Thursday, September 11, 2008

I was reading the blog of a friend of mine (Paul Kind) this morning and it started me thinking about the role of community in modifying behavior.

Here is a portion of his post:

"It seems to me that selflessness over selfishness is a near universal value. Every faith points us in this direction. Whether you follow the teachings of Jesus, Abraham, Muhammad, Siddhartha, or otherwise, selflessness over selfishness is at the core. It's trumpeted in politics, in the church, and in the workplace. And yet I imagine you would agree with me that so many of us have a long way to go in this quest.

Would it be accurate to say that the quest from selfishness to selflessness is at the core of every faith system?
Is this one of the main quests of life???"
(W)hat role can other people play in helping us along in this quest?

My response:

A different spin -

What if the naturalists are correct and there is a "selfish" gene and a mutated version of the same gene that I will call the altruism gene... Then, our natural tendency would be to get everything we can so we can spread our genes as far and wide as possible. He who has the most toys, fathers the most children, and wins a swim in the deep end of the gene pool.

But - in our present society altruism is seen as a virtue. Denying self holds a high place of honor. This would tend to favor the emergence of the altruism gene. The trouble is this: does personal altruism increase or decrease the ability of the individual to reproduce? Is the altruistic trait passed on, or genetically squelched out?

An individual who sacrifices themselves for the sake of others may be more likely to die before reproducing thereby reducing the tendency for altruism to be passed to his offspring. However, if the individual is part of a community that holds heroism and altruism in high esteem the trait may still be preserved. This is because of another mechanism that regulates the way genes are expressed known as epigenetic modification. The environment, or the local community, can increase the tendency toward certain behaviors by modifying gene expression. Notice the difference, the community is not changing the sequence of the gene for selfishness, simply altering its ability to be expressed.

Religion offers an opportunity to move away from our natural tendencies of selfishness and toward selflessness. In closely knit religious communities it is fairly common for an individual to sublimate their own needs to meet the needs of others. This tendency is reinforced constantly by the community ethos and conversation. These communities may cause epigenetic modification of the "selfish gene" thereby preventing, or at least decreasing, its expression.

As with most complex human behaviors it is imprudent, and probably unwise, to suggest that a single gene controls what a person does. Behavior is complex and likely controlled by genetic factors, brain structure, experience, and a host of other factors. Still, the role of community and faith in shaping the genetic component of behavior is fascinating.

Christianity may offer the best path to selfless behavior because of its emphasis on the supernatural nature of the pursuit. I cannot claim to know how the supernatural intersects with the natural - God works in mysterious ways - but what if one of the ways he works is by drawing people into community, thereby affecting gene expression, and changing behavior. That would be a tremendously complex system to bring about a simple result... sounds a lot like biology to me.

Friday, August 22, 2008

Germs, cancer, and providence

The August 1, 2008 edition of the Journal of Immunology contains a fascinating article by the AAI’s new president, Olivera Finn. Dr. Finn has been a cancer researcher for more that 20 years, working on the mechanisms whereby the human immune system recognizes (or fails to recognize) tumors. She is the discoverer of MUC-1, a glycoprotein that is found in an altered form in many different kinds of cancers. Dr. Finn’s contributions to the science of immunology are impressive, but her article reveals a woman who thinks even more deeply about the roots of disease and wellness as they relate to immune system function throughout life.

For the last few years there have been suggestions in the literature that exposure to infectious agents early in life is essential for the prevention of allergies later in life. The hygiene hypothesis implies that rearing children in an environment that is too clean might cause them to have more allergic illnesses in adulthood. In he paper, Dr. Finn extends the hygiene hypothesis to include cancer as well. In her work, both in vitro and in vivo, patients who had certain infections at a young age developed protective immunity against both the infectious agent and to a group of antigens called tumor-associated antigens. As adults these individuals had lower incidence of cancer.

Have you ever been confronted by someone who says: “How can you believe in a God when the world is full of disease and suffering?” What if it turns out that there are reasons for infection and disease that are part of an even larger plan we know nothing about? While I am not suggesting that I know the whole reason, research like this makes me wonder if we are just seeing the tip of some infinite rationale?

Even more intriguing is Dr. Finn’s penultimate paragraph where she suggests that there might be a very small subset of proteins that could comprise a “universal vaccine” capable of preventing all forms of infectious disease, cancer, and autoimmune disease. Her theory is intriguing, though scientifically mind-bending. It makes me wonder, is this a form of divine providence, heretofore unknown? Time will tell.

Saturday, August 16, 2008

Update from APA

For the first time since my wife completed her PhD I am a guest at a professional conference. It is really a terrific feeling seeing Kay in her element and respected for her work. But that is not the subject of this entry.

I attended an interesting talk yesterday afternoon on Rhesus monkeys. The researcher, Dr. Steven Sumi, has worked with a large colony of these animals for over 20 years. They are genetically similar to humans, as are most primates, but are not our closest genetic relative.

If you carefully observe these animals you will notice that there are several sub-populations within the larger family groups. The subject of this study was a population (5-10% in the wild) that is overly aggressive and prone to taking serious risks, including alcoholism and binge drinking. These little monkeys are mostly male, and - if their behavior cannot be corrected - are kicked out of the family and not allowed to return. Aggressive behavior is not welcome in these matriarchal family groups.

