The Exposome: Finally, a way to measure nature vs. nurture.

15 12 2010

Today I attended The Sixth Annual Symposium on Predictive Health, Human Health: Molecules to Mankind at the Emory Conference Center.   The tagline was ambitious and meant to inspire:  “THE END of DISEASE, the BEGINNING of a NEW KIND of HEALTH CARE.” I was only able to go to Session V “Ethical Manipulation of the Human Exposome.”

The Exposo-wha??? Let’s back up.  Remember the genome? Remember when we sequenced the human genome 7 years ago, and people were really excited because this meant now we would not only understand what it meant to be human, but also how to predict and prevent every disease from which humans suffer?  Goodbye aging, goodbye sickness. Hello, ever-lasting health and answers to the previously unanswerable questions about humanity. Why didn’t that happen?

Well it goes back to nature vs. nurture.  You are the cumulative result of your genes and your environment.  Genes might give you a prediction about your susceptibility to developing diseases, but they rarely independently genuinely cause a disease. Given that environments are so complex and so varied from person to person, it’s staggeringly difficult to fully understand what the consequences of all these variables will be with your genes.  Enter the Exposome.  The exposome is a new body of generalizable data that explicitly talks about the intersection of your genes and your environment.  The exposome is a map of all your environmental exposures.

One example of the exposome is the metabolome, or a map of stuff your body has metabolized. A metabolite, represents something that has passed through your body’s cellular processes and can be measured by taking a blood, urine, or plasma samples. By collecting your metabolite profile, researchers are able to get a map of clues to your environmental exposures, and then possibly predict what diseases you may develop or what may have caused you to develop a disease. These data can be combined with your genetic data  to better understand how your body’s genes made you (in)capable of metabolizing agents in your environment (whether it be emotional stress or plant pesticides).  As you can imagine, your body responds to a number of agents at any given moment and can also be influenced by the current circumstances of your exposure (e.g. are you already sick, are you young, are you old, are you a healthy eater, etc). Actually, clearly isolating one culprit in disease causality isn’t as easy as it seems, even with the human genome sequenced. In addition, some things are metabolized and are quickly broken down, leaving barely a trace. Some things leave a longer lasting trace and others leave a temporary trace that you might only see at night or early in the morning.  Finding the right window to detect metabolites can also present a challenge.

Despite these challenges, we shouldn’t underestimate the power of combining the data from the Human Genome Project and now the Human Metabolome Database can potentially have amazing consequences on health care and the way we live.

At today’s symposium, some researchers stated that they were a bit puzzled about why they were asked to discuss the ethical implications of their work stating “I’m not an ethicist” or made statements that they felt their job as *public health* researchers was to put a wall between their research and how their data might affect legislation. They weren’t the first scientists who had their laundry list of excuses to not get involved with ethics. While I was a bit disappointed with these responses, I was glad there was interest enough to devote one of their sessions to ethical discourse.  Ethics sessions like these are necessary to ensure that public health researchers are not  blind-sighted by how their findings might actually hurt, not help the public if they don’t understand how to maximize the benefits of their work. While some interesting points were brought up during the session, I still wanted to know their thoughts, as public health researchers, on how this might actually change or lead to “a NEW KIND of HEALTH CARE” as inspired from their flier.

The Department of Health and Human Services (who is in charge of helping to determine your health and healthcare) have a mission to generate not only preventative, but personalized medicine.  Metabolomics could fit very nicely with these goals.  Metabolomics could tell you how to prevent certain diseases by unintentional exposure to toxins such as pesticides in the environment.  Metabolomics could also tell you how to prevent diseases by preventing behaviors that tipped your genetically vulnerable self into a state of disease.  It could revolutionize the way we live into healthier, longer-living, happier humans.

But what else could it do? What are other ways, the exposome could impact the way I live?

First, we need to better understand exactly how strong the predictive power of “metabolomics” for humans is.  Don’t these studies tell us more about association than actual causation? Many follow-up basic research studies will need to be done to confirm causality. And what  if my metabolic profile as an adult tells a sad story: my unfortunate environmental exposure profile has destined me to get a terrible incurable disease- what will I do with that information?   Should I just take the cyanide pill and warn my children not to make the same mistakes? Would the average citizen know how to interpret their metabolome results, or would hospitals now need to have a staff of genetic and metabolomic counselors?  Will my health insurance need to be informed of my pre-exisiting metabolome condition? Should my healthcare provider know this information?  After all, wouldn’t it help my doctors to give me better treatments and more personalized medicine?  Would I be required to tell my life insurance agent, my employer, or my employer’s lawyer? Extreme care will be needed to ensure that exposome data is secure and in the right hands.

