Paul Goldberg

Dr. Anil Potti, the Duke University cancer researcher whose resume and research are under scrutiny, is the ideal target for Paul Goldberg, the editor of The Cancer Letter. Goldberg, who has an uncanny sense for hubris, is building a reputation for outing bad apples among cancer researchers, and he has dug up some interesting documents about Potti.

I met Goldberg a year ago at a training course the National Institutes of Health put on for science writers. He was one of the speakers and talked about a lunch cancer researcher whose research was flawed and who failed to disclose the $3.6 million she had received from a cigarette maker.

After I read The Cancer Letter’s special issue about Potti, I called Goldberg and got his permission to link to the documents supporting the stories.

There is:

• A copy of the letter more than two dozen biostatisticians wrote to Dr. Harold Varmus, newly appointed director of the National Cancer Institute, urging for a public inquiry.
• A copy of the American Cancer Society letter that notified Dr. Sandy Williams, vice chancellor for academic affairs at Duke’s Medical Center, that payments were being halted on a $729,000 grant Potti had been awarded.
• Three versions of Potti’s resume. One version that includes his now disputed claim of being a Rhodes scholar, a second version that also includes the claim and a third version that doesn’t. Potti used the two versions that include the claim while he was a research fellow at Duke. At the time of the third version, he was already an assistant professor in Duke’s department of medicine and the Institute for Genome Sciences and Policy.
• A copy of Potti’s residency application at the University of North Dakota School of Medicine, which includes his educational history in India, a transcript from his medical college in India and a personal statement.
• A faculty profile of Potti, which was published in 2007 in Genome Life, a newsletter of Duke’s Institute for Genome Sciences and Policy. The profile calls him a Rhodes scholar.

Resume padding to gain academic stature is nothing new.

A few months ago, a former Harvard students was indicted for falsifying the resume that got him into the Ivy League school and several scholarships. Last year, California regulators found out that a new law to regulate air pollution was based on statistical work done by a researcher who hadn’t earned a doctorate in statistics from the University of California at Davis as he had claimed. Three years ago, the dean of admissions at the Massachusetts Institute of Technology had to resign when it became clear she had inflated her resume with degrees she never received.

Dr. Anil Potti

But Duke has bigger problems than suspected resume padding by a rising star. The Lancet Oncology, a British medical journal, and the American Cancer Society are investigating potential errors in Potti’s research, because other researchers have been unable to independently replicate breakthrough statistical findings that promised to predict which chemotherapy is best for each cancer patient.

Questions about possible statistical errors in Potti’s research came up last year. Duke halted three clinical trials Potti was involved in and investigated, but didn’t allow outsiders to double-check the data in question, according to Goldberg.

Being able to repeat an experiment and come up with the same results is a basic tenet of research. It’s the litmus test to separate fact from fiction in science.

Duke has had problems with basics before.

• In 2003, Jesica Santillan, a 17-year-old Mexican immigrant, died after receiving a heart-lung transplant at Duke University Hospital. The transplant was from a donor with the wrong blood type.
• In 2005, surgical instruments at two hospitals in the Duke University Health System were washed in used hydraulic fluid instead of detergent. The mixup wasn’t detected for weeks, because administrative staff failed to heed multiple complaints by staff.
• In 2008, research of Homme Hellenga, a Duke professor of biochemistry known for his work with designer enzymes, came under fire and he had to retract two research papers because other researchers who repeat his experiments cannot get the same results. According to a story in the magazine Nature, a student in Hellinga’s lab had raised questions about the experiments before the results were published.

Dr. Anil Potti, a Duke cancer researcher, was suspended last week after his claim to have been a Rhodes scholar could not be confirmed. Duke also halted enrollment in three clinical trials that Potti lead. The trials used gene-based test results of drug sensitivity to predict cancer patients’ responses to chemotherapy drugs.

Potti and colleagues at Duke also did the statistical analysis for a report published in the Lancet Oncology three years ago. The report was based on results from a clinical trial involving breast cancer patients. The published report was titled, “Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy.”

The report, which had 19 co-authors, was an important step toward personalized medicine.

But the Lancet Oncology today expressed concern over errors that two of the report’s authors detected in the statistical analysis by Potti and his Duke colleagues.

Here it is: S0140673610701856

The Lancet investigation goes way beyond potentially false claims of one Duke researcher being a Rhodes scholar. Questions of research methods and errors reach beyond one possibly rogue researcher and potentially put patients’ lives at risk.

Dan Vorhaus

Dan Vorhaus is a lawyer with Robinson Bradshaw and Hinson in Charlotte, N.C. where a portion of his practice comprises the growing field of personal genomics law. Given the interest in personal genomics in the Triangle, I thought I’d create an expanded version of the short question-and-answer interview I did with him for an up-coming issue of the Sci-Tech section in the Charlotte Observer and the Raleigh News and Observer (be on the lookout for that next Monday in print and online), and post it here. Vorhaus also authors the Genomics Law Report, a blog about the legal side of personal genomics, and he will be giving testimony to the Food and Drug Administration in the near future as the agency attempts to sort out particulars of how it plans to regulate genomic diagnostic testing.