Tie to genetics - In humans several genes have been associated with risk taking behaviors, alcoholism, aggression, etc, including (but not limited to) an uptake transporter for the neurotransmitter serotonin (5-HIAA). According to Dr. Sumi there is a single nuceotide polymorphism (SNP) that causes the amount of the transporter to be dysregulated (lower than normal). (At this point I need to pause and point out that I am at a psychology meeting and not a neuroscience meeting. While the behavioral aspects of Dr. Sumi's talk were excellent, his presentation of the genetic and molecular data was rather weak. I suspect that he collaborates with a group of geneticists who do that aspect of the work.)

Back to the presentation - interestingly, the mutation in 5-HIAA that we see in humans also shows up in the Rhesus monkey... and only in the group that is overly aggressive! There seems to be a strong, positive correlation between the presence of the mutated 5-HIAA and aggressive, risky behaviors.

Left alone the correlative relationship of gene to behavior would be interesting, but watch this: if a baby monkey with the bad version of 5-HIAA is reared by an experienced mother with good mothering skills the effect of the bad gene can be completely reversed!!! This represents an excellent example of nurture overwhelming nature.

What's missing? Quite a bit actually. First, Dr. Sumi never intimated whether these animals were homozygous or heterozygous for the mutated 5-HIAA, so we have no way of knowing how much of a contribution was made by the mutated gene. As far as I can tell, no knock-in, knock-out, or RNAi experiments have been done on these animals to determine the full measure of gene involvement. I would suggest that this research needs to be expanded by the molecular biology community.

One last observation made by Dr. Sumi bears mention. The mutated form of 5-HIAA is only seen in the most widely dispersed and biologically successful primates: Rhesus monkeys and humans. He suggested that the reason this gene stays around in the gene pool is that it is necessary for our survival as a species.

Monday, July 28, 2008

One of my favorite places

I am sitting in a lodge on the side of a mountain in Grand Lake, Colorado and I must confess that this is one of my favorite places in the world. Partly for the scenery, but mostly for the community, solitude, and environmental ethic of this little corner of heaven. Shadowcliff lodge was founded several decades ago on the premise that a mountain resort could be built on sustainability principles. Since that time, they have endeavored to buy locally (as much as possible), recycle everything possible, use limited electricity (purchased from renewable sources), and limit the amount of water used. They have been very successful and this place has become a summer-time haven for like-minded people who enjoy the mountains.

So, I will be here for the next few days. Internet access is somewhat limited, but there is plenty to do. Adam, you would love it here.

Friday, July 18, 2008

Over the reaction

Whew - The FDA announced today that all tomatoes are safe to eat! Yeah! We can all go back to enjoying one of the most healthy and widely distributed foods on the planet. Careful now - the FDA did not announce that the Salmonella outbreak was over - or that the source was discovered - just that tomatoes are OK.

In all 1220 people got sick and 224 were hospitalized - there were no reported deaths.

In some ways we are a safety obsessed society. We throw up our arms about food safety when 1200 people get sick from eating fresh veggies (or fruits) and complain that the FDA is not doing enough to ensure the safety of our food supply!!! If it were ever discovered where the contamination took place, you can be sure that the unfortunate farmer, harvester, wholesaler, distributor, handler, and retailer would be promptly sued by a bevy of lawyers all claiming that if we do not "punish" the "wrongdoer" these incidents will continue. (Reality check here - salmonella is a naturally occurring organism. There is no way to keep it completely out of the food supply.)

Let's examine the science just a bit closer - Salmonella is a bacterium that is found in many places in the environment. It is extremely common in reptiles (think pet turtles and lizards) and in poultry. In fact - it is probably normal for them to carry salmonella; just like we carry the much maligned E. coli. There are several strains of salmonella, but most cause a mild to severe diarrhea-like illness. If you are a generally healthy person, chances are that you will not even know you have been infected. Most people who ingest Salmonella have a case of the runs that lasts a few days - then their immune systems reject the organisms and they return to healthy life. Only the very young, very old, and the immunocompromised actually get sick enough to go to the doctor - even then, very few get antibiotics! Salmonella infections generally resolve on their own, without drugs.

So why all the fuss?

My take - I think we are a culture obsessed with placing blame on things that are out of our control so we do not have to take responsibility for the things we can control. If we divert enough attention to peripheral and relatively minor issues like salmonella, then we can ignore the real killers of our time. Salmonella is an easy whipping boy (bug) it takes little political will to be against it - everybody's against it.

I often wonder, if tobacco came up before the FDA would they approve it for use in humans? No - obviously not. And yet it is unquestionably a drug, and under their purview. Should the FDA monitor portion size at fast food restaurants? Is there any reason that the average person should ingest 2000+ calories at a single meal? (I realize there are a few exceptions, people doing hard physical labor and the people only eating one meal a day.) Should there be weekly limits on the amount of alcohol that a person can purchase? Stricter laws against being drunk? We certainly know that tobacco, excess food and alcohol can kill people more quickly that poor little salmonella - but we do little to stop them beyond public service announcements.

What if the FDA announced that they were going to stop monitoring food safety and just encourage consumers to carefully wash and cook their food before eating it? While you would probably see a slight increase in infections, it would still be a more effective approach (in terms of illness and death) than PSAs on overeating, tobacco, and alcohol.

Tuesday, July 8, 2008

Female sperm?

