The Future Holds Promise and Problems

I am not a historian, but history provides standards for the way we view ourselves and our future.

Oliver Wendell Holmes said, "When I want to understand what is happening today, or try to decide what will happen tomorrow, I look back." He also said, "A page of history is worth a volume of logic." Let me take a look back at the history of VHL, and offer some glimpses into its possible future.

A German ophthalmologist, Eugen von Hippel, well known for his interest in congenital eye defects is usually cited as the first to describe the retinal vascular abnormality which he later recognized as a retinal angioma, also called a hemangioblastoma. He named this abnormality angiomatosis retinae in 1911.

Arvid Lindau, the pathologist and Swedish military physician, published a 1926 monograph describing his study of cerebellar cysts. Lindau's monograph associated angiomatosis retinae with cerebellar and spinal hemangioblastomas and cysts of the kidneys, pancreas and epididymis. Lindau named his syndrome central nervous system angiomatosis.

The work of many other physicians proceeded von Hippel and Lindau and allowed them to make their discoveries.

By the close of the 1800's many important things had happened in medicine, setting the stage for the remarkable development of modern medicine since 1900. Bacteriology was a new science, Pasteur's germ theory of infection had been postulated. Most people didn't believe it when he first talked about it. Lister's work on asepsis and how to properly care for patients without them developing infections was done in the 1800's. Anesthesia and aseptic surgery were developed at the end of the 1800's. In 1903, Orville and Wilbur Wright made their first flight in North Carolina. We didn't even have a concept of a gene until 1909.

In 1996 the online Mendelian Inheritance in Man (OMIM) listed 5,127 genetic disorders with an established gene locus, and only 15, just 25 years before in 1971. OMIM is available to anyone with Internet access.

Allow me to pose some questions. My present duty includes administration of the Army Clinical Research Program. My questions for you are similar to those that I am frequently asked about our

research.

The questions are:

What did it cost to identify the VHL tumor suppressor gene? I have told you the story of how this has developed over the last 100 years. Can you put a cost on the discovery?

How long did it actually take to identify the gene? Do you start in 1895? or do you start in 1978? When did the quest for the VHL gene begin?

Who paid the cost for the VHL gene discovery? I suppose it depends on when you believe the search began and who performed the search, but who paid the cost, and who benefits from the discovery?

These questions are rhetorical because you cannot answer them. However, I think the questions are important and you should carefully consider them, because similar questions are asked about all our medical research, not only with regard to von Hippel-Lindau disease, but all our medical research.

In the accompanying figure you will see a concise segmentation of VHL history into 50-year epochs. I'm going back to 1879 which is roughly the time of the first VHL cases, the first time VHL was reported, and there was no definition of what VHL was at that time. 50 years later, by 1929, there was a VHL definition that had been formulated by Lindau after all the work of many others. There was inadequate or really no treatment for VHL in 1929.

In the next 50 years there was adequate treatment for the problems associated with VHL, but the treatment often depended on early diagnosis, and in 1979, which was just at the beginning of CT scan availability, there were really inadequate VHL diagnostic tests. I don't know how many of you have ever had or know about a pneumoencephalogram or myelography, or cerebral arteriography. Those tests were primitive compared to what we have now for discovering or following and diagnosing the central nervous system lesions of von Hippel-Lindau disease.

Now, in 1996, which is 17 years since that last 50-year epoch ended in 1979, we have adequate diagnostic tests, I believe, and we have identified the gene. The question is, what about the next 50-year epoch? In the year 2029, what will we face? What will things be like?

Imagine yourself to be a VHL patient in each of these epochs. You may understand how far we have traveled, and understand the enormous problems faced by past VHL patients.

Is there any discernable pattern in these past events? Consider some of these generalizations that I came up with as I thought about this.

Important events have many causes, many antecedents, many things that preceded them. Consider a technique like computed tomography. Consider all the work by all the different people that have gone into developing that particular technique. So the event of the discovery and development of computed tomography had many things it depended upon. Events often cause each other. Things do not happen in isolation.

For us up to this point, there has been great pressure to use technology in medicine. Any time a technological innovation is discovered, it is rapidly adopted by the medical profession. Again, I'll use computed tomography as an example. By the time the EMI scanner was first made available in the United States in 1972, within four years computed tomography was a common finding in major U.S. hospitals. Sometimes I think perhaps we in the medical profession adopt a technology too quickly without considering what it gives us compared to how much it costs, but there is an imperative to use technology in medicine, and it is rapidly adopted.

There have been some misconceptions, but modern medicine is self-critical, self-correcting, and is always improving over the last 100-200 years. Modern medicine is based on the scientific method.

