Renowned neuroscientist Mu-Ming Poo is playing a key role in China’s contribution to the push by national and regional governments to set up gargantuan neuroscience research endeavors. The China Brain Project has yet to put forward funding specifics. But Poo, who directs the Institute of Neuroscience of the Chinese Academy of Sciences and has held multiple academic posts at U.S. universities, is helping to shape the project’s 15-year timeline.
To circumvent the paucity of drugs for neurological illnesses, Poo’s own team wants to focus on finding solid evidence for video games and other behavioral training methods that might produce near-term cognitive benefits for China’s aging population. Poo talked to Scientific American recently about these plans.
[An edited transcript of the interview follows.]
Can you tell us about the Chinese Brain Project?
Its goal is similar to the brain projects that have been launched in other regions but I think we’ve put more emphasis on the brain disease aspect than the U.S. project has. The U.S. project is more concentrated on developing new technologies for observing and manipulating the activity of brain circuits.
In China there is a particular urgency to solve problems related to brain diseases because of its large population and an aging society saddled with neurodegenerative diseases. If we don’t find a solution for Alzheimer's by 2050, the entire medical system is going broke. In China there is an estimate that there could be many tens of millions of Alzheimer's or Parkinson’s disease patients by 2050 if no cure is found, given the rate of increasing life expectancy.
How will the Chinese project move forward?
We cannot wait until we understand how the brain works. It will take 20 years before we figure out even the entire circuitry of the rodent brain and fully understand how it works. For humans, it may be 30, 40 years. That’s too long.
Going forward, we've got to first find some way, for instance, to diagnose deficiencies in brain function. The general opinion is that the best hope in dealing with brain diseases is to diagnose early and intervene early, hoping to prevent or delay the onset of the disease.
But right now there’s a lot of qualitative symptom-based diagnosis, unlike other systems in the body. In the cardiovascular system you know your blood pressure and cholesterol level quantitatively, but we do not have standard measures of brain function quantitatively. So I think that's clearly a problem we need to address. This can be done with the technology and the expertise we have now.
Describe a bit more these diagnostic techniques.
At a small scale, we have already started to make a tool kit for brain function measurements. At a larger scale, we plan to make broader measurements: from perception to multisensory integration; working memory—remembering a phone number for long enough to dial, for instance; attention and decision-making; and so on. In most measurements you just interact with a computer or take a simple measurement with an EEG. So imagine measuring 10 brain functions and coming up with a score for each function, and you will have reliable measures of your brain functions for the physician to make a quantitative evidence-based evaluation. In our program we hope to be able to monitor progressive changes of these functions with time over a large population of people, and eventually find parameters that could be predictive for brain diseases.
We are also interested in developing intervention approaches to prevent the deterioration of specific brain functions. So in the future neurologists or psychiatrists will look at scores of various brain function tests for an individual. They will then prescribe the medicine that addresses specific functional deficits or prescribe an interventional approach, such as specially designed mental exercises to improve specific functions. They will not classify you as having bipolar disorder or schizophrenia or Alzheimer's diseases. All these labels are very bad for people who are resistant to going to a psychiatrist because they don’t want to be labeled as suffering from these diseases. But if you said your working memory score is getting low and you should do some exercise, there would be less stigma attached to a mental problem.
Has any of this started to make its way into clinical practice?
We're actually trying to persuade the Shanghai health care organizations to integrate this type of brain function testing into regular health checkups in local hospitals, so people will go through this brain checkup besides a checkup of other systems. Then if we have enough data over a 10- or 15-year period, we can really have reliable early indicators of brain disorders for the physicians to prescribe treatments.
What are some of the specific measures that can be implemented now or relatively soon?
We’ve started to realize that you can prevent progression of some diseases by training, such as by playing video games. You can do this, for instance, to recover vision for people with amblyopia. Some of these discoveries are relatively recent and haven’t been applied to the general population.
The major effort in the U.S. biomedical sciences is still drug development. I think that is actually necessary, but it hasn’t been paying off for brain diseases. It's paying off for other diseases but drug development for brain diseases is largely a failure so far. We are still using psychiatric drugs from the 1950s. There are very few new drugs since then.
We are interested in various noninvasive programs that help to improve memory and prevent deterioration of memory. It's basically playing well-designed games that get harder as the player gets better. It's very much like Mike Merzenich's program of Fast ForWord [referring to the well-known neurophysiologist from the University of California, San Francisco] to treat hearing and language deficits in school children.
Does China have certain advantages in taking this approach?
China has the largest population for any major disease—that's obvious. For instance, Shanghai Mental Health Center kept continuous medical records for about 100,000 mental disease patients. The problem is that a lot of data are out there but not being standardized well.