A report out today from the Butantan institute in Brazil has reported the development of sperm cells from stem cells extracted from the teeth of male donors. The results will be presented officially tomorrow at the European Society of Human reproduction and Embryology meeting in Barcelona, Spain. In this study the researchers isolated stem cells from the extracted teeth of donors and transplanted them into the testes of mice. In this environment the stem cells began developing into human sperm cells.

While these results are preliminary - and not without scientific controversy - they do raise an intriguing possibility. In addition to allowing infertile men to father children, this technique might allow women to "father" children who are genetically their offspring. For example, lesbian couples might be able to donate egg and stem cells (from a tooth or some other source) and parent children that are genetically related to both of them (not just one). The children generated from this union would legally be the responsibility of both women, not just the biological mother (as is the case now). Another possibility might be for a single woman to be both father and mother to her offspring. The child would not be a clone of the parent, there is a significant amount of genetic rearrangement that occurs during sperm development, but they would be more closely related to mom/dad than "normal".

This research may seem a little bit far fetched, but it does represent yet another of the moral/ethical quandaries we have entered (will enter) during the age of freedom of reproductive choice. Hair color, IQ, and freedom from disease aside, the church will need to be ready to respond to this kind of reproductive choice. Would the church raise any ethical issues if a woman decided to be both father and mother? Falling back on the quadrilateral do scripture, tradition, reason, or experience have anything to offer us when investigating this kind of reproductive freedom? Are the questions raised substantially different from the current practices of in vitro fertilization?

Sorry guys - no word yet on generating eggs from your stem cells - at present, they are just far too complex.

Monday, July 7, 2008

Cost of biking in terms of milk

I was recently challenged to figure out the "mileage" a friend of mine gets on his bicycle as a function of gallons of milk ingested. More succinctly, how many miles does he get per gallon of milk when riding his bike. Of course this depends on the type of fuel (Whole milk, 2%, or skim), the speed at which you are riding, body weight, percent body fat, basal metabolic rate, etc. For the purpose of these calculations we will assume a normal adult male of about 160 lbs. Of course we are also assuming that you ingest nothing but milk...

To wit - you can expect the following mileage:

Pretty efficient really - or is it? Just how much energy does it take to get a gallon of milk from the cow to you? How much energy does it take to grow the cow?

For now, let's assume that the cost of milk is roughly equal to the cost of regular gasoline and look at a direct cost analysis/mileage. Both my Prius and my scooter beat the milk as fuel alternative for my bike. (I drink only skim milk). Whole milk is the best fuel - and riding slow gives me a bigger bang for my buck - but the three hour commute each way would make getting my job done a difficult trick. For now I will stick with my motorized vehicles for commuting and my bike for shorter trips, and for fun.

117 deaths from West Nile Virus

The Centers for Disease Control (CDC) just announced that there were 117 deaths in the United States from the mosquito borne virus known as West Nile Virus. Out of an estimated 175,000 who were infected by this virus, 35,000 came down with West Nile fever, 1,227 developed West Nile encephalitis, 63 were paralyzed, and 117 died. The disease incidence was highest in the states where the Rocky Mountains begin - Colorado, Wyoming, and Idaho. While this is an epidemic which bears watching, let's make a few observations.

1. The emergence of this virus in the US population is fairly early and we have not developed strong "herd" immunity as yet. While there is an animal reservoir for West Nile strong immunity in the human population can result in a decreasing rate of infection over time.

2. Vaccines for West Nile are being developed.

3. Bad as this virus is, it is not a huge public health threat - yet.

4. We can avoid being infected by avoiding the mosquitos that carry the disease.

Finally, let's compare West Nile to another mosquito borne illness - Malaria. Each year the plasmodia species which cause Malaria infect an estimated 500 million people - approximately 2 million die of the infection each year, most of them children.

Conducting research is important to limit the spread of both of these diseases, but I would argue for a proportionate response. As Christians it is our moral responsibility to carefully argue for more research funding to be directed toward diseases like Malaria. Not only because they affect more people, but because the people affected are precisely the ones Jesus said we should help - the poor, the sick, and the oppressed. I am not saying we should fund one type of research exclusively, we should simply work to ensure that our national and investment priorities are informed by the correct rationale.

Thursday, July 3, 2008

Ribbon of light

OK, it's not biology - so I am out of my element a bit - but this is really cool. Check out the image to the right.

This is a ribbon of light that is expanding its way through the universe at the rate of about 10 million kilometers per hour. The astronomers who snapped this amazing pic believe that this is the shock-wave of a star that went through supernova about 8000 years ago. While that is extremely cool, look closely at the image. All of those points of light are not stars. A few of them are stars, but most are actually GALAXIES!!! Collections of thousands of stars. The milky way is the galaxy we live in.

When I think of the universe in these terms, I am always astounded that we exist at all. Who is man that you are mindful of him? Of course, it also reminds me of Carl Sagan's prediction that life is out there somewhere else as well. I wonder... It seems to me that God is far too creative to have stopped with just one earth - but who knows.

Wednesday, June 18, 2008

Good behavior alters gene expression

For decades scientists and physicians have been telling us to eat right and exercise as a way to reduce our risk of disease - now there is a genetic correlation.

Dean Ornish and his colleagues at UCSF have really uncorked the bottle. They assayed healthy prostate tissue from 30 men before and after a major lifesytle change that included diet, exercise, stress reduction, and psychotherapy. What they found was amazing - several of the genes associated with driving cancer cell division were down regulated and while genes associated with anti-cancer immune function were up-regulated.