How did you become interested in concentrating on personal genomics as an area of the law?
I have a master’s in bioethics; I did that degree before I went to law school. So as I started thinking about the areas of law and policy that were most interesting to me, that was clearly one of them. And it seemed like there was a tremendous opportunity for a field that is developing and emerging and creating all sorts of new and exciting legal issues. And it’s something that I’ve always had an interest in the underlying science and technology, and I was fortunate enough in law school to start working with some real pioneers in the field, specifically George Church in the personal genome field. Everything sort of built from there. Now, it’s how I make my living, it’s my career. And I love it. It’s something new and fascinating every single day and I can’t get enough of it.

It sounds like the bioethics degree had a big influence on you.
It did, although I already had this interest before, that was what caused me to pursue the bioethics degree. And I knew I was going to law school. I kind of applied those two things simultaneously. So, they have kind of worked together simultaneously. And I decided kind of early on that I was more interested in pursuing the law than some of the pure policy or philosophy or ethical issues behind a lot of these technologies. I think there is a real need… One thing you find with the law is that new areas tend to lag in new areas of technology and new areas of social development. And that is certainly true in the areas of personal genomics, personalized medicine, there is a long way for the law to go to catch up to where science and technology already are. And they continue to press on ahead. And the law continues to play catch up. So it seems that there is a real opportunity to be involved in helping to lay the legal framework for what I think will be important and meaningful technologies and services in people lives for years and decades to come.

That formalizes what I had suspected, with some of the things I’ve read about the Myriad ruling and the FDA announcing its intent to regulate direct-to-consumer genomic testing, it does seem that these formal regulations and policies are lagging behind the business practices.
That’s right. Both the examples you gave, the Myriad litigation — and really, the state of biotechnology patents more broadly – and the FDA and Congress’s involvement in genetic testing, especially consumer genetic testing, both of those are areas where there is a lot of uncertainty right now whether the law today is doing as good a job as it could be as far as protecting individuals and enabling commerce, and really striking the right balance between allowing the science and the technology to press forward while making sure that we have the right protections in place for people using these technologies. That is always going to be a tension in this area, I don’t ever foresee that dissipating; but that does not mean that we should work any less hard to get that balance as close as we can as quickly as we can.

You’ve posted about the Myriad gene patent litigation, in which a federal judge invalidated patents that Myriad held for human genes, BRCA-1 and BRCA-2, which are used to test for the likelihood of developing breast cancer. What was the most unusual thing about this ruling, because it seems to have caused quite a splash?
You’re right, it does cause a splash, but I would say the splash that it caused is probably greater than its legal significance, at least for right now. It’s important to keep in mind that this was a district court ruling, so without getting to much into the weeds, there is a long way to go with this litigation before it gets to the point where it will really impact the commercial landscape, before it really impacts what people feel comfortable doing in laboratories – whether it is research laboratories or commercial laboratories – it needs to .. It’s already been appealed to the federal circuit, which is the federal appeals court that hears patent cases. And it’s quite possible that from there it will go to the Supreme Court, and we’re talking at least another year. Perhaps two. Maybe even three more years before we get a final resolution in this case. The reason I think it garnered so much attention is because it really struck a nerve – and going back to this idea of law not always keeping up with where science is – it really struck a nerve when people heard that there were companies out there that held patents on human genes. And we are talking about isolated human genes, genes outside the body, no one owns you, but it is the case that some companies have patents on genes, and they have the ability if they want – and Myriad has done this because of the way patents work – they grant the patent holders monopoly rights, they have the ability to keep other people from doing tests to analyze those genes, to sequence those genes, to ask what does this mean, in the case of BRCA, for the susceptibility of a woman’s or a man’s, risk of getting breast cancer. And I think that struck a nerve with a lot of people.

It’s not the only sort of development with this area… [Other reports] have gone to the Secretary of Health and Human Services that looked at these issues and looked at the gene patent landscape and said this is a problem, this is impeding our ability to do the type of diagnostic or clinical work that we need to do, to advance the state of science and technology. There is another supreme court case that will likely come out on Monday, that also may be significant as far as the extent of biotech patents, in terms of how far they can reach. And it all goes back to this question of trying to strike the right balance. In the case of patents, we’re trying to strike the right balance of information disclosure and getting these technologies out there and allowing people to benefit from them, and preserving the commercial incentive to investments. That is how our legal system works, we build up this body of law over years and decades – in this case, patenting of human genes which reaches back to a 1980s Supreme Court case, probably even further, and it built up incrementally. And science does not work that way, it moves much faster. It was only 10 years ago that we published the first draft of the human genome sequence, and now, 10 years later, we are routinely sequencing whole genomes, let alone individual genes. And so, again, it’s that pace of technological innovation and scientific advancement that is much faster than we have the ability to move in the legal realm. So that causes a conflict in cases like Myriad where now everyone has to sit down and ask, do we have the right balance here? Should genes be patentable? Is this where we want to be? I think there is plenty of debate about that. It may be something that litigation solves, or maybe Congress steps in, or maybe there are people out there working on industry private solutions to work things out without having to wait on the courts to solve it.