You may think, "How can we know less as time goes on? How is that possible?" There have been precedents in medicine in the past. Medicine developed by the Romans, for example, military medicine, was advanced, but all the lessons that the Romans learned were forgotten in the Dark Ages, and things actually regressed, as far as medical care was concerned, because of religious bias, superstition, reliance on scholastic reasoning to generate knowledge, and the fact that scientists of the time ignored the facts, ignored things they observed or measured, so that medicine actually slipped backwards. In military medicine we did not regain the level achieved by the Romans until the year 1700 or so. So it is possible for things to regress because of religious bias, narrow-mindedness, nationalism, etc. In the future we hope that won't be the case. We hope that things will continue to improve.

Medical information is generally shared for the collective good, or at least that is the way it has been in the past. Information is usually not proprietary in any significant way. New discoveries are made, and the information is made available to those patients and practitioners that might benefit, regardless of nationality. So there is an important sharing of information.

Another thing to keep in mind is that VHL is a small problem for society. If you look at the other problems that are faced by the world, diseases like tuberculosis, malaria, diarrhea in children, the toll taken by wars, economic problems, HIV/AIDS, breast cancer - you can think of any of a number of medical issues or problems, and for society as a whole, VHL is a small issue. The group of families affected by VHL will need to continue to work to maintain focus and investment on this problem.

Another thing I think it is safe to conclude as we look at the past, particularly where we are now, technological advances in medicine usually outpace our social and ethical abilities to deal with them. For example, the presymptomatic genetic testing for VHL. I never thought that if the test was developed and it was possible to diagnose with certainty that a person had VHL early on - at birth, or early childhood, or even in utero, before birth, I never imagined that someone would not want that test done for fear of losing insurance, for example.

Consider the question of elective abortions for genetic diseases. There are some diseases where there is not much question that termination of pregnancy is a reasonable technique. But look at VHL, where you have a disease that really doesn't manifest itself until later in life, and it could be mild. It might not even begin to cause problems until the age of 40 or so. Is it acceptable to perform elective abortion on a fetus who has VHL? Or is that not a reasonable thing to do? The whole question of abortion in our society is unresolved right now, and there may never be true consensus.

In the field of intensive care medicine in which I am actively involved there are many ethical problems. We are able to maintain bodily functions in people who are in a vegetative state. We can keep the body going, but they have lost their central nervous system, their cognitive functions, and so on, and we have a hard time dealing with that in society. So I think the social acceptance, ethical guidelines, for dealing with these new technologies that are emerging, but there is a lag there where we need our ethics to catch up with where we are technologically.

I began by telling you that I'm not a historian. I'm not really a futurist either. Futurists make profound predictions as shown in one recent newspaper headline: The Future Holds both Progress and Problems. Obviously that is correct. It is simultaneously trivial and profound. That headline could also refer to VHL, so it is the title of this article.

There have been radical and unpredictable medical developments that are particularly important for VHL, such as the discovery of x-rays, antibiotics, the discovery of DNA, computed tomography, and the discovery of the VHL gene - all momentous and very important things.

There have been radical and unpredictable technology developments as well, like the airplane, radio, television, and the computer. No one imagined in 1900 that there would be such a thing as a computer which is such an important part of our lives right now and in our research and treatment of VHL.

And finally there have been some radical and unpredictable important social events that have occurred as well, such as the 1918 influenza epidemic in which 1% of the world's population died - 21 million people. The wars of this century, AIDS, drug addiction, crime, changing family organization, are important, radical and probably unpredictable events that have occurred in the recent past that are important for VHL and the future of VHL.

Here's where I'll take a chance on predicting a future which is basically unpredictable. I will say that by the year 2029, which is 150 years after that first recorded VHL case, that third 50-year epoch of VHL, I predict that there will be cancer therapy based on the VHL tumor-suppressor gene protein and there will be VHL-gene therapy as well. In other words, I believe there is a good chance that it will be possible to insert the corrected VHL tumor-suppressor gene into those that have VHL by the year 2029.

I don't know how the 2029 health care system will be managed, or how much health care will cost, and I don't know how society will finance and support medical research and education. Now we are embarking on a course where there will be less investments in things that build the future, like education and research, especially the medical research that has enabled the progress on VHL. I'm not sure that will be sustained. Certainly we hope that it will. I do not know how society will treat its most vulnerable members, the unborn and the seriously ill. I do not know if the technical miracles of the developed nations will be shared by the developing nations.

I do not know how society will deal with a powerful tool like gene therapy if it becomes available. If we are able to correct a defective VHL tumor suppressor gene, it may be possible for us to insert genes for a certain hair color, eye color, whatever gene we want. I'm not sure how a thing like this will be implemented in the future. The power and risks of gene therapy are at least as great or greater than the power and risks of atomic energy as faced by humankind fifty years ago. We have been very lucky so far in avoiding outright nuclear war - we've come close to it a few times. We will face equal challenges with the power that will be available to us with gene therapy. So these are the challenges from my perspective in implementing VHL gene therapy within the next 33 years, by the year 2029. It will be easy compared with confronting and solving our serious social and ethical and economic problems.

As published in the VHL Family Forum, 4:3, September 1996. For permission to reprint, please contact the VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.