer, not all of it, of course-- is absolutely staggering. Once again, persuading us of something that no longer requires us to be persuaded of-- that is that these various kinds of cancers are not simply a random breakdown of the human body, that their Incidence is encouraged by different ways we treat our bodies.

And that causes us now to focus on the disease of cancer to try to understand what it is biologically. And so doing, we go to a little bit of 701. A little bit of biology. I don't mind doing that since that's the way I earn my living around here.

Here's what a normal tissue looks like. We have something like 30 trillion, 3,000 billion cells in our body. Here's a small slice of that.

And what we see if we look in a normal tissue is that the cells in a normal tissue are well-ordered, that they form a very exquisitely organized architecture. And that this architecture is disrupted when a tumor arises in the body. A tumor, when viewed microscopically, is just seen as a jumble of cells, large numbers of cells whose only objective in life is to make more copies of themselves. These cells in the cancer are not interested in creating finely tuned architecture that functions in one or another tissue.

The cells in this tissue-- in this cancerous tissue-- are only interested in multiplying. That is the only item on their agenda. And if we want to understand how that happens, we have to understand that normal cells grow for a certain finite number of doublings in a normal tissue. And then they stop growing.

And cancer cells, in stark contrast, they continue to multiply without limits, and ultimately yield so many descendants that the mass of descendant cells-- billions and hundreds of billions of cells-- ultimately compromises one or another vital organ in the human body.

Having said that, I want to make one other point about cancer. We might imagine there are normal cells and there are cancer cells in the body. We might imagine that correctly.

And having said that, and looking at the large mass of cells in a human tumor, we might ask how they arise. And there in fact are two countervailing theories as to how they arise.

One theory says that all the cells in the tumor are the descendants of a number or founder cells, each of which cross the boundary from normalcy to malignancy, each of which became independently transformed from a normal cell into a cancer cell. And once transformed, that cell began to multiply exponentially, yielding the large flock of descendant cells.

Mind you, if you see a small human tumor the size of only half an inch by half an inch, that already has a billion cells in it.

The other theory-- the other model-- is that all the cells in the tumor are the descendants of a single founding cell, which began to multiply exponentially. And it's clear now from the detailed studies of all the cells in the human tumor, we now realize that all the cells in the human tumor descend from a single common founding ancestor, that it is a so-called monoclonal population of cells. Monoclonal referring to the fact that all of the cells are in a single flock, a single genetically descended group of cells, all deriving from a common ancestor that crossed the boundary from normalcy into malignancy.

Having said that, one's attention is focused on the behavior of that founding cell, trying to understand what causes it now to behave abnormally, and trying to understand ultimately the environmental factors that have driven or provoked that conversion, that transformation. And in so doing, we focus on a single cell. This is what a normal cell looks like under the microscope. And what we want to do is to focus ultimately on the nucleus of the cell.

This is what an artist's depiction of a cell is. And like artist's depiction of almost everything biological, has not even a vague connection with what a real cell looks like. But here's the nucleus of the cell. And we want to explore the nucleus of the cell, because it's in the nucleus of the cell that the heart and the mind of the cell lie. That's where the brains of the cell are. That's where the control mechanisms are that tell the cell when to grow or not to grow.

And thus we look at the chromosomes within the human cell. In the nucleus of the human cell there are 46 of them. And they contain the genetic information in the form of the double helices of DNA discovered by Watson and Crick, that determine not only how tall we are and what color our eyes are, but also instruct the individual cell as to whether it should grow or not grow. In other words, the individual cell take takes its instruction from the genes that are carried in the chromosomal DNA in the nucleus of the cell.

We also want to focus on the fact that the DNA encodes information in the form of sequences of bases. Here we see them. G-A-C-T-A-G-T. And these sequences of bases, these DNA molecules, like all physical entities in the world, are subject to damage.

And thus when they are damaged-- when a segment of DNA is cut out-- or when the identity of one or another base is changed, for example, going from a c to a t, or from going from a c to a g-- then the information content of the DNA sentence is changed in the same way that dog and dig represent changes in information content. Obviously, in the context of DNA, we call these changes "mutations."