One thing that confused me about this, is the idea of patenting human genes. In the case of Myriad, one of the things I was wondering was why do they have to patent a human gene? Why can’t they just patent their test? That seems like a more level playing field.
You’re right, that would be a more level playing field, and I think the simple answer is that if you are going to invest a lot of money into developing a test and researching an association between a gene a certain disease, and then figuring out the corresponding test, you may not want a level playing field. You may want to do all the testing, and that is what Myriad does. I should mention, there are other companies out there that have patents on human genes, and they have a patent that allows them to have exclusive rights to practice that patent. So, to conduct a test, or even to examine the gene, if the patent is one the gene itself; but they license out that patent or set of patents. Myriad, for example, I think has several dozen patents with almost two hundred claims, so we’re not talking about one or two patents, they have a whole suite of patents, that protects this business they’ve built around diagnostic testing for breast cancer, but there are other companies out there that have similar patents that do license them out to other people, and they say, here you can use this technology, you can use this gene that we’ve patented, there is going to be some sort of commercial terms with that, you’ll pay us some sort of royalty, or some kind of fee based on tests that you do, but you can get in the game too and essentially provide the same sort of service that we are providing.

Or, Myriad is a good example. They did not actually patent this themselves, they licensed this from the University of Utah. And so it is interesting because one of the reasons why Myriad was swept up in this litigation is because there are thousands of genes that are patented, Myriad only has patents on a handful, but the reason they became a target in this litigation is partly due t otheir practice of not licensing out their IP, their intellectual property, and not giving people a chance to conduct or to develop competing gene tests. But that is the prerogative of a patent-holder. You have the right to exclude everybody else from practicing your patented invention. You can wave that right, in the form of a license, out to other people, if you want, but you don’t have to. So that is why there is this big question over what should be patentable. The technical discussion centers around section 101 of the Patent Act which defines what is patentable subject matter. And the question is, are genes patentable subject matter, or are they what is considered to be a product of nature?

Is it that things in the natural world can’t be patented?
Well, it doesn’t specifically say that in the Patent Act, but that is the way it has developed in the case law over time. The 1980 case that I referred to earlier … said that what is patentable is anything under the sun made by man. And there is this products of nature doctrine, and it says, well the Supreme Court says, that something that is a product of nature can’t be patented. And then the question is, what is a product of nature? And Myriad argues, in this case, that this is not a product of nature because you are taking genes, which occur naturally in the body, and you are separating them out, you are isolating them, you are doing things to them technically that make them no longer products of nature. And in the technical sense, that is correct because genes do not naturally occur in laboratories. But what Judge Sweet ruled is that what is fundamentally important in these genes, what really makes them significant, is the information that they carry. And that is the same whether you are talking about a BRCA gene in your body, in my body, or in Myriad’s laboratory. The information content is the same, and that is what is significant, so they are products of nature and they can not be patented. Whether that ruling stands up, remains to be seen. There is quite a good chance that it won’t.

That’s an interesting interpretation.
And it’s one that people share. I think it resonates quite strongly with people at a gut level. But again, there are limits to how that can be implemented by law in courts. Congress of course has the ability to change the law. As has happened in many, many cases, if Congress does not like a law they have the ability to go out and change the law.

The Food and Drug Administration is constricting regulations for direct-to-consumer genetic testing services offered by companies that scan a person’s genome and offer analysis for health risks or ancestry. What are the FDA’s specific concerns?
It’s interesting… since the whole Walgreens-Pathways thing blew up about five or six weeks ago now, they went after five or six companies. They’ve taken a step back and said, you know, we think we need to regulate all genetic testing. It’s important to remember that most genetic testing is not what is known as DTC [direct to consumer] or commercial or consumer genetic testing. Most of it occurs in a clinical context, done in clinical laboratories, and that is the vast majority of genetic testing on the market right now. Now, the concerns they raise about taking a risk-based approach to regulation, and specifically they are concerned about the safety and efficacy of these tests. So, making sure that the tests are accurate, making sure that – accurate in the sense that when you test for X, you actually get X – that’s what’s called analytical validity.

And then also what is known as clinical validity, which is making sure that the association or the link reported by the tests so that if you do have X, that means you have an increased risk of getting breast cancer, is actually a valid one. And in an area of science that is so new and so changing, that is something that can be difficult to show. Or it may be controversial. So there is a lot of recorded genetic associations that require confirmation, maybe they need more traditional studies to confirm the results, and some studies that have disproved associations, so that is a concern too.