Genetic expression was altered by behavioral change in healthy tissue. While this is not earth shattering data; the before/after nature of this study is somewhat unique (in humans).

What I find intriguing about this report is its possible parallels with spiritual transformation. Anyone who has been around the church for very long as seen people whose lives have been dramatically altered by a spiritual experience.

My question is this: If changed behavior can alter gene expression; can spiritual transformation of behavior do the same thing? Is one of the benefits of going to church regularly the gene expression that it evokes? Does altered gene expression lead to changes in behavior? Is this one of the mechanisms God uses to work the miraculous?

I am not trying to explain miracles really - or be too reductionist - I am just asking the questions.

Tuesday, June 17, 2008

The next breakthrough in IVF

Today in the journal Reproductive Biomedicine Online a report on new technique for freezing eggs harvested for use in in vitro fertilization was reported. According to research done at McGill University in Montreal, CA 200 children were conceived in vitro with eggs harvested and frozen using a technique call vitrification. Most importantly, the success rate nearly identical to that of eggs harvested, fertilized, and stored (frozen) as embryos. This is a significant and exciting breakthrough in reproductive medicine.

Human eggs are rather complex and large structures. Their complexity and size has precluded them from being stored without first being fertilized and allowed to divide a few times. Embryos - it turns out - can be frozen much more easily. That is, until now.

For those who believe that life begins at conception this technique should be talked about openly and heralded as the end of an era. At present there are hundreds of thousands (perhaps millions) of fertilized embryos sitting in liquid nitrogen tanks around the world. The vast majority of these embryos will never become children. They will either be stored indefinitely or thawed and discarded. Vitrification can change all of that - if we can store human eggs reliably and safely, there should be no reason to have all those fertilized embryos in ethical limbo.

Though it is probably too early to write your senators and congressmen, it is probably time to think about how you might phrase the letter.

Monday, June 16, 2008

Brain structure and sexual orientation:

This week in the Proceedings of the National Academy of Sciences (PNAS) Ivanka Savic and her colleagues reported an interesting finding: The brains of homosexual males resemble those of heterosexual females (MRI of the brain) while the brains of lesbian females resemble those of heterosexual males. This observation was supported by PET scans of the blood flow to the amygdala – a region of the brain associated with emotions like fear and aggression.

While differences in the brains of homosexual and heterosexual individuals has been seen before, this research is unique in that it is believed these brain structures are more-or-less stably developed in infancy. This study is not alone. In the past several years there have been a small flood of research studies linking homosexual behavior to either structural or genetic origins. While this does not preclude some environmental stimulus affecting brain structure, it does limit it. Indeed, the researchers comment that they cannot determine from this research whether the difference in brain structure and blood flow are due to genetic differences or due to exposure to hormones (like testosterone) early in development ie. in utero.

At risk is the age-old nature v. nurture debate that has been raging around behavioral science for many years. Are the differences seen in brain structure the cause or the consequence of whatever behavior is being studied. My wife, a psychologist, and I frequently “debate” this issue late into the night. As a person trained in the biological sciences, I tend to fall on the “nature” side of this debate. While she is beginning to come round to my side of the debate, she often counters with the recent studies in epigenetics, which indicate that behavior CAN change gene expression. When talking about things like eating disorders and depression, it is pretty easy to say that it doesn’t really matter what the cause is, so long as we can find a medication to treat the symptoms. We all realize that in the case of sexual orientation, the debate has a lot more riding on it.

For the Christians in the holiness tradition, discoveries like those presented in this paper may have profound implications. Lately, a colleague in the religion department and I have been thinking about these implications at some length.
Some would argue that this smacks of genetic/structural determinism. There are at least two diametrically opposed conclusions that a rational person might reach from this research:

1. If God made me this way, then it must be in his will for me to act out on the way He made me.
2. These structures are abnormal and we need to look for a way to correct them – whether that be surgically or medicinally – there must be a “cure”.

The trouble is; both of these conclusions have flaws.

“God made me this way” is probably not a viable sole defense for any behavior. For example, I have a sweet tooth. At times it is nearly impossible for me to control my overpowering desire to eat doughnuts, chocolate, and ice cream. These items are OK in moderation, but my desire for them goes way beyond that. Indeed, I have determined that it is best for my health to avoid certain sweet foods altogether because they cause me to overindulge. Similar arguments could be made for alcohol, drugs, smoking, pornography, etc. For me, and for many, it is best that we simply avoid these items altogether. No license to indulge here; rather an opportunity to exercise self-control. Please don’t misunderstand; I am not implying that sexual orientation is as easy to “control” as my oral delight in sweets. I am simply pointing out that there are other behaviors it is wise to subdue. Indeed, many heterosexuals find it difficult to manage their sexual desires within the context of God’s design. Controlling sex drive is a human issue, not a gay issue.

Seeking chemical or structural modification as a solution to certain behaviors may be similarly flawed – though for different reasons. The brain is a very complex organ – it is the seat of personality, cognition, creativity, and (many would argue) the very soul itself. Making organic changes to the brain may run the risk of altering substantial components of the self. At times, this can make life easier – treatment for chronic depression is a great example - but how much do we actually lose in the process? A very dear friend of mine is a schizophrenic. When he is faithfully taking his medication he does marginally well in society. He has friends; he can get around and live by himself. When he is not taking his medication (which occasionally happens) he becomes paranoid, hears voices, and might be dangerous to himself. Here is the tough part. When he is off his medication, he is one of the most gifted artists I know – near genius level creativity! When he is taking the meds his gift suffers from a lack of inspiration. His art becomes predicable, bland, and rather mundane.