How will this change the way we view “disease” and  accountability?  Environmental toxins like lead, or pesticides are not the only bad things you’re exposed to in your environment. Certainly everyone wants big business, Pharma, the military, and industry to be held accountable for the exposure that the public will unknowingly gets. What about the known, voluntary exposure to toxins?  The passive suicide cocktail of bad eating habits, smoking, and not controlling their stress or exercising?  This will  all show up in your metabolome.  Remember when drug abuse and depression were thought of as moral failures?  Sure some people still think this, but the popular mind has grown to understand that these conditions actually have a physiological substrate just like any other bonafide disease.  Let’s look at Parkinson’s disease or Alzheimer’s disease.  This is a disease where people don’t generally assume you have due to a moral deficit.  Parkinson’s disease is linked to unknowing, involuntary environmental exposure to pesticides.  What if it was linked to a series of voluntary choices?  Would we then say things like, “You gave yourself Parkinson’s disease?” How these data could and should be used will need to be clearly expressed to the public.

In fact, one could argue that all your activities in your history from your emotions to your ingestion of foods will be identified in your metabolome,  maybe even replace a fingerprint. Who should have access or own this information? Would certain exposome patterns be used to predict bad behavior?  If growing up in low socio-economic areas resulted in poor nutritional patterns, predicting subsequent criminal behavior, should preventative measures be taken?  The session at today’s symposium was about *manipulation* of the human exposome– should we manipulate this person’s exposome to try to then change or pre-empt his/her undesired behavior? Can this even be done?  These are the types of  basic research model experiments that are needed that need to be done in parallel to the human studies.  Not just asking, what are the associated changes in the exposome, but can we change them, and what would changing them do for people and society.  This information will also be required for making new health care policy changes. It is critical that the researchers doing this work be able to translate these data for public audiences. Researchers need to think more deeply about the ethical consequences of their work.  You don’t need to be an ethicist to do this, you just need to think critically and genuinely care.

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Back to the Future: Stem cells

27 08 2010

What are stem cells and why is everyone up in arms about them? A very good FAQ can be found here on NIH’s website about stem cells and here for historical policy on stem cells and we’ll discuss it a bit more below.

Stem cells are what people are referring to when you hear the popular media talking about growing new organs in a dish.  The running idea is that stem cells, some types of stem cells, are a special type of cell that can be convinced to become whatever kind of cell you need.  So far, they have been successfully used in patients with diabetes to replace malfunction Islet cells that no longer know how to let your body store glucose, and are the reason why my friend Merriet survived leukemia in high school. These kinds of scientific innovations have revolutionized medical therapies and now scientists want to move onto the big guns, they want to re-grow your brain.  The precise model to use it in is Parkinson’s disease, a disease that does not become detectable to clinicians or even the affected patients until over 60% of a specific set of brain cells that produce dopamine and facilitate normal movement are long gone.

Parkinson’s disease (PD) is a severely debilitating movement disorder, characterized by slowed movement, muscle rigidity, postural instability, and difficulty initiating and terminating movements.  One Parkinson’s patients said that, “It’s like driving with the parking break on.” One of the most famous cure-for-PD crusader’s is Michael J. Fox, teen star of Family Ties and plucky hero of Back to the FutureMichael J. Fox has been an ardent supporter of stem cell research for PD and private grant support from his foundation has been critical for stem cell researchers given the ban of using Federal funding for stem cell research. Who knew he’d be driving that DeLorean back from the 21st century in a battle with zeroth century Christian faith.

But I thought Obama took care of that? Well, he did, sort of. But to understand this, we have to go back a little.  In 2001,  former President George Bush issued an statement that federal funds could be used for research on stem cells only if 1) stem cell lines were already established before August 2001 or 2) embryos that were initially for reproductive purposes, but were no longer needed. And of course, no one can receive money for giving up their embryos.  To be clear, it’s not that anyone has said “Stem cell research is not allowed.” They just said, you cannot use federal funding for it. Incidentally, this is an excellent way to kill a research project as NIH by far provides the lion’s share of funding for medical research. But in June 2007, Bush issued an Executive Order that “Expanded approved stem cell lines in ethically responsible ways.”

What does “ethically responsible ways” mean?  Basically, it means no stem cells from human embryos.  Stem cells from embryos are special in that their are “multipotent”.  This means they have the potential to be turned into any kind of cell.  After you were no longer just a sparkle in your parents’ eyes, you were a cluster of rapidly dividing cells.  Just a big mass of identical cells with the same genetic blueprints in each cell.  At some point, those cells choose what part of the blueprint to actualize.  Meaning some cells turn on genes to become or differentiate into skin cells, other become brain cells and some cells in the body actually stay in an on-call  undifferentiated state like in your bone marrow. If you capture some of these cells early enough, scientists have the technology to choose what these cells become. But this is not what Bush’s administration wanted scientists to study.  Bush’s order would provide federal funding for scientists to work on technology to make “pluripotent cells”. This means taking adult, differentiated cells and tricking them into going backwards into thinking that they have the potential to become many different types of cells.  This is an exciting area of research because this could mean that stem cells would be much easier to come by.  You could just scrape off a skin cells from any adult, even your own cells, put them into a dish, de-program them, and then reprogram them.  Additional work has attempted to utilize locally injected viruses that could reprogram your cells for you.  Unfortunately, in some studies this has led to cancer.  Also, “old” cells will naturally develop more genetic errors and mutations (essentially what cancer is).  Because these embryonic cells are brand new, they are relatively defect free. But the plus side for pluripotent cells is that they can be generated from the person who needs them, so you can have a better chance of avoiding rejection by the host’s immune system that you might otherwise see with the embryonic stem cells.