Then there is a third problem which is what is known as clinical utility which is that even if you measure the association correctly and it does mean what you say it does, so you have X, you’ve actually measured X accurately and it does mean that you have an increased risk of disease Y, then clinical utility asks, Can I do anything with this? Can I take this to my doctor and can he start me on a new medication, or tell me that if I lose 15 pounds, then I can prevent myself from developing condition Y. That’s the clinical utility prong, and there is a lot of disagreement there about whether that is something the FDA should really be concerned with, or if that is something that should be left up to individuals. And there are varying definitions as to what constituted clinical utility. Alzheimers is a good example. There aren’t many drugs on the market right now that can be used to reverse the effects of Alzheimers, or be used as a preventative measure for preventing Alzhiemers.

But there are a lot of lifestyle changes that have some evidence that they might help. And there are lot of people that argue that for me, clinical utility means just knowing. If I want to know, then I should be able to know because then I can engage in family planning. I might decide to take an earlier retirement. I might do other things differently. There is going to be a big public meeting July 19 and 20 in DC where I will be at the FDA to talk about some of these issue and give them feedback as they start writing regulations. And of course, in addition to the FDA, the House of Representatives, Congressman Waxman’s committee, have gotten involved with writing letters and they appear to be gearing up to hold hearings and maybe do something in this area. I heard recently that Senator Hatch has a bill out that would address genetic tests and specifically create a new division within the FDA to address those. There is another bill on the House side, I think,… that would also wade into this area. So there are a number of different pathways on the table right now for how the regulation of genetic tests may develop. It’s a bit of a scramble right now.

Even though you said that direct-to consumer genomic tests are a small slice of the genomic testing pie, what legal concerns do consumers need to be aware of when using personal genomic testing?
Well, it is a small… let me back up by saying that consumer genetic testing is a small slice of the overall genetic testing pie, but diagnostics — and that includes an increasingly large percentage of what we think about when we talk about personalized health care – and there are some people that believe that within the not-to-distant future, it’s going to be diagnostics riving therapeutics, so drugs and pharmaceuticals, and not the other way around. Right now, you’ve got these big diagnostic companies, and you’ve got big pharmaceutical companies, but that may flip. We are really looking at, I think, a shift coming down the road. There are some questions associated with consumer tests. A lot of the issues are similar to just the issues associated with learning about genetic information in any context. You want to know that you understand… what information you will find out, if it will be useful to you.

There have always been concerns about somebody else getting ahold of that information and somebody else using that against you. That’s one reason we passed the information non-discrimination act in 2008, to prevent employers and health insurers from using that information. But, that doesn’t mean that other people can not potentially get access to that information and use it against you. That could be your friends, or your co-workers or your family workers.

One thing you hear happening is non-paternity as a result of genetic testing, so you go get tested and your father gets tested and you find out, wait a second, our DNA doesn’t match. I think it’s something like a 10 percent non-paternity rate in this country, which is pretty high compared to what the known rate of non-paternity is. So there is a lot of those cases out there that I think are probably unknown to the family. So you can find out information that might be upsetting to you, or that might be surprising to you. You can also find out information that might be very useful, or interesting to you. That is a balance that everybody needs to sort of strike for themselves and think carefully about. So there are privacy concerns, discrimination concerns. The accuracy of the information… you have to be prepared that it’s not always accurate. There is clinical genetic testing and consumer genetic testing.

Have you tested your genome?
I have. I’ve had myself genotyped by 23AndMe, which is one of the companies that is in the middle of all this. Probably one of the most prominent companies. I paid for it myself. I did not want a conflict of interest because they have gien away a number of reduced cost or low-cost kits and I did not want to have any conflict there. And I think that is all I’ll say about that, because I’m going to be talking publicly about that in the not-too-distant future.

Today, I asked Tom Linden from the UNC School of Journalism and Mass Communication to answer a few questions:

Welcome to A Blog Around The Clock. Tell us a little more about your career trajectory so far: interesting projects past and present?

My passion always has revolved around journalism. When as a scrawny 13-year-old, I failed to make the starting nine on my JV high school baseball team, I was devastated. Rather than wait for my body to catch up to my aspirations, I jumped into journalism, eventually becoming my high school newspaper’s sports editor and editor-in-chief. I loved words and stories and so continued on my writing path through college where I was a columnist and editor for the Yale Daily News. As a senior at Yale, I covered for the Los Angeles Times the pretrial hearings of several Black Panthers accused of murder in New Haven, Conn. After graduation I worked on the city desk of the Times.

After taking a year off to do research for a book (that never materialized), I suffered a case of writer’s block and decided to pursue a career that would give me tools to travel around the world and practice a new craft… medicine. Within weeks of registering for med school, I realized that the journalism bug never left me. I completed med school and a residency in adult and child psychiatry at the Menninger Foundation, then in Topeka, Kans., and started a private practice in which I subsidized what I would call my “journalism addiction.” I worked at a small local television station in the northern Sacramento Valley where I became the health reporter and eventually the 5 o’clock news anchor. In 1989 CNBC hired me to join their start-up cable news venture as both a medical and environmental reporter and a financial news anchor. For the next eight years I worked for a variety of television stations and networks, including the Financial News Network, KRON-TV (San Francisco), Fox-11 (Los Angeles) and Lifetime Medical Television. I also started anchoring Journal Watch Audio, produced by the Audio-Digest Foundation and the Massachusetts Medical Society. In 1995 I co-authored one of the first books on the medical Internet, Dr. Tom Linden’s Guide to Online Medicine. In 1997 the University of North Carolina at Chapel Hill hired me to start a medical journalism program in the School of Journalism and Mass Communication.

