Connectome (34 page)

Behavioral signs will also be informative for some disorders. Some schizophrenics exhibit mild behavioral symptoms when they are children, before the first onset
of true psychosis. Perhaps careful detection of such early symptoms, combined with genetic testing and brain imaging, could accurately predict schizophrenia.

Early diagnosis of neurodevelopmental disorders will pave the way for prevention. Connectomics will help us identify exactly which processes of brain development are involved, making it easier for us to develop drugs or gene therapies that prevent connectopathies or other abnormalities from developing.

The goal of prevention seems ambitious enough; it's even more challenging to repair the brain when the damage has already been done. After injury or degeneration has caused neuron death, is there any recourse? A pessimistic answer comes from regeneration denial, one flavor of connectome determinism. Since it's generally true that no new neurons are added in adulthood, the brain has limited power to heal itself after injury. Is there any way to overcome this?

Other animal species, such as lizards,
are able to regenerate large parts of their nervous systems after injury. And human children regenerate better than adults do. In the 1970s, when physicians realized that children's fingertips regenerate like lizards' tails, they stopped attempting to reattach severed fingertips through surgery; now, they simply let the fingertips grow back.
Hidden powers of regeneration might lie dormant in adults, and the new field of regenerative medicine seeks to awaken them.

Injury naturally activates
regenerative processes in the adult brain. A main site of neuron creation is known as the subventricular zone. Immature neurons, known as neuroblasts, normally migrate from there to the olfactory bulb, a brain structure dedicated to smell. Stroke increases the creation of neuroblasts and can divert them from
the bulb to the injured brain region. Since this natural process might contribute to recovery after stroke, some researchers are trying to develop artificial means to promote it.

Another route to regeneration is to transplant new neurons directly into the damaged region. This might work better than trying to promote migration from a distant location like the subventricular zone. Parkinson's disease, as I've mentioned, involves the death of dopamine-secreting neurons. Researchers have attempted to replace them by transplanting healthy neurons from fetuses. Amazingly, some neurons were shown to survive in recipients' brains
for over a decade, although it's unclear whether the transplants actually
did much to alleviate the symptoms. The experiments, conducted with cells isolated from aborted fetuses, raised thorny ethical issues. A further complication of transplantation was that patients' immune systems could reject the new cells as foreign.

We can now avoid both of these problems, thanks to a recent advance that allows the culturing of new neurons customized to a particular patient. A skin cell can be “deprogrammed” to become a “stem cell,” one that has effectively “forgotten” its former life as a skin cell. Owing to its newly ambiguous identity, this stem cell can now be “reprogrammed” to divide
and produce neurons in vitro
.
(The Latin term
in vitro
, which means “in glass,” refers to the artificial environment used for culturing molecules, cells, or tissues isolated from an organism. At first that environment was typically a glass container, but plastic ones are more common now.) Researchers have used this method to create dopamine-secreting neurons from the skin cells of Parkinson's
patients. They are planning to transplant the neurons back into the patients' brains to treat them.

Whether created naturally
or added by transplantation,
most new neurons die. Without “taking root,” new neurons presumably cannot survive. Regenerative treatments will thus require enhancing the integration of new neurons into the connectome, a process that depends on promoting the other three R's—rewiring, reconnection, and reweighting.

The adult brain may hold untapped potential for making these changes. Earlier I referred to the fact that most recovery happens during the three-month period just after stroke. According to one speculation, this is a critical period, analogous to the one during brain development, with production of similar molecules that promote plasticity.
Once this window closes, plasticity plummets and the rate of recovery slows. Perhaps stroke therapies should aim at keeping the window open, extending the natural processes of recovery.

As we've seen, rewiring may be difficult in the adult brain. After injury, though, neurons appear to grow new axonal branches
more easily. If researchers can identify the molecular reasons why, it may be possible to promote rewiring of the adult brain by artificial means, which would help integrate new neurons into the brain as well as allow existing neurons to change their functions. Similarly, since creation of new synapses happens at a greater rate in the injured brain, there may be natural molecular processes
that could be manipulated to promote reconnection.