Information has accumulated over the last two decades that within the DNA of cancer cells there lie mutant genes. And these mutant genes are responsible for redirecting, reorchestrating the behavior of the cell, forcing it to behave no longer like a normal cell, but rather like a cancer cell.

And some of that information is inspired by the work of a professor at Berkeley, Bruce Ames, who began to investigate the relationship in a number of chemicals between their ability to cause cancer and independent of that, their ability to damage the genes inside cells. Ames was a proponent of the theory that perhaps the way by which carcinogens-- cancer-causing chemicals-- act is to enter into the cells in the body, damage genes, and thereby trigger the outgrowth of tumors.

And his research revealed the following very provocative outcomes. If he studied the ability of various chemicals to induce mutations in his test, these mutations being represented here on the abscissa, he could find some chemicals which in this plotting were very potent in their ability to cause mutations, to damage the DNA-- the double helices of the DNA. And conversely he found other chemicals which were very weak in their ability to damage DNA.

And independent of these kinds of data, these results, he plotted on the ordinate, on the vertical axis-- I know I don't have to tell you that-- that the ability of these various chemicals to induce tumors in mice and rats. So he compared the mutagenicity-- the ability to damage DNA-- with the tumorigenicity-- their ability to induce cancers. And what he discovered was that chemicals that were extraordinarily potent in their ability to induce cancer and lay on this end of the ordinate were also extraordinarily potent in their ability to induce mutations. And conversely, chemicals-- oh, sorry. Wrong button. After 40 years, still haven't learned.

And chemicals which are very weak in their ability to induce cancer are weak in their ability to induce mutations. And that had led to the thinking that the way by which many carcinogens act is that they enter into cells in the body, attack the chromosomal DNA, damage the sequence of bases in the DNA, thereby generating mutant genes which, once mutated, then begin to release instructions to the cell, which drives the cell into unrelenting cycles of growth and division and replication.

And one could test this kind of model directly and experimentally in the following way. One can take DNA from cancer cells. So here we have cancer cells growing in the Petri dish. The model, the theory, we're trying to test here is the following-- that within the DNA of cancer cells there lie mutant genes which are responsible for the aberrant behavior of these cells. Until now this has been a speculation.

But here I'll show you a real experiment to prove it's true. So one takes-- oh. Wrong button again. Could we go-- there we go. Okay.

So one takes cancer cells growing in the Petri dish and prepares their DNA. And these DNA molecules clearly contain the genes of the cancer cells. And then one can take these DNA molecules from the cancer cell and introduce them into normal cells that are growing in the Petri dish here, and ask the following question. If we put the genes of the cancer cell into these normal cells, will these previously normal cells begin to themselves behave like cancer cells? All that they've received are the genes from the cancer cell.

And in fact, such an experiment succeeds, because if one takes genes and DNA from cancer cells, puts it into normal cells here, some of these normal cells-- previously normal cells-- undergo a conversion, a transformation, that enables them to grow now like cancer cells. Here's what such an experiment looks like under the microscope.

Oh. This is not good. There we go. Okay.

Here are some normal cells growing under the Petri dish. And here are the descendants of a normal cell, which acquired a gene from a cancer cell called an oncogene-- a cancer-causing gene. And now these cells grow abnormally on the Petri dish. And if one plucks these cells out of the Petri dish and injects them into a young mouse, they'll start growing into a tumor.

And such a simple experiment proves unequivocally the point that within the DNA, within the genes of a cancer cell, there lie cancer-causing genes, oncogenes, that can drive normal cells into cycles of malignant growth. And thus the very existence of these genes is no longer a matter of speculation.

One can isolate such genes using modern recombinant DNA technology. Here's the way one would depict such a gene as isolated by DNA cloning. It's a single segment of DNA. It's 6,000 bases long. This is only a minute fraction of the total genetic complexity of the human cell, where there are 3 billion bases of DNA.

And this gene is present both in normal cells and in cancer cells. But the difference between this gene in normal cells and cancer cells is that in cancer cells this oncogene-- in this case, retrieved from the human bladder carcinoma-- has suffered damage. The gene is 6,000 bases long. And the essential difference between the two genes is a single one of these 6,000 bases, as is indicated here.