As part of our program in medical and science journalism, my students and I have produced a couple documentaries with an environmental focus and more than 25 feature stories for North Carolina Public Television. I also just authored a book, The New York Times Reader: Health and Medicine, published by CQ Press. The book is both a compendium of great stories from The Times and a how-to manual for aspiring medical and health writers.

For the future I’m interested in producing a sequel to our Environmental Heroes documentary and continuing to help educate medical and science journalists.

Would you, please, tell my readers a little bit more about yourself?

I grow most of my own vegetables and fruit from May through November. I’ve just planted seven fig trees that I cloned over the winter and have more starter tomatoes, peppers and eggplants than I know what to do with. I voraciously follow the news and love walking in the forests of North Carolina. My family loves to travel, but travel and maintaining a major garden (small farm) don’t always mesh. I also love to hear good music. In North Carolina there’s lots of it.

Where are you coming from (both geographically and philosophically)?

I was born in California and have lived on both coasts and on the Plains (Kansas) which is very oceanic if you live in the countryside. If I had unlimited resources, I would live by the sea. Philosophically, I am a skeptic and question just about everything.

What is your (scientific) background?

As I said above, I went to medical school and took the usual courses. Science used to intimidate me, but does no longer. I’ve learned more about medicine by reporting on it, than I did in the hours and days that I spent studying it.

What is taking up the most of your time and passion these days?

Writing The New York Times Reader: Health & Medicine took most of my free time over the last year and a half. Now that the book has been published, I’m looking for a new project. I keep getting drawn to environmental issues since climate change and the destruction of the earth’s natural habitats loom as the biggest issues facing humankind. The challenge is to find stories that inspire action and not just induce fear.

What are your goals?

I’d like to see young people (i.e., everyone under the age of 30) do a better job of taking care of the planet than their parents and grandparents. I’d like to help them do that in any way that I can.

What aspect of science communication and/or particular use of the Web in science interests you the most?

Clearly the Web is the pipeline through which knowledge will travel over the next couple decades. I’m looking for ways to reach non-scientists with information that will both engage and inform them. As a television journalist, I see video as probably the most powerful tool to reach masses of people. The challenge is to how tell video stories in ways that both entertain and educate.

How does (if it does) blogging figure in your work? How about social networks, e.g., Twitter, FriendFeed and Facebook? Do you find all this online activity to be a net positive (or even a necessity) in what you do?

I have a blog, “Dr. Tom Linden’s Health Blog“, but am still trying to figure out what my blog voice is. I’ve taken a little hiatus in updating the blog during the course of writing my latest book, but hope to post more often in the days ahead. In tweeting a lot at a recent conference of the Assn. of Health Care Journalists, I got an appreciation for how much fun tweeting is.

Online activity is both a joy and a burden. I love staying connected with what’s happening around the world, but find it hard to control the beast. If you’re a journalist, you need to be comfortable with the entire toolkit.

When and how did you first discover science blogs? What are some of your favourites? Have you discovered any cool science blogs by the participants at the Conference?

David Kroll (Abel Pharmboy) and Anton Zuiker were my first science blogging mentors. I’m a fickle blogging reader and will follow a link at anything that piques my interest.

What was the best aspect of ScienceOnline2010 for you? Any suggestions for next year? Is there anything that happened at this Conference – a session, something someone said or did or wrote – that will change the way you think about science communication, or something that you will take with you to your job, blog-reading and blog-writing?

I love the networking that goes on at ScienceOnline. After each session I pore over the Web reading about the people I’ve just met. I liked Ivan Oransky’s suggestion in a previous Q&A about having full disclosure for all speakers and panel members at future conferences. Also, it would be nice to get back to the un-conference mode of the first few ScienceOnline meetings. Keep up the great work, Bora, David, Anton and everyone else who brings us this ScienceOnline gift every year.

It was so nice to see you again and thank you for the interview. I hope to see you again soon.

Patients, doctors and researchers have been particularly frustrated by how difficult it is to figure out the genetic nature of complex diseases such as diabetes, heart disease and Alzheimer’s, diseases that are costly because they are chronic and affect an increasing number of people.

A Personal Genomics Symposium that Duke University’s Institute for Genome Sciences and Policy held Wednesday took stock of how far science has yet to go seven years after researchers completed mapping of the human genome and how bumpy the road can be.

Dietrich Stephan

Dietrich Stephan, one of four presenters at the symposium, said the goal is to pinpoint hard-wired susceptibilities to diseases early on by sequencing the genome of each newborn. Once the risks are known for each person, medicine can intervene to keep people healthy longer by preventing or delaying disease. Stephan, a personalized medicine pioneer and chief executive of the Ignite Institute in Herndon, Va., called that approach “managing people from birth to death individually.”