So the China Brain Project's hope is that this large patient population will be of use for developing diagnostic or intervention tools by setting standards for data collection and data handling. If you don’t have uniform and internationally acceptable standards, the large number doesn't make a difference.
We are putting together teams to create a comprehensive brain-function tool kit. That involves 10 to 15 principal investigators. They work on that part-time. They spend probably 10 to 20 percent of their time working on designing the most effective five-minute test for a specific cognitive function. They will not get Nobel Prize out of this work but they will get the satisfaction that their contribution has been used by and helped a large population of people.
Will you have to build the educational infrastructure for this project?
Most areas of biological sciences in China are not very competitive internationally, as compared to other disciplines in China such as physical and material sciences. This is true for neuroscience. There is thus a great need for building the research capacity in neuroscience. There are now about 6,000 members in the Chinese Society for Neuroscience, as compared to about 45,000 in the U.S. Among these 6,000 members, many active scientists are young investigators or graduate students. Actually basic neuroscience is still not formally recognized by Chinese educational systems as an independent academic discipline, and significant research support from the government for basic neuroscience only began 10 to 15 years ago. With this limited research base, what do you do to really make a difference on the international scene? Many of the institutions are now filled with young people who have their small groups that are productive. But most of them are not producing groundbreaking or pioneering work in their fields. What they are doing is mostly a continuation of their postdoctoral work, following the major trend in the field. They can publish a few good papers in the top journals but very few are making real impact. I think the key for Chinese neuroscientists to have a true impact is to form research teams that have a unique combination of expertise, with a goal of addressing major unsolved scientific or technological problems.
Has there been some improvement?
I think the scientific quality is clearly increasing, partly because there are now many returning Chinese who were trained abroad in the U.S. and Europe. After postdoctoral research it's harder for them to get a good position in the U.S. Even if they have a good position, they still have to spend a lot of time writing grants. A lot of the people returning are of very high quality. If they were still in the U.S., they could be competitive as assistant professors in major research universities.
So that's the reason why the publications from China have been improving dramatically in the last 10 years. What's lacking is more senior established scientists who are recognized leaders in the field, who could chart out an approach to doing the pioneering work and know what to do, and can organize large groups of people. That type of senior person is rare and takes time to develop. It will take 10, 15 years for a senior leader to emerge.
There is also the cultural aspect. The current funding and evaluation system in Chinese scientific institutions does not encourage risk-taking. New innovation and groundbreaking work often require one to take a risk. Most scientists tend to do safe projects that could ensure good funding.
On another topic, can you tell us about primate research in China and how that might have an impact on the brain sciences?
The use of nonhuman primates [monkeys in particular] as animal models is increasingly difficult in the U.S. and in Europe. This is a bad sign. Given the importance of nonhuman primates for basic research on higher cognitive functions and for studying pathogenesis and potential therapeutic treatments for human brain diseases, we have to sustain the use of these animal models. In this area I think Chinese neuroscientists may offer an important contribution. There are large monkey resources in the country and many neuroscientists are interested in working with monkeys.
Can you give an example?
There's a recent breakthrough that occurred in my own institute in generating genetically manipulated macaque monkeys. We published a paper in Nature this January describing monkeys that express a human MECP2 gene in the brain, and these monkeys emulate several behavioral deficits similar to that of autistic patients, including stereotyped motion, higher anxiety and deficits in social interaction with other monkeys. We were also able to obtain a second generation of the monkeys carrying the human MECP2 gene within about two and a half years whereas it normally takes five years for only one generation. We got it down to a shorter time using tricks that speed up sperm maturation by incubating the sperm under the skin of mice.
Given the recent rapid development in gene-editing technology in mice (such as deleting a gene or replacing a gene with an edited copy), there is hope that gene-editing technology will become applicable to monkeys in order to develop a gene-edited monkey model for brain diseases that have a strong genetic basis.
There is still a serious problem in that the gene-editing technology does not make the desired genetic alterations in all of the different cell populations in a single animal. That problem, known as mosaicism, needs to be solved to produce useful animal models. In mice you can deal with this by breeding. In a few generations you can get mice with the same genetic manipulation in all cells. We cannot use the breeding to solve this problem in monkeys because the reproductive cycles are too long, even using some tricks to speed up sperm maturation.
But rapid progress is being made in new gene-editing methods. I believe the problem of mosaicism will be solved for monkeys in the near future, and we will then be able to produce many genetically uniform monkey models that will greatly facilitate scientists who study the pathogenesis and treatment of human brain diseases.