Could we also correct neurodevelopmental disorders, fixing the brain after it has wired up improperly? If you're a connectome determinist, you'd probably regard correction as futile and instead focus all your efforts on prevention. But it's not clear whether completely accurate and early diagnosis of neurodevelopmental disorders will be possible, so we have no choice but to think about correction too. This will require the most extensive connectome changes of all, and therefore the most advanced control of the four R's.

I've stressed the treatment of malfunctioning brains, since these are the connectomes most in need of change, but people also want drugs for enhancing normal brain function. Many university students drink coffee while studying. While caffeine may help them stay awake, it has little effect on learning and memory.
Nicotine improves the mental abilities of smokers, but that's only relative to their substandard performance when deprived of cigarettes.
 Can we find more effective drugs than these?  For example, we'd really like a drug that promotes the connectome changes necessary for learning or remembering new information or skills. Also useful would be drugs to help us forget. Perhaps these could promote the elimination of cell assemblies or synaptic chains formed after traumatic events, or those implicated in bad habits or addictions.

 

We have a long wish list for drugs, both for preventing brain disorders and for correcting them. Unfortunately, the pace of discovery is slow. New drugs appear on the market every year, often with great fanfare, but many are not really new; they're just variants of old drugs, and unlikely to be significantly more effective. Most antipsychotics and antidepressants are variants of drugs discovered by accident over half a century ago. Few drugs are truly new; few draw on recent advances in neuroscience.

The challenges of drug development are not unique to mental disorders, of course. Creating new pharmaceuticals is a hugely risky business. It can take many years to develop candidate drugs. Only those deemed most likely to succeed are tested in human patients, yet nine out of ten
fail in this last stage, turning out to be toxic or ineffective. This is a huge waste of money, given that clinical trials incur a significant fraction of the investment required to bring a new drug to the marketplace. (Total cost estimates range from one hundred million to a billion dollars.
) Everyone desperately wants better drugs—those who suffer from diseases, those who treat them, and those who invest huge sums of money trying to develop therapies. How can drug discovery be accelerated?

Historically, most drugs have been discovered by chance. The first antipsychotic was chlorpromazine, known in the United States by the trade name Thorazine. This belongs to the phenothiazine class of molecules, the earliest of which were originally synthesized in the nineteenth century by chemists attempting to create dyes for the textile industry. In 1891 Paul Ehrlich discovered that one of them could be used to treat malaria. During World War II, the French pharmaceutical company Rhône-Poulenc (a forerunner of today's Sanofi-Aventis) tested many phenothiazines looking for more malaria drugs; when they failed to find any effective ones, they started looking for antihistamines. (You may have taken medications of this type for allergies.) Then a physician discovered that phenothiazines could enhance the actions of surgical anesthetics. Rhône-Poulenc researchers switched to testing for this new application, and discovered that chlorpromazine was effective. After giving the drug to psychiatric patients as a sedative, doctors realized that it specifically reduced symptoms of psychosis. By the end of the 1950s, chlorpromazine had swept through the psychiatric hospitals
of the world.

The first antidepressant medications,
iproniazid and imipramine, were discovered around the same time, in stories with similar twists and turns. Iproniazid was originally developed for tuberculosis, but had the unexpected side effect of making patients unreasonably happy. Psychiatrists eventually realized that it could be used to treat victims of depression. Meanwhile, the Swiss company J. R. Geigy (an ancestor of Novartis), having heard about Rhône-Poulenc's success with chlorpromazine, decided to play catch-up by looking for an antipsychotic of their own. They tried testing imipramine, which chemists had synthesized by modifying a phenothiazine. It was a failure for treating psychosis, but fortunately it turned out to relieve depression.

So researchers did not intend to develop the first antipsychotics and antidepressants. They were just lucky and alert enough to stumble upon them during this golden age of the 1950s.
More recently, there has been growing excitement about “rational” methods of drug discovery built upon our modern understanding of biology and neuroscience. How do these methods work?