It’s an approach, Stephan suggested, that is necessary to get a handle on run-away health care costs.

The U.S. spent 17.3 percent of its gross domestic product on health care last year, according to a recent report from the Centers for Medicare and Medicaid Services. The CMS estimated that by 2019 U.S. health care costs could nearly double.

The potential benefits are alluring, but personalized medicine also raises questions that go beyond how long it will take researchers to pin down genetic disease triggers.

How much control do patients have over the massive amounts of sensitive, individual data that would be collected? Should the search for gene-based tests and treatments be driven by patients, by institutions, by industry or by the government? Does the entity that pays for the research own parts of the human genome? How much of the data should be made public?

Misha Angrist

Already, patients are bringing results of gene-based tests to doctor visits, said Misha Angrist, an assistant professor at Duke’s Institute for Genome Sciences and Policy who’s interested in ethical and social issues that personalized medicine raises. But “the infrastructure for this stuff isn’t there yet,” Angrist said.

Three years ago, Angrist became the fourth person whose entire genome was sequenced, linked to disease risks and made public as part of the Personal Genome Project.

While the ethical and social implications of personalized medicine remain open questions, researchers are discovering genetic links to one disease after another.

Variations in one specific gene may be common to as many as half of those with age-related macular degeneration, a leading cause of vision loss in older Americans. One version of the apolipoprotein E gene increases the risk of late-onset Alzheimer’s disease. Up to 10 percent of thyroid cancer patients carry a mutation they inherited from a parent. Genetic variations increase the risk for urinary bladder cancer and skin cancer. A group of researchers has even discovered genetic variants that are associated with an increased risk of heart attack.

To pinpoint genetic traits that can be matched to diseases is like finding needles in a haystack. One company, deCODE Genetics, is collecting genetic information in Iceland, a country where residents can trace their lineage particularly well.

Dr. Kari Stefansson

At the Duke symposium, Dr. Kari Stefansson, co-founder and CEO of deCODE, spoke about the population-based approached his company has taken. Using the Icelandic database, DeCODE researchers have found genetic links to schizophrenia, diabetes and prostate cancer, Stefansson said.

DeCODE researchers also discovered that African-Americans who carry a particular gene are 3.5 times more likely to suffer a heart attack than people of European descent who carry the same gene.

David Goldstein

David Goldstein, director of Duke University’s Center for Human Genome Variation, used a similar approach to discover two genetic variants that explain why patients of European descent are more than twice as likely to be cured from chronic hepatits C than patients of African descent.

The two variants protect from anemia, a side effect from the standard treatment for chronic hepatitis C infections that can be severe.

“You can personalize the treatment of patients with hepatitis C,” Goldstein said.

But to find genetic triggers for most common diseases, Goldstein favors another approach. He has argued that only a few rare diseases can be linked to changes that affect one common gene, or two, or three. Goldstein suggests that complex diseases are caused by a combination of many rare genetic variants -  missing genes as he calls them, because they are so difficult to find.

He’s using the approach to look into epilepsy, schizophrenia that runs in families and resistance to HIV/AIDS.

The visitors made it clear they and other investors remain skittish, but they also noted signs of hope, such as the handful of initial public offerings by biotech companies in past months and an adjustment in venture funding last year in favor of early-stage companies.

Stephen Sands

“When we look at a year ago, we’re really all taking a breath of relief that the Dow [Jones stock index] is over 10,000,” said Stephen Sands, vice chairman of U.S. investment banking in Lazard’s healthcare group, who moderated a panel addressing the future of biotech funding at the conference.

But Sands and panel members, which included Cecilia Gonzalo, managing director at Warburg Pincus, a firm that has invested more than $35 billion in the past 40 years; Ed Mathers, a partner at the venture capital firm New Enterprise Associates; and Lauren Silverman, managing director of an investment fund Swiss drugmaker Novartis established in 2007; provided few clues about new ways of financing innovation and job creation to help the U.S. compete with lower-cost countries such as China and India.

Mathers suggested companies take more advantage of government grants, which are becoming more plentiful, especially for the development of “green” technology. But don’t become a government contractor, Silverman warned.

So what’s an entrepreneurial researchers to do whose innovation doesn’t catch the eye of a traditional investor?

Dr. Allen Roses

Dr. Allen Roses, a Duke University professor and former executive at GlaxoSmithKline’s U.S. Headquarters in RTP who spent years researching genetic risks of developing Alzheimer’s disease, offered one solution at the conference: “You can go it alone,” he said.

That’s what Roses did to develop a novel approach that promises to delay the onset of Alzheimer’s. The approach combines a test to detect a genetic marker linked to an increased risk for Alzheimer’s and a medicine that addresses the gene-based risk factor. Such a combination of test and therapy is generally known as personalized medicine, a new area of drug development.