Okay, so Bush orders that you can do this research by “Expanding” it by only if it’s in “Ethically Responsible Ways,” read: only if it’s not using new human embryos (but cells isolated from old human embryos before 8/2001 are okay. Those are sitting in cell “banks”). In March 2009, Obama ordered an Executive Order carefully worded in response “Removing Scientific Barriers to Responsible Research Involving Human Stem Cells.” But the underlying barrier was not, in fact, removed says Judge Royce Lamberth because we didn’t go back far enough.  In 1996, the Dickey-Wicker amendment was passed by Congress and stated main points 1) human embryos could not be created for research purposes and 2)  a human embryo should not be discrimated against based on whether it’s in a uterus or not, meaning you couldn’t not put the embryo in danger or destroy it for research. The recent suit came from Dr. James Sherley, pluripotent (generated from adults) stem cell researche vs. Secretary of Health and Human Services, Kathleen Sebelius. Dr. Sherley, Nightlight Christian Adoptions, and others initially brought a failed suit to Judge Lamberth suggesting that Obama’s Executive Order would result in an unjustified competition with funds with those doing embryonic stem cell research. Nightlight Christian Adoptions, has a program called “Snowflakes”-a frozen embryo adoption program.

What did Dr. Sherley and others bring to light this time that caught Judge Lamberth’s attention. The first stem cells were derived from mice in the 80s and the first human embryonic stem cells were not derived until 1998. During the Clinton administration, NIH requested that funding for the development of embryos for human purposed be funded but Clinton recommended against this, but would permit funding for research of stem cells derive from remaining embryos from fertility clinics. Congress followed after with the Dickey-Wicker ruling came in 1996, 2 years before human stem cells were derived. The problem has never been that people don’t want to eliminate diseases or regenerate cells. The problem is that a law had been established that you could not “destroy human embryos for research” and Obama’s Executive Order hoped that it would get around this by saying that the scientists are not actually involved in the piece where embryos are “destroyed.”  Scientists can just take the isolated cells (isolated without federal research money) and research them (with federal money) said Harriet Rabb, Health and Human Services General Counsel.  While researchers were eager to move forward with embryonic stem cell research, they failed to realize the how legally vulnerable Obama’s Order was and some ethicists immediately saw this coming. And now, the Dickey-Wicker amendment and the Snowflake brigade come back to haunt us with the relatively simple logic, that you cannot get stem cells from human embryos without destroying them-even if you technically get someone else to destroy them for you.

While all this is going on, can we say whether replacing dopamine cells is actually going to help PD patients? The major problems for PD are three-fold 1) We have no cure 2) Even if we had a cure, we can’t detect the disease until most of those dopamine cells are obliterated and 3) With the exception of a small percentage of patients with genetically linked PD, we still don’t know what causes most case of the disease. What PD patients need are early detection and something that can reverse or halt the disease early. Right now, it’s actually not that grim.  PD patients have for the most part, excellent treatments for the motor symptoms of the disease.  As a PD neurologist recently told me, what does them in is falling (retropulsion, or falling backwards-most people fall backwards) and dementia. These are not features of the disease that are reversed with current dopamine replacement therapies.

And this is where basic scientists and clinicians often have different perspectives.  PhDs are going to look deeply into mechanism-most won’t think about using something therapeutically if it doesn’t work whereas often MDs don’t care how it works if it’s something they can prescribe to patients to give them some relief. Honestly, the latter is how patients generally feel too.  Stem cells geared at replacing dead cells is indeed valuable and has incredible medical promise for numerous medical conditions. That said, we must think of the bigger picture too.   If the quality of life of patients and their families is more impacted by dementia than by relatively treatable motor symptoms, it seems that these might be a more relevant brain target(s).  Once again, we must look at a disease not only piecemeal, but continually revisit a step back.  In this case, maybe optimizing the delivery of factors that can re-program cells to a pre-disease state before they die would be valuable.  For instance, once proposed hypothesis is that neuronal inclusions or plaques predict cell death staging throughout the brain in both Alzheimer’s disease and Parkinson’s disease. In the end, we hope that true ethical principals are driving people’s arguments and not a prideful religious stance. For now, we can keep watching to see what’s next for stem cell researchers and those who might benefit from this research.