So where is the middle ground? How can we genuinely help a person who wants to be different without squashing the spirit of those who want to be who they are? Does it come down to choice? Will some choose to be as they are (whatever the issue) while others choose to be different? Isn’t that what the Holy Spirit is supposed to do – draw people toward God? Isn't it also the role of the Holy Spirit to convict a person of sin? Do we run the risk of "playing God" on either side of this issue? Sorry, no answers – just more questions.

Friday, June 13, 2008

Providence and the fuel shift

Most scientists are essentially optimistic. We believe in a sort of providence - ie. nature has provided all that we need to survive and flourish here on earth. It's a strong ideological statement - but I think I can back it up in a number of ways. The most recent example can be found at Sapphire Energy's website: where they just announced the production of 91 octane gasoline and jet fuel from a genetically engineered strain of algae.

This is not just another form of alternative biofuel - no - this is actual gasoline that is purified and refined using the existing infrastructure and internal combustion engines. The difference? It is almost completely green in its production. (Almost, because there is some cost for plant manufacture and operation) The company's website claims that the production of their fuel is 10 - 100 times less energy intense than any other biofuel - biodiesel and ethanol.

Sapphire claims that their product does not use food crops, take up arable land, or use significant amounts of potable water. Even better? It uses CO2, water, sunlight, and a genetically engineered algae to produce gasoline in a sustainable and scalable manner. Following a recent infusion of cash from several venture capital firms (including the such heavy hitters as the Wellcome Trust), Sapphire is poised to be in full scale production with their first plant by 2011 with a production target of 10,000 barrels a day! While that may seem like a lot of oil, the US imported over 129 thousand barrels each day in March of 2008. We would need over a dozen of these plants just to ease our current dependence on foreign oil.

This announcement represents one of the first fundamental shifts away from drilled crude oil.

How quickly can the production of this kind of carbon-neutral oil be scaled up? What impact will it have on the global oil market? What impact will it have on US foreign policy? What's the meaning of all this in the larger world?

I would argue that this provides another piece of evidence indicating the absolute dependence of the scientific enterprise on providence. As scientists, we believe that the "answers are out there" all we have to do is discover and then harness their potential. We (humans) have made energy transitions several times in our past. We started with power from wood, moved to vegetable and animal oils (whale fat, etc), transitioned to coal and then to crude oil as well as natural gas. We are now moving back to wind, sun, and plants as solutions to our energy needs. As scientists, we believe that we need to get more creative in our solutions and nature will provide the answers.

As a Christian - who also happens to be a scientist - I would add that this providence is, in fact, God's providence. God created a universe full of things to discover, full of the potential solutions that we might need as we continue to develop. Our job, our responsibility, is to find and implement them. Eventually, someone will get the credit for "changing the world" by producing inexpensive, sustainable energy. It might be Sapphire, or it might be someone else. The thing to remember is this: the answers are out there, the solutions are provided; we just need to find them.

Friday, June 6, 2008

Sometimes luck favors the prepared mind

This week in the journal Cell: Stem Cell – Steven Goldman’s lab reported the successful transplant of stem cells into the brains of mice with a rare demyelinating disease. Within hours of the study’s release, the BBC and other news outlets were heralding it as a possible breakthrough in our ability to treat multiple sclerosis. While this study does represent some really significant technological advances, a little reality needs to be injected into the hype. Before we talk about what this study means to stem cell treatments, lets talk about a few of the technical problems with linking this series of experiments to human medicine.

1. The stem cells were partially differentiated glial cells (oligodendrocytes) harvested from the remains of five aborted human fetuses.
Regardless what you think about abortion, not many people would find it palatable for the remains of a fetus to be injected into their brains.
2. The stem cells were injected into diseased mice that had been genetically modified so that they do not have functioning immune systems. These mice (called rag -/-) cannot mount a specific immune response to anything, and must be kept in a sterile environment from birth. Simple bacterial and viral infections will kill them. This was necessary because mice will normally reject human tissues that are transplanted into their bodies. Needless to say – this is a HUGE hurdle that must be overcome before any kind of fetal tissue transplantation could be come feasible in humans.
3. The mice were injected in the cranial cavities (in the brain) within one day of birth. Long before any symptoms of this disease were evident, these mice were treated. Of course, that is because the researchers knew the mice would be diseased; they were engineered that way. Humans, on the other had, are not diagnosed with MS for many years after birth – at least for now.
4. MS is an autoimmune disease; “shiverer” mice are affected with a congenital disease. Some might think – aren’t all demyelinating diseases the same? No, they are actually quite different. From what we know now, MS is an autoimmune disease – the immune system begins attacking and killing the myelin in the central nervous system. Shiverer mice never really develop much myelin. In addition, the mice used in this experiment did not even have immune systems – if they did, and the graft was able to “take” the presence of an immune system would have eventually led to the development of MS… not a cure.
5. Over ¾ of the mice in the treatment group died at the same time as the untreated controls. Only a small percentage of the mice had any benefit – with only four surviving to live normal lifespans.