Roses said he used his house to borrow money from the bank and established three companies to generate revenue and pursue regulatory approval of the test-and-therapy combo over the next five years. One company offers consulting services to large drugmakers also looking into personalized medicine. A second company develops diagnostics, including the test for the Alzheimer’s marker. The third company is focused on getting the rights to a diabetes drug that, Roses believes, addresses the gene-based risk factor that about one-fourth of the U.S. population carry for developing Alzheimer’s.

The test, which will be used in a clinical study the Food and Drug Administration approved of in October, looks for a protein that transports cholesterol in the bloodstream. A gene provides the instructions to make the protein, known as apolipoprotein E4, or APOE4. Research involving the APOE gene has shown that Type 2 diabetes may be linked to dementia, but it is unclear how.

GSK studied rosiglitazone, also known as its diabetes drug Avandia, as an Alzheimer’s therapy, but the clinical trial results were disappointing.

Roses declined to provide details about the diabetes drug he’s interested in for his test-and-therapy combo.

“It’s a new way of looking at a complex disease,” he said.

I could attend only the Monday morning portion of the meeting, but Sabine Vollmer was at the Symposium for the whole thing and wrote two blogs posts about the rest of the program here and here with a lot of details.

There were four broad themes entertained by the symposium: Personalized Medicine, Behavioral Neuroscience of Alcoholism, Global Climate Change and Education Opportunity and Achievement. Each of the themes had its own breakout session later, but Monday morning was reserved for Keynote Speakers, one on each of the four topics, each of interest to me in one way or another.

Let me first dispose of the things I did not like about the conference before I get into things I liked. Over the past few years, most of the conferences I go to are informal, unconference or unconference-like events: from Scifoo in Mountain View, to Science FEST in Trieste, to ConvergeSouth in Greensboro, to our own ScienceOnline meetings. Even the ‘real’ science meeting I like to go to, the SRBR meeting, is very relaxed and informal – shorts-and-Hawaiian-shirt-clad scientists giving funny and entertaining talks about their new findings in my own field, with internal jokes, calling out friends in the audience and occasional hackling joke from the room (OK, OK, I overstate – folks are mostly nice and polite, especially when the talk is given by someone younger, e.g, a properly dressed graduate student, waiting in attentive silence until the end and then asking proper questions afterwards, but still, the general atmosphere is friendly and relaxed).

I realize of course that different conferences require different setup and different levels of formality. Not everything is a Bar Camp. While I was personally uncomfortable wearing my suit-and-tie costume at the IASP meeting, I understood that this was a business meeting in a business venue with businessmen (and a handful of businesswomen) in business attire talking about business. But this one, I think, was a mismatch. All (or almost all) speakers were scientists talking about science. Almost everyone in the audience were scientists. For this kind of meeting, the organization was far too formal. And not just in pomp and ceremony and dress-code. For example, if you look at the abstracts, they don’t really say anything about the topic of the talk – they go in great detail about the speaker, including all the past and present appointments, awards and honorary degrees. This indicates that the organizers were more interested in the power hierarchy (i.e., ‘look at VIPs we managed to get here to talk’) instead of the substance of what they are saying. It felt more like a big corporate show-off than a conference meant for an exchange of ideas.

Then, there was no time designated for Question & Answer periods after the talks. I wanted to ask questions, but there was just no mechanism for doing so. I understand there were panels afterwards, but even those were built strangely – with panelists, after each gave a separate talk, sitting at a table on a podium above the audience, physically looking down at the audience, thus psychologically inhibiting all but the bravest from actually speaking up. I do not know how it went, but I doubt it was a free-wheeling discussion. Then, the talks. Two speakers actually read their talks. Arrrgh! Yawn (and I was FULL of caffeine).

Others were much better. Howard McLeod gave a good, clear introduction into personal genomics and personal medicine, its pros and cons. Robert Jackson from Duke provided a good summary of the current state of science of climate change. Ronald Dahl talked about adolescent brain development (something I am very interested in, both professionally and as a father of two adolescents), especially the lengthening of the period between onset of puberty which arrives earlier and earlier (the timing of which is not matched by an earlier development of other brain functions, including self-control) and the delay of societally approved age for onset of sexual activity (including marriage). Thus the duration of the period during which adolescents are sexually mature (but not entirely emotionally mature) but discouraged from sexual activity is getting longer and longer – which is an obvious problem. Couple that with the tendency of adolescents to be unable to resist, despite personal fear, engaging in risky behaviors, problems like teen alcoholism and traffic accidents are on the rise.