Recall that cells are composed of a huge variety of biological molecules, which are involved in many kinds of life's processes. (Earlier I talked about the important class of biomolecules known as proteins, which are synthesized based on blueprints encoded in genes.) A drug is an artificial molecule
that interacts with the natural ones in cells. Ideally, according to the magic-bullet principle, the drug should interact with a specific type of biomolecule but not with other types.

Rational drug discovery, therefore, starts from biomolecules involved in the processes that malfunction during disease. Researchers have begun to identify many such biomolecules, which can serve as targets for therapies. The tempo of target identification has quickened with the advent of genomics, engendering increasing optimism about finding new drugs by rational means.

Once a drug target is identified, the first task is to find artificial molecules that bind to it, like a key fitting into a lock. Researchers create a variety of candidates, based on educated guesses, and proceed to test them empirically. If they manage to hit the target with a candidate, they refine its structure, progressively improving its binding with the target. This first stage of drug development is conducted by chemists.

Let's jump ahead for the moment to the last stage, human testing. Physicians manage this stage, administering candidate drugs to patients to see whether symptoms improve. It's neither economical nor ethical to test a drug on people unless there is already good reason to believe that the drug is likely to be safe and effective. Even so, nine out of ten candidates fail at this point, as I mentioned earlier, and the attrition rate
is even higher for disorders of the central nervous system. These depressing statistics suggest that something is going wrong between the first and last stages
of drug development. Before commencing human testing, how can researchers be more certain that a candidate drug will not only bind to its target biomolecule in vitro but also be effective at treating the disease? Finding more evidence, or evidence that's more reliable, would make it faster and cheaper to develop new drugs.

One method is to test in animals first, but it's even more difficult to create animal models for mental disorders than for other kinds of diseases. As I've mentioned, researchers are using the genetics of autism and schizophrenia to develop mouse models. But mice may not be enough like humans to have these disorders, so some researchers are planning to develop models based on nonhuman primates.

Drugs can also be tested on in vitro disease models. One exciting approach is based on the “stem cells” that can be created from a patient's skin cells and reprogrammed to divide into neurons. Earlier I described the plan to transplant these neurons back into the patient's brain to treat neurodegenerative disorders. Another option is to keep such neurons alive in vitro and use them for drug testing. Cultured neurons generate spikes and transmit messages through synapses, much as in the brain, and hence can be used to assay the effects of drugs on these functions. These neurons wire up very differently from those inside the brain, however, so in vitro models might not be useful for mental disorders that are caused by connectopathies.

Finally, it's possible to “humanize” animal models by growing human neurons from stem cells and then transplanting them into animal brains. This might yield better animal models than the approach based on inserting defective human genes. Researchers are already adopting similar strategies to create humanized mouse models
for diseases other than mental disorders.

Along with creating better in vitro and animal models, we must also figure out how to evaluate success when testing candidate drugs on them. The obvious approach for animal models is to administer the drug and then quantify the resulting changes in behavior. To do this, we need to observe some animal behavior that is analogous
to a symptom of the human mental disorder. But it's no easy task to define such behaviors. (What exactly is a psychotic mouse?) That's why it's not so obvious how to evaluate drugs with tests of animal behavior.

Could there be some other way? Drugs for neurodegenerative diseases such as Parkinson's can be tested for their effectiveness in preventing the death of neurons in animal models of these diseases. Likewise, it might be better to evaluate drugs for autism and schizophrenia by looking at their effects on neuropathologies rather than behavioral symptoms. But this approach has been blocked by the failure to identify clear and consistent neuropathologies. If autism and schizophrenia turn out to be caused by connectopathies, it will be important to identify analogous miswiring in animal models. Then drugs could be tested for their effectiveness in preventing or correcting such miswiring. To make this approach practical, we'd have to speed up the technologies of connectomics in order to compare many animal brains quickly.