Here's the sequence of the basis of the normal gene. It goes G-G-C-G-C-C-G-G-C-G-G-T and so forth. And then the cancer-causing gene, retrieved by gene cloning from the cancer cell and sequence-- the sequence has been determined, the sole and exclusive difference that converts the previously normal growth-regulating gene into a cancer-causing gene is a single change of the DNA base from a G to a T.

And I mention this to illustrate the fact that the powers of modern molecular biology can now dissect with extraordinary precision and specificity the molecular changes inside cancer cells that are responsible for their aberrant growth. It's no longer a matter of speculation that mutant genes drive cancerous growth. The mutant form with a T here causes normal cells to undergo malignant transformation.

The normal gene, which resides in all our normal cells and has not suffered mutation, programs normal cell proliferation. And we know how such genes work. For example, the normal gene and the cancer-causing gene both encode the structure of a protein. As is the case with all genes, it's the protein that does the dirty work of the gene.

And this protein works as a molecular switch-- an on/off switch-- which is continually flipping back and forth. When the cell receives a growth stimulatory signal, the switch is turned on. And when the cell no longer receives a signal, the switch is turned off. And that's the way the normal molecular switch works.

But in the molecular switch that derives and is found in the cancer cell, instead of going from an on state to an off state, the molecular switch is left to run in the on state for indefinite periods of time, being unable to shut itself off. And therefore, a vital component of the signaling circuitry of the cell, which normally should be on for a brief moment in time, releasing a pulse of growth stimulatory signals into the cell, is left on at full blast for an extended period of time, driving incessant, unrelenting growth on the part of the cancer cell.

We even know now by looking into the innards of the cell, on the basis of work from hundreds of laboratories, about a complex circuitry, an interrelating cohort of proteins within the cell. Here's the limiting membrane of the cell. And here are proteins which talk to one another, which communicate with one another, and process growth stimulatory signals in the cell, helping the cell to decide whether or not it should grow.

When one of these proteins-- the one I showed you just before, which happens to be located right here-- is disrupted through a mutation in the gene that determines its structure, this circuitry malfunctions. So we now not only understand the identities of many of the genes, but we begin to understand the intercommunicating proteins inside the cell, which operate much like components in a circuit board-- mini computer inside the cell-- which helps to determine whether or not a cell grows.

And when the components of the circuit board-- of the mini computer-- are disrupted through mutations of the gene that determine their structure, then the circuit as a whole is disrupted, and decision-making goes awry.

Here's yet another way of depicting that. And I'm not going to quiz you on the details of this graph. I only mean to impress on you the notion that we now begin to understand the innards of the cell with great precision, the intercommunicating components which enable cells to receive signals, to process these signals, and to converge in a normal cell on the decision as to whether it should grow or not grow.

Knowing that, one can begin to imagine how disruption of one or another critical component of the circuitry can then lead to unrelenting growth. We know as well about yet other kinds of genes. The genes I talked about before are called oncogenes.

And when they are present in mutant form in the cell, they drive unrelenting growth. They are, in effect, operating like accelerator pedals in cars. In the normal cell, the accelerator pedal-- the normal proto-oncogene, the normal version of this gene-- stimulates growth only briefly by being pushed down and then flipping back up.

In the cancer cell, the oncogene, the malfunctioning oncogene, operates like a stuck accelerator stuck to the floor, driving unrelenting cell proliferation, driving the car to to move forward without any limits. There are yet other genes which operate in an exactly opposite, or countervailing fashion, in the cell. These other genes operate like breaking mechanisms, like brake linings, by stopping cell proliferation. And often they're called growth suppressor genes, or tumor suppressor genes.

And we've learned about these growth suppressor genes by studying, among other things, a rare eye tumor called retinoblastoma. One of the interesting things about cancer research is that by studying tumors in one organ, one very often learns lessons about cancers occurring in many other sites throughout the body. So the lessons about studying the rare eye tumor retinoblastoma, a tumor of young kids up to the age of maybe 5 or 6, seen in only one 1 of 20,000 children, is illustrative of the principles that govern the growth of cells throughout the body.

In the case of the retinoblastoma tumor, we know that its origin is do not to be hyperactivation of a growth-promoting gene, but on the contrary, to the inactivation of a growth-suppressing gene. And the consequence is that a gene which is normally 190,000 bases long. Look at the line that's labeled N here and goes from here all the way over to here, in many cancer cells, major parts of the gene are missing. They're eviscerated, they're cut out through mutations.