Lunch Keynote Speaker, Ralph Tarter, was the biggest dissapointment. His talk about bridging the Two Cultures and lessons from Hollywood was surprising for its naivete easily detectable by anyone who’s been reading science blogs for more than a year or so (including Framing Wars, response to Sizzle and response to Unscientific America, along with bloggers who routinely write about history of science). It was infused with nostalgia for good old days when scientists and poets drank wine and talked together (ehm, scientists and poets at the time were the one and the same people – that was Victorian era when gentlemen of means could afford to indulge themselves in such pastimes as philosophy, natural history and poetry and meeting their like-minded buddies at the pub). Science today is a very different business, specialized, expensive, profesionalized and rightly so. That’s progress. The worst part was the lunch talk was the last point – a very erroneous analogy between peer-review of grants and movie reviews. First error: grants are reviewed before they are funded – movies are reviewed after they are funded. Second, as much as the grant review is prone to error, it is still done by well-meaning teams of scientists who are at least trying to evaluate the proposals according to their merits. Yes, outlandish proposals have a harder time than bandwagon stuff or conservative approaches, but it is at least attempted to be done fairly. Which movie gets funded is totally up to whims of movie moguls and producers. I bet even smaller percentage of submitted movie scripts gets actually made into movies than a proportion of grant proposals that gets funded. And while grant reviewers may look at the past publishing records of the grant submitters, the movie magnates are not in any way swayed by the statistics of positive or negative views of particular actors by movie critics in the media.

The highlight of the day was the talk by James Evans. I know Jim well, but I have never seen him speak before. And he blew me away. He knew that all the other speakers on the Personalized Medicine topics will be over-optimistic, so he took it on himself to provide a counter-view, a summary of cautionary notes backed up by data and a nice dose of humor. It was a very energetic and fun talk that explained very clearly what claims by personal genomics companies really mean, why they are so seductive if you don’t stop to think about them, and how they stack up against reality.

But that’s exactly what a panel of experts did Monday at the RTI Fellows Symposium at the University of North Carolina’s Friday Center in Chapel Hill.

Personalized medicine – the idea of using gene-based information to individualize medical care – was one of eight hot research areas that RTI International’s scientific advisors recommended for further scientific scrutiny. Other areas addressed at the two-day symposium, the fourth since the inception of the RTI fellows program in 2002, include biofuels and the role computers play in accelerating innovation.

On the first day, personalized medicine attracted more listeners among the about 400 people who had registered for the symposium than any other topic.

The four members on the panel agreed that gene-based research, also known as genomics, and its offshoots, proteomics and metabolomics, have advanced medicine. The pursuit of personalized medicine has improved the understanding of diseases, reduced side effects from certain drugs and brought about new treatments.

But after about 20 years of research, the ‘omics are still far from being a crystal ball to assess a person’s risk for disease, said Eric Juengst, director of the Center for Genetic Research Ethics and Law at Case Western Reserve University School of Medicine in Cleveland, Ohio.

Predictive genetic risk assessment is rather like a weather forecast, said Juengst (photo at left). “We all watch it but we take it with a grain of salt.”

The idea of consulting the genome to improve on health care is alluring, said Howard McLeod, director of the UNC Institute for Pharmacogenomics and Individualized Therapy in Chapel Hill.

Prescription medicines approved to treat a particular disease generally work in only about half of all patients, said McLeod (photo at right).

A good number of patients don’t respond to certain medicines – 25 percent cannot activate the blood thinner Plavix, 10 percent don’t respond to tamoxifen, which reduces the recurrence of breast cancer – because of genetic reasons, he said.

Genetic differences among patients also require significantly different doses of Warfarin, a blood thinner that is similar to rat poison and just as toxic if taken incorrectly.

“We don’t really know how medicines work to the degree we need to know,” McLeod said. “It’s Yogi Berra pharmacology: We know what we know, but we don’t know what we don’t know.”

The ‘omics are helping to unravel some of the unknowns, said Susan Sumner, a chemist who works in the RTI Biomarkers and Systems Biology group.

Researchers have found metabolites – products of chemical reactions in cells – that help predict drug-induced liver injury, the predominant reason why experimental drugs fail. The metabolites can be found in urine samples.

Similarly, biomarkers in urine tests are early warning signs during pregnancy for premature labor, said Sumner (photo at left).

The technology is becoming available to delve deeper into what triggers disease and understand individualized risk factors for expensive, chronic diseases such as Alzheimer’s and diabetes.

Research centers advancing genomics, proteomics and metabolomics have sprung up and federal research funding is flowing to companies in pursuit of the $1,000 genome analysis per person. There’s even a bill before Congress that could give personalized medicine a role in the debate about health care reform.

The promise of personalized medicine is to reduce health care costs as technological advances make the ‘omics cheaper and faster. But embracing genetics in medicine too fast has its pitfalls, said Dr. Jim Evans, an internist, professor of genetics at UNC-CH and the editor-in-chief of the journal Genetics in Medicine.

Very little is known about how genes interacting with genes or with the environment can affect disease, said Evans (photo at left).

Sometimes, tests to screen for disease risks turn out to do more harm than good. A test to measure the amount of a protein called prostate-specific antigen, or PSA, as a tumor predictor is one such example, he said.

Sometimes, it’s not clear what the significance of certain genetic risk factors is. Researchers have found 19 genetic risk factors for Type 2 diabetes, but each has such a miniscule odd to cause the disease it becomes irrelevant.

Evans is a big believer in data that proves personalized medicine goes beyond the promise and actually promotes an outcome.

“It’s so seductive to believe that a good idea improves health,” he said. “But it’s really hard to prove it does.”