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Paul Hoffman:  I would like to welcome our first speaker, Dr. Harry Ostrer. He is the director of the Human Genetics Program in NYU [New York University] Medical School. He is a professor of Pediatrics Pathology and Medicine there.

He has a wide range of interests which is pursued in his laboratory. He has worked on the genetics of prostate cancer and other forms of cancer. He’s worked on genetics of ancestry, particularly in Jewish and Latino populations. He’s worked on the genetics of male sexual development. And he has been very involved in issues involving the fair use of genetic information, and in that capacity he’s been an adviser to the National Institutes of Health. He has been an adviser to the Defense Department and the New York Bar Association, in which he’s been involved in every piece of legislation that’s pending or inactive that has to do with genetic testing, with reproductive technology and human cloning.

So welcome Dr. Ostrer.

 

Dr. Harry Ostrer: I would like to thank Paul Hoffman and his fellow organizers of Big Think for inviting me to participate this evening as Francis Collins’ understudy.

This invitation has left me wondering whether there might be an NIH directorship in my future, or whether I will be left with a happy fate of being a medical geneticist, free to pursue my own research leads.

There are three areas that I currently explore, the first is the genetic control of male sexual development. Normally a switch on the Y chromosome turns on the pathway that causes half of us in the population to develop testes, male reproductive structures, to develop as men. But this switch, or it’s downstream relays, make go awry causing effected individuals to develop as women, or to have ambiguous sexual development.

These people with disorders of sexual development, present the experiments of nature that we geneticists so value because they represent an opportunity for understanding the whole cascade of genes in the male sexual development pathway. In my lab, we’ve recently identified one of these regulatory genes for male sexual development, and we think that it is not a relay for the master regulator, rather it regulates the on switch for the master regulator.

We studied the populations of Jewish and Hispanic Latino people. Together these groups comprise 12 and 20% of the population of New York City. We’re tracing the Jewish Diaspora back and forth across the Mediterranean Basin into Europe and into the New World. Jews form their own distinctive genetic clusters with each group of the Diaspora forming its own sub-cluster.

Puertor Ricans and Dominicans are for the most part, the variable descendants of Europeans and Africans, whereas Mexicans and Ecuadorians and Colombians are the descendants of Native Americans and Europeans. We’re using methods that recognize this admixed ancestry to map genes for traits such as susceptibility to breast cancer.

In fact, my NYU collaborators and I are working to develop predicted genetic tests for breast, prostate cancer as well as melanoma, envisioning the day, perhaps five years hence, when it will be possible to perform the test in which the results will be reproducible and meaningful.

If we thought of the test that are offered by direct to consumer, genetic testing companies were valid, then we would use them at our cancer genetics risk evaluation program, where we see nearly a thousand people each year as such in their risk of breast, ovarian and colon cancers.

When a new genetic test is introduced into clinical practice, we’re looking for three things: analytical validity, clinical validity and clinical utility. The tests that are performed in my clinical genetics laboratory, and in the other laboratories that I use to assess the risk from my patients at NYU, meet all of these criteria. Let’s look at each of these in turn.

Analytical validity is the ability of a test to accurately and reliably measure the genotype of interest. From many DNA chips, the call rates are in the range of 98 to 99.9 %. That sounds great, but let us throw in some numbers. This means on a DNA chip with a million probes, one thousand to twenty thousand results are being missed. That’s okay in my research lab, but it sure isn’t in my clinical lab where I have to guarantee to the patients and to the Department of Health that I can provide complete results to every patient.

Now let’s throw in the recent computer software, and we learn from [IB] who runs the DNA chip core facility at Yale, that the false positive rate as 1%. This is a false positive rate anywhere on the chip. Not in the probe for breast cancer or Type II diabetes. My patients in the Department Of Health would say, “Well, Dr. Ostrer that just isn’t good enough.”

So what about chronicle validity? This is the ability of the test to detect or predict the associated disorder. It must be great, no? Why else would these directing consumer companies be offering tests to consumer? Jeffrey Drazen, the Editor of “The New England Journal of Medicine” has written, “even the ardent proponents of genetics susceptibility testing would agree that for most diseases we are still at the early stages of the identifying with full risk susceptibility associated variance.”

We know from research studies that most common diseases--diabetes, various cancer and heart disease--are caused by multiple gene variants acting together within environmental factors. The studies that are now identifying these factors, and their interactions, are only now being conducted, and their validation for clinical use will come later.

As you will hear from a fellow panelist, no two companies can agree on her risk of disease. Barbers who have used direct-to-consumer genetic testing have written about how their diabetes or colon cancer was not predicted by the DNA chip.

Kenneth Offit, the head of Cancer Genetics of Memorial Sloan-Kettering Cancer Center, has written: “The companies often state that the services offered are not medical tests, but they are provided for informational purposes only.”

But seriously folks, if you are learned that you were at increase risk for heart attack or colon cancer or type II diabetes, wouldn’t you want to discuss this with your doctor? And wouldn’t you feel rather foolish when he said, but seriously Ted let’s not make too much out of this. Or would he start ordering tests, a stress EKG, colonoscopy, a glucose tolerance test to follow up on the false positive results that are the bane of the physician’s practices.

This raises the third issue of clinical utility, or the balance of associated risks and benefits. Jeffrey Drazen from the “New England Journal” has written: “This is the arena in which there is virtually no data on the health impact of genome wide analysis. There are very few observational studies and almost no clinical trials that demonstrate the risks and benefits associated with screening for individual gene variance, let alone testing for many hundreds and thousands of variance.”

And what might we do, and what might the recommendations be? Lose weight, eat better, stop smoking, exercise more? Who needs a thousand dollar genetic test to tell her to engage in lifestyle changes that will have broad health effects? Suppose she was learns she has an increase risk for breast cancer as women who are BRC1 carriers do. Will she take drugs that would put her into menopause? Or have her breast remove to lower the risk? Or would she just worry her way from one mammogram to the next?

So what can we do now that is reasonable? Get diagnosed if you have a genetic disease. Get treated and learn about it. Knowledge is power. Learn about your family history. If based on your family history that you are high risk for colon cancer, heart disease, blood clots or a host of other conditions, consult with the medical geneticist. There may be a specific genetic test that is appropriate for you. Get carrier testing before marriage, before pregnancy, during pregnancy. Get the other tests that are appropriate for people in your stage of the life cycle. Learn your risk and act. You don’t need a thousand dollar genetic test to spur you into action.

Now the purveyors of direct-to-consumer genetic testing would say that this is the old fashion Neanderthal Luddite practice of medical genetics. But I would beg to differ. We medical geneticist and genetic counselors are the age of progress of genetic discovery. We have reinvented our profession many times, and we are leading the way to discover the analytical validity, the clinical validity and the clinical utility of new genetic tests. We admire the community activism that brought us new treatments for HIV/AIDS, expanded genetic screening for breast cancer via a mammography and validated new genetic testing for many conditions.

We want to build the bridge to somewhere. We’re looking forward to that day when a 61-year-old man walks into our office with the pill rolling trimmer, and we can insert his DNA sequence micro disk into our genetic risk reader and it can state with high likely head that he has Parkinson’s disease type VII. Moreover, it would tell us that he would benefit from treatment with drug C because of his personal risk benefit genetic ratio.

That day is not far off and it will be coming one disease at a time. In the meantime, I fear that the purveyors of direct-to-consumer genetic testing, with their faulty claims, will scare away our patients and betray the public’s trust in medical genetics.

Thank you very much for listening.

 

 

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