Having said all of that – this work still represents a stride forward for stem cell research. And it does hold some promise for future research. It represents one of the first times that stem cells have been successfully used to treat a demyalinating disease in the central nervous system. From a methodologic point of view, this is a huge step forward. It is good news that the injected stem cells were able to spread around the brains of these mice and wrap themselves around axons – this holds some hope for MS patients. Initially low success rates are expected in highly technical research like this – so again, I am not too worried about the relatively small percentage of animals helped in this experiment.

What needs to happen next is for someone to generate glial stem cells, not from the brains of aborted fetuses, but from the developing cell mass of an SNT embryo. Done correctly, this procedure could by-pass the need for immune incompetent animals and may open the door for potential treatment of more fully developed animals and humans. Much work still needs to be done – and most of it can be done in animals, thereby delaying the ethical dilemma of using human cells.

Thursday, June 5, 2008

The shrinking box

Sometimes students ask the most interesting questions at the most inappropriate times. I was recently conducting a “peer review” in a Human Biology class with a colleague who was up for promotion when a student asked an intriguing question: “If we know all this about how the body works, what does that leave for God to do?” Because I work at a university that is owned and operated by a protestant denomination we are able to freely talk about all kinds of issues that are taboo for my colleagues at state universities. The question was a good one; though it was just a bit distracting for a professor being rated on how well he could teach the respiratory system’s ability to carry oxygen. His in-class answer was adequate and the student was satisfied, but after the class I became deeply troubled by the origin of the question.

It seems to me that many religious people place their faith in a God of the unknown rather than in a God who transcends both the known and the mysterious. “If I know how something works there is no need for faith.” The deep problem with this approach is that as science becomes better and better at understanding how the physical universe works, faith and by extension, God, gets placed in a progressively smaller box.

The “God of the unknown” approach works well in a culture where little is known about how things work. In agrarian or hunter-gatherer societies much of what happens is ascribed to the gods or God. His “will” replaces coincidence as the cause for rain, snow, wind, hurricanes, or tornados. On a personal level, God mysteriously controls even the minute events of daily life. There is no room for chance; the unknown is accepted as a matter of faith. More than that, many people ascribe religious value to the unknowable – as if it is the only place for faith.

On some levels I have absolutely no difficulty with faith in the unknown. I, for one, believe in the existence and sovereignty of one Supreme Being – God. I do not think that there must be natural explanations for everything. Some things are mysterious and probably beyond the ability of science to adequately explain: the existence of a soul, the afterlife, a few truly miraculous events and the deeper “why” questions which fall in the realm of philosophy, not science. Apart from these, there are probably very few things that we will not be able to explain at some point in the future.

Perhaps the problem lies more in our lack of aesthetic and spiritual appreciation for beauty in complexity than in the realm of the unknown. The most basic unit of life, the cell, is an amazingly complex, dynamic, synthetic, and mysterious place. However, 25+ years of cellular and molecular biology has begun to chip away at the layers of mystery that wrap the cell in its shroud of faith. We are catching glimpses of how genes work, what regulatory proteins do, and how the structures of the living cell are altered in response to changes in the environment. If we could see the interconnected network of cellular responsiveness as a living work of art declaring the intelligence and foresight of a seemingly random designer, perhaps we could come to grips with the scientist who holds back the veil long enough to catch a glimpse of the glorious complexity which lies beyond. Perhaps, in knowing, we might also sense the inexplicably spiritual.

Small events, big pictures

One of the hidden dangers in the way much of biological and medical science is being conducted in the early 21rst century is that we tend to draw too many conclusions from a reductionist approach to the scientific method. Allow me to illustrate:

It’s late Christmas night, you are tired beyond description from a day filled with the nagging details of other people’s lives (your in-laws) and in the glow of your favorite computer monitor you decide that it is time to figure out what makes that 5.1 megapixel digital camera really work. If you are a male, like me, you will not look for the six pound instruction manual – it’s written in French anyway – and you will not be satisfied by messing around with the buttons on the back of the little gizmo. No, for this task a tiny Philips screwdriver is a must! Four impossibly small and soon completely stripped screws later you have the camera apart and you are gazing with wonder at the array of circuits, photosensors, lenses, and motors that make up the modern camera.

Next you grab your trusty dissecting microscope – you don’t have one? No worries, I have two – and begin to really look at the motor that automatically used to focus your little camera. It has some small gears and tracks, but is generally electronic in nature. Just to the right there is a tiny chip that is connected to the motor. Closer examination reveals that this chip has little pathways painted in a very intricate, almost petroglyphic design. Whoever made this must have believed in a God of order and simplicity, buried in the complex mechanism of the camera.

Now, if you are really careful you can see how this thing works. Take your scalpel, (or borrow mine) and scratch a little nick in one of the lines on the petroglyph. Be careful not to touch anything else as you reassemble the camera. Finally, turn the power back on and see what happens. If you have done your work correctly and only nicked one line, everything should function perfectly except perhaps one feature. Maybe the perimeter of the photo is now out of focus. From this you conclude that the circuit line you cut is responsible for sharply focusing one specific aspect of your photos.