And as a consequence, this braking mechanism that operates to slow down cell proliferation, is disabled.

I mention that to indicate that we now realize that in most cancer cells, there are at least two kinds of genetic changes of mutant genes in the cell, which result in two distinct changes in control. One are the mutant oncogenes which drive unrelenting proliferation, like the stuck accelerator.

And the other are of the defective tumor suppressor genes, which operates like defective brake linings in the cancer cells. And therefore the forward motion of the cancer cell in terms of its proliferative power, derives from both of these things converging and conspiring. A stuck accelerator pedal and a defective brake lining, in this case being disabled by mutations that destroy the integrity of the gene, that templates the functioning of the braking mechanism

We also learn about these tumor suppressor genes because when they are inherited in mutant form-- in defective form-- from one generation to the next, they are often responsible for heritable kinds of breast cancer-- certain kinds of cancer-- I'm sorry-- in this case. And in the case of other tumor suppressor genes, yet other kinds of human malignancies.

We now believe that between 5% and 10% of human cancer is due to inherited tendencies to one or another kind of disease. Rather than accidents occurring to one's cells in one's genes in one's lifetime, some individuals between, 5% and 105 of cancer patients come down with cancer, not because of the way that they abuse the cells in their body or because of bad luck occurring to their cells and genes during their lifetime, but because they had the bad luck of inheriting a defective gene from one or another parent.

And in such families, one now sees the appearance of cancers at high frequency. Here is a retinoblastoma cancer family. I mentioned before that this cancer otherwise only occurs in one out of 20,000 in the population.

And here you see that in a kindred in which the tumor suppressor gene is inherited and passed on from generation to generation in defective form, the cancer is seen in very high rates. And we know that similar situations obtained in the case of heritable colon cancer, and heritable breast cancer, and a number of other heritable tumors where a portion of the tumors seen in the population are due to an inborn susceptibility.

And finally, I mention one other recent discovery in cancer research that has been most exciting and provocative. And that deals with the ability of cancer cells to proliferate without limits.

What do I mean by that? If one takes a normal cell and puts that cell into a Petri dish and allows it to grow, then that normal cell will proliferate only for a limited number of times in the Petri dish before stopping to grow. If one takes a cancer cell and puts it in a Petri dish, the cancer cell will double forever. And that's really a provocative finding, because it suggests that the normal cell has a built in intrinsic alarm clock that tells the cell it can double for a certain number of times before it must stop growing.

And the cancer cell, on the contrary, has acquired the ability to double without limits. The cancer cell is said to become immortalized. Not the human being, but the endometrial cancer cell, because it can continue to double forever, which apparently is an essential part of its ability to form tumors.

And we now realize the molecular nature of the clocking mechanism that operates in normal cells and inside cancer cells to determine the replicated potential. It turns out that at the ends of chromosomes, there are DNA sequences that are known as telomeres. And we realize that within normal cells, these telomeres grow increasingly short each time a cell goes through a cycle of growth and division.

And when they become critically shortened, these telomeres are no longer able to protect the ends of their chromosomes, which is the normal role of the telomeres. They function in effect like the little shield at the end of our shoelaces, to prevent the chromosomal DNA from frame.

And when normal cells go through increasing cycles of generations of doubling, their telomeres get shorter and shorter, until they finally have shortened so much that they are no longer able to protect the chromosomal DNA. The telomeres and the chromosomes collapse, and the cells die.

Cancer cells, we've learned over the last two or three years, are able to forestall and prevent this telomeric collapse by developing an enzyme called telomerase, that is able to repair and elongates these telomeres, thereby disabling and disrupting this generational clock that prevents normal cells from growing forever.

So even here we've developed an increasing molecular insight into the origins of aberrant cancer cell growth. Here we see the telomeres at the ends of chromosomes. Here they're highlighted in yellow. And here we see a chromosome which has lost its telomeres. It has no yellow on the end of it. And the cell carrying this chromosome is soon going to die by virtue of the fact that the telomere is no longer here at the end of the chromosome to protect the physical integrity of the chromosome, enabling the cell to grow forever.