This approach is really the same one most biologists use to attempt to figure out what each of the genes in the human genome is actually responsible for doing. Essentially, the nucleus is the circuit and the genes coded in the DNA are the painted lines on the circuit. When a biologist wants thinks she has isolated a gene that causes, say diabetes, she will create a mouse (or rat) that has had that specific gene cut out. These little animals are called knockout (KO) mice because they have had a gene, quite literally knocked out of their genome. If our scientist is correct in guessing the function of the gene, the mouse gets diabetes, becomes obese, and watches infomercials all day while the scientist celebrates, publishes a paper in a Nature, gets tenure, and watches infomercials all day... or something like that☺

But that’s not how it always happens. As often as not the camera stops working – the mouse is non-viable. In other words, the gene that she was studying controlled more than just diabetes and the mouse does not live. When this happens, primary investigators curse, post-docs cry, and graduate students get to “stick around a little longer”. There is no paper in Nature, no tenure… weeping, gnashing of teeth… get the picture?

To be sure many interesting and significant discoveries have been made using the knockout approach to biology. I am not diminishing this approach to discovery, but I do think we need to place it into context. When conclusions in medicine are made on the strength of the evidence in KO mice, there are bound to be problems in more complex and highly interactive systems like humans. Early studies may indicate that a gene is responsible for a disease, only to give way to later evidence that contradicts the first papers. This happens all the time in science and is part of the process: part of the search for scientific truth. Trouble is, people who report for the Wall Street Journal and the Marion Chronicle Tribune do not want to wait for the longer more complex studies and we get premature science published in the general media as fact.

Reductionism (looking for answers in the infinitely small) alone is a flawed approach to science and to life. To be understood completely, genes must be viewed in the context of their regulators, and the things they regulate. In science, this has led to the anti-reductionism or “whole animal” movement in recent years. So, the next time you see a study that claims “ the gene for schizophrenia has been identified in KO mice” be skeptical, wait a while, and ask for the context.

… it builds character

If you watch the commercials running on television during the daytime you might get the idea that the most pressing problem in the United States today is not the war on terror, homelessness, illiteracy, or AIDS; it is bacteria. Yes, common average everyday bacteria, molds and viruses that people like me call flora – the normal microbiota of everyday life. These poor organisms have been maligned as germs, called pathogens, and killed with everything from Lysol to phenol. Now we are doing everything possible to screen them out of existence with hepa filters on our furnaces, vacuum cleaners and air-conditioning units. Some folks are even filtering out almost every microorganism with specific air filters that run constantly and remove almost all of the particulate matter from the air.

Trouble is, humans are not designed to live in a sterile environment. Neither are other animals. About the same time HIV hit the scene in the early 1980’s people started raising animals in sterile environments to see how they would develop and to study the way their bodies would react to infectious agents for the first time. Almost immediately scientists began to discover something very interesting: Animals raised in sterile environments developed a much higher incidence of allergic and autoimmune disease.

In a country so fearful of what we cannot see the tiny terrorists are among the most deadly and repulsive. We hear about AIDS, bird flu, E. coli, and salmonella; but when someone wants to talk about the beneficial aspects of the micro world no one wants to listen. It’s just not news. In the past 25 years or so, what we observed in mice has become a fairly widely accepted scientific hypothesis in humans as well. In the United States the incidence of allergy and asthma have increased dramatically in one generation and autoimmune disease is at an all time high. We are the most pampered, protected, and proscribed society in history and yet the incidence of these diseases is on the rise?

It appears that those infections we got as children (if you are over 40) were good for you. Dad was right when he said, “ Don’t worry dear, “it” builds character in small boys”. A growing body of evidence now indicates that being exposed to a variety of infectious and commensal organisms at a young age triggers a type of immunity called TH1 immunity which, in turn primes the immune system away from an allergic phenotype. In people who are not exposed to these organisms there is a higher incidence of allergy, which is dominated by TH2 immunity. We are almost to the point of being able to identify which infections are beneficial and which are not… we may soon be able to vaccinate people against developing allergies by infecting them with mild forms of other organisms.

As strange as that sounds, I wonder how well the same concept could translate into other areas of our lives; specifically our lives in the church. Do those of us in the church protect ourselves and our children from too many things in the world around us? Would we be wiser to experience the world in small doses at the appropriate time, not to harden our hearts and minds but to prepare them to take what the world around us is going to dish out. I wonder if we were more aware of the outside world, would we be less apt to turn on people within the body? Just a thought.

To be sure, I am not advocating a complete abandonment of cleaning and disinfecting products. Nor am I saying that we should avoid the use of antibiotics and other medications that help us control the most pathogenic organisms. Certainly, there are certain people with compromised immune systems that need extra protection. What I am saying is this; there is no need to become overly obsessive with the near sterility of the world around us. As long as you (or your children) have healthy immune systems, let them play in the dirt! Turns out there is a purpose for those little buggers after all.

And through the loop we slip

According to a recent announcement in the New England Journal of Medicine it will soon be possible to conduct most of the interesting forms of stem cell research in the United States and many other countries around the world. The reason for the “breakthrough” in stem cell research is that there is an apparent loophole in the laws most countries have enacted regarding research in this highly controversial and hotly contested field. This issue is this: Most countries prohibit the creation of stem cells from human embryos but not work on established cell lines derived from embryos that have already been sacrificed. Indeed, George Bush has said that to not use established cell lines would be morally wrong.

All it takes is one country.

Woo-Suk Hwang, a stem cell biologist at the Seoul National University, has announced that his organization, the World Stem Cell Hub, will provide custom made stem cell lines to anyone in the world who requests them. Because South Korea does not have laws governing the production of human embryos they are free to create and destroy embryos and then offer them to whoever commissioned their existence in the first place. What’s more, Hwang’s research associates are willing to travel to the site of research (let’s say San Francisco) recruit egg and nuclear materials donors, and take their samples back to South Korea for the creation of embryos by the technique known as somatic nuclear transfer (SNT - commonly called cloning). After the process of embryogenesis is complete, a cell line will be established which can be sent back to the lab in San Francisco for research purposes.

This development in the ongoing story of stem cell research raises several interesting questions that will likely take much more space than can be allocated to a single SNF segment, but let’s take a crack at a one of them.

Let’s start with the technique. In SNT you must start with an egg cell (oocyte) extracted from a willing female. This oocyte contains exactly half of the information necessary to create a new human life, without a sperm cell there will be no newly developing embryo. No genetically unique life. This oocyte is essentially held stationary by a small set of tweezers, and almost all of the genetic material is extracted through a very small needle – essentially the nucleus and polar bodies are removed. We now have an oocyte, sans DNA. Left to itself this ghost of a cell will cease to exist in a few hours. Next the researchers implant a nucleus taken from and adult cell that contains all of the DNA needed to allow it (the cell) to reproduce. In essence, the cell that begins to divide is an egg cell with a transplanted nucleus. SNT is a difficult technique to master using the eggs and nuclei of higher vertebrates. Just getting the cells to survive the procedure is difficult and has a fairly high failure rate.

So what are we to think of this newly cloned cell? If we were to implant it into a willing female there is at least a slight chance that it would continue to grow into a fully formed human child that is genetically identical to the donor of the nucleus. To date, no one has successfully demonstrated that this procedure would work in humans; however, it has been successfully demonstrated in many lower vertebrate species. If, on the other hand, we were to disrupt the slowly growing clump of cells that results from SNT, we would have a stem cell line that could (theoretically) be used to research many different diseases. While most people agree that reproductive cloning is not a direction this research should take many others would advocate the use of SNT technology to generate pseudoembryos-come-cell lines that can be used for research.

The loophole in current US law is a clause that allows researchers in the United States (in every state except South Dakota) to import these newly created stem cell lines from outside the country.

So, what are we to think about this new wrinkle in the saga of stem cell research? Should we mourn the loss of these embryos and then benefit from their sacrifice? Are these SNT generated embryos different in some qualitative manner from sperm/egg embryos that make them OK to use in research? And when does life begin, anyway? How can we know?

I wish I had solid, scientifically or doctrinally based answers to each of these questions. Unfortunately, with techniques this revolutionary that are pushing our definitions of unique human life we are left to grapple with the subtleties of an ever-shifting spectrum painted in shades of gray.

Total recall, or not

Sometimes the most interesting and potentially insidious science happens for the best of reasons. For more than a decade psychologists have been waiting for geneticists to figure out which genes are involved in the propensity toward and the formation of addiction to habit-forming drugs like cocaine and Mary Jane. Although there have been many candidate genes identified, none of these discoveries has led to the “holy grail” of addiction counseling: a cure for addiction.

Recently, in the journal Neuron, two studies have been reported that take a very different approach to the problem of addiction. Instead of focusing on the dopamine receptor these studies are focusing on another component of addiction… memory of the pleasurable component of addicting events. In one study a drug was administered to rats immediately after their first hit of cocaine. The rats exposed to this second drug were unable to remember their way back to the cocaine. Essentially, the rats forgot where the cocaine was located, and in essence lost their desire for the drug. As interesting as this is in rats, humans might not want to have their short-term memory messed with, or might not make it to the clinic immediately after that first hit with an addictive substance.

The second study is far more interesting. Dr. J. Lee of Cambridge University reported that if he inhibited a particular gene in the amygdala, the part of the brain that links memory to feeling, he could inhibit the memory of rats in such a way that the normal stimuli that would cause them to crave the addictive drugs would no longer function. In this study the rats lost their ability to remember the events that made them become drug addicts. This would be akin to a human who sees bright neon lights as a trigger to enter his favorite bar, but has forgotten the link between the lights and the alcohol. As a result, he does not enter the bar and does not get drunk. Advertisers beware!

Just think about the potential benefits for this kind of research. In the United States alone we spend nearly half a billion dollars rehabilitating people with drug and alcohol addictions. In addition, there are dozens of diseases related to chronic substance abuse, thousands of police and ambulance calls that are drug and alcohol related, and all of the death and destruction associated with them. Next consider the addictions to porn, sex, and video games! What if we could cause people to forget why those things seem fun and, by simply modifying gene expression cause them to forget the very triggers for addictive behavior? Think of the marriages that could be saved! Think of all of the college students who could study instead of playing video games until their grades are as dead as the monsters they have been repeatedly killing. The decreased crime rates alone should make this a very attractive therapy.

As noble as these two groups of researchers are attempting to be, there is a potential dark side to their work. Erasing short-term memory with a non-invasive drug may not be such a great idea after all. What if we could selectively remove memories of trauma, or embarrassment, or love? Who would administer these drugs? Psychologists, physicians, the government? Could someone maliciously tinker with the thoughts and motivations of an unsuspecting causing them to commit a crime then forget they have done it?

Maybe… but not yet.

I am definitely not calling for a cessation to these avenues of research; there is too much potential benefit. My conclusion is simply this: As with so many new technologies the benefit/harm analysis must be done along the way to maximize the benefit and minimize the